ARTICLE OPEN ACCESS SARS-CoV-2 Infection in Multiple Sclerosis Results of the Spanish Neurology Society Registry Georgina Arrambide, MD, PhD, Miguel Ángel Llaneza-González, MD, PhD, Correspondence Dr. J. Meca-Lallana Lucienne Costa-Frossard França, MD, Virginia Meca-Lallana, MD, Eva Fernández- Dı́az, MD, pmecal@gmail.com Irene Moreno-Torres, MD, PhD, Jose Manuel Garcı́a-Domı́nguez, PhD, Gloria Ortega-Suero, MD, Lucı́a Ayuso-Peralta, MD, Mayra Gómez-Moreno, PhD, Javier J. Sotoca-Fernández, MD, Ana Belén Caminero-Rodrı́guez, MD, Luis A. Rodrı́guez de Antonio, MD, Marcial Corujo-Suárez, MD, Marı́a A. Otano-Martı́nez, MD, Francisco Carlos Pérez-Miralles, PhD, Virginia Reyes-Garrido, MD, Teresa Ayuso-Blanco, MD, José Jesús Balseiro-Gómez, MD, Mercedes Muñoz-Pasadas, MD, Inmaculada Pérez-Molina, PhD, Carmen Arnal-Garcı́a, MD, Ángela Domingo-Santos, MD, Cristina Guijarro-Castro, MD, PhD, Cristina Íñiguez-Martı́nez, MD, PhD, Nieves Téllez Lara, PhD, Fernando Castellanos-Pinedo, MD, Tamara Castillo-Triviño, MD, Debora Marı́a Cerdán-Santacruz, PhD, Ángel Pérez-Sempere, MD, Berta Sebastián Torres, MD, Amaya Álvarez de Arcaya, MD, Eva Costa-Arpı́n, PhD, Eduardo Durán-Ferreras, PhD, Marta Fragoso-Martı́nez, MD, Montserrat González-Platas, MD, PhD, Lamberto Landete Pascual, PhD, Jorge Millán-Pascual, PhD, Celia Oreja-Guevara, MD, PhD, and José E. Meca-Lallana, MD, PhD Neurol Neuroimmunol Neuroinflamm 2021;8:e1024. doi:10.1212/NXI.0000000000001024 Abstract Objective To understand COVID-19 characteristics in people with multiple sclerosis (MS) and identify high-risk individuals due to their immunocompromised state resulting from the use of disease- modifying treatments. Methods Retrospective and multicenter registry in patients with MS with suspected or confirmed COVID-19 diagnosis and available disease course (mild = ambulatory; severe = hospitalization; and critical = intensive care unit/death). Cases were analyzed for associations between MS characteristics and COVID-19 course and for identifying risk factors for a fatal outcome. Results Of the 326 patients analyzed, 120 were cases confirmed by real-time PCR, 34 by a serologic test, and 205 were suspected. Sixty-nine patients (21.3%) developed severe infection, 10 (3%) critical, and 7 (2.1%) died. Ambulatory patients were higher in relapsing MS forms, treated with injectables and oral first-line agents, whereas more severe cases were observed in patients on pulsed immunosuppressors and critical cases among patients with no therapy. Severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course, and higher disability. Fifteen of 33 patients treated with From the Centro de Esclerosis Múltiple de Cataluña (G.A.), (Cemcat), Instituto de Investigación Vall d’Hebron, Hospital Universitario Vall d’Hebron, Universidad Autónoma de Barcelona; Complejo Hospitalario Universitario de Ferrol (M.Á.L.-G.); Hospital Universitario Ramón y Cajal (L.C.-F.F.), Madrid; Hospital Universitario de la Princesa (V.M.L.), Madrid; Complejo Hospitalario Universitario de Albacete, (E.F.D.); Hospital Universitario Fundación Jiménez Dı́az (I.M.T.), Madrid; Hospital General Universitario Gregorio Marañón (J.M.G.-D.), Madrid; Hospital La Mancha Centro (G.O.-S., Á.D.S.), Alcázar de San Juan; Hospital Universitario Prı́ncipe de Asturias (L.A.P.), Alcalá de Henares; Hospital Universitario Infanta Leonor (M.G.M.), Madrid; Hospital Universitario Mútua Terrasa (J.J.S.-F.); Complejo Asistencial de Ávila (A.B.C.-R.), Ávila; Hospital Universitario de Fuenlabrada (L.A.R.A.), Madrid; Hospital Universitario Son Espases, Palma de Mallorca (M.C.S.); Complejo Hospitalario de Navarra (M.A.O.-M., T.A.B.), Pamplona; Hospital Universitario y Politécnico La Fe (F.C.P.-M.), Valencia; Hospital Regional Universitario de Málaga (V.R.G.); Hospital Universitario de Getafe (J.J.B.-G.), Madrid; Hospital Santa Barbara (M.M.P.), Puertollano; Hospital Virgen de la Salud (I.P.M.), Toledo; Hospital Universitario Virgen de las Nieves (C.A.G.), Granada; Hospital Universitario Puerta del Sur (CINAC), Madrid (C.G.C.); Hospital Clı́nico Universitario Zaragoza (C.Í.M.), Zaragoza; Hospital Clı́nico Universitario Valladolid (N.T.L.,), Valladolid; Hospital Virgen del Puerto (F.C.P.), Plasencia; Hospital Universitario Donostia (T.C.T.), San Sebastian; Hospital General de Segovia (D.M.C.-S.), Segovia; Hospital General Universitario de Alicante (Á.P.S.), Alicante; Hospital Universitario Miguel Servet (IIS Aragón) (B.S.T.), Zaragoza; Hospital Universitario Araba (A.Á.A.), Vitoria; Hospital Clı́nico Universitario de Santiago de Compostela (E.C.A.), Santiago de Compostela; Hospital Universitario Juan Ramón Jiménez (E.D.-F.), Huelva; Hospital de Terrasa (M.F.M.), Terrasa; Hospital Universitario de Canarias (M.G.P.), San Cristobal de La Laguna; Hospital Universitario Dr Peset de Valencia (L.L.P.), Valencia; ́ Complejo Hospitalario Universitario de Cartagena (J.M.P.), Murcia; Hospital Clinico San Carlos (C.O.-G.),Facultad de Medicina, Universidad Complutense de Madrid, IdISSC, Madrid; and CSUR Unidad de Esclerosis Múltiple y Neuroinmunologı́a Clı́nica (J.E.M.-L.), Hospital Clı́nico Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Cátedra de Esclerosis Múltiple y Neuroinmunologı́a Clı́nica, UCAM, Universidad Católica San Antonio, Murcia, Spain. Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the Spanish Neurology Society. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary ANOVA = analysis of variance; CI = confidence interval; DMT = disease-modifying treatment; EDSS = Expanded Disability Status Scale; ICU = intensive care unit; IQR = interquartile range; IVMP = IV pulses of methylprednisolone; MS = multiple sclerosis; OR = odds ratio; RT = real time; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2. rituximab were hospitalized. Four deceased patients have progressive MS, 5 were not receiving MS therapy, and 2 were treated (natalizumab and rituximab). Multivariate analysis showed age (OR 1.09, 95% CI, 1.04–1.17) as the only independent risk factor for a fatal outcome. Conclusions This study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19 but evidenced that people with MS with advanced age and disease, in progressive course, and those who are more disabled have a higher probability of severe and even fatal disease. The COVID-19 pandemic is representing a challenge for