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. 2023 Mar 23;18(3):e0283538. doi: 10.1371/journal.pone.0283538

Multiple sclerosis and COVID-19: A retrospective study in Iran

Behnaz Sedighi 1, Aliakbar Haghdoost 2, Parya Jangipour Afshar 3, Zohre Abna 4, Shamimeh Bahmani 5, Simin Jafari 1,5,*
Editor: Anza Bilal Memon6
PMCID: PMC10035930  PMID: 36952532

Abstract

Objectives

Previous studies suggested a higher rate of COVID-19 infection in patients with multiple sclerosis than in the general population, and limited studies addressed the impact of COVID-19 and its vaccination in patients with multiple sclerosis in Iran. We decided to investigate the factors associated with COVID-19 infection, the effects and side effects of the COVID-19 vaccination in patients with multiple sclerosis (MS).

Methods

We used the data of the patients with multiple sclerosis registered in a referral clinic in Kerman, one of the large cities in Iran (a population of 537,000 inhabitants), to explore the association between demographic variables, the history of COVID-19 vaccination, and the clinical outcomes.

Results

Of the 367 participants in this study, 88.3% received the COVID-19 vaccine, 35.4% were confirmed COVID-19 cases, and the incidence of COVID-19 was much higher before vaccination (24.5% before vaccination versus 10.1% after vaccination). The multivariable logistic regression model showed that male gender (OR = 2.64, 95% confidence interval: 1.21, 5.74) and current employment (OR = 3.04, 95% confidence interval: 1.59, 5.80) were associated with an increased risk of COVID-19. The only factor associated with the adverse effects of COVID-19 vaccination was the type of vaccine (AstraZeneca).

Conclusion

Our findings showed that the vaccination protected MS cases considerably against COVID-19. In addition, the side effects of the vaccines were not noticeably high in these cases as well. Among all COVID-19 vaccines, AstraZeneca had the most common side effects, so people must be aware of them before vaccination. The male gender and employment were the most important variables in the prevalence of COVID-19 in patients with multiple sclerosis in our study.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for COVID-19, which was first seen in Wuhan, China, in 2019 [1]. This disease is very contagious and manifests with fever, cough, myalgia, and dyspnea. The virus spread all over the world, resulting in a pandemic that killed 5.4 million people and infected more than 304 million people until January 9, 2022 [2]. COVID-19 posed a great challenge to all healthcare systems around the world, with the greatest impact on the health organizations of each country [3].

Multiple sclerosis (MS), one of the most disabling CNS diseases, is an autoimmune inflammatory demyelinating pathology that affects approximately 2.8 million people worldwide [4,5]. Many patients with multiple sclerosis have a suppressed immune system due to disease-modifying therapy (DMT), so they are more at risk for infectious diseases than the general population [6].

The COVID-19 outbreak has caused many issues for patients with multiple sclerosis in various aspects of their lives, including fragile mental health, poor treatment follow-up, and increased annual hospitalization [7,8]. The suppressive immune system due to DMT has also raised concerns about the facilitation of COVID-19 infection in patients with MS [9–11].

Fortunately, initiating vaccination against COVID-19 has controlled the spread of the disease and improved the medical status of patients with MS [12,13]. Previous studies showed that COVID-19 has a higher rate of infection and hospitalization in patients with MS than in the general population, while early vaccination may be effective in reducing these rates [14]. Numerous studies were conducted on the patients with MS in Iran during the COVID-19 pandemic [7,8,15]. However, limited studies investigated the factors affecting COVID-19 infection, the effectiveness of vaccination, and the complications of vaccination in patients with MS in Iran. Most of these studies were conducted at the beginning of the pandemic [14,16–18]. The current study investigated the factors associated with COVID-19 infection, the impact of vaccination, as well as factors affecting the side effects of vaccination in patients with MS in Kerman Province, Iran.

Materials and methods

Study design and participants

This retrospective study aimed to investigate the factors associated with the COVID-19 and the effectiveness and side effects of vaccination in patients with MS in a referral clinic in Kerman, one of the large cities in Iran, from March to December 2021.

