key: cord-0818584-thmn64vu
authors: Alroughani, Raed; Inshasi, Jihad; Al-Hashel, Jasem; Alkhaboury, Jaber; Alsalti, Abdullah; Al Suwaidi, Reem; Hassino, Loqman H.; Farouk Ahmed, Samar
title: Prevalence, severity, outcomes, and risk factors of COVID-19 in multiple sclerosis: An observational study in the Middle East
date: 2022-02-24
journal: J Clin Neurosci
DOI: 10.1016/j.jocn.2022.02.033
sha: 3ed19657b53afe84ce64eca8bb8e0ffa1c3b3587
doc_id: 818584
cord_uid: thmn64vu

A cross-sectional hospital records-based study was conducted to evaluate the prevalence, severity, outcomes, and identify demographic and clinical risk factors of coronavirus disease (COVID-19) in patients with MS. The study was conducted at multiple clinics in Oman, Kuwait, and the United Arab Emirates (UAE) from March 2020 to February 2021. The association of patient demographics, MS disease characteristics, and use of disease-modifying therapies with outcomes of COVID-19 illness were evaluated using odds ratio. A total of 134 MS patients with COVID-19 (prevalence rate of 3.7%) having a median age of 35.5 years were analyzed in the study. A majority (126 [94.0%]) of patients had mild COVID-19 illness and 122 (91.0%) made a full recovery, while 1 (0.7%) patient died. The median EDSS score reported in the study was low (1.0). Univariate regression analysis showed high EDSS scores, progressive MS disease, and use of anti-CD20 therapy such as rituximab as risk factors for moderate to severe COVID-19 requiring hospitalization. Comorbidities were associated with a higher risk of non-recovery from COVID-19 in both univariate and multivariate analyses. Age, sex, smoking history, and duration of MS did not show a significant association with severity or adverse COVID-19 disease outcome. Identification of risk factors can aid in improving the treatment and monitoring of pwMS and COVID-19.

The emergence of the coronavirus disease 2019 (COVID-19) pandemic has raised substantial concerns regarding its impact on populations affected by auto-immune diseases. MS, an autoimmune neurodegenerative disorder of the central nervous system, is being studied for its correlation with COVID-19. [1, 2, 3] MS patients are considered a high-risk population for COVID-19, due to the high prevalence of disability and widespread use of immunosuppressive disease-modifying therapy (DMT). [4] Among MS patients, those who belong to an older age group or have a more progressive form of the disease have been shown to develop complications in addition to respiratory tract symptoms during a COVID-19 infection. [5] Indeed, MS patients are found to be at a greater risk of exacerbations and relapses due to this viral infection. [4, 6] The exact relationship between COVID-19 and MS is still unclear. There are contradictory reports regarding the relation between COVID-19 severity/risk and immunosuppressive medications. The primary aim of our study was to evaluate the prevalence, severity, and were also extracted from the records. The data were confirmed by either contacting patients by phone or when they visited the clinics for their routine scheduled visits or due to their concern about their DMTs. The patients were asked to complete a self-administered survey sent via email or filled at the clinic that retrospectively collected details of the course of their COVID-19 illness such as symptoms, investigations performed, and requirement of hospitalization. Information was also obtained from their medical records. The severity of COVID-19 was categorized as mild (not requiring hospitalization), moderate (hospitalized), and severe (requiring intensive care). MS patients older than 18 Table 1 . Ninety-eight patients (73.1%) were female, with the median age of the cohort being 35.5 years, and a mean (SD) disease duration of 8.83 (6.0) years. Nonsmokers accounted for 88.8% of the total cohort with 91% reporting no morbid obesity.

Relapsing-remitting MS accounted for 86.6% of all types of MS patients analyzed in the cohort. The majority (90.3%) had no comorbidities. Hypertension/cardiovascular disease Notably, fever (temperature more than 38 °C), fatigue, dry cough, and sore throat were more frequent in patients, along with anosmia. Eight (6.0%) patients were hospitalized; of these, 3 (2.2%) were in the intensive care unit and 2 (1.5%) required ventilator support. In evaluating COVID-19 outcome in terms of recovery and non-recovery, we found that 122 (91.0%) patients recovered, and one (0.7%) patient died. At the time of writing this manuscript, 9 (6.7%) patients had an ongoing COVID-19 infection, and the outcome was unknown in 2 (1.5%) patients.

