key: cord-0778902-r2enjna9 authors: Moreno‐Torres, Irene; Meca Lallana, Virginia; Costa‐Frossard, Lucienne; Oreja‐Guevara, Celia; Aguirre, Clara; Alba Suárez, Elda María; Gómez Moreno, Mayra; Borrega Canelo, Laura; Sabín Muñoz, Julia; Aladro, Yolanda; Cárcamo, Alba; Rodríguez García, Elena; Cuello, Juan Pablo; Monreal, Enric; Sainz de la Maza, Susana; Pérez Parra, Fernando; Valenzuela Rojas, Francisco; López de Silanes de Miguel, Carlos; Casanova, Ignacio; Martínez Gines, Maria Luisa; Blasco, Rosario; Orviz García, Aida; Villar‐Guimerans, Luisa María; Fernández‐Dono, Guillermo; Elvira, Víctor; Santiuste, Carmen; Espiño, Mercedes; García Domínguez, José Manuel title: Risk and outcomes of COVID‐19 in patients with multiple sclerosis date: 2021-07-18 journal: Eur J Neurol DOI: 10.1111/ene.14990 sha: dca445428518b70ec4feaf821244886c1afe4a02 doc_id: 778902 cord_uid: r2enjna9 BACKGROUND AND PURPOSE: Limited information is available on incidence and outcomes of COVID‐19 in patients with multiple sclerosis (MS). This study investigated the risks of SARS‐CoV‐2 infection and COVID‐19‐related outcomes in patients with MS, and compared these with the general population. METHODS: A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit admission, and death in patients with MS and COVID‐19. National government outcomes and seroprevalence data were used for comparison. The study was conducted at 14 specialist MS treatment centers in Madrid, Spain, between February and May 2020. RESULTS: Two‐hundred nineteen patients were included in the registry, 51 of whom were hospitalized with COVID‐19. The mean age ± standard deviation was 45.3 ± 12.4 years, and the mean duration of MS was 11.9 ± 8.9 years. The infection incidence rate was lower in patients with MS than the general population (adjusted incidence rate ratio = 0.78, 95% confidence interval [CI] = 0.70–0.80), but hospitalization rates were higher (relative risk = 5.03, 95% CI = 3.76–6.62). Disease severity was generally low, with only one admission to an intensive care unit and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease‐modifying treatment and hospitalization risk. CONCLUSIONS: Patients with MS do not appear to have greater risks of SARS‐CoV‐2 infection or severe COVID‐19 outcomes compared with the general population. The decision to start or continue disease‐modifying treatment should be based on a careful risk–benefit assessment. Patients with multiple sclerosis (MS) are at increased risk of infection and infectious complications, due to the effects of both the disease and disease-modifying treatments (DMTs) [1] . Infections are an important cause of hospitalization in patients with MS [2, 3] , with almost 8% of those hospitalized requiring intensive care [3] . Several factors are associated with an increased risk of infection-related hospitalization in patients with MS, including older age, longer disease duration, comorbidities, immunosuppression, prior hospital admission, obesity, and diabetes [2, 4, 5] . In December 2019, the first cases of pneumonia caused by an unknown virus were reported in Wuhan, China [6] . The pathogen causing the infection was subsequently identified and named SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), and on 11 March 2020 the World Health Organization declared a pandemic [7] . SARS-CoV-2 is a zoonotic RNA virus similar to SARS-CoV (severe acute respiratory syndrome coronavirus) and MERS-CoV (Middle East respiratory syndrome coronavirus). In infections caused by those coronaviruses, immunosuppression does not appear to be associated with an increased risk of severe disease or death [8] . To date, no increase in the development of clinical or severe lung disease has been reported in patients with SARS-CoV-2 infection who have undergone solid organ transplantation or received chemotherapy [8, 9] . Specific data on outcomes in treated patients with MS and coronavirus infection are, however, scarce. We performed an observational study to quantify the risks of infection, hospitalization, admission to intensive care, and death due to SARS-CoV-2 infection (henceforth referred to as COVID-19, except where the virus itself is being discussed) among patients with MS relative to the general population, and to identify factors associated with risk of hospitalization. The study was conducted in the Madrid region of Spain. A regional COVID-19 registry was set up by members of the Study Group for Demyelinating Diseases, representing 14 MS centers across the region. Between 9 February and 29 May 2020, all patients who were treated for MS at one of these centers and in whom COVID-19 was confirmed or highly suspected were included in the registry, regardless of whether they were admitted to hospital. Clinical and demographic data, laboratory test results, MS-specific information, and details of treatment for COVID-19 were entered into the registry. This study was conducted according to the principles of the Declaration of Helsinki. The study protocol was approved by the ethics committee at the Jiménez Díaz Foundation University Hospital, Madrid; all patients gave informed consent to be included in the registry. Patient data were anonymized, and measures were implemented to prevent