We used the data of patients registered in the referral hospital in Kerman province. Out of 548 registered cases, we recruited 367 (66.9%) and excluded those who disagreed or had a major non-communicable disease, such as diabetes, hypertension, cardiovascular, cerebrovascular, and respiratory diseases. The final diagnosis of MS in this registry was confirmed by neurologists who are affiliated with the Shafa hospital and the Kerman University of Medical Sciences, based on the revised McDonald criteria (2017) [19].

Outcomes measurement

Data were collected using three questionnaires: 1. demographic information (age, gender, BMI, education level, employment status, number of children, place of residence (urban or rural), no common comorbidities (complications accompanying MS other than diabetes, hypertension, cardiovascular, cerebrovascular, and respiratory diseases), tobacco, alcohol, and substance abuse (opioids, heroin, methamphetamine, or other stimulants)); 2: COVID-19-related information (including vaccine injection, type, and side effects; confirmed COVID-19 that was based on physician judgment, which used lab tests including PCR and clinical signs and symptoms since the beginning of the pandemic; infection with COVID-19 before or after vaccination; and the time (days) to infection after vaccination); 3: Multiple sclerosis-related information (duration of illness and the Expanded Disability Status Scale).

The expanded disability status scale (EDSS) of MS patients was designed by John Kurtzke. It assesses the functioning of systems such as pyramidal, cerebellar, brainstem, sensory, bowel, and bladder, visual and cerebellar regions [20], The score varies from 0 (a normal neurological state) to 10 (MS-induced death): 0–2.5 refers to people with a mild degree of disability, 3–5 refers to people with a moderate degree of disability, and 5.5–10 refers to people with a severe degree of disability.

Statistical analysis

SPSS 26 was used to analyze the data. Descriptive statistics were used to describe qualitative (number and percentage) and quantitative variables (mean and standard deviation). A multivariable logistic regression model was used to determine the factors related to COVID-19 and its side effects in patients with MS. A significant level of 0.05 was considered.

Ethics statement

This study was approved by the Ethics Committee of Kerman University of Medical Sciences (IR.KMU.REC.1400.566). Written informed consent was obtained from all the participants.

Results

The study included 367 participants, of whom 305 (83.1%) were female and 62 (16.9%) were male. Participants were between 17 and 67 years old, with a mean age of 37.99±9.80. The mean duration of multiple sclerosis was 8.26 ± 5.60 years, and the mean EDSS score was 1.18±1.60 out of 10, which was categorized as a mild category. Most of the patients had 12–16 years of academic education (80.4%), were unemployed (67.8%), lived in urban areas (93.5%), did not use tobacco or other substances (89.4%), received a vaccine against COVID-19 (88.3%), did not acquire COVID-19 (64.6%), and had mild disease activity (84.2%). Tables 1 and 2 present other demographic characteristics.

Table 1. Demographic characteristics (N = 367).

Variables group Number Percent
Gender Female 305 83.1
Male 62 16.9
Education(years) <12 45 12.3
12–16 295 80.4
>16 27 7.4
Number of children
none 90 24.5
≤2 211 57.5
>2 66 18.0

Job 		Unemployed 249 67.8
Self-employed 49 13.4
Employed 69 18.8
Location Urban 343 93.5
Rural 24 6.5
comorbidities No 309 84.2
Yes 58 15.8
Addiction No 328 89.4
Yes 38 10.4
Vaccination No 43 11.7
Yes 324 88.3
Adverse effects after vaccination No 175 47.7
Yes 143 39.0
Getting COVID-19 No 237 64.6
Yes 128 34.9
Time of catching COVID-19 Before injection 90 24.5
After injection 37 10.1
EDSS (0–2.5) Mild 309 84.2
Moderate (3–5) 44 12.0
Sever (5.5–10) 13 3.5
DMT Injectable 136 37.05
Anti CD20 63 17.17
S1P receptor modulator (Fingolimod) 43 11.72
Natalizumab 18 4.91
Oral (Dimethyl fumarate, Teriflunomide) 71 19.35
None 36 9.80
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The sum of subgroups may be less than total because of missing data.

DMT: Disease-modifying therapy, S1P: Sphingosine 1-phosphate, EDSS = Expanded Disability Status Scale.

Table 2. Mean and standard deviation of variables.