the diarrhea) and radiologic features (chest x-ray or chest CT care of patients with immune-mediated diseases such as findings of pneumonia), although no confirmatory test was multiple sclerosis (MS) requiring immunomodulatory or performed. All patients included had available information on immunosuppressive disease-modifying treatments (DMTs). the COVID-19 outcome (recovery or death), and data were retrospectively collected from symptom onset. The Spanish For coronaviruses, the aberrant host immune response is re- Neurology Society created a web-based platform and invited sponsible for the severe respiratory failure during infection1 that member sites in Spain to participate in the collection of the may lead 21% of patients with MS to be hospitalized and 3.5% to data. The database is still open for neurologists to continue die.2 A key issue is identifying inherent factors of MS that may submitting cases. put patients at an increased risk of severe COVID-19 beyond the well-established older age and comorbid diseases in the general Standard Protocol Approvals, Registrations, population.3 Theoretically, the repression of immune hyper- and Patient Consents activation underlying the efficacy of immunosuppressants is The Ethics Committee of Hospital Virgen de la Arrixaca precisely what could confer on patients a worse prognosis by (Murcia, Spain) approved the study, and all patients gave their allowing viral replication, which, in turn, may also prevent them oral or written informed consent for the use of medical data from developing an acute respiratory distress syndrome by following the Declaration of Helsinki and local regulations. limiting the aberrant inflammatory response. Anti-CD20 drugs are speculated to confer protection4-6 despite minimal B cell Data Collection involvement at the initial viral response,7 but also susceptibility.8 Data collection included demographics, MS course and du- S1P modulators and DMTs inducing pronounced lymphopenia ration, the last Expanded Disability Status Scale (EDSS) score such as cladribine, alemtuzumab, and dimethyl fumarate have before COVID-19 infection, current—and time on—DMT, been found to be involved in both severe9-12 and uncomplicated decisions over DMTs during COVID-19 (delaying, inter- severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rupting, keeping, or switching treatment), exposure to IV infection.13,14 However, to date, there are no conclusive data in pulses of methylprednisolone (IVMP) in the last 2 months, this regard. This article describes the cases entered in the Spanish and comorbidities at the time of infection. As for COVID-19, registry of patients with MS with suspected or confirmed we collected any neurologic symptom highly suggestive of COVID-19 between March and June 2020. We believe in its SARS-CoV-2 infection (hyposmia/anosmia, dysgeusia, potential to reinforce—or question—previous data and offer headache, and myalgia), treatment, lymphocyte count during new insights in the clinical management of patients with MS the infection, and COVID-19 course and outcome (recovery more likely to experience fatal outcomes from COVID-19. or death). Clinical evolution of COVID-19 was grouped into the following severity of illness categories: mild (ambulatory patients), severe (patients who were hospitalized), and critical Methods illness (patients who were admitted in the intensive care unit [ICU] or died). This is a national, multicenter and observational study of adult patients with MS who tested positive for SARS-CoV-2 on a Statistical Analysis real-time (RT)-PCR (on nasopharyngeal swabs) or serologic Descriptive statistics were used to summarize data; quantita- test, or with highly suspected COVID-19 based on clinical tive variables were described with measures of central ten- (fever, persistent cough and/or sore throat, dyspnea, and dency and dispersion (mean ± SD or median [interquartile 2 Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 Neurology.org/NN range [IQR]) and qualitative variables with absolute (n) and Table 1 Demographic and Clinical Characteristics of relative (%) frequencies. Statistical comparisons between Patients With MS and COVID-19 in the Spanish continuous variables were performed with independent t tests Registry (n = 326) for the analysis of 2 groups and with the analysis of variance Value (ANOVA) for more than 2 groups. The χ 2 test or Fisher exact test was applied to categorical variables. The significance level Age, y of 0.05 was used for statistical testing, and missing data were Mean ± SD 44.8 ± 11.5 not imputed. Median (IQR) 43.5 (37–51) Sex, female 221 (67.8) For the analysis of variables associated with the clinical course of COVID-19, DMTs were categorized as follows: (1) injectable Time since MS diagnosis, y (interferons and glatiramer acetate); (2) oral first-line agents Mean ± SD 11.0 ± 8.0 (teriflunomide and dimethyl fumarate); (3) reversible immu- Median (IQR) 9 (5–17) nosuppressants (natalizumab and fingolimod); (4) pulsed im- Disease course munosuppressants (alemtuzumab, ocrelizumab, rituximab, and cladribine), and (5) other drugs. To identify risk factors for RRMS 263 (80.7) critical COVID-19 course and death, the independent variables SPMS 43 (13.2) age, sex, comorbidities, MS phenotype, EDSS score, DMTs, PPMS 20 (6.1) IVMP in the last 2 months, and treatment for COVID-19 were EDSS score analyzed using the univariate logistic regression model. The phenotype of MS was grouped as relapsing vs progressive, and Mean ± SD 2.6 ± 2.2 DMTs were grouped by level of immunosuppression as inject- Median (IQR) 2.0 (1.0–3.5) ables + oral first-line agents vs the rest of treatments. Comor- Grouped DMTs bidities, IVMP use, and treatment for COVID-19 were treated as categorical variables (yes vs no). Injectables 49 (15.0) Oral first-line agents 78 (24) A multivariate regression model was performed via automated Reversible immunosuppressive therapy 53 (16.2) forward stepwise selection of variables with p values <0.2. Pulsed immunosuppressive therapy 80 (24.5) Results are expressed as ORs and 95% CIs. An exploratory analysis was performed to assess the disease course in patients Other 7 (2.1) treated with B cell–depleting therapy for less or more than 24 None 59 (18.1) months, assuming that the immunosuppressive effect is sta- Time on current DMT bilized