Neurological Sciences https://doi.org/10.1007/s10072-020-04519-x COVID-19 Real-time assessment of COVID-19 prevalence among multiple sclerosis patients: a multicenter European study Gloria Dalla Costa 1,2 & Letizia Leocani 1,2 & Xavier Montalban 3 & Ana Isabel Guerrero 3 & Per Soelberg Sørensen 4 & Melinda Magyari 4 & Richard J. B. Dobson 5,6 & Nicholas Cummins 7 & Vaibhav A. Narayan 8 & Matthew Hotopf 9 & Giancarlo Comi 1 & on behalf of the RADAR-CNS consortium Received: 3 June 2020 / Accepted: 16 June 2020 # Fondazione Società Italiana di Neurologia 2020 Abstract We assessed the prevalence and impact of COVID-19 among multiple sclerosis (MS) patients across Europe by leveraging participant data collected as part of the ongoing EU IMI2 RADAR-CNS major programme aimed at finding new ways of monitoring neurological disorders using wearable devices and smartphone technology. In the present study, 399 patients of RADAR-MS have been included (mean age 43.9 years, 60.7% females) with 87/399 patients (21.8%) reporting major symptoms suggestive of COVID-19. A trend for an increased risk of COVID-19 symptoms under alemtuzumab and cladribine treatments in comparison to injectables was observed. Remote monitoring technologies may support health authorities in monitoring and containing the ongoing pandemic. Keywords Multiple Sclerosis . Remote monitoring technologies . COVID-19 Introduction situation-reports). However, the real prevalence and impact of the disease are unknown. SARS-CoV-2 is a coronavirus first identified in December 2019 Remote Assessment of Disease and Relapse in Central in China as the cause of a cluster of pneumonia cases (COVID- Nervous System Disorders (RADAR-CNS) is an Innovative 19 disease) of previously unknown aetiology [1]. The virus has Medicine Initiative-funded project aimed at monitoring major since spread globally, with the World Health Organization depressive disorders, epilepsy, and multiple sclerosis (MS) (WHO) declaring a pandemic state in March 2020 (https:// using wearable devices and smartphone technology [2]. www.who.int/emergencies/diseases/novel-coronavirus-2019/ Through the ongoing remote monitoring of MS patients in Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10072-020-04519-x) contains supplementary material, which is available to authorized users. * Giancarlo Comi 5 The Department of Biostatistics and Health informatics, Institute of comi.giancarlo@hsr.it Psychiatry, Psychology and Neuroscience, King’s College London, London, UK 1 Institute of Experimental Neurology, IRCCS Ospedale San Raffaele, 6 via Olgettina 60, 20132 Milan, Italy Institute of Health Informatics, University College London, London, UK 2 Neurorehabilitation Unit, IRCCS Ospedale San Raffaele, Milan, Italy 7 3 Multiple Sclerosis Centre of Catalonia (Cemcat), Department of Embedded Intelligence for Health Care & Wellbeing, University of Neurology/Neuroimmunology, Hospital Universitari Vall d’Hebron, Augsburg, Augsburg, Germany Universitat Autònoma de Barcelona, Barcelona, Spain 8 Janssen Research and Development, LLC, Titusville, NJ, USA 4 Danish Multiple Sclerosis Centre, Department of Neurology, 9 Copenhagen University Hospital Rigshospitalet, The Department of Psychological Medicine, Institute of Psychiatry, Copenhagen, Denmark Psychology and Neuroscience, King’s College London, London, UK Neurol Sci Italy, Spain, and Denmark, we aimed to explore the preva- fumarate, teriflunomide), fingolimod, natalizumab, anti- lence and impact of the current pandemic among MS patients CD20 (ocrelizumab), immune system resetting drugs across Europe. (alemtuzumab, cladribine). p values < 0.05 were deemed sta- tistically significant. Computing environment R was used for all statistical analyses (R Development Core Team, 2005). Methods Study participants The MS work package of RADAR-CNS started recruiting in June 2018 with the aims to assess, through Results remote monitoring, the impact of MS on the emotional state of recently (< year) diagnosed patients and to monitoring disabil- Cohort