Variables Mean ±SD Min Max
Age (year) 37.99±9.80 17 67
The duration of MS (year) 8.26±5.60 1 30
BMI (kg/m2) 24.69±4.08 15 39.84
Time between injection and catching COVID-19 (day) 39.56±25.22 2 120
EDSS 1.18±1.60 0 7
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BMI = body mass index, EDSS = Expanded Disability Status Scale.

The multivariable logistic regression model showed that gender (OR = 2.64, 95% confidence interval: 1.21, 5.74), and employment status (OR = 3.04, 95% confidence interval: 1.59, 5.80), were all associated with an increased risk of COVID-19 infection in the patients with MS. (Table 3).

Table 3. Logistic regression analysis of factors associated with COVID-19.

Subgroup Odds ratio (95% CI) P-value
Gender
Female Reference
Male 2.64 (1.21,5.74) 0.01*
Education(years)
<12 Reference
12–16 0.82 (0.38,1.76) 0.61
>16 0.74 (0.23,2.34) 0.61
Job
Unemployed Reference
Self-employed 1.113 (0.50,2.47) 0.79
Employed 3.041 (1.59,5.80) 0.00*
Location
Urban Reference
Rural 0.47 (0.18,1.23) 0.12
Vaccination
No Reference
Yes 0.61 (0.30,1.24) 0.17
Addiction
No Reference
Yes 1.09 (0.48,2.50) 0.82
comorbidities
No Reference
Yes 1.26 (0.66,2.39) 0.46
EDSS
Mild (0–2.5) Reference
Moderate (3–5) 1.05 (0.47,2.31) 0.90
Sever (5.5–10) 2.08 (0.52,8.21) 0.29
Age 0.98 (0.95,1.01) 0.24
BMI (kg/m2) 1.02 (0.96,1.08) 0.35
The duration of MS (year) 1.02 (0.97,1.07) 0.31
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The sum of subgroups may be less than total because of missing data.

BMI = body mass index; CI = confidence interval; EDSS = Expanded Disability Status Scale.

*Is significant at P<0.05.

According to a multivariable logistic regression model, only the type of vaccine (AstraZeneca) (OR = 23.578, 95% confidence interval: 3.041,182.80) was a risk factor for adverse effects of COVID-19 injection in the patients with MS (Table 4).

Table 4. Logistic regression analysis of factors associated with adverse effect of vaccination.

Subgroup Odds ratio (95% CI) P-value
Gender
Female Reference
Male 0.75 (0.35,1.59) 0.46
Education (years)
<12 Reference
12–16 0.84 (0.39,1.81) 0.66
>16 0.93 (0.29,2.97) 0.91
Job
Unemployed Reference
Self-employed 0.92 (0.41,2.08) 0.85
Employed 0.67 (0.34,1.31) 0.25
Location
Urban Reference
Rural 0.49 (0.15,1.51) 0.21
EDSS
Mild (0–2.5) Reference
Moderate (3–5) 0.88 (0.40, 1.91) 0.75
Sever (5.5–10) 0.57 (0.13,2.52) 0.46
EDSS
No Reference
Yes 0.94 (0.48,1.82) 0.86
Addiction
No Reference
Yes 0.66 (0.28,1.53) 0.33
Type of vaccine
Sinopharm Reference
Barekat 0.56 (0.13,2.27) 0.33
AstraZeneca 23.57 (3.04,182.80) 0.00*
Sputnik 0.82 (0.14,4.80) 0.83
Age 0.98 (0.95,1.01) 0.38
BMI (kg/m2) 1.05 (0.99,1.12) 0.06
Duration of disease 1.00 (0.96,1.05) 0.74
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The sum of subgroups may be less than total because of missing data.

BMI = body mass index; CI = confidence interval; EDSS = Expanded Disability Status Scale.

*Is significant at P<0.05.

We compared the frequency of post-vaccination side effects among patients based on the types of vaccines. Our results showed that the patients with multiple sclerosis who received AstraZeneca and Sinopharm had significant adverse effects (Table 5). Also, our results showed that the patients had side effects such as injection site pain, tenderness, redness, fever, headache, fatigue, nausea, diarrhea, and muscle pain after vaccination. The most common adverse effect was pain at the injection site (31.3%) (Table 6).

Table 5. Type of vaccine and adverse effect of vaccine in each group.