after 24 months of exposure despite the different ad- <6 mo 18/266 (6.8) ministration regimens adopted with ocrelizumab and rituximab. Analyses were performed with the Statistical 6–24 mo 77/266 (29.0) Package for the Social Sciences version 22.0 (SPSS Inc, >24 mo 171/266 (64.0) Chicago). IVMP pulses in the last 2 mo 7 (2.1) Data Availability COVID-19 diagnosisa All data collected in this study are available following data Confirmed by RT-PCR 120 (36.8) availability policy in an effort to promote data transparency. Confirmed by a serologic test 34 (10.4) Highly suspected based on clinical and/or 205 (62.9) radiologic features Lymphocyte levels during infectionb, cells/μL 145 (44.5) Results Mean ± SD 1,233.4 ± 742.2 As of 15 June 2020, a total of 336 cases were entered in the registry, 9 of whom were still active, whereas another corre- Abbreviations: BMI = body mass index; DMT = disease-modifying therapy; sponded to a patient younger than 18 years. The number of EDSS = Expanded Disability Status Scale; IQR = interquartile range; IVMP = IV methylprednisolone; PPMS = primary progressive multiple sclerosis; RRMS cases evaluable in the analysis was 326, 120 (36.8%) of whom = relapsing-remitting multiple sclerosis; RT-PCR = real-time PCR; SPMS = tested positive for SARS-CoV-2 by RT-PCR, 34 (10.4%) by a secondary progressive multiple sclerosis. Data are n (%) unless otherwise indicated. Injectables (interferons, n = 36, serologic test, and 205 (62.8%) were highly suspected cases and glatiramer acetate, n = 13); oral first-line agents (dimethyl fumarate, n = 41, and teriflunomide, n = 37); reversible immunosuppressive therapy (fin- with clinical symptoms and/or radiologic findings compatible golimod, n = 27, and natalizumab, n = 26); pulsed immunosuppressive with SARS-CoV-2 infection. The mean age of patients was therapy (rituximab, n = 33, cladribine, n = 6, ocrelizumab, n = 23, and alemtuzumab, n = 18). 44.8 ± 11.5 years; most were female (n = 221; 67.8%) and had a b Multiresponse variable. a relapsing course of MS (n = 263; 80.7%). The mean MS Calculated on patients with the available blood lymphocyte count at the date of examination. duration was 11.0 ± 8.0 years, and the median EDSS score at COVID-19 infection was 2.0 (IQR: 1.0 to 3.5). One hundred Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 3 Table 2 Patient Characteristics by the Clinical Course of COVID-19 Clinical coursea Mild (ambulatory) Severe (hospitalization) Critical (ICU admission/death) (n = 244) (n = 69) (n = 10) p Value Age, y <0.001c Mean ± SD 42.7 ± 10.3 51.1 ± 12.7 55 ± 12.4 Median (IQR) 42 (36–49) 49 (42–61) 56.5 (47–68) Sex, female 175 (71.7) 39 (56.5) 4 (40) <0.05d MS duration, y <0.05c Mean ± SD 10.3 ± 7.6 13.6 ± 8.9 14 ± 9.6 Median (IQR) 9 (4–16) 12 (7–20) 13 (5–25) MS course <0.001d RRMS 218 (89.3) 37 (53.6) 5 (50) SPMS/PPMS 26 (10.6) 32 (46.4) 5 (50) EDSS score <0.001c Mean ± SD 2.2 ± 1.9 4.1 ± 2.4 4.4 ± 2.7 Median (IQR) 1.5 (1–3) 3.5 (2–6.5) 3.7 (2–6.5) Current DMT Interferon beta 31 (12.7) 5 (7.2) 0 (0) NS Glatiramer acetate 12 (4.9) 1 (1.4) 0 (0) NS Teriflunomide 28 (11.4) 7 (10.1) 1 (10) NS Dimethyl fumarate 40 (16.3) 0 (0) 1 (10) <0.001d Natalizumab 21 (8.6) 3 (4.3) 1 (10) NS Fingolimod 24 (9.8) 3 (4.3) 0 NS Alemtuzumab 16 (6.5) 1 (1.4) 1 (10) NS Ocrelizumab 15 (6.1) 8 (11.6) 0 NS Rituximab 17 (6.9) 15 (21.7) 1 (10) <0.05d Cladribine 6 (2.4) 0 (0) 0 NS Other 4 (1.6) 1 (1.4) 0 NS Time on current DMT NS <6 mo 15 (6.1) 3 (4.3) 0 6–24 mo 60 (24.5) 15 (21.7) 1 (10) >24 mo 139 (57.0) 27 (39.1) 4 (40) IVMP in the last 2 mo 3 (1.2) 4 (5.8) 0 (0) NS Patients with comorbiditiesb 105 (43) 39 (56.5) 8 (80) <0.05d Smoking 39 (15.9) 7 (10.1) 0 (0) NS 2 Obesity (BMI >30 kg/m ) 21 (8.6) 15 (21.7) 3 (30) <0.001d Arterial hypertension 16 (6.5) 14 (20.2) 3 (30) <0.001d Diabetes mellitus 7 (2.8) 4 (5.8) 5 (50) <0.001d Bronchopathy 5 (2.0) 3 (4.3) 1 (10) NS Ischemic cardiomyopathy 0 (0) 2 (2.9) 1 (10) <0.05d Continued 4 Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 Neurology.org/NN Table 2 Patient Characteristics by the Clinical Course of COVID-19 (continued) Clinical coursea Mild (ambulatory) Severe (hospitalization) Critical (ICU admission/death) (n = 244) (n = 69) (n = 10) p Value Health care personnel 19 (7.7) 0 (0) 1 (10) <0.05d Lymphocyte levelse during infection, cells/μL 84 (34.4) 49 (71.0) 10 (100) Mean ± SD 1,474.93 ± 774.9 916.5 ± 545.8 650.1 ± 345.6 0.001c COVID-19 treatment 41 (16.8) 65 (94.2) 8 (80) <0.001d Abbreviations: BMI = body mass index; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; ICU = intensive care unit; IQR = interquartile range; IVMP = IV methylprednisolone; NS = not significant; NTZ = natalizumab; PPMS = primary progressive multiple sclerosis; RRMS = relapsing- remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis. Data are n (%) unless otherwise indicated. a Clinical course of COVID-19 was available for 323 patients of the total included. b Multiresponse variable. c p Value for ANOVA comparison. d p Value for Fisher test comparison. e Calculated on patients with the available blood lymphocyte count at the date of examination. thirty-three patients (40%) were receiving reversible or pulsed developed severe COVID-19 (figure 2A). High rates of ICU/ immunosuppressive therapy, and 171 (64%) were treated deaths (8.6%) and hospitalizations (41.4%) were observed in with the current DMT for at least 2 years. Baseline charac- patients who were not receiving DMTs (figure 2B), and we teristics are presented in table 1. Continuing the current DMT found statistical differences in the percentage of patients on was the most common approach, regardless of their level/type different COVID-19 courses according to DMT (Fisher exact of immunosuppression (injectables, 43 [91.5%]; oral first-line test p value < 0.001). Ambulatory cases were particularly agents, 57 [80.3%]; reversible immunosuppressants, 32 higher in patients receiving injectables (87.8%), oral first-line [65.3%]; and pulsed immunosuppressants, 49 [65.3%]. The agents (88.3%), and reversible immunosuppressors (86.5%), next planned dose was delayed in 13 (34.2%) patients on whereas a higher rate of hospitalization was found in patients rituximab, 12 (31.6%) on natalizumab, and 9 (23.7%) on on pulsed immunosuppressive therapy (30.0%) (figure 2B). ocrelizumab. Dimethyl fumarate and rituximab