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Long‐term outcome after COVID‐19 infection in multiple sclerosis: A nation‐wide multicenter matched‐control study

Abstract Background and purpose Long‐term outcome after COVID‐19 in patients with multiple sclerosis (pwMS) has scarcely been studied, and controlled data are lacking. The objective of this study was to compare long‐term outcome after COVID‐19 in pwMS to a matched control group of pwMS without COVID‐19. Methods We included pwMS with polymerase chain reaction‐confirmed diagnosis of COVID‐19 and ≥6 months of follow‐up and, as a control group, pwMS matched 1:1 for age, sex, disability level, and disease‐modifying treatment type. Results Of 211 pwMS with COVID‐19 (mean age = 42.6 years [SD = 12.2], 69% female, median Expanded Disability Status Scale = 1.5 [range = 0–7.5], 16% anti‐CD20), 90.5% initially had a mild COVID‐19 course. At follow‐up, 70% had recovered completely 3 months (M3) after COVID‐19, 83% after 6 months (M6), and 94% after 12 months (M12). Mild initial COVID‐19 course was the only significant predictor of complete recovery (odds ratio [OR] = 10.5, p < 0.001). The most frequent residual symptoms were fatigue (M3: 18.5%, M6: 13.7%, M12: 7.3%), hyposmia (M3: 13.7%, M6: 5.2%, M12: 1.7%), and dyspnea (M3: 7.1%, M6: 6.6%, M12: 2.8%). Compared to matched controls, fatigue, hyposmia, and dyspnea were significantly more frequent at M3 and still slightly more frequent at M6, whereas there was no difference at M12. pwMS with COVID‐19 had neither a significantly increased risk for relapses (OR = 1.1, p = 0.70) nor disability worsening (OR = 0.96, p = 0.60). Conclusions Long‐term outcome of COVID‐19 is favorable in a large majority of pwMS, with only a small proportion of patients suffering from persistent symptoms usually resolving after 3–6 months. COVID‐19 is not associated with increased risk of relapse or disability.

A broad body of evidence indicates that in patients with multiple sclerosis (pwMS), COVID-19 severity is also primarily determined by age and concomitant comorbidities, but also the degree of physical disability, whereas multiple sclerosis (MS) itself is not associated with increased risk of severe COVID-19 [2][3][4][5]. Reassuringly, most immunotherapies used for disease-modification (disease-modifying therapy [DMT]) in MS are not associated with COVID-19 severity, although B-cell-depleting anti-CD20 monoclonal antibodies seem to be associated with a moderately increased risk [2,6].
Whereas it is well established that the large majority of pwMS have a mild initial COVID-19 course evading hospitalization or worse, long-term outcome of pwMS surviving COVID-19 is scarcely studied and controlled data are lacking [5,7]. Thus, it is not clear whether pwMS display differences in the degree of long-term sequelae or speed of recovery, nor whether COVID-19 influences parameters of MS outcome such as frequency of relapses or physical disability. Some reports have hinted at an increased risk of MS relapse in relation to SARS-CoV2 infection, but these studies are hampered by low sample size and lack of a control group [8,9].
The objective of this study was therefore to describe long-term outcome after COVID-19 in pwMS in comparison to a matched control group of pwMS without COVID-19.