Vaccine Adverse effect Frequency Percent p-value
AstraZeneca (n = 20) No 1 5.0 <0.00*
Yes 19 95.0
Barekat (n = 11) No 8 72.7 0.13
Yes 3 27.3
Sinopharm (n = 281) No 162 56.8 0.01*
Yes 119 41.8
Sputnik (n = 6) No 4 66.7 0.41
Yes 2 33.3
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*Is significant at P<0.05.

Table 6. Frequency and percent of the adverse effect of vaccines.

Adverse effect Frequency percent
Injection site pain 115 31.3
Tenderness 17 4.6
Redness 6 1.6
Fever 41 11.2
Headache 54 14.7
Fatigue 46 12.5
Nausea 36 9.8
Diarrhea 20 5.4
Muscle pain 36 9.8
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The number of subgroups may be more than total (143) because some people may have more than one side effect.

Furthermore, we compared the prevalence of COVID-19 in patients with MS based on the type of DMT, and our results showed no significant difference in the prevalence of COVID-19 based on the kind of DMT taken by the patients. (Table 7).

Table 7. Type of DMT and getting COVID- 19 in each group.

DMT Covid-19 P-value
Yes No
Injectable 49 86 0.14
Anti CD20 23 40
S1P receptor modulator (Fingolimod) 20 22
Natalizumab 2 16
Oral (Dimethyl fumarate, Teriflunomide) 23 48
None 11 25
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Discussion

We investigated the factors associated with COVID-19 infection, the impacts and side effects of vaccination in patients with multiple sclerosis in Kerman Province, Iran.

We found that the male gender and employment status of the patients with MS played a significant role in evaluating factors associated with suspected or confirmed COVID-19, and the type of vaccine (AstraZeneca) was the only factor associated with the adverse effects of COVID-19 vaccination.

We revealed that the prevalence of COVID-19 in the patients with MS was approximately 35%, but Naghavi et al. indicated that the suspected rate of COVID-19 in the patients with MS was 20.4%, with 11.7% having PCR confirmation [21], and Zabalza et al. reported that COVID-19 was prevalent in 6.3 percent of the patients with MS. The difference between these studies and our study could be due to genetic and racial differences, disease-modifying therapies, and poor compliance with COVID-19 protection protocols [22–26].

Another finding of this study indicated that 70 percent of the COVID-19 infection occurred before vaccination, supporting the fact that vaccination against COVID-19 can reduce the infection rate of the coronavirus. Large-scale vaccination could be the only way to prevent COVID-19 [12,27,28].

We discovered, like Moss and Jehi et al., that the male gender and employment could increase the prevalence of COVID-19 in MS patients [6,29]. But Naghavi et al. reported no association between gender and COVID-19. They found the presence of comorbidity, EDSS scores, DMT, hospitalization rate due to COVID-19 infection could be associated with gender [21]. Rostami et al. reported that autoimmune diseases, DMT, age, gender, and high EDSS increased COVID-19 incidence and hospitalization in patients with multiple sclerosis [24]. The high incidence of COVID-19 in men and employed people could be due to strict self-protection, self-isolation, and social distancing in women more than men, and also high exposure to the coronavirus in employed people.

In this study, we did not find any significant difference in contracting COVID-19 between users and non-users of DMT. And also, no association was found between COVID-19 prevalence and the type of DMT, even in patients receiving anti CD20 therapies. These findings are in line with Alonso and Parrotta et al. [30,31], which found no association between DMT and the risk of COVID-19. It could be due to the small sample size in this study, the younger participants, or the lower EDSS. Recent large studies have shown that patients with MS treated with anti-CD20 DMTs (rituximab or ocrelizumab) were at higher risk of developing severe COVID-19 than other DMTs [32,33]; however, strict adherence to health protocols and self-isolation might be an important reason for the low prevalence and severity of COVID-19 infection among our patients.

Studies suggest that the COVID-19 pandemic has affected patients with multiple sclerosis, so the development of multiple vaccines against COVID-19 could be promising for the control and eradication of the disease. According to the current study, 88% of the patients received at least one dose of the vaccine, indicating their willingness to receive COVID-19 vaccines; Also, in the patients on the anti B cell therapies, vaccination was done one month before taking the next dose of the drug or three months after taking the drug (as a result of the previous studies on the efficacy of the vaccines in the patients treated with these drugs). Previous studies found that patients with multiple sclerosis were less reluctant to receive the COVID-19 vaccines after healthcare providers prepared adequate information for them [27].

