The prevalence of COVID-19 infection in patients with multiple sclerosis (MS): a systematic review and meta-analysis.

BACKGROUND: The prevalence of COVID-19 is different in studies conducted in different countries. The aim of this systematic review and meta-analysis is to estimate the pooled prevalence of COVID-19 in patients with MS.
METHODS: Two independent researchers independently searched PubMed, Scopus, EMBASE, Web of Science, and google scholar along with gray literature up to April 2021. The search strategy included the MeSH and text words as (((coronavirus OR Wuhan coronavirus OR novel coronavirus OR coronavirus disease OR COVID-19 OR 2019 novel coronavirus infection OR 2019-nCOV OR severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2) AND (Multiple Sclerosis OR Sclerosis, Multiple) OR Sclerosis, Disseminated) OR Disseminated Sclerosis) OR MS (Multiple Sclerosis)) OR Multiple Sclerosis, Acute Fulminating).
RESULTS: We found 1466 articles by literature search, and after deleting duplicates, 1029 remained. Twelve articles remained for meta-analysis. Totally, 101,462 patients were evaluated and the total number of possible/confirmed cases was 1394. Mean age ranged from 35 to 54 years. Totally, 49 patients died. The pooled prevalence of suspected COVID-19 in MS patients was 4% (95% CI: 3-4%) (I2 = 98.5%, P < 0.001). The pooled prevalence of hospitalization in infected cases was 10% (95% CI: 7-12%) (I2 = 95.6%, P < 0.001). The pooled prevalence of death in hospitalized cases was 4% (95% CI: 1-6%) (I2 = 82.4%, P < 0.001).
CONCLUSION: Hospitalization rate is higher among MS patients based on COVID-19 infection while the pooled infection rate is estimated as 4%.

Introduction

COVID-19 (severe acute respiratory syndrome coronavirus 2 [SARSCoV-2]) disease infection is in pandemic stage and fever, dry cough, shortness of breath, hyposmia/anosmia, and hypogeusia/ageusia are among the common manifestations [1]. Concerns were raised for patients who received immunomodulatory or immunosuppressive medications such as patients with multiple sclerosis (MS) [2]. Based on mechanism of action of disease-modifying therapies (DMTs), risk of infection differs between MS cases [3]. Multiple Sclerosis International Federation (MSIF) declared that patients with MS should continue their medications during pandemic stage and in the case of positive COVID-19 tests or infection confirmation, they have to consult with the neurologist [4]. Overall, literature shows that MS patients are not at higher risk of severe infection and the rate of infection is not great [2]. Studies which were conducted in different countries reported different prevalence of COVID-19 infection in MS cases. So, we designed this systematic review and meta-analysis to estimate the pooled prevalence of COVID-19 in patients with MS.

Methods

Two independent researchers independently searched PubMed, Scopus, EMBASE, Web of Science, and google scholar along with gray literature up to April 2021.

The search strategy included the MeSH and text words as (((coronavirus OR Wuhan coronavirus OR novel coronavirus OR coronavirus disease OR COVID-19 OR 2019 novel coronavirus infection OR 2019-nCOV OR severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2) AND (Multiple Sclerosis OR Sclerosis, Multiple) OR Sclerosis, Disseminated) OR Disseminated Sclerosis) OR MS (Multiple Sclerosis)) OR Multiple Sclerosis, Acute Fulminating).

Inclusion criteria were cross-sectional studies and articles which had been published in the English language.

Exclusion criteria were cohort, case-report, and RCT studies.

We collected data regarding first author, country of origin, number of enrolled patients, number of possible/confirmed cases, mean age, F/M ratio, mean EDSS, mean duration of the disease, number of hospitalizations, ICU admissions, and death.

Risk of bias assessment

We evaluated the risk of potential bias by the Newcastle–Ottawa quality assessment scale (adapted for cross-sectional studies) [5]. It includes seven questions with the maximum total score of 10. The higher the score, the better the quality of the study.

Statistical analysis

All statistical analyses were performed using STATA (version 14.0; Stata Corp LP, College Station, TX, USA). We used random effects model.

To determine heterogeneity, inconsistency (I2) was calculated.

Results

We found 1466 articles by literature search, after deleting duplicates 1029 remained. Eighteen articles remained for meta-analysis (Fig. 1).

Fig. 1

Flow diagram summarizing the selection of eligible studies

Totally, 101,462 patients were evaluated and the total number of possible/confirmed cases was 1394.

Mean age ranged from 35 to 54 years. Totally, 49 patients died. The quality assessment score ranged between 4 and 10 (Table 1).