Patients and definitions
The Austrian MS-COVID-19 registry (AUT-MuSC) comprises patients with a confirmed diagnosis of MS aged ≥18 years and with a diagnosis of COVID-19 (defined by a positive SARS-CoV-2 polymerase chain reaction [PCR]) recruited in an ongoing nationwide multicenter observational study. Details of the study design and the data collected are described elsewhere [4,10].
For the present study, we included all patients from AUT-MuSC with (i) symptomatic and survived PCR-confirmed diagnosis of COVID-19 established between 1 January 2020 and 30 June 2021 and (ii) clinical follow-up of ≥6 months.
As a control cohort, we included patients from the Vienna MS database with (i) confirmed MS diagnosis according to McDonald criteria and (ii) no history of a positive SARS-CoV-2 PCR or clinical suspicion of  who were matched with the AUT-MuSC cohort for age (±5 years), sex, disability (Expanded Disability Status Scale [EDSS] ± 0.5 if AUT-MuSC EDSS was <4 and EDSS ± 0 if AUT-MuSC EDSS was ≥4), and DMT group.
The primary endpoint for long-term COVID-19 outcome was defined as complete recovery of all COVID-19-associated symptoms at 3 (M3), 6 (M6), and 12 (M12) months of follow-up after SARS-CoV2 infection. As secondary endpoints, specific COVID-19-associated symptoms (new or increased hyposmia, new or increased dyspnea, new or increased fatigue) were assessed at M3, M6, and M12 and classified as either completely remitted or persistent.
Endpoints for long-term MS outcome were occurrence of relapse (defined as patient-reported symptoms with objectively confirmed signs typical of an acute central nervous system inflammatory demyelinating event with a duration of at least 24 h in the absence of fever or infection, separated from the last relapse by at least 30 days) and disability worsening (defined as a confirmed EDSS increase of ≥1.5 points in patients with a baseline score of 0, ≥1.0 points in patients with a baseline score of 1.0-5.5, or ≥0.5 points in patients with a baseline score of >5.5 sustained for at least 3 months) [11,12].
DMT groups were defined according to DMT status at the time of SARS-CoV-2 infection as receiving either no DMT, moderately effective DMT (comprising dimethyl fumarate, glatiramer acetate, interferon-beta preparations, and teriflunomide); highly effective DMT (comprising alemtuzumab, cladribine, fingolimod, natalizumab, ozanimod, and siponimod), or anti-CD20 monoclonal antibodies (CD20; comprising ocrelizumab, ofatumumab and rituximab) to account for differences in the risk for severe COVID-19 course as well as differences in efficacy in preventing MS disease activity.
Severity of initial COVID-19 was defined as the clinical status at the most severe point of COVID-19 course as either a mild course (no pneumonia or mild pneumonia without hospitalization) or a severe course requiring hospitalization and fulfilling at least one of five criteria (breathing rate > 30/min; SpO 2 ≤ 93%; PaO 2 /FiO 2 ratio < 300; pulmonary infiltrate > 50% within 24-48 h; requirement of noninvasive ventilation, high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation).
A priori risk of COVID-19 severity was quantified according to an established risk score (MS-COV-risk; range from −6 to 15, with higher scores predicting an increased COVID-19 severity) taking into account age, EDSS, smoking status, obesity (body mass index ≥ 30), and presence of cardiovascular disease (coronary heart disease and/or ischemic heart failure and/or cardiac valve disease), arterial hypertension, chronic kidney disease, chronic pulmonary disease (asthma, chronic obstructive pulmonary disease, or pulmonary fibrosis), and diabetes mellitus [13].

Statistical analysis
Statistical analysis was performed using SPSS 26.0 (IBM). Categorical variables were expressed in frequencies and percentages. Continuous variables were tested for normal distribution by Lilliefors test and expressed as mean and SD or median and range as appropriate. Univariate group comparisons were conducted by independent t-test, Mann-Whitney Utest, or chi-squared test as appropriate. Univariate correlation analyses were calculated by Pearson or Spearman test as appropriate.
To investigate predictors of long-term COVID-19 outcome, we To assess predictors of long-term MS outcome, we calculated multivariate binary logistic regression models with relapse and disability worsening as dependent variables and group (MS + COVID vs. controls) as the independent variable adjusted for sex, MS-COV-risk score (age and EDSS are already included in the MS-COV-risk score), severity of initial COVID-19, MS disease course (relapsing-remitting vs. progressive MS), MS disease duration, and DMT group.
Robustness of the statistically significant differences to unidentified confounders was quantified with Rosenbaum sensitivity test for Hodges-Lehmann Γ [14]. Missing values were handled by multiple (20 times) imputation using the missing not at random approach with pooling of estimates according to Rubin's rules [15]. A twosided p-value < 0.05 was considered statistically significant.

Ethics
The study was designed and conducted in accordance with the

RE SULTS
Of 320 eligible pwMS, we included 211 pwMS with COVID-19 (MS + COVID) from the AUT-MuSC registry, and recruited 211 matched controls. Overall characteristics of the study groups are given in Table 1.