reidentification or access by unauthorized parties. Follow-up was until recovery from COVID-19 or death. Confirmed COVID-19 was defined as a positive reverse transcriptase-polymerase chain reaction (RT-PCR) nasopharyngeal swab or serologic (enzyme-linked immunosorbent assay [ELISA]) test for SARS-CoV-2. COVID-19 was highly suspected in patients who had at least two cardinal symptoms of COVID-19 (e.g., persistent dry cough, difficulty breathing, anosmia/ageusia, Results: Two-hundred nineteen patients were included in the registry, 51 of whom were hospitalized with COVID-19. The mean age ± standard deviation was 45.3 ± 12.4 years, and the mean duration of MS was 11.9 ± 8.9 years. The infection incidence rate was lower in patients with MS than the general population (adjusted incidence rate ratio = 0.78, 95% confidence interval [CI] = 0.70-0.80), but hospitalization rates were higher (relative risk = 5.03, 95% CI = 3.76-6.62). Disease severity was generally low, with only one admission to an intensive care unit and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease-modifying treatment and hospitalization risk. Patients with MS do not appear to have greater risks of SARS-CoV-2 infection or severe COVID-19 outcomes compared with the general population. The decision to start or continue disease-modifying treatment should be based on a careful risk-benefit assessment. COVID-19, incidence, multiple sclerosis, severe acute respiratory syndrome coronavirus 2, Spain and fever) and/or positive radiologic findings, and a high circumstantial probability of infection in a pandemic setting (e.g., a positive test in a close family member), in the absence of a confirmatory test result. avoid the separation problem [10] . The penalized model also helps to enhance the interpretability of the results by excluding irrelevant variables. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for each variable, with p < 0.05 considered significant. In addition, we calculated the incidence rate (IR; defined as the number of cases divided by the total population at risk) of COVID-19 for both the MS population and the general Spanish population aged 15-79 years; this range was chosen because it corresponds to the age distribution of the MS population. IRs for patients with MS were derived from registry and local data on the MS population, whereas data from the ongoing National Study of Serological Epidemiology of COVID-19 (NSSE-C19) [11] were used to generate IRs for the general Spanish population. In NSSE-C19, the percentage of the Spanish population infected with SARS-COV-2 was estimated by measuring the prevalence of antibodies to the new virus. The size of the MS population for the 14 centers was estimated from local pharmacy registries, and increased by 10% to account for untreated patients. IRs were then used to calculate IR ratios (IRRs), defined as the IR for the MS population divided by the IR for the general population, to allow for comparison between populations. The risk of hospitalization in patients with MS and COVID-19, relative to the general COVID-19 population in Spain [12] , was calculated by comparing the ratios of hospitalizations to cases in both populations. Lastly, the case-fatality rate (number of deaths divided by number of reported cases) for the registry (COVID-19/MS) population was compared with national data [12] . Of 5641 patients with MS treated at the 14 participating centers, 219 (3.9%) had confirmed or highly suspected COVID-19, and were entered into the registry. COVID- 19 [11, 13] , the registry had a higher percentage of patients aged 30-50 years; however, no significant difference was found in the percentage of cases by age group in the MS and general populations ( Figure S1 in Appendix S1). Consistent with this, comorbidities of interest were uncommon in the COVID-19/MS population; among patients with PCR-confirmed disease, diabetes, pulmonary disease, and cardiovascular disease were all significantly less prevalent than in the corresponding general Spanish COVID-19 population (Table 2) . Lymphopenia was absent in most patients for whom data were available (152/177, 85.9%). Patients with MS had broadly similar symptoms of COVID-19 to the general population, but had a significantly higher incidence of pneumonia, colds, and diarrhea (Table 2 ). In our study population, 63% of COVID-19 cases were in females, similar to the general Spanish COVID-19 population (p = 0.12). However, after adjusting for the approximately threefold greater prevalence of MS in females than in males [14] , the risk of developing COVID-19 was found to be 1.67-fold higher in males versus females with MS. Fifty-one patients (23.3%) were hospitalized due to COVID-19. One patient (0.45%) was admitted to ICU, but did not require mechanical ventilation. This patient, a 36-year-old male, had been diagnosed with RRMS 2 years previously, had an Expanded Disability Status Scale (EDSS) score of 2.0, and was receiving alemtuzumab. Sequential Organ Failure Assessment (SOFA) and CURB-65 scores were available for 71 and 57 patients, respectively; only one patient had a SOFA score of greater than 4, and two patients had CURB-65 scores of 3 or greater. Five patients died: four males aged 48-61 