key: cord-0819106-q581h8ry
authors: Alshamrani, Foziah; Alnajashi, Hind; Aljumah, Mohammed; Almuaigel, Mohammad; Almalik, Yaser; Makkawi, Seraj; Alsalman, Sadiq; Almejally, Mousa; Qureshi, Shireen; Aljarallah, Salman; AlKhawajah, Nuha; Kedah, Hanaa; Alotaibi, Hessa; Saeedi, Jameelah; Alamri, Abdulla
title: Registry of patients with multiple sclerosis and COVID-19 infection in Saudi Arabia
date: 2021-05-07
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2021.103004
sha: 766eea74b3a57eaffca2cd909248f11a51d0ea17
doc_id: 819106
cord_uid: q581h8ry

BACKGROUND: The outbreak of coronavirus disease 2019 (COVID-19) has rapidly spread and developed as a pandemic threatening global health. Patients with multiple sclerosis (MS)–an autoimmune demyelinating inflammatory disease of the central nervous system (CNS)–are predominantly treated with immunomodulatory/immunosuppressive disease-modifying therapies (DMTs), which can increase the risk of infection. Therefore, there is concern that these patients may be at increased risk of COVID-19. In response to growing concerns of neurologists and patients, this study aimed to determine the prevalence, severity, and possible complications of COVID-19 infection in patients with MS in Saudi Arabia (SA). METHODS: In this prospective cohort study, demographic and clinical data were obtained from patients residing in SA with MS who had a positive result for COVID-19 per reverse transcription-polymerase chain reaction test or viral gene sequencing, using respiratory or plasma samples. Comparison of COVID-19 severity groups was performed using one-way ANOVA or Kruskal-Wallis test for numerical variables and Chi- squared test for categorical variables. RESULTS: Seventy patients with MS and COVID-19 (71% female) were included in this analysis. Of the 53 (75.7%) patients taking DMT at the time of COVID-19 infection, the most frequently used drugs were fingolimod (25%) and interferon-beta (25%). Nine (13%) patients had MS relapse and were treated with intravenous methylprednisolone in the four weeks before COVID-19 infection. The most common symptoms at the peak of COVID-19 infection were fever (46%), fatigue (37%), and headache (36%). The symptoms lasted for a mean duration of 8.7 days; all symptomatic patients recovered and no deaths were reported. COVID-19 severity was categorized in three groups: asymptomatic (n=12), mild–not requiring hospitalization (n=48), and requiring hospitalization (n=10; two of whom were admitted to the intensive care unit). Between the three groups, comparison of age, body mass index (BMI), Expanded Disability Severity Score (EDSS), MS disease duration, and DMT use at the time of infection showed no significant differences. A higher percentage of patients who were admitted to hospital or ICU (40%; p=0.026) presented with an MS relapse within the prior four weeks compared with those who were asymptomatic or had a mild infection (both 8.3%). CONCLUSION: These findings present a reassuring picture regarding COVID-19 infection in patients with MS. However, patients with MS who have had a relapse in the preceding four weeks (requiring glucocorticoid treatment) may have an increased risk of severe COVID-19.

The outbreak of coronavirus disease 2019 has rapidly spread and developed as a pandemic threatening global health. Patients with multiple sclerosis (MS)-an autoimmune demyelinating inflammatory disease of the central nervous system (CNS)-are predominantly treated with immunomodulatory/immunosuppressive disease-modifying therapies (DMTs), which can increase the risk of infection. Therefore, there is concern that these patients may be at increased risk of COVID- 19 . In response to growing concerns of neurologists and patients, this study aimed to determine the prevalence, severity, and possible complications of COVID-19 infection in patients with MS in Saudi Arabia (SA).

In this prospective cohort study, demographic and clinical data were obtained from patients residing in SA with MS who had a positive result for COVID-19 per reverse transcription-polymerase chain reaction test or viral gene sequencing, using respiratory or plasma samples. Comparison of COVID-19 severity groups was performed using one-way ANOVA or Kruskal-Wallis test for numerical variables and Chisquared test for categorical variables.