baseline characteristics (Table 1) ity and fatigue on relapsing-remitting (RRMS) and secondary progressive (SPMS) patients. Since then, passive (a As of March 1, 2020, 499 patients have been enrolled in the smartwatch device and mobile sensors) and active monitoring RADAR-MS studies and 403 (81%) remained under active strategies (questionnaires, cognitive, and physical tests) have and passive remote monitoring. The COVID-19 questionnaire been in place. Figure S1 shows the full inclusion criteria and was completed at least once by 399 patients (99%). assessment schemes. Approval of the protocol was obtained from hospitals’ ethical committees and informed consent ob- tained from all patients. Table 1 Baseline characteristics of the study cohort Characteristic n = 399 COVID-19 data A questionnaire to collect data systematically on COVID-19-related adverse events (Fig. S2) was sent to Age, years 43.9 ± 10.7 patients twice at a two-weekly interval (on March 25, 2020, Sex, n (%) and April 8, 2020, and data collected until April 15, 2020), Females 242 (60.7) through the RADAR-CNS active monitoring system. The re- Males 157 (39.3) sults are based on the combination of the surveys. All data was Smokers 84 (21.1) managed by the open-source RADAR-based platform BMI 24.47 ± 5.7 (www.radar-base.org) [2]. Healthcare workers 19 (4.7) Course of disease, n (%) COVID-19 case definitions WHO guidelines define suspected Clinically isolated syndromes 5 (1.3) cases as patients with fever, signs/symptoms of respiratory dis- Relapsing-remitting 305 (76.4) ease and travels/residence in a location reporting community Secondary progressive 89 (22.3) transmission of COVID-19, or in contact with confirmed/ Disease duration, years 13.1 ± 10.3 probable COVID-19 cases in the 14 days prior to symptom Expanded Disability Status Scale 3.5 (2.0–4.0) onset, or people requiring hospitalization in the absence of alter- Presence of comorbidities, n (%) 144 (36.1) native diagnosis [3]. As most of the confirmed COVID-19 cases Cardiovascular/hypertension 51 (12.8) do not fulfill these criteria [4] and considering the questionnaire Diabetes 5 (1.3) was performed in areas with known community transmission of COPD 1 (0.3) COVID-19, two alternative definitions were used: patients Malignancies 2 (0.5) experiencing fever or anosmia/ageusia + any other COVID-19 Ongoing MS treatments, n (%) 359 (90) symptoms, or respiratory symptoms + two other COVID-19 Interferons/glatiramer acetate 81 (20.3) symptoms (case definition 1), and patients experiencing fever + Dim. fumarate/teriflunomide 108 (27.1) any other COVID-19 symptoms, or respiratory symptoms + Natalizumab 44 (11.0) anosmia/ageusia (case definition 2). Laboratory-confirmed cases were included in both case definitions. Fingolimod 67 (16.8) Anti-CD20 44 (11.0) Statistical analysis Univariate and multivariate penalized like- Alemtuzumab/cladribine 15 (3.8) lihood logistic regression models (Firth method) have been Other ongoing treatments, n (%) used to assess predictors of COVID-19 occurrence [5]. The Vitamin D supplements 237 (59.4) impact of MS treatments on COVID-19 risk was first evalu- ACE inhibitors 40 (10.0) ated separately for each drug (Fig. S3) and then analyzed BMI, body mass index; COPD, chronic obstructive pulmonary disease; according to the following treatment groups: injectables (in- MS, multiple sclerosis; DMD, disease-modifying drugs; mean ± standard terferons and glatiramer acetate), oral treatments (dimethyl deviation; number (percentage) Neurol Sci Prevalence and predictors of COVID-19 by case Odds ratios (yellow points) and 95% confidence intervals definition (horizontal bars) have been estimated through the use of lo- gistic regression models with a penalized likelihood method Major symptoms suggestive of COVID-19 infection have for rare events (Firth method), adjusted for age, sex, and been reported by 87 patients (21.8%, 95% CI 17.8–25.9). course of the disease. Case definition 1: patients experiencing Among these, 31 (7.8%) had a fever, 73 (18.3%) had