To estimate the risk factors associated with COVID-19 severity, hospitalization, and outcomes, we calculated the odds ratios (ORs) from univariate and multivariate logistic regression models. Since all moderately ill patients were also hospitalized, the statistical results of the association of various covariates were similar for both, hospitalization, and COVID-19 severity. Univariate analysis showed a statistically significant higher risk of moderate/severe COVID-19 severity and hospitalization in patients with higher EDSS scores (OR: 8.06; 95% CI 1.290 -50.453, p = 0.026) and in patients with progressive disease (OR 8.85; 95% CI 1.786 -43.855, p = 0.008) [ Table 2 ]. The association between age and COVID-19 severity was found to be non-significant (p = 0.082) with a 3.8 times higher risk of moderate/severe disease and hospitalization in patients aged 45 and above.

The presence of at least one comorbidity was significantly associated with a 5.3 times higher risk of non-recovery from COVID-19 (95% CI 1.174 -24.225, p = 0.03) [ Table 3 ].

Univariate analysis of DMT use showed a statistically significant higher risk of developing moderate/severe COVID-19 and consequent hospitalization in patients on rituximab (6.2 times higher risk) (95% CI 1.319 -29.830, p = 0.021). However, patients on other DMTs including ocrelizumab did not show an association with COVID-19 severity. The category of anti-CD20 therapy (rituximab and ocrelizumab combined data) showed significant association with COVID-19 severity (5.3 times higher risk) (95% CI 1.203 -23.639, p = 0.028) [ Table 4 ]. There was no association between DMT use and the outcome of COVID-

Multivariate regression analysis did not show a significant association of any of the covariates tested with the severity of COVID-19 or hospitalization [ Table 5 ]. However, similar to univariate analysis, a significant association of non-recovery was found with the presence of comorbidities. There was a significant 1.5 times higher risk of non-recovery in patients with any comorbid condition, eliminating the effect of all other covariates (95% CI 1.073 -2.134, p = 0.018) [ Table 6 ].

This hospital records-based observational study analyzed cohorts of MS patients from three clinics in Kuwait and one clinic each in UAE and Oman for eleven months. The prevalence rate of COVID-19 (3.7%) in the analyzed MS cohort is marginally lower than the overall prevalence of COVID-19 in the general population of Kuwait (5.3%), Dubai MS patients (6.3%) was found to be similar to that in the general population of the Catalan region of Spain (6.1%). [1] Similarly, Sepulveda et al conducted a cross-sectional study to investigate the incidence of COVID-19 in a cohort of MS patients at a single center in Barcelona, Spain. The study found that the cumulative incidence of confirmed COVID-19 cases (1.27%) was similar to that of the general population (1.32%). [3] The results of these studies corroborate our findings of similar or only slightly lower prevalence of COVID-19

in MS patients compared to that in the general population of that region or country.

The hospitalization rate (6.0%), the requirement of intensive care (2.2%), and the mortality rate (0.7%) in our cohort were low. It could be possible that the younger age (median age, [9] ; a European and US study with 17% of confirmed cases of COVID-19 in MS patients described 5.6% of hospitalizations and no deaths [10] , and an Italian program with 24.5% of confirmed cases reported 4% of patients with mild disease and 2.1% of mortality [11] . In contrast, higher rates of hospitalization (21.0%-25.6%) were found in studies with a higher proportion of confirmed cases. [5, 12, 13] Clinical characteristics of COVID-19 in MS patients in our study do not differ greatly from those in the general population and are similar to those seen in other published articles. [14, 15, 16] In our cohort, fever, fatigue, dry cough, and sore throat were the most common symptoms.

In univariate analyses, higher EDSS scores (≥ 5) and progressive disease were identified as risk factors for increased COVID-19 severity and consequent hospitalization, while risk factors for an unfavorable outcome in terms of recovery and non-recovery were the presence of comorbid conditions. A similar multicenter, retrospective, observational cohort study was conducted by Louapre et al. to evaluate risk factors and outcomes of COVID-19 in MS patients in France. The study used the Covisep registry and identified greater age, male sex, comorbidities, progressive disease, and higher EDSS as risk factors for increased COVID-19 severity in their univariate analyses. [5] In the general population, the risk for severe COVID-19 illness increases with age, and older adults are at the highest risk.