years and one female aged 57 years (Table S1 in Appendix S1). Their median EDSS score Compared with nonhospitalized patients, hospitalized patients in our registry were significantly older (mean age ± SD = 51.2 ± 13.7 vs. 43.4 ± 11.4, p < 0.01) and had higher EDSS scores (mean ± SD score = 4.26 ± 2.87 vs. 2.27 ± 1.85, p < 0.01), as shown in Figure 2 and Table S2 in Appendix S1. In addition, hospitalized patients had significantly lower lymphocyte counts, and significantly higher Creactive protein and fibrinogen levels, than nonhospitalized patients. Compared with patients in the Villar et al. registry (hospitalized patients with COVID-19, but without MS), hospitalized patients from the study population were significantly younger and had lower Creactive protein levels. In the univariate logistic regression analysis, the relapsingremitting phenotype was associated with a reduced risk of hospitalization, whereas progressive forms of MS, an EDSS of greater than 3.0, and a history of smoking, diabetes, or arterial hypertension were associated with an increased risk of hospitalization ( Figure 2 and Table S3 in Appendix S1). However, in multivariate logistic regression, the only variable confirmed to reduce the risk of hospitalization was the relapsing-remitting phenotype (Figure 2 ; OR = 0.18, 95% CI = 0.08-0.41, p < 0.001). No variable or specific DMT was associated with an increased risk of hospitalization in the multivariate analysis. Using estimated IRs obtained from NSSE-C19 [11] , the IRR for the registry population was 0.78 (95% CI = 0.70-0.80). IRRs were less than 1 for all subgroups defined by age, except for patients aged 15-29 years ( We present outcomes and incidence data from a registry of pa- Time since MS diagnosis, years 11.9 ± 8.9 Type of MS, n (%) In the general population, older age is a clear risk factor for diagnosis of COVID-19 [15] [16] [17] . However, data from NSSE-C19 show that the distribution of antibodies to SARS-CoV-2 by age group is consistent with the population pyramid for Spain [11] . Thus, increasing age does not augment the risk of SARS-CoV-2 infection per se; however, it does increase the risk of a more severe clinical course, hospitalization, and death [16] . In agreement with this, we found that patients with MS who were hospitalized with COVID-19 were significantly older than those who were not hospitalized. Because of a lack of published data specific to the Spanish population, we were not able to adequately adjust our results for In agreement with the observations of other researchers [18] [19] [20] [21] , we also believe that the low disease severity in many of our patients may be related to a protective effect of therapeutic immunosuppression against cytokine storm. Cytokine storm is associated with increased morbidity and mortality in COVID-19 [15, 22] , and has been described as a consequence of lymphocyte dysregulation leading to overactivity in other parts of the immune response [22, 23] . Most DMTs used in MS either deplete or modulate these overactive cells, and there is therefore a mechanistic basis for protection against cytokine storm in DMT-treated patients with MS. Some authors have proposed that DMT-treated patients with MS are at a higher risk of infection with SARS-CoV-2 or of having a more severe outcome due to their immune status [24] [25] [26] [27] . However, in our study, none of the DMTs used in MS was associated with an increased risk of hospitalization. Our results are similar to those reported by the Dutch group [28] , and indicate that no apparent difference exists in DMT use and COVID-19 disease course. In contrast to the Italian group [29], we did not find an association between the use of anti-CD20 monoclonal antibodies, interferon, or corticosteroids and the outcome of COVID-19 in MS patients. With regard to anti-CD20 monoclonal antibodies, we found a higher percentage of hospitalized patients taking these drugs, but these patients were also more likely to have SPMS or PPMS. For this reason, we did not find an increased risk of hospitalization for patients taking anti-CD20 monoclonal antibodies in multivariate analysis. We believe that treatment in this case acts as a dependent factor, and that the true factor involved in the risk of hospitalization is the MS phenotype. The small number of patients who died or were admitted to ICU does not permit correlation analysis, but our findings suggest that the course of COVID-19 in patients with MS is, overall, no worse than in the general population. Although men and women appear to have an equal risk of SARS-CoV-2 infection [30, 31] , the probability of a severe disease outcome or death is higher for men, both in Spain [12] and globally [30] [31] [32] . Our results in patients with MS are consistent with these findings. We found that the probability of COVID-19 (relative to the general population) was higher for male than female patients with MS. Additionally, the risk of hospitalization for COVID-19 (again, relative to the general population) was higher for males with MS than for females. Four of the five deaths in our study population were in men. The reasons for sex-based differences in disease course and outcome are not yet clear. Our study has