were the only DMT sig- nificantly associated with the course of infection. Forty pa- Clinical Course of COVID-19 tients of the 41 receiving dimethyl fumarate were ambulatory Common neurologic symptoms at onset included hyposmia/ (p < 0.001), and 15 of the 33 patients on rituximab were anosmia in 95 (29.5%) patients and dysgeusia in 71 (21.8%). hospitalized (p < 0.05). Patients treated with rituximab were Headaches and myalgia were observed in 14 (4.6%) and 8 on average 49.3 (8.5) years old (median 47 [43–54]), and (2.45%) patients, respectively. Most cases (244/323; 75.5%) 60% (20/33) presented progressive MS. When disease course were ambulatory, 69/323 (21.3%) were severe, and 10 (3%) was analyzed according to B cell–depleting therapy and time were critical. Of the 326 patients with MS and COVID-19 of exposure, results showed that treatment with rituximab/ included in this cohort, 7 (2.1%) patients died, of which 4 ocrelizumab for less than 24 months was significantly asso- were admitted to the ICU. The median length of hospital stay ciated with the course of the infection (Fisher p = 0.002), with was 10 days (IQR, 6–15 days), and the median length of ICU almost half of patients (48.3%) hospitalized. stay was 10 days (IQR, 9–16 days). Compared with ambu- latory cases, patients with severe or critical disease were more The median age of 7 fatal cases was 61 (IQR, 52–68) years, 4 likely to be older, male, have a longer MS duration, higher were female, 4 had secondary progressive course, and the median EDSS scores, and a progressive MS course (table 2 and figure EDSS score was 4.5 (IQR, 3.5–8.5) (table 3). Five of the 7 1). Patients with critical infection were more likely to have at patients who died of COVID-19 were not receiving DMTs, and least 1 comorbidity, with diabetes, obesity, hypertension, and the remaining 2 were on immunosuppressive agents (one in ischemic heart disease being the most common. The pro- each natalizumab and rituximab) for >24 months. These 2 pa- portion of health care personnel was 10% (1/10) among tients had their treatment dose temporarily delayed. None of the patients with critical course and 7.7% (19/244) among am- deceased patients was a smoker, and obesity, diabetes, and hy- bulatory cases (table 2). Having received IVMP in the last 2 pertension were reported in 3 patients (43%). One deceased months was not significantly associated with the infection’s patient was a health care worker. Three (43%) of the 7 deceased clinical course (table 2). patients showed neurologic symptoms compatible with COVID-19. Age, MS duration, MS course, and EDSS score were Most patients with relapsing MS (83.8%) were ambulatory, observed to be significantly associated with the COVID-19 and half of the patients with progressive forms (50.8%) outcome (table 3). A significant relationship was found between Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 5 Figure 1 COVID-19 Course by MS Characteristics: (A) Age; Discussion (B) EDSS Score This large series describing COVID-19 course in people with MS shows that most patients developed a mild/moderate dis- ease, which is in line with findings from the Italian program in which 85% of patients presented a mild infection.15 We confirm an overall mortality rate of 2.1%, which is lower than that in the French registry (3.5%)2 and that reported among individuals from the general population aged <65 (4.5%–11.2%) in Euro- pean countries.16 Although patients without a confirmed positive COVID-19 test may have contributed to lowering the rates of hospitalization and deaths attributed to the coronavirus, our data altogether suggest that patients with MS do not seem to be at a higher risk of life-threatening complications from SARS-CoV-2 compared with the general population. These results may be influenced by the hypothetical more rigorous confinement measures adopted by immunosuppressed patients, determining a lower risk of COVID-19 infection, especially those most vul- nerable because of older age and greater disability, which is supported by the median EDSS score of 2.0 in our population. In general, our data show that patients of older age, with longer disease duration and progressive forms of MS, were more likely to be admitted to the ICU and die. Mortality was particularly high in patients older than 52 years. An increased admission rate to the ICU was observed in patients aged 47 years and older, with comorbidities and higher EDSS scores, which normally correspond to progressive courses of MS. Patients with diabetes, obesity, ischemic heart disease, and hypertension were linked to more hospitalizations and ICU admissions. Altogether, these findings reflect the undoubted consequences of age and the contribution of aging-related factors in a more severe evolution of the infection. In this MS cohort, health care personnel accounted for 6.1% (20/326) of Box plots show medians and IQRs. Means are shown with a rhombus. all infections, and although we are limited in drawing con- Outliers are shown with small circles. Differences in age and EDSS score between groups reached statistical significance (ANOVA comparison p val- clusions because the number of patients, this study suggests ues < 0.001). EDSS = Expanded Disability Status Scale; ICU = intensive care that health care workers with MS may be at a high risk of unit; IQR = interquartile range; MS = multiple sclerosis. evolving critically. Of interest, we could not demonstrate any association be- not being treated with DMTs and mortality from COVID-19 tween the immunosuppressive therapy and the severity of compared with treated patients (n = 5, [71.4%] and n = 2 COVID-19 as the vast majority of patients receiving immu- [28.6%], respectively, Fisher exact test p value < 0.001). Patients nosuppressants recovered from disease. Of note, patients on not treated with DMTs had a mean age of 53.5 (13.2) years DMTs were mostly ambulatory, patients without MS treat- (median 53 [43–65]) and a mean EDSS score of 3.75 (2.8) ment reported the higher admission rates to hospital and ICU (median: 3 [1.5–6.5]). admission in this study, and 5 of the 7 patients who died were not receiving DMTs. Similar to what is observed in clinical Risk Factors for Critical COVID-19 Course practice, we observed an elevated proportion of progressive and Mortality MS forms among untreated