Furthermore, we showed that 39 percent of the patients had side effects such as injection site pain, tenderness, redness, fever, headache, fatigue, nausea, diarrhea, and muscle pain after vaccination. Most of them received Sinopharm vaccines, and a few of them received Barekat, AstraZeneca, and Sputnik vaccines. We found a significant relationship between the type of vaccine and side effects after vaccination; all vaccines had side effects, but AstraZeneca had the most common side effects. Zare et al. supported this result [34], in contrast Babaee and Omeish et al. rejected it [35,36]. Previous studies reviewed the effect of other vaccines on patients with MS and found that those on immunosuppressive drugs experienced serious side effects and a relapse after vaccination; thus, patients with MS should seek medical advice before receiving vaccines [12,28].

Conclusion

We found that the prevalence of COVID-19 in the patients with MS was higher than in the other studies, which could be an alarm for patients with chronic and immunosuppressive diseases in the healthcare system in Iran.

In our study, men and employed people were more susceptible to COVID-19 infection, which could be due to their high exposure to SARS-CoV-2. The incidence of COVID-19 infection was much higher before vaccination, indicating an important role of vaccination in COVID-19 prevention. This study showed that a significant percentage of the patients with MS received at least one dose of vaccine, recalling the important role of vaccination in the control of COVID-19. The AstraZeneca vaccine caused the most common side effects among vaccines, so people should be aware of vaccine side effects before receiving vaccination. Future studies should address severe side effects to make more evidence-based decisions.

Acknowledgments

The researchers would like to thank all the patients with multiple sclerosis for participating in this study. This study was approved by the neurology research center of Kerman University of Medical Sciences.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author received no specific funding for this work.

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Decision Letter 0

Anza Bilal Memon

19 Sep 2022

PONE-D-22-22791Multiple sclerosis and covid-19: a retrospective study in IranPLOS ONE

Dear Dr. Jafari,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Nov 03 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Anza Bilal Memon, MD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. 

In your revised cover letter, please address the following prompts:

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b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: First, the grammar is very poor. The entire manuscript needs a significant revision for grammar.

Regarding the content, there are several major problems.

1. What does COVID infection mean? Does it mean symptomatic + PCR confirmation? Does it mean antigen testing? Is it patient reported or physician confirmed?

2. Employed vs. unemployed needs to be further explored. At a condition that associated with COVID, were employed people working in a private office or in a crowded market with exposure to many other people? Were unemployed people confined to their homes or moving around their urban centers?

3. What is "addiction"? Addiction to what - smoking?

4. What is "physical disease"?

5. What medications were these patients using for their MS?

6. Other risk factors for COVID include diabetes, hypertension, lung disease, etc - did these patients have those?

Reviewer #2: Sedighi et al present a retrospective evaluation of CoVID-19 related outcomes in patients with MS in a referral clinic located in Kerman, Iran. The authors assessed factors associated with COVID-19 infection, along with the effectiveness and untoward effects of the CoVID-19 vaccine. It is helpful to get a report on the impact of CoVID19 on the Iranian MS population. There are several points that should be addressed in the article:

1. The references for the global prevalence of MS are not current and should be updated. The most recent data puts the world MS prevalence estimate at 2.8 million based on the 3rd edition of the Atlas of MS (Walton C, et al. Mult Scler. 2020 Dec; 26(14): 1816–1821. doi: 10.1177/1352458520970841).

2. How representative is the 367-study sample of the Kerman MS clinic population? How many patients were excluded either due to failure to obtain consent or for other reasons? Was this a convenience population based on lab testing or clinic follow-ups? These issues should be documented and explained.

3. How was SARS-CoV2 infection confirmed in the study population and over what period of time? It is difficult to judge the 35% incidence of “getting CoVID-19” in the study population if the details are not presented. Was the diagnosis made in laboratory-confirmed patients based on either polymerase chain reaction or serology tests vs. presumptive diagnosis based on symptoms or exposures? Also, the time period of tracking infections is important with the arrival of various CoVID-19 variants which have different infectivity rates. These data should be documented in the methods.