limitations that are common to many registry stud- The risk of COVID-19 appears to be no greater in patients with MS than in the general Spanish population. We found a low risk of severe outcomes (ICU admission and death) in patients with MS and COVID-19, and a lower risk of COVID-19-related hospitalization for patients with RRMS versus other forms of MS. Our findings also suggest that outcomes of COVID-19 may be more severe in men, patients with SPMS, and those with greater disability. We did not find an association between the use of specific DMTs and an increased risk of hospitalization. MS is a debilitating disease, and the potential risks and benefits of starting or continuing DMTs must be carefully considered, alongside other factors such as age and comorbidities, in the context of the current pandemic. The data that support the findings of this study are openly available in Mendeley at http://dx.doi.org/10.17632/ cczx4 5n32y.1 [33] . We would like to thank Richard Crampton of Springer Healthcare and participates as a subinvestigator and coordinator of a Roche-sponsored clinical trial. L.B.-C. has received honoraria for lecturing, consulting, or travel expenses from Bayer has received honoraria for lecturing, consulting, or travel expenses from Biogen-Idec has received funding for research projects, conference fees, mentoring, and assistance for conference attendance from Teva, Merck has received honoraria for lecturing or assistance for conference attendance from Bayer Genzyme. E.M. has received honoraria for lecturing or assistance for conference attendance from Roche, Sanofi-Genzyme, Almirall, Biogen-Idec, and Merck, and research grants from Merck. S.S.d.l.M. has received funding for research projects or support in the form of conference fees, mentoring, and assistance for conference attendance from Sanofi-Genzyme Biogen-Idec, Novartis, Bial, Daichii-Sankyo, and Roche. I.C. has received funding for travel or speaker honoraria from Bayer None of the other authors has any conflict of interest to disclose Virginia Meca Lallana: Conceptualization (equal), data curation (equal), formal analysis (equal), investigation (equal) Conceptualization (equal), data curation (equal), formal analysis (equal), investigation (equal) Elena Rodríguez García: Investigation (equal) Francisco Valenzuela Rojas: Investigation (equal). Carlos López de Silanes de Miguel: Investigation (equal). Ignacio Casanova: Investigation (equal) Aida Orviz García: Investigation (equal) Víctor Elvira: Formal analysis (equal), software (equal). Carmen Santiuste: Investigation (equal) Infection risk in patients on multiple sclerosis therapeutics Predictors of hospitalization in a Canadian MS population: a matched cohort study All-cause hospitalizations in multiple sclerosis patients Hospital admissions and MS: temporal trends and patient characteristics Seasonal influenza factsheets World Health Organization. Novel coronavirus -China World Health Organization. WHO Director-General's opening remarks at the media briefing on COVID-19 -11 Coronaviruses and immunosuppressed patients: the facts during the third epidemic COVID-19: consider cytokine storm syndromes and immunosuppression A solution to separation in binary response models Estudio ENE-COVID19: primera ronda Estudio Nacional de Sero-epidemiología de la Infección por SARS-CoV-2 en España: informe preliminar 13 de mayo de 2020 Análisis de los casos de COVID-19 notificados a la RENAVE hasta el 10 de mayo en España. Informe COVID-19 no Servi cios/Vigil ancia Salud Publi caREN AVE/Enfer medad esTra nsmis ibles/ Pagin as/Infor mesCO VID-19.aspx Increase in the prevalence of multiple sclerosis over a 17-year period in Osona The prevalence of MS in the United States: a population-based estimate using health claims data Clinical characteristics of coronavirus disease 2019 in China Cardiovascular disease, drug therapy, and mortality in Covid-19 COVID-19 cases and case fatality rate by age COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role? COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal Multiple sclerosis and the risk of infection: considerations in the threat of the novel coronavirus, COVID-19/SARS-CoV-2 Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis Dysregulation of immune response in patients with COVID-19 in Wuhan, China Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore SARS-CoV-2 and multiple sclerosis: not all immune depleting DMTs are equal or bad Bar-Or A. COVID-19 and MS diseasemodifying therapies Multiple Sclerosis Autonomous Community of Madrid) document for the management of patients with multiple sclerosis during the SARS-CoV-2 pandemic COVID-19 pandemic and the risk of infection in multiple sclerosis patients on disease modifying therapies: "what the bleep do we know? COVID-19 in multiple sclerosis: The Dutch experience Disease modifying therapies and COVID-19 severity in multiple sclerosis Sex-specific SARS-CoV-2 mortality: among hormone-modulated ACE2 expression, risk of venous thromboembolism and hypovitaminosis D COVID-19: the gendered impacts of the outbreak Gender differences in patients with COVID-19: focus on severity and mortality. Front Public Health Database COVID-19 EMCAM Registry; Mendeley