Seventy patients with MS and COVID-19 (71% female) were included in this analysis. Of the 53 (75.7%) patients taking DMT at the time of COVID-19 infection, the most frequently used drugs were fingolimod (25%) and interferon-beta (25%). Nine (13%) patients had MS relapse and were treated with intravenous methylprednisolone in the four weeks before COVID-19 infection. The most common symptoms at the peak of COVID-19 infection were fever (46%), fatigue (37%), and headache (36%). The symptoms lasted for a mean duration of 8.7 days; all symptomatic patients recovered and no deaths were reported. COVID-19 severity was categorized in three groups: asymptomatic (n=12), mild-not requiring hospitalization (n=48), and requiring hospitalization (n=10; two of whom were admitted to the intensive care unit). Between the three groups, comparison of age, body mass index (BMI), Expanded Disability Severity Score (EDSS), MS disease duration, and DMT use at the time of infection showed no significant differences. A higher percentage of patients who were admitted to hospital or ICU (40%; p=0.026) presented with an MS relapse within the prior four weeks compared with those who were asymptomatic or had a mild infection (both 8.3%).

Coronaviruses are structurally enveloped pathogens containing a large plus-strand RNA genome that can cause a variety of severe diseases, including respiratory tract illnesses and gastroenteritis in amphibians, birds, and mammals(1). To date, several human coronaviruses have been identified, including severe acute respiratory syndrome coronavirus (SARS-CoV)(2) and, most recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was discovered, which causes the coronavirus disease named

The outbreak of the highly-transmissible COVID-19, first reported on December 31, 2019, in Wuhan, China(4), has since spread rapidly, becoming a pandemic in March 2020, threatening global health (5) . As of 31 January 2021, there have been more than 102 million cases reported worldwide, >367,000 of which were in Saudi Arabia (SA)(6-8). In the era of COVID-19, there are significant concerns for individuals with pre-existing co-morbidities, such as cardiovascular, pulmonary, and immune-mediated diseases (9) . Occasionally, coronaviruses can result in neuroinvasion due to their tropism for the central nervous system (CNS), resulting in potential neurological damage, which may carry heightened implications for patients with pre-existing neurological diseases with associated demyelination (10, 11) .

One such disease is multiple sclerosis (MS), an autoimmune demyelinating inflammatory disorder of the CNS(12), affecting over 2.8 million people worldwide in a 2:1 female to male ratio (13) . Patients with MS are predominantly treated with immunomodulatory/immunosuppressive disease-modifying therapies (DMTs), which alter the immune response, potentially increasing the risk of infection (9, 14) . Therefore, there is concern that these patients may be at increased risk of COVID-19 infection or severe outcomes.

Alongside neurologist's concern for their patients, a study of 176 patients with MS conducted in SA showed 46% of patients had anxiety over taking their DMT medication, and a further 32% missed hospital appointments, highlighting the significant impact of the COVID-19 pandemic on the healthcare of patients with MS (15) .

In response to the growing uncertainty and anxiety of health care professionals and patients alike, this study aimed to determine the prevalence, severity, and possible complications of COVID-19 infection in patients with MS in SA.

This was a prospective cohort study conducted across 12 hospitals in SA. Demographic and clinical data, including gender, age, type of MS diagnosed, type of DMT prescribed, symptoms of COVID-19 infection, and hospital admissions, including those to the ICU, were obtained from medical records and patients;

through a face-to-face interview process, conducted at the respective hospitals. This study was approved by the ethics committee or institutional review board of each centre involved. Informed verbal consent was obtained from all patients for inclusion in the study.

Patients Individuals were discounted if they were pregnant, lactating, had a history of substance abuse, or there was the presence of another neurological disorder.

Prevalence-based sample size was determined using "Qualtrics" sample-size calculator; it quantified that 

Across SA, 70 patients with MS and COVID-19 infection were included, of whom 50 (71%) were female (Table 1) . Geographically, the highest percentage of patients were from the central region (47%), followed by the eastern region (24%) and the western region (23% 

As presented in Table 2 , the most common initial symptoms of COVID-19 amongst these patients with MS were fever (54%), headache (33%), and dry cough (30%), while the most common symptoms at the peak of infection were fever (46%), fatigue (37%), and headache (36%). The mean (SD) approximate duration of COVID-19 symptoms was 8. (Table S1 ). All symptomatic patients recovered and no deaths were reported.