4. The MS disability status (EDSS) is obtained on only 57/367 study participants. This is missed opportunity to assess how neurological disability impacts the study outcomes. In several studies in other countries, neurological disability made CoVID19 infection more severe and more likely to be recognized. On a related note, I’m wondering if the MS population at the clinic was more severely impaired neurologically than comparable MS populations with such a high (69%) unemployment rate in a young adult population.

5. Were MS disease modifying therapies documented in the study population? If not, why not. Patients with MS taking CD20 disease modifying therapies (e.g., rituximab and ocrelizumab) have been shown to be at increased risk for CoVID-19 and have less robust responses to vaccines.

6. Significant digits after the decimal point for odds ratios and confidence intervals should be limited to 1 or 2 (e.g., 1.1 or 1.11).

7. Clear labeling of the risk factor of interest should be presented in the abstract in results as opposed to the generic variable label. Male sex vs. sex and current employment vs employment status.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Mar 23;18(3):e0283538. doi: 10.1371/journal.pone.0283538.r002

Author response to Decision Letter 0

14 Nov 2022

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Thank you for your note. The manuscript is based on the formatting guidelines.

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

We will upload data as Supporting Information files.

3. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

It was corrected in the manuscript.

Review Comments to the Author

Reviewer #1:

First, the grammar is very poor. The entire manuscript needs a significant revision for grammar.

Thank you for your note. We revised the manuscript for English language and grammar.

Regarding the content, there are several major problems.

1. What does COVID infection mean? Does it mean symptomatic + PCR confirmation? Does it mean antigen testing? Is it patient reported or physician confirmed?

The diagnosis was based on the physician's judgment, which used lab tests, including PCR and clinical signs and symptoms.

2. Employed vs. unemployed needs to be further explored. At a condition that associated with COVID, were employed people working in a private office or in a crowded market with exposure to many other people? Were unemployed people confined to their homes or moving around their urban centers?

Employed means having a job working for a company or another person with usual exposure to other people, while unemployed means not having a permanent job or being a university student and also may have usual exposure to other people.

We didn’t feel the need for further exploration with our patients since they were strict about self-protection and self-isolation due to their underlying disease. Conversely, our patients were completely informed on the protocols for preventing the contraction of COVID infection since the beginning of the pandemic.

3. What is "addiction"? Addiction to what - smoking?

In this study, we asked the patients about their lifestyle habits, such as tobacco, alcohol, and substance abuse (opioid, heroin, methamphetamine, or other stimulant substance). We added details in the methods section.

4. What is "physical disease"?

In this study, we only recruited subjects without any important chronic diseases, such as diabetes, hypertension, cardiovascular, cerebrovascular, and respiratory diseases, and "physical disease" means complications accompanying MS other than the conditions noted above.

5. What medications were these patients using for their MS?

The patient's medications were added in table 1.

6. Other risk factors for COVID include diabetes, hypertension, lung disease, etc - did these patients have those?

The patients who had chronic non-communicable diseases (diabetes, hypertension, cardiovascular, cerebrovascular, and respiratory diseases) and those who did not agree to participate in the study were excluded.

Reviewer #2:

Sedighi et al present a retrospective evaluation of CoVID-19 related outcomes in patients with MS in a referral clinic located in Kerman, Iran. The authors assessed factors associated with COVID-19 infection, along with the effectiveness and untoward effects of the CoVID-19 vaccine. It is helpful to get a report on the impact of CoVID19 on the Iranian MS population. There are several points that should be addressed in the article:

1. The references for the global prevalence of MS are not current and should be updated. The most recent data puts the world MS prevalence estimate at 2.8 million based on the 3rd edition of the Atlas of MS (Walton C, et al. Mult Scler. 2020 Dec; 26(14): 1816–1821. doi: 10.1177/1352458520970841).

Thank you for your note. We updated the MS prevalence.

2. How representative is the 367-study sample of the Kerman MS clinic population? How many patients were excluded either due to failure to obtain consent or for other reasons? Was this a convenience population based on lab testing or clinic follow-ups? These issues should be documented and explained.