patients with MS (44%), which Univariate analyses revealed that age, COVID-19 treatment, MS accounted for 19.3% of the whole cohort. Therefore, the phenotype, and EDSS score were all significantly associated with unfavorable COVID-19 course in this particularly susceptible an increased risk of critical course and mortality (table 4). group is not surprising.2,17 In addition, although limited by the Multivariate analysis confirmed a significant association of very small number of deceased patients, our results are in line mortality and older age (OR, 1.09, 95% CI, 1.04–1.17; p = 0.001, with those from the French cohort in which the proportion of per year increase), whereas levels of lymphocytes were identified hospitalized/deceased patients was higher in the group not as significantly associated with a reduced risk of critical course receiving MS treatment.2 Similarly, in this Spanish cohort, the (OR 0.99, 95% CI 0.996–1; p = 0.015). exposure to DMTs, regardless of type, was not found to be a 6 Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 Neurology.org/NN Figure 2 MS Phenotype (A) and DMT (B) Distribution Differences in the percentage of patients with different COVID-19 courses by MS phenotype and DMT reached statistical significance (Fisher exact test p value < 0.001). Injectables (interferons and glatiramer acetate); oral first-line agents (dimethyl fumarate and teriflunomide); reversible immunosuppressors (natalizumab and fingolimod); pulsed immunosuppressors (alemtuzumab, ocrelizumab, rituximab, and cladribine). COVID-19 = coronavirus disease 2019; DMT = disease-modifying treatment; ICU = intensive care unit; MS = multiple sclerosis. predictor of critical COVID-19 in the multivariate model. Although our patients shared baseline characteristics with the However, the relationship that we observed between ritux- French and Italian cohorts, the limitation that data are likely imab and the course of infection deserves attention given the to be biased by incomplete case ascertain in particular patients association with a higher risk of a severe COVID-19 course with very mild or mild COVID-19 has to be considered. They seen in the Italian cohort of 784 patients.15 It is also unclear were a mean of 10 years older and had a longer MS duration why 15 patients treated with rituximab were hospitalized, but than that of the Iranian cohort reported by Safavi et al.,8 in it may be related to the drug’s mechanism of action, the strong which all patients suspected of having COVID-19 had full immunosuppressive effect, and its routine use in progressive recovery even if they were on B cell–depleting agents. The forms of MS and older patients. The finding that being treated fact that in our study the patients hospitalized had a with B cell–depleting therapy for less than 24 months led to a reference lymphocyte count and that critical patients showed more severe clinical course of infection may be cautiously lymphopenia regardless of whether they had been exposed to assumed to be a delayed immunosuppressive effect of treat- MS treatments is only presumed to the virus but might ment during the first 24 months and a greater systemic in- question again the role of maintenance immunosuppression flammatory response in these patients compared with those in the spectrum of disease severity in SARS-CoV-2. treated for more than 24 months. Such results will be high- lighted in the forthcoming updated registry data. If common A similar percentage of patients reported here were treated with features in deceased patients of having a higher EDSS score immunomodulatory and immunosuppressive therapies for more and progressive MS led to a critical outcome, this also merits than 2 years in the majority of cases. The general trend in de- further studies. Based on our data, we did not find the course cisions regarding treatment was toward maintaining medication of MS and disability as risk factors for critical course and death regardless of the type of DMT, but in several cases, neurologists in multivariate analysis as other studies showed,2 possibly considered temporarily delaying the restart of treatment of because of the limited number of patients and sample natalizumab, rituximab, and ocrelizumab, probably due to the distribution. uncertainty surrounding the pandemic. Nevertheless, and Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 7 Table 3 Patient Characteristics by COVID-19 Outcome Patients deceased from Patients recovered from COVID-19 (n = 7) COVID-19 (n = 319) p Value Age, y <0.001a Mean ± SD 60.7 ± 8.6 44.5 ± 11.4 Median (IQR) 61 (52–68) 43 (37–50) Sex, female 4 (57.1) 217 (98.2) NS MS duration, y <0.05a Mean ± SD 17.4 ± 9.2 10.9 ± 7.9 Median (IQR) 15 (11–27) 9 (5–17) MS course <0.001b RRMS 2 (28.5) 261 (81.8) SPMS 4 (57.1) 39 (12.2) PPMS 1 (14.3) 19 (5.9) EDSS score <0.001a Mean ± SD 5.4 ± 2.6 2.6 ± 2.2 Median (IQR) 4.5 (3.5–8.5) 2 (1–3) DMT <0.001b Yes 2 (28.6) 265 (83.0) None 5 (71.4) 54 (16.9) IVMP in the last 2 mo 0 (0) 7 (2.2) NS Presence of comorbidities NS Yes 6 (85.7) 147 (46.0) No 1 (14.3) 172 (54.0) c Lymphocyte levels during infection, cells/μL n=7 n = 138 Mean ± SD 704.4 ± 396.6 1,260.31 ± 746.46 NS Abbreviations: DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; IQR = interquartile range; IVMP = IV methylprednisolone; NS = not significant; PPMS = primary progressive multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis. Data are n (%) unless otherwise indicated. a p Value for t test comparison. b p Value for Fisher test comparison. c Calculated on patients with the available blood lymphocyte count at the date of examination. despite patients on rituximab tending to have a severe course in distinguish between moderate and severe forms of COVID-19 our study, we consider this moment difficult to advocate for any infection in patients with MS hospitalized, except the critical cases management approach owing to the continuously update ad- resulting in ICU admission or death. This is important as not all vice,18 except recommending prescribers to carefully balance the deaths occurred among patients admitted to ICU and not all particular risks to each patient and educate them on preventive patients admitted to ICU died. Data were also lacking on the time measures. to the ICU from the time of hospital admission and on laboratory and