COVID-19 in multiple sclerosis: The Dutch experience

Here, we provide an extensive overview of all reported COVID-19 cases in multiple sclerosis (MS) patients in the Netherlands between 27 February and 9 June 2020, gathered by the Dutch MS Taskforce of the Netherlands Society of Neurology. A total of 86 MS patients were reported, 43 of whom tested positive for COVID-19. Of 43 patients who tested positive, 22 patients were hospitalized. Three intensive care unit (ICU) admissions and four deaths were reported. Our findings show no apparent difference in disease-modifying treatment (DMT) use and COVID-19 disease course in Dutch MS patients. In addition, a clear link between low lymphocyte count and severe disease was not observed.


Introduction
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly around the world, the need for reliable information about the susceptibility to severe COVID-19 disease in multiple sclerosis (MS) patients is becoming increasingly urgent. The effect of disease-modifying treatment (DMT) on COVID-19 disease course is crucial to the therapeutic management, since MS patients with certain treatments are considered as at-risk populations. Consequently, this has led to alterations of immunomodulatory treatment strategies or treatment gaps. Paradoxically, it has been hypothesized that certain immunomodulatory treatments have a beneficial effect on COVID-19 infection. 1 Although emerging data do not suggest an unfavorable course of COVID-19 disease in patients with MS, data to guide the management and clinical decision making of MS patients during the COVID-19 pandemic are limited. 1-6 Therefore, we provide an extensive overview of all reported COVID-19 cases in MS patients in the Netherlands, gathered by the Dutch MS Taskforce of the Netherlands Society of Neurology.

Methods
After the first patient was confirmed in the Netherlands on 27 February, Dutch MS neurologists were requested to report confirmed or suspected COVID-19 MS patients. Data on demographics, MS type, Expanded Disability Status Scale (EDSS), DMT, lymphocyte count, comorbidity, hospital (intensive care) admission, outcome, COVID-19 test confirmation, and level of suspicion were obtained. Descriptive statistics were used to present the data.

Results
Between 27 February and 9 June 2020, 86 MS patients were reported (Table 1), 43 of whom tested positive. In total, 37 patients had a positive polymerase chain reaction (PCR) on swabs, 4 patients were tested positive based on pathognomonic computed tomography (CT) findings, and in 2 patients antibodies against SARS-CoV-2 were detected by enzyme-linked immunosorbent assay (ELISA). Forty-three patients were suspected of COVID-19, but were not tested according to national regulations.
Of 43 patients who tested positive, 22 patients were hospitalized. The 21 patients who did not require hospitalization were considered to have a mild COVID-19 infection. Hospitalized patients were older, relatively more often male, were more often of the secondary-progressive multiple sclerosis (SPMS) subtype, had a higher EDSS score, and had more comorbidity, compared to the non-hospitalized patients (Table 1).
Three patients were admitted at the intensive care unit (ICU), two using ocrelizumab and one using dimethyl fumarate. In addition, four deaths were reported: one patient with obesity and EDSS 4.0 without DMT, one patient with EDSS 7.0 and asthma without DMT, one patient with EDSS 6.0 and chronic obstructive pulmonary disease (COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 2 using ocrelizumab, and one patient with severe cognitive impairment using fingolimod. The first patient had a fulminant disease course and died before he could be intubated. The latter three patients deliberately decided not to be admitted at the ICU.
Importantly, there was no association between severity of COVID-19 and low lymphocyte count ( Figure  1). One patient who received autologous stem cell transplantation 5 months before symptom onset had mild COVID-19 disease and good recovery. Two months before COVID-19 symptom onset, the lymphocyte count was 1.42 × 10 9 /L (reference range: 1.00-3.50 × 10 9 /L) and the neutrophil count 3.0 × 10 9 /L (reference range: 1.50-7.50 × 10 9 /L). At the first onset day, characterized by fever (38.8°C), malaise, muscle aches and mild dyspnea, a lymphocyte count of 0.81 × 10 9 /L, and a neutrophil count of 0.57 × 10 9 /L were observed. Based on clinical parameters, there was no need for hospital admission: supplemental oxygen was not required and the patient presented with mild symptoms. However, the patient was hospitalized due to social indication. Due to neutropenic fever, most likely caused by the Corona virus and incomplete bone marrow recovery after stem cell transplantation, levofloxacin and filgrastim were administered at the second day of admission until neutrophil recovery to 1 × 10 9 /L. After 8 days, the patient was symptom-free except for a sore throat, with a neutrophil count of 7.95 × 10 9 /L and lymphocyte count of 2.68 × 10 9 /L.

Discussion
The possible negative effect of immunomodulatory treatment in MS patients with SARS-CoV-2 infections is a major concern during the pandemic. Although our findings should be interpreted with caution in this small cohort, we did not see a trend of a worse outcome in MS patients on DMT in general. Known risk factors for severe COVID-19 disease such as male sex, comorbidity, and age could be confirmed. 7 In addition, a clear link between low lymphocyte count and severe disease was not observed. This is of importance as some neurologists advise dose reduction or discontinuing treatment in lymphopenic patients. 1,3 To date, data on lymphocytes and DMT use in MS patients are lacking.
Compared to current evidence, a relatively high proportion of patients using ocrelizumab were observed in our cohort, of which the vast majority of the positively tested was hospitalized. 2,4 However, this may be attributed to indication bias and/or reporting bias. Overall, our findings show no apparent difference in DMT use and COVID-19 disease course in Dutch MS patients, which is similar to that reported in an Italian cohort. 2 Even though our data are reassuring, long-term data acquisition is crucial to gain more knowledge about the potentially protective or harmful nature of immunosuppressive agents in COVID-19 disease, risk factors associated with severe COVID-19, and antibody formation in MS patients.

Author Contributions
F.C.L., E.H., Z.L.E.v.K., J.K., and J.P.M. contributed to acquisition of data, analysis and interpretation of data, and drafting and revising the manuscript.

Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.C.L., J.P.M., and Z.L.E.v.K. report no disclosures. J.K. and E.H. have accepted speaker and consulting fees from Merck, Biogen, TEVA, Sanofi, Genzyme, Roche, and Novartis.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.