We used the registry of MS patients who received care from the only referral hospital in Kerman province. Out of 548 registered cases, we recruited 367 (66.9 %); those who did not agree or had a major non-communicable disease such as diabetes, hypertension, cardiovascular disease, cerebrovascular disease, and respiratory disease were excluded. We added details in the methods section.

3. How was SARS-CoV2 infection confirmed in the study population and over what period of time? It is difficult to judge the 35% incidence of “getting CoVID-19” in the study population if the details are not presented. Was the diagnosis made in laboratory-confirmed patients based on either polymerase chain reaction or serology tests vs. presumptive diagnosis based on symptoms or exposures? Also, the time period of tracking infections is important with the arrival of various CoVID-19 variants which have different infectivity rates. These data should be documented in the methods.

The patients with COVID-19 in this study were those who had the disease since the beginning of the pandemic that includes various CoVID-19 variants and the diagnosis was based on physician judgment, which used lab tests including PCR and clinical signs and symptoms. We added details in the methods section.

4. The MS disability status (EDSS) is obtained on only 57/367 study participants. This is missed opportunity to assess how neurological disability impacts the study outcomes. In several studies in other countries, neurological disability made COVID-19 infection more severe and more likely to be recognized. On a related note, I’m wondering if the MS population at the clinic was more severely impaired neurologically than comparable MS populations with such a high (69%) unemployment rate in a young adult population.

Based on the information in table 1, EDSS was obtained from all the patients, of whom 309 were categorized as mild and 57 as moderate to severe.

The EDSS provides a total score ranging from 0 to 10: 0-2.5 refers to people with a mild degree of disability, 3-5 refers to people with a moderate degree of disability, and 5.5-10 refers to severe disability.

We must add that the majority of the samples are women and unemployment is not just because of their MS conditions, a considerable proportion of healthy young adult women or university students do not have full-time jobs, so the unemployment rate in our sample is high.

5. Were MS disease modifying therapies documented in the study population? If not, why not. Patients with MS taking CD20 disease modifying therapies (e.g., rituximab and ocrelizumab) have been shown to be at increased risk for CoVID-19 and have less robust responses to vaccines.

Table. Type of DMT and getting COVID- 19 in each group

Covid-19

DMT Yes No P-value

Injectable 49 86 0.14

Anti CD20 23 40

S1P receptor modulator (Fingolimod) 20 22

Natalizumab 2 16

Oral (Dimethyl fumarate, Teriflunomide) 23 48

None 11 25

In response to the comment, we assessed and recorded the history of patients including disease modifying therapies. In summary, and incompatible with our expectation, we did not find any significant difference in contracting covid-19 between users and non-users of these drugs (table above), however, some finding was also reported in some references in the following.

Based on the above explanation, we added the following sentences in the result section.

We compared the prevalence of COVID-19 in patients with MS based on the type of DMT, our result showed that there is not a significant difference in the prevalence of COVID-19 according to their medications.

1. Bsteh G, Assar H, Hegen H, Heschl B, Leutmezer F, Di Pauli F, Gradl C, Traxler G, Zulehner G, Rommer P, Wipfler P. AUT-MuSC investigators. COVID-19 severity and mortality in multiple sclerosis are not associated with immunotherapy: Insights from a nation-wide Austrian registry. PLoS One. 2021;16(7): e0255316.

2. Louapre C, Collongues N, Stankoff B, Giannesini C, Papeix C, Bensa C, Deschamps R, Créange A, Wahab A, Pelletier J, Heinzlef O. Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis. JAMA neurology. 2020 Sep 1;77(9):1079-88.

6. Significant digits after the decimal point for odds ratios and confidence intervals should be limited to 1 or 2 (e.g., 1.1 or 1.11).

It was corrected in the manuscript.

7. Clear labeling of the risk factor of interest should be presented in the abstract in results as opposed to the generic variable label. Male sex vs. sex and current employment vs employment status.

It was corrected in the abstract section.