radiologic findings on admission. A further limitation would A criticism of the study could be the lack of a clear definition of be the incomplete ascertain in some cases of patients with very severe COVID-19 infection. Hospitalization data were limited to mild or mild COVID-19. The limited access to RT-PCR tests at admissions but no complications on hospitalization such as the the beginning of the pandemic in Spain explains the low per- need for supplemental oxygen or the use of ventilators (non- centage of patients tested for RT-PCR. As is common in all invasive and mechanical) were recorded, nor presenting re- registries, selection bias and the lack of systematic assessment spiratory symptoms (dyspnea, hypoxia, pneumonia, and acute of patients cannot be ruled out, nor that the hypothetical respiratory distress syndrome). Therefore, this study cannot more rigorous compliance with confinement measures by 8 Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 Neurology.org/NN Table 4 Univariate Analyses of Risk Factors for Critical COVID-19 Course and Mortality Critical COVID-19 course Mortality OR (95% CI) p Value OR (95% CI) p Value Age (y) 1.07 (1.01–1.12) 0.007a 1.11 (1.04–1.17) 0.001a Sex (male vs female) 3.24 (0.90–11.75) 0.073 0.62 (0.13–2.85) 0.546 b a MS phenotype (RRMS vs PMS) 0.23 (0.06–0.81) 0.022 0.09 (0.02–0.47) 0.046a DMT (injectable + oral first-lineb vs other therapies) 0.38 (0.08–1.82) 0.227 c 0.938 EDSS score 1.33 (1.05–1.69) 0.018a 1.55 (1.15–2.08) 0.003a IVMP (yesb vs no) c 0.983 c 0.999 b Comorbidities (yes vs no) 4.69 (0.98–22.46) 0.050 7.02 (0.84–58.9) 0.072 COVID-19 treatment (yesb vs no) 7.81 (1.63–37.44) 0.010a 4.82 (0.92–25.23) 0.062 Lymphocyte levels (cells/μL) 0.99 (0.99–1) 0.014a 0.99 (0.99–0.99) 0.060 Abbreviations: EDSS = Expanded Disability Status Scale; IVMP = IV methylprednisolone; MS = multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis; PMS = progressive multiple sclerosis. a Significant variables. b Reference category. c Nonestimable because of sample distribution. immunosuppressed patients, even during the de-escalation phase, committee; Biogen, Bristol-Myers Squibb, Merck, Roche, may have favored our results. Differences in clinicians’ awareness Sanofi, and Teva for the financial support for writing, of the infection may have resulted in differences in monitoring, statistical analysis, and editorial assistance. prevention, and advising measures with regard to patients. Study Funding In conclusion, this study confirms the absence of a critical role This work was funded by the Spanish Society of Neurology of MS DMTs in the evolution of SARS-CoV-2 infection. In- for the writing, editorial assistance, statistical analysis and the stead, older patients, with a progressive course of MS, higher Article Processing Charge. Other contributions related to fi- disability, and comorbidities, might be more vulnerable to nancial support for writing, statistical analysis, and editorial severe outcomes of COVID-19, and the surveillance of this assistance were supported by Biogen, Bristol-Myers Squibb, group should continue. Importantly, we observed a proba- Merck, Roche, Sanofi, and Teva. bility of critical course among health care personnel with MS that has not been addressed in previous studies. There is an Disclosure urgent need for more research to be done to confirm these G. Arrambide has received compensation for consulting ser- preliminary findings and allow refinement of guidelines on the vices or participation in advisory boards from Sanofi, Merck, management of patients with MS during the COVID-19 and Roche; research support from Novartis; travel expenses pandemic. The cases of new variants of coronavirus and pa- for scientific meetings from Novartis, Roche, Stendhal, and tients vaccinated entering the registries that are active ECTRIMS; speaking honoraria from Sanofi, Merck, and worldwide will offer an update that probably changes the main Roche; and is a member of the International Women in conclusions drawn from our results and other studies pub- Multiple Sclerosis (iWiMS) network executive committee. lished in the MS population with COVID-19. M.A. Llaneza-González has received honoraria as a consultant to advisory boards, and as a chairman or lecturer in meetings, Acknowledgment and has participated in clinical trials and other research pro- The authors sincerely thank all the clinicians and patients jects promoted by Almirall, Bayer, Biogen, Celgene, BMS, participating in the registry; Isabel Caballero of Dynamic Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. L. Science, S.L, for writing and editorial assistance; Nuria Pajuelo Costa-Frossard França has received honoraria as a consultant of Dynamic Science, S.L, for statistical analysis assistance; to advisory boards, and as a chairman or lecturer in meetings, Board of directors of Spanish Society of Neurology for and has participated in clinical trials and other research pro- institutional and financial support of the registry; Marisa Sanz jects promoted by Almirall, Bayer, Biogen, Biopas, Celgene, and Juan Luis Siruela of the IT Department of Spanish Society Ipsen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. of Neurology for the creation of the web support of the V. Meca-Lallana has received honoraria as a consultant to registry and data upload; Francisca Iniesta Martı́nez for the advisory boards, and as a chairman or lecturer in meetings, assistance in administrative procedures and preparation of and has participated in clinical trials and other research pro- documentation for approval of the registry by the ethics jects promoted by Almirall, Biogen, Celgene, Merck, Novartis, Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 9 Roche, Sanofi, Terumo, and Teva. E. Fernández-Dı́az has a scientific advisory board or speaking from Almirall, Biogen, received research support, compensation for participating on Bayer Schering Pharma, Merck Serono, Novartis, Roche, advisory boards, speaking fees, and/or funding for travel from Sanofi-Aventis, and Teva. B. Sebastian Torres has received Almirall, Bayer, Biogen, Sanofi-Genzyme, Merck, Novartis, honoraria for lecturing, travel expenses for attending meet- and Roche. I. Moreno-Torres has received honoraria for ings, or financial support for research from Biogen, Merck lecturing or assistance for