fever/anosmia/ageusia and any other COVID-19 symptoms or respiratory symptoms, 38 (9.5%) had gastrointestinal distur- cough/dyspnea and two other COVID-19 symptoms; case bances, 17 (4.3%) had conjunctivitis, and 17 (4.3%) definition 2: patients experiencing fever and any other experienced ageusia and anosmia. Two patients had COVID-19 symptoms or cough/dyspnea and anosmia/ COVID-19 pneumonia, and one patient was hospitalized. ageusia. Patients with a laboratory-confirmed diagnosis of No one died of COVID-19. COVID-19 were also considered cases for both definitions. In the cohort, 52 patients (13.0%, 95% CI 9.7–16.3) met the case definition 1, and 37 (9.3%, 95% CI 6.4–12.1) met the Impact of COVID on MS patients case definition 2 criteria. Ten patients were tested for SARS-CoV-2 through naso- Changes in daily activities because of COVID-19 were report- pharyngeal swab: four of them were positive, and one tested ed by 344 patients (86%): 148 (37%) started working from negative but had COVID-19 pneumonia upon X-ray exami- home, 66 (17%) took care of children, and four (1%) cared for nation and swab test which was performed 26 days after a sick relative. No outdoor hobbies or social activities were symptom onset. Figure S4 shows the occurrence of suspected reported by 228 patients (57%), and the daily average time COVID-19 cases. spent outside was 1.8 h. On the emotional level, 132 patients Patients with SPMS were at lower risk than relapsing- (33%) were deeply worried by the pandemic, 233 (58%) mod- remitting MS of fulfilling either definitions (case definition erately worried, and 32 (8%) were unaffected. 1: OR 0.36 (0.13–0.84); case definition 2: OR 0.23 (0.05– 0.71), p < 0.01 for all cases, Table 1). A trend for patients on cladribine/alemtuzumab to be more likely classified as Discussion COVID-19 cases than patients with injectables was observed, independently of age, sex, and disease course (case definition A number of newly diagnosed COVID-19 cases are updated 1: OR 3.78 (1.00–15.93), p 0.05; case definition 2: OR 4.87 daily (https://www.who.int/emergencies/diseases/novel-coro- (1.10–21.04), p 0.04, Fig. 1, Table S2). navirus-2019/situation-reports), but these are clearly Fig. 1 Disease-modifying drugs and risk of suspected COVID-19 infection diagnosis. Gl. acetate glatiramer acetate; DMF, dimethyl fumarate; TRF, teriflunomide; Alem, alemtuzumab; Cladr, cladribine Neurol Sci underestimated [6] as diagnosis depends on local availability Conflict of interest VAN is an employee of Janssen Research & Development LLC and may own equity in the company. of the test. In our study, five confirmed COVID-19 cases (four with positive swab tests and one patient with COVID-19 Disclaimer This communication reflects the views of the RADAR-CNS pneumonia) were reported (1.3%); a low prevalence as just consortium, and neither IMI nor the European Union and EFPIA are ten patients (2.5%) of the cohort were tested for the virus. liable for any use that may be made of the information contained herein. Using different case definitions, the percentage of MS patients with symptoms suggestive of infection varied between 9 and Data sharing The scientific data used in this paper is collected under the project: EU/EFPIA IMI RADAR-CNS (grant agreement no. 115902). 13%. These figures align with a recent study suggesting that The data usability and sharing are performed under the agreed guidelines the prevalence of the disease in Europe, in particular Italy, of the RADAR-CNS consortium. The anonymized data will be shared maybe nine times higher than officially reported [6]. upon request subject to RADAR-CNS consortium approval. Pending the According to our results, there is no evidence of a worse aforementioned approval, data sharing will be made in a secure setting, on a per-case-specific manner. Please submit such requests to the corre- COVID-19 evolution in patients affected by MS: two patients sponding author of the paper. The shared data cannot be used for publi- only developed pneumonia and one was