Of the 70 patients, there were 12 asymptomatic cases, 48 mild cases (not hospitalized), and ten hospitalized cases. There were no significant differences in age, BMI, EDSS score, or MS disease duration among the three COVID-19 severity groups (Table 3) , nor between the three groups with regards to DMT use at time of COVID-19 infection (Table 4 ). There were also no significant differences observed between patients who presented with symptomatic or asymptomatic COVID-19 infection (Table S2 and   Table S3 ). However, it was noted that a higher percentage of patients who were admitted to hospital or the ICU (40%; p=0.026) had presented with an MS relapse within four weeks prior to COVID-19 infection compared with those who were asymptomatic or had mild symptoms (both 8.3%; Table 5 ).

In (19) , as well as the low rates of non-ambulatory status and low median EDSS score reported in this study cohort (20) . In this cohort, no significant associations between age or BMI and COVID-19 severity were observed. This contrasts with the numerous reports identifying age as a major risk factor of COVID-19, widely noted since the early stages of the pandemic (21, 22) . Other studies with larger patient groups have also indicated that obesity (BMI >30) correlates with a poorer COVID-19 prognosis (20, (23) (24) (25) (26) .

MS disease duration and disability, assessed by EDSS, did not influence the severity of COVID-19 in this study. At the same time, EDSS has been identified as an independent risk factor of severe COVID-19 in patients with MS in reports (20, 27) .

DMT use at the time of infection was not associated with COVID-19 severity in this cohort of patients with MS, which corresponds with other recent data showing no significant correlation between COVID-19 severity and the use of DMTs for the treatment of MS (20, (28) (29) (30) . This lack of association between DMT type and COVID-19 severity supports a recent management consensus from experts in MS care from Saudi Arabia, which generally recommends continuing most DMTs during the COVID-19 era(31).

Consensus was not reached with regards to continuing ocrelizumab given that anti-CD20 therapies have been associated with an increased risk of severe COVID-19 infection (25, 30, 32) . Correspondingly, in our study, two of the four patients receiving ocrelizumab at the time of infection had severe disease, including one who required mechanical ventilation.

As was the case in this study, MS relapses are commonly treated with glucocorticoids, e.g., methylprednisolone. Nine patients treated with methylprednisolone following an MS relapse within four weeks before their diagnosis of COVID-19 were at a significantly higher risk of developing a more severe infection, requiring hospital or ICU admission and potentially mechanical ventilation. This is in line with findings from an Italian cohort of MS patients, which showed recent treatment with high-dose methylprednisolone was associated with increased risk (OR 6.0; p=0.007) of severe forms of COVID-19 (30) . Therefore, broad immunosuppression with glucocorticoids before COVID-19 contraction may be associated with a more severe COVID-19 infection(32).

These findings are also similar to observations with other autoimmune diseases. For example, a case series of 600 patients with rheumatic disease found that patients exposed to glucocorticoid ≥10 mg/day before COVID-19 infection were significantly more likely to require hospitalisation (OR 2.05 [95% CI 1.06-3.96]) (23) . Interestingly, a study conducted in China found that two patients with neuromyelitis optica spectrum disorder (an autoimmune disease of the CNS(33)), that had previously been treated with oral methylprednisolone, were diagnosed with more severe COVID-19 infection and associated pneumonia (34) . Furthermore, it may be hypothesised that the dampening effect of methylprednisolone on the inflammatory cytokine cascade, activation of T cells, and extravasation of immune cells into the CNS could be factors leading to poorer outcomes of COVID-19(35).

This study was limited by the relatively small sample size, especially in some subgroups. However, this was still more than the minimum sample of 40 patients required to be recruited.

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The authors would like to thank all the patients for their participation in this study alongside King Abdullah International Medical Research Center. Medical writing assistance was provided by Anna Khan of inScience Communications, Springer Healthcare Ltd, UK, and funded by Merck KGaA, Darmstadt, Germany.

Medical writing support was funded by Merck KGaA, Darmstadt, Germany.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article. All authors had access to the study data and take responsibility for the integrity of the data and the accuracy of the data analysis, and have given their approval for this version to be published.

This study was approved by the ethics committee or institutional review board of each individual center involved. Informed verbal consent was obtained from all patients for inclusion in the study.

Duration of COVID-19 symptoms, mean (SD), days 8.7 (9. 3)

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