conference attendance from Bayer, Serono, Sanofi-Genzyme, and Novartis. A. Álvarez de Arcaya Biogen, Merck, Teva, Novartis, Roche, and Sanofi-Genzyme has received speaking honoraria from Merck, Sanofi, Biogen, and research grants from Novartis. J.M. Garcı́a-Domı́nguez and Roche. E. Costa Arpı́n has received compensation for has received honoraria for consulting services, travel expenses, consulting services and speaking honoraria in scientific and speaking honoraria from AbbVie, Almirall, Biogen, meetings from Biogen, Sanofi-Genzyme, Novartis, Merck Merck, Sanofi-Genzyme, Novartis, Celgene, and Roche. Serono, Teva, Roche, Almirall, and Bial. E. Durán-Ferreras has G. Ortega Suero and Lucı́a Ayuso-Peralta report no disclo- received honoraria from Almirall, Biogen, Sanofi-Genzyme, sures relevant to the manuscript. M. Gómez-Moreno has re- Merck, Novartis, Roche, and Teva. M. Fragoso-Martı́nez has ceived honoraria for assistance in meetings promoted by received honoraria for consulting services from Neuraxpharm, Roche, Merck, Biogen, and Sanofi. J.J. Sotoca-Fernández has Bial, and Sanofi. M. González Platas has received honoraria for honoraria for speaking engagements, travel expenses for sci- speaking and/or consultancy from Biogen, Merck, Roche, and entific meetings, and consulting services from Almirall, Bayer, Sanofi-Genzyme. L. Landete Pascual has received honoraria Biogen, Merck, Novartis, Sanofi, Roche, and Teva. A.B. for participation in scientific and educational activities from Caminero Rodrı́guez reports no disclosures. L.A. Rodrı́guez Almirall, Bayer, Biogen, Bristol-Myers, Sanofi-Genzyme, de Antonio has received travel support and honoraria for Merck, Novartis, UCB Pharma, Roche, and Teva. J. Millán- speaking engagements from Biogen, Roche, and Sanofi- Pascual has received sponsorship for attending medical con- Genzyme. M. Corujo-Suárez and M.A. Otano-Martı́nez re- gresses and speaking honoraria from Biogen, Novartis, Sanofi- port no disclosures. F. Pérez-Miralles has received compen- Genzyme, Merck Serono, Roche, Almirall, and Teva. He has sation for serving on scientific advisory boards from Roche received compensation for consulting services or participa- and Sanofi-Aventis or speaking honoraria from Almirall, tion in advisory boards from Roche, Novartis, Merck Serono, Biogen, Sanofi-Genzyme, Merck Serono, Mylan, Novartis, and Biogen. C. Oreja-Guevara has received honoraria for Roche, Sanofi-Aventis, and Teva. V. Reyes-Garrido reports no speaking and/or consultancy from Biogen, Celgene, Merck, disclosures. T. Ayuso-Blanco has received speaking honoraria Novartis, Roche, Sanofi-Genzyme, and Teva. J.E Meca- and support for meeting assistance from Biogen, Merck, Lallana has received grants and consulting or speaking fees Genzyme-Sanofi, Novartis, and Teva. J.J. Balseiro-Gómez has from Almirall, Biogen, Bristol-Meyers Squibb, Genzyme, participated in clinical trials and other research projects pro- Merck, Novartis, Roche, and Teva. Go to Neurology.org/ moted by Biogen, Novartis, and Teva and honoraria support NN for full disclosures. for scientific courses from Almirall, Lundbeck, and Allergan. M. Muñoz-Pasadas has received honoraria as a lecturer in Publication History meetings from Sanofi-Genzyme and honoraria support for Received by Neurology: Neuroimmunology & Neuroinflammation scientific courses and congress from Pfizer, Daiichi Sankyo, January 5, 2021. Accepted in final form April 12, 2021. and Biogen. I. Pérez-Molina has received speaking honoraria from Merck, Novartis, Teva, Biogen, and Sanofi-Genzyme. C. Appendix Authors Arnal-Garcı́a has received speaking honoraria in meetings from Biogen, Merck, Novartis, Sanofi, Teva, and Roche. A. Name Location Contribution Domingo-Santos and C. Guijarro-Castro report no disclo- Georgina Arrambide, Centro de Esclerosis Data acquisition, data sures relevant to the manuscript. C. Íñiguez-Martı́nez has MD, PhD Múltiple de Cataluña analysis, interpretation, received honoraria as a consultant to advisory boards, and as a (Cemcat); Instituto de statistical analysis, and Investigación Vall drafting, revision, and chairman or lecturer in meetings, and has participated in d’Hebron; Hospital final approval of the clinical trials and other research projects promoted by Universitario Vall manuscript d’Hebron; Universidad Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi- Autónoma de Genzyme, and Teva. N. Téllez Lara has received compensa- Barcelona, Barcelona, Spain tion for serving as a consultant or speaker from Biogen, Novartis, Roche, Sanofi-Genzyme, Teva, Merck, Merck Miguel Ángel Llaneza- Complejo Hospitalario Data acquisition, design González, MD, PhD Universitario de Ferrol, and conceptualization Serono, and Bristol-Myers. F. Castellanos-Pinedo has re- Ferrol, Spain of the study, and final ceived research support and honoraria for scientific approval of the manuscript courses from Roche, Novartis, Teva, Sanofi, Merck, and Biogen. T. Castillo-Triviño has received speaking/consulting Lucienne Costa- Hospital Universitario Data acquisition, data Frossard França, MD Ramón y Cajal, Madrid, analysis, interpretation, fees and/or travel funding from Almirall, Bayer, Biogen, Spain statistical analysis, and Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. D. Marı́a drafting, revision, and final approval of the Cerdán-Santacruz reports no disclosures. A. Pérez-Sempere manuscript has received personal compensation for consulting, serving on 10 Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 Neurology.org/NN Appendix (continued) Appendix (continued) Name Location Contribution Name Location Contribution Virginia Meca- Hospital Universitario Data acquisition, data Inmaculada Pérez- Hospital Virgen de la Data acquisition and Lallana, MD de la Princesa, Madrid, analysis, interpretation, Molina, PhD Salud. Toledo, Spain final approval of the Spain statistical analysis, and manuscript drafting, revision, and final approval of the Carmen Arnal-Garcı́a, Hospital Universitario Data acquisition and manuscript MD Virgen de las Nieves, final approval of the Granada, Spain manuscript Eva Fernández-Dı́az, Complejo Hospitalario, Data acquisition and MD Universitario de final approval of the Ángela Domingo- Hospital La Mancha Data acquisition and Albacete, Albacete, manuscript Santos, MD Centro. Alcázar de San