hospitalized. Global cation purposes without the explicit consent of the RADAR-CNS con- data indicates that morbidity is lower in younger COVID-19 sortium. The additional related documents are available (e.g., study pro- patients [7], as our data also suggests. Patients with SPMS had tocol, statistical analysis plan, informed consent form) upon request. a lower risk of infection compared with RRMS, maybe be- cause they are less treated and with less-frequent social con- tacts. Disease-modifying treatments did not significantly change the risk and severity of COVID-19; however, a trend References for an increased risk of infection with immune-resetting drugs 1. Zhou P, Yang XL, Wang XG et al (2020) A pneumonia outbreak (alemtuzumab and cladribine) was observed compared with associated with a new coronavirus of probable bat origin. Nature injectables, despite low numbers prevent any definite conclu- 579(7798):270–273 sion. This aligns with previous studies showing a generally 2. Ranjan Y, Rashid Z, Stewart C et al (2019) RADAR-base: open increased risk of infections with cladribine and alemtuzumab source mobile health platform for collecting, monitoring, and ana- [8, 9]. The COVID-19 pandemic has had a heterogeneous lyzing data using sensors, wearables, and mobile devices. JMIR Mhealth Uhealth 7(8):e11734 impact in different countries. Our patients come from highly 3. World Health Organization (2020) Surveillance case definitions for affected areas in Europe; therefore, our results may be partial- human infection with novel coronavirus (nCoV): interim guidance ly representative of the general MS population. However, the v1, January 2020. World Health Organization. https://apps.who.int/ study highlights the importance of remote monitoring technol- iris/handle/10665/330376. License: CC BY-NC-SA 3.0 IGO. Accessed 1 Jul 2020 ogies that have shed some light on the impact of COVID-19 in 4. Huang C, Wang Y, Li X et al (2020) Clinical features of patients our MS patients in real time and may provide support to health infected with 2019 novel coronavirus in Wuhan, China. Lancet authorities in monitoring and containing the pandemic. 395(10223):497–506 5. Firth D (1993) Bias reduction of maximum likelihood estimates. Acknowledgments We thank Maria Libera La Porta, Matteo Martinis, Biometrika [Internet]. 80(1):27–38 and Lucia Roselli for their support to the study 6. Lachmann A, Jagodnik KM, Giorgi FM, Ray F Correcting under- reported COVID-19 case numbers: estimating the true scale of the Author’s contributions G.D.C., A.I.G., P.S.S., M.M., N.C., V.A.N., pandemic. medRxiv 2020.03.14.20036178. https://doi.org/10.1101/ M.H., and G.C. contributed to the study design. G.D.C. contributed to 2020.03.14.20036178 the data analysis, figures drawing, and manuscript writing. L.L., X.M., 7. Republic of Korea Center of Disease Control. Updates on COVID- A.I.G., P.S.S., M.M., N.C., R.J.B.D., V.A.N., M.H., and G.C. contributed 19 in Republic of Korea, 3/13/2020. to the critical revision of the manuscript. R.J.B.D. contributed to the 8. Giovannoni G, Comi G, Cook S et al (2010) A placebo-controlled platform design and implementation. X.M., P.S.S., N.C., R.J.B.D., trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med V.A.N., M.H., and G.C. contributed to the administrative, technical, 362:416–426 and clinical support of the study. G.D.C., A.I.G., and M.M. contributed 9. Cohen JA, Coles AJ, Arnold DL et al (2012) Alemtuzumab versus to data collection. interferon beta 1a as first-line treatment for patients with relapsing- remitting multiple sclerosis: a randomised controlled phase 3 trial. Funding information This study was supported by EU/EFPIA IMI Joint Lancet 380:1819–1828 Undertaking 2 (RADAR-CNS grant no. 115902). Publisher’s note Springer Nature remains neutral with regard to jurisdic- Compliance with ethical standards Approval of the protocol tional claims in published maps and institutional affiliations. was obtained from hospitals’ ethical committees and informed consent obtained from all patients.