[16] In our study, we found age to be a risk factor with 3.8 times higher risk of moderate/severe COVID-19 in MS patients who are above the age of 45 years, but this association was not statistically significant. This may be attributed to a lower number of patients (20) in the older age group (≥ 45) in our cohort. In the study conducted by Parotta et al., critically ill COVID-19 infected MS patients were older (mean age of 57.7 years). [12] It is established that respiratory dysfunction is common in pwMS an EDSS of 7 or more and is linked to impairment of expiratory muscles. [17] In our univariate analyses, EDSS was an independent risk factor for a severe form of COVID-19. The cohort we analyzed had a low level of neurological disability as assessed by EDSS scores, with 94.8%

reporting scores between 0 -4.5; however, higher disability scores prognosis. [5] Univariate and multivariate analysis in our study also showed the presence of co-morbidities as an independent risk factor for COVID-19 outcome with a higher chance of non-recovery. Due to the insufficient number of patients, we were unable to establish the association of specific comorbidities with COVID-19 severity or outcome.

Relapsing-remitting MS is typically known to be the most common type of MS and most patients are diagnosed initially with this type. The disease takes a more progressive course after several decades. The majority of patients in our cohort had RRMS (86.6%).

Considering the lower age of the participants, this is understandable. Progressive disease was associated with increased COVID-19 severity in our cohort. This was similar to the results of studies conducted by Louapre et al. and Parotta et al. that found progressive MS to be a risk factor for developing more severe COVID-19. [5, 12] Disease-modifying therapies are known to modify the risk of COVID-19 infection based on their mechanisms of action. In our study, we found a statistically significant higher risk of developing moderate/severe COVID-19 and consequent hospitalization in patients on rituximab (6.3 times higher risk) and anti-CD20 therapy (5.3 times higher risk). However, a few studies have found that the type/class of DMT is not a predictor for increased severity of COVID-19 or of poor outcome. [3, 5, 8, 12, 18, 19] A large electronic health recordbased observational study conducted by Reder et al. in 2021 found that pwMS taking interferons and glatiramer acetate had the lowest risk of COVID-19 whereas patients receiving anti-CD20 therapies had the highest risk. [20] Another study by Fragoso et al.

carried out using data from five Latin American countries in patients with MS and confirmed diagnosis of COVID-19 reported the use of anti-CD20 therapies as the only risk factor associated with hospitalization and death. [21] Other studies including one with a large multinational sample of MS patients have also implicated anti-CD20 therapy (either rituximab or ocrelizumab) in increasing the risk of severe COVID-19 and hospitalization/ICU admission. [22, 23, 24] The results of these studies corroborate our results and can be explained by the fact that anti-CD20 therapies impact the humoral immune response and decrease the levels of IgG and IgM over time. [25] However, any association with DMTs should be inferred with caution as results may be attributed to inadequate sample size and may vary if a larger cohort with the use of any of the DMTs is analyzed. A study by Zabalza et al. [1] found longer MS disease duration to be a risk factor for COVID-19; however, this association was not seen in our study.

Our study has several notable limitations that include the lack of a structured pre-defined data collection format; it also involved voluntary reporting by health care professionals, which may have led to biased reporting towards more severe cases. CI, confidence interval; CIS, clinically isolated syndrome; COVID-19, coronavirus disease 2019; DMT, disease modifying therapy; EDSS, Expanded Disability Severity Scale; MS, multiple sclerosis; PPMS, primary progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis. 

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Dr. Rupali Bahri from Medcytes, Dubai provided medical writing services for the development of this manuscript.

 Prevalence of COVID-19 in the studied MS cohort was marginally lower to that in the general population.  The COVID -19 disease course was mild and outcomes were mostly favorable. Most patients did not require hospitalization. High EDSS score, progressive MS disease, and anti CD20 therapy use were risk factors for moderate to severe disease requiring hospitalization.  Comorbidities were associated with a higher risk of non-recovery from COVID-19.