final approval of the Spain Juan, Spain manuscript Irene Moreno-Torres, Hospital Universitario Data acquisition and Cristina Guijarro- Hospital Universitario Data acquisition and MD, PhD Fundación Jiménez final approval of the Castro, MD, PhD Puerta del Sur (CINAC), final approval of the Dı́az. Madrid, Spain. manuscript Madrid, Spain manuscript Jose Manuel Garcı́a- Hospital General Data acquisition and Cristina Íñiguez- Hospital Clı́nico Data acquisition and Domı́nguez, PhD Universitario Gregorio final approval of the Martı́nez, MD, PhD Universitario Zaragoza, final approval of the Marañón. Madrid, Spain manuscript Zaragoza, Spain manuscript Gloria Ortega-Suero, Hospital La Mancha Data acquisition and Nieves Téllez Lara, Hospital Clinico Data acquisition and MD Centro. Alcázar de San final approval of the PhD Universitario Valladolid. final approval of the Juan, Spain manuscript Valladolid, Spain manuscript Lucı́a Ayuso-Peralta, Hospital Universitario Data acquisition and Fernando Hospital Virgen del Data acquisition and MD Prı́ncipe de Asturias, final approval of the Castellanos-Pinedo, Puerto. Plasencia, Spain final approval of the Alcalá de Henares, manuscript MD manuscript Spain Tamara Castillo- Hospital Universitario Data acquisition and Mayra Gómez- Hospital Universitario Data acquisition and Triviño, MD Donostia, San final approval of the Moreno, PhD Infanta Leonor, Madrid, final approval of the Sebastián, Spain manuscript Spain manuscript Debora Marı́a Hospital General de Data acquisition and Javier J. Sotoca- Hospital Universitario Data acquisition and Cerdán-Santacruz, Segovia, Segovia, Spain final approval of the Fernández, MD Mútua Terrasa. Terrasa, final approval of the PhD manuscript Spain manuscript Ángel Pérez- Hospital General Data acquisition and Ana Belén Complejo Asistencial de Data acquisition and Sempere, MD Universitario de final approval of the Caminero-Rodrı́guez, Ávila. Ávila, Spain final approval of the Alicante, Alicante, Spain manuscript MD manuscript Berta Sebastián Hospital Universitario Data acquisition and Luis A. Rodrı́guez de Hospital Universitario Data acquisition and Torres, MD Miguel Servet (IIS final approval of the Antonio, MD de Fuenlabrada, final approval of the Aragón), Zaragoza, manuscript Madrid, Spain manuscript Spain Marcial Corujo- Hospital Universitario Data acquisition and Amaya Álvarez de Hospital Universitario Data acquisition and Suárez, MD Son Espases, Palma de final approval of the Arcaya, MD Araba, Vitoria, Spain final approval of the Mallorca, Spain manuscript manuscript Marı́a A. Otano- Complejo Hospitalario Data acquisition and Eva Costa-Arpı́n, PhD Hospital Clı́nico Data acquisition and Martı́nez, MD de Navarra, Pamplona, final approval of the Universitario de final approval of the Spain. manuscript Santiago de manuscript Compostela, Francisco Carlos Hospital Universitario y Data acquisition and Santiago de Pérez-Miralles, PhD Politécnico La Fe, final approval of the Compostela, Spain Valencia, Spain manuscript Eduardo Durán- Hospital Universitario Data acquisition and Virginia Reyes- Hospital Regional Data acquisition and Ferreras, PhD Juan Ramón Jiménez, final approval of the Garrido, MD Universitario de final approval of the Huelva, Spain manuscript Málaga, Málaga, manuscript Spain Marta Fragoso- Hospital de Terrasa, Data acquisition and Martı́nez, MD Terrasa, Spain final approval of the Teresa Ayuso-Blanco, Complejo Hospitalario Data acquisition and manuscript MD de Navarra, Pamplona, final approval of the Spain manuscript Montserrat González- Hospital Universitario Data acquisition, design Platas, MD, PhD de Canarias, San and conceptualization José Jesús Balseiro- Hospital Universitario Data acquisition and Cristobal de La Laguna, of the study, and final Gómez, MD de Getafe, Madrid, final approval of the Spain approval of the Spain manuscript manuscript Mercedes Muñoz- Hospital Santa Barbara, Data acquisition and Lamberto Landete Hospital Universitario Data acquisition and Pasadas, MD Puertollano, Spain final approval of the Pascual, PhD Dr Peset de Valencia, final approval of the manuscript Valencia, Spain manuscript Continued Neurology.org/NN Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 5 | July 2021 11 4. 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Mult Scler Relat Disord. 2020;39:102073. Celia Oreja-Guevara, Hospital Clı́nico San Data acquisition, design 8. Safavi F, Nourbakhsh B, Azimi AR. B-cell depleting therapies may affect susceptibility MD, PhD Carlos; Facultad de and conceptualization to acute respiratory illness among patients with multiple sclerosis during the early Medicina, Universidad of the study, and final COVID-19 epidemic in Iran. Mult Scler Relat Disord. 2020;43:102195. Complutense de approval of the 9. Barzegar M, Mirmosayyeb O, Nehzat N, et al. COVID-19 infection in a patient with multiple Madrid; IdISSC, Madrid, manuscript. sclerosis treated with fingolimod. Neurol Neuroimmunol Neuroinflamm. 2020;7(4):e753. Spain 10. Foerch C, Friedauer L, Bauer B, Wolf T, Adam EH. Severe COVID-19 infection in a patient with multiple sclerosis treated with fingolimod. Mult Scler Relat Disord. 2020;42:102180. José E. Meca-Lallana, CSUR Unidad de Data acquisition, design 11. Möhn N, Pul R, Kleinschnitz C, et al. 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Fernandez-Diaz E, Gracia-Gil J, Garcia-Garcia JG, Palao M, Romero-Sanchez CM, Universidad Católica Segura T. COVID-19 and multiple sclerosis: a description of two cases on alemtu- San Antonio, zumab. Mult Scler Relat Disord. 2020;45:102402. Murcia, Spain 15. Sormani MP, De Rossi N, Schiavetti I, Carmisciano L, Cordioli C, Moiola L. Disease modifying therapies and COVID-19 severity in multiple sclerosis. Ann Neurol. 2021; 89(4):780-789. 16. Ioannidis JPA, Axfors C, Contopoulos-Ioannidis DG. Population-level COVID- References 19 mortality risk for non-elderly individuals overall and for non-elderly indi- 1. Shi Y, Wang Y, Shao C, et al. COVID-19 infection: the perspectives on immune viduals without underlying diseases in pandemic epicenters. Environ Res. 2020; responses. Cell Death Differ. 2020;27(5):1451-1454. 188:109890. 2. Louapre C, Collongues N, Stankoff B, et al. Clinical characteristics and outcomes in patients 17. Ferini-Strambi L, Salsone M. 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