DISCUSS ION
In this nationwide multicenter study, we investigated long-term outcome after COVID-19 in pwMS in comparison to a closely matched group of pwMS without COVID-19.
A recent study in the UK using online questionnaires of selfreported symptoms showed complete recovery of COVID-19 symptoms in 87% of pwMS after ≥12 weeks, with female sex, higher pre-COVID-19 disability, and probable anxiety/depression as predictors of incomplete recovery [7]. In our study, mild initial COVID-19 course was the only significant predictor of long-term outcome, indicating a 10-fold increased likelihood of complete recovery, with no significant effect of sex, MS course, level of disability, or diseasemodifying treatment. This discrepancy is most likely explained by the UK study excluding patients who were hospitalized due to COVID-19, therefore excluding patients with severe course, and using reported (questionnaire) instead of confirmed data [7].  [19,20]. One study reported that 20% of pwMS develop new MS symptoms, and another showed a twofold increased risk of relapse within 2 weeks before and 4 weeks after SARS-CoV2 infection [8,9]. However, these studies are hampered by a low sample size, lack of a control cohort, and lack of objective assessment of symptoms, probably explaining the increased relapse rate. In our study, which includes a closely matched control cohort of pwMS without COVID-19, we found neither a significant increased risk of relapses (OR = 1.1) nor disability worsening (OR = 0.96).
Previous studies have suggested an increased risk of MS exacerbations associated with other infections. However, these studies were uncontrolled and lacked methodologically sound distinction of relapses from pseudorelapses, that is, Uhthoff's phenomena, typically occurring in association with infection-induced fever [21][22][23][24][25]. The consistently reported absence of an association between infections and occurrence of new magnetic resonance imaging lesions-an objective measure of MS disease activityportends that the apparent increase of MS exacerbations in timely Values >/< 1 indicate higher/lower probability of severe COVID-19. b MS-COV-risk score: MS COVID-19 severity risk score (range from −6 to 15), with higher scores predicting an increased COVID-19 severity (see Rosenbaum and Rubin [14]). c Defined as moderately effective DMT comprising dimethyl fumarate, glatiramer acetate, interferon-beta preparations, and teriflunomide. d Defined as highly effective DMT comprising alemtuzumab, cladribine, fingolimod, natalizumab, ozanimod, ponesimod, and siponimod.

Strengths and limitations
The main strengths of this study are its population-based approach and the detailed characterization of the study cohort provided by the high-quality data from certified specialized MS centers. We have to acknowledge some potential limitations inherent to the study design.
The endpoints of incomplete/complete recovery were primarily based on patient reports rather than objective testing. This is especially important for symptoms such as dyspnea or hyposmia, where subjective perception and objective degree of impairment may vary.
Also, we were unable to investigate or adjust for the effect of SARS- Due to the study period, our cohort likely comprises the wild-type as well as the Delta variant.
There may also be confounders influencing long-term outcome of COVID-19 in pwMS unaccounted for in this study. However, Rosenbaum bounds indicated only a small potential impact of hidden bias not accounted for in the multivariate models [14].

CON CLUS IONS
We showed in a population-based cohort of pwMS suffering from COVID-19 that long-term outcome is generally favorable in a large majority of pwMS, with only a small proportion of patients suffering from prolonged symptoms usually resolving after 3-6 months.
Against the background of a closely matched MS control group, COVID-19 is not associated with increased risk of relapse or disability.

ACK N OWLED G M ENTS
We thank all the AUT-MuSC investigators, clinical research staff, and especially the patients for helping to collect these data. The named individuals were not compensated for their help.

Results
Participants 13 a (a) Report numbers of individuals at each stage of study-e.g., numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analyzed 9-10 (b) Give reasons for nonparticipation at each stage (c) Consider use of a flow diagram Descriptive data 14 a (a) Give characteristics of study participants (e.g., demographic, clinical, social) and information on exposures and potential confounders 9, Table 1 (b) Indicate number of participants with missing data for each variable of interest 9-10 (c) Cohort study: Summarize follow-up time (eg, average and total amount) 9 Outcome data 15 a Cohort study: Report numbers of outcome events or summary measures over time

9-10
Case-control study: Report numbers in each exposure category, or summary measures of exposure Cross-sectional study: Report numbers of outcome events or summary measures Main results 16 (a) Give unadjusted estimates and, if applicable, confounderadjusted estimates and their precision (e.g., 95% confidence interval); make clear which confounders were adjusted for and why they were included 9-10, Summarize key results with reference to study objectives 11-13

Limitations 19
Discuss limitations of the study, taking into account sources of potential bias or imprecision; discuss both direction and magnitude of any potential bias

12-13
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence

11-13
Generalizability 21 Discuss the generalizability (external validity) of the study results

11-13
Other information Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based

14
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the websites of PLoS Medicine at http:// www.plosm edici ne.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.Abbreviation: STROBE, Strengthening the Reporting of Observational Studies in Epidemiology. a Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and crosssectional studies.