Table 1

Data extracted from included studies

Study	Country	Whole MS population	COVID-19 positive patients	No. of positive PCR	Age	Sex	EDSS	Disease duration	No. of hospitalization	ICU admission	Death	Quality assessment
Ciampi et al. [6]	Chile	400	14	11	41.20 (11.4)	F 288 M 116	NR	NR	3	0	0	4/10
Barzegar et al. [7]	Iran	543	9	2	35.28 (8.11)	F 441 M 102	0.0 (0.0–2.0) M	7.0 (4.5–10) M	2	1	1	6/10
Ciampi et al. [8]	Chile	280	3	3	41 M	F 199 M 81	NR	NR	3	NR	0	7/10
Safavi et al. [9]	Iran	712	34	NR	35.0 (8)	F 559 M 153	NR	7.7 (7.7)	2	0	0	7/10
Crescenzo et al. [10]	Italy	1034	29	11	NR	F 765 M 269	NR	NR	2	0	0	10/10
Dalla Costa et al. [11]	Multi center	399	52	4	43.9 (10.7)	F 242 M 157	3.5 (2.0, 4.0) M	13.1 (10.3)	1	NR	0	7/10
Moss et al. [12]	USA	3028	90	17	50.26	F 2275 M 753	2.76	16.43	5	NR	0	7/10
Mantero [13]	Italy	275	15	1	46.4 (13.2)	F 181 M 94	1.5 (1–4) M	11.8 (9.3)	0	0	0	10/10
Sahraian [14]	Iran	4647	68	NR	36.84 (9.21)	F 3622 M 1025	NR	6.79 (5.43)	17	NR	2	8/10
Vogel [15]	USA	1019	7	7	54.2	F 810 M 209	NR	NR	0	0	0	10/10
Álvarez [16]	Spain	330	12	9	47.91	F 247 M 83	1.92	NR	NR	NR	1	6/10
Evangelou [17]	UK	3910	237	37	NR	NR	NR	NR	3	NR	0	6/10
Kovvuro [18]	USA	42,899	115	NR	52 (15.5)	F 83 M 32	NR	NR	38	10	5	9/10
Reder [19]	USA	30,478	344	344	NR	F 22,883 M 7595	NR	NR	74	NR	32	9/10
Zabalza [20]	Spain	758	93	47	44.93	F 525 M 233	2	14.45 (13.1)	19	NR	2	8/10
Sepulveda [21]	Spain	407	51	5	47.49	F 273 M 134	Median: 1.93	15.04	6	1	1	9/10
Moreno-Torres [22]	Spain	5641	219	88	45.2(12.4)	F 138 M 81	2.74 (2.28)	11.9 (8.9)	51	1	5	-
Fernandes [23]	UK	4702	246	17	NR	F 3279 M 1422	NR	NR	NR	NR	5	8/10

The pooled prevalence of suspected COVID-19 in MS patients was 4% (95% CI: 3–4%) (I2 = 98.5%, P < 0.001) (Fig. 2).

Fig. 2

The pooled prevalence of COVID-19 in MS patients

The pooled prevalence of hospitalization in infected cases was 10% (95% CI: 7–12%) (I2 = 95.6%, P < 0.001) (Fig. 3).

Fig. 3

The pooled prevalence of hospitalization in infected MS patients

The pooled prevalence of death in hospitalized cases was 4% (95% CI: 1–6%) (I2 = 82.4%, P < 0.001) (Fig. 4).

Fig. 4

The pooled prevalence of death in infected MS patients

Discussion

To our knowledge, this is the first systematic review and meta-analysis of COVID-19 prevalence in MS patients.

The result of this systematic review and meta-analysis showed that the pooled prevalence of COVID-19 in MS patients is 4%. We also found that pooled hospitalization rate was 10%.

It is assumed that patients with MS are at higher risk of COVID-19 infection due to immunosuppressive or immune-modulatory agents administration while the pooled estimate and the point estimates of each study showed that the prevalence is not high in MS patients.

Conversely, the course of COVID-19 was not severe in affected cases and they had better outcome than the general population [9, 24]. Different factors such as age, disability status, immobility-related obesity, respiratory comorbidities, referring to medical center for magnetic resonance imaging, clinical visits, and laboratory examinations are considered to play role in COVID-19-related mortality and morbidity in MS patients [25].

It is reported that these patients follow quarantine rules strictly and they use masks and gloves regularly [26]. On the other hand, the first-line treatments for MS patients which are used widely are interferons (IFNs) and glatiramer acetate that are low-risk medications for MS treatment during this pandemic [25]. INFs are useful for inhibiting replication of the viruses which will be helpful for treating COVID-19 infection [27]. Anti-CD20 medications that deplete peripheral B cells are considered high-risk medications [2]. Sormani et al. found that severe infection mostly occurred in cases who were under treatment with anti-CD20 agents [28].

It is shown that patients who are under treatment with B-cell-depleting antibodies had higher risk of infection than others [9, 24].

MS patients who received B-cell-depleting agents were found to have higher rate of hospitalization in some studies [7, 9] while others believed that there is no relationship between type of medications and COVID-19 susceptibility [14].

As it is shown in Table 1, the rate of hospitalization and ICU admission was low among MS patients and four out of 570 suspected/confirmed patients died which is lower than the rate in healthy population. In Sahraian et al. study (the most number of patients) which was conducted in Iran, 4647 MS patients were evaluated, 68 were suspected/confirmed COVID-19 cases, and 17 were hospitalized while only 2 deaths were recorded [14]. The pooled estimate of hospitalization was found as 15%. In the study which was done by Ciampi et al., all suspected/confirmed cases were hospitalized but none of them died [8].

Parrotta et al. evaluated 76 suspected MS patients with COVID-19. They found 37 confirmed cases, 18 hospitalization (23.7%), and 6 (7.8%) related death [29]. Older age and progressive course of the disease were related with critical illness or death in these patients.

On the other hand, physicians are tended to hospitalize these patients more to observe MS patients carefully and do supportive care and treatments.

The results of included studies also show that the death rate was not high among infected MS patients and mortality rates were along with the general population [30, 31]. The pooled prevalence of death was 0 which ranged from 0 to 11%.

This systematic review and meta-analysis had some strengths. First, it is the first systematic review and meta-analysis. Second, we considered hospitalization and death rates.

Conclusion

Hospitalization rate is higher among MS patients based on COVID-19 while the pooled infection rate is estimated as 4%.