Attachment

Submitted filename: response to reviewers.docx

Click here for additional data file. (27.2KB, docx)

Decision Letter 1

Anza Bilal Memon

28 Dec 2022

PONE-D-22-22791R1Multiple sclerosis and covid-19: a retrospective study in IranPLOS ONE

Dear Dr. Jafari, 

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. The authors have made some significant changes to the manuscript, as recommended by the reviewers. However, I agree with reviewer # 2 that it requires some additional changes to refine the manuscript to meet the standards of PLOS One Journal publication. These changes are not difficult to make and should be done soon, and revised version should be submitted for my review and approval. Authors must pay special attention to manuscript formatting and grammar. I suggest that authors should seek some professional help for manuscript editing. Please carefully read the comments of reviewer # 2 and respond accordingly with your manuscript edits.

 Please ensure that your decision is justified on PLOS ONE’s publication criteria and not, for example, on novelty or perceived impact.

Please submit your revised manuscript by 1/18/2023 If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Anza Bilal Memon, MD

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: While many of the comments were addressed in the revision, there are still issues that remain in the updated manuscript. The authors should address the following:

1. Significant grammatical errors remain in the revised article making several sections difficult to read.

2. In the abstract, it would be more informative to include quantitative numerical descriptions rather than qualitative statements. For example, in the abstract it states that Kerman is “one of the largest cities in Iran.” It would be helpful if the abstract mentioned the numerical population of the city. Instead of stating “most of the patient with multiple sclerosis in this study received at least one dose of the vaccine,” it would be helpful to state what percentage of the patients in the study received the vaccine.

3. In the first paragraph of the results section, it would be helpful to list the mean EDSS score of the patient and explain how the patients’ disease activity was stratified into mild, moderate or severe based on the EDSS score.

4. The table in the results section references "physical disease,” but this term is not further explained in the results or the methods sections. Without further explanation of this term earlier in the paper, the reader will have difficulty understanding what this term refers to.

5. In the results section, it states that there was no difference in the prevalence of COVID-19 between the different DMT groups. It would be helpful to mention in the discussion section whether Anti CD20 agents were included. If anti-CD 20s were not included, it may be helpful to discuss that this may have impacted the data as other studies have demonstrated that Anti-CD use impacted vaccine efficacy.

6. Table 5 lists the number of adverse effects, but the types of adverse effects were never defined. It would be beneficial to list in the table the different types of adverse effects that were included.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Michael Levy

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2023 Mar 23;18(3):e0283538. doi: 10.1371/journal.pone.0283538.r004

Author response to Decision Letter 1

20 Jan 2023

While many of the comments were addressed in the revision, there are still issues that remain in the updated manuscript. The authors should address the following:

1. Significant grammatical errors remain in the revised article making several sections difficult to read.

Thank you for your note. We revised the manuscript for English grammar.

2. In the abstract, it would be more informative to include quantitative numerical descriptions rather than qualitative statements. For example, in the abstract it states that Kerman is “one of the largest cities in Iran.” It would be helpful if the abstract mentioned the numerical population of the city. Instead of stating “most of the patient with multiple sclerosis in this study received at least one dose of the vaccine,” it would be helpful to state what percentage of the patients in the study received the vaccine.

It was revised in the abstract section.

3. In the first paragraph of the results section, it would be helpful to list the mean EDSS score of the patient and explain how the patients’ disease activity was stratified into mild, moderate or severe based on the EDSS score.

It was revised in the method and result section.

4. The table in the results section references "physical disease,” but this term is not further explained in the results or the methods sections. Without further explanation of this term earlier in the paper, the reader will have difficulty understanding what this term refers to.

It was corrected in the manuscript.

5. In the results section, it states that there was no difference in the prevalence of COVID-19 between the different DMT groups. It would be helpful to mention in the discussion section whether Anti CD20 agents were included. If anti-CD 20s were not included, it may be helpful to discuss that this may have impacted the data as other studies have demonstrated that Anti-CD use impacted vaccine efficacy.

It was added in the discussion.

6. Table 5 lists the number of adverse effects, but the types of adverse effects were never defined. It would be beneficial to list in the table the different types of adverse effects that were included.

It was added in the table.

Attachment

Submitted filename: response to reviewers2.docx

Click here for additional data file. (20.1KB, docx)

Decision Letter 2

Anza Bilal Memon

2 Mar 2023

PONE-D-22-22791R2Multiple sclerosis and covid-19: a retrospective study in IranPLOS ONE

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Anza Bilal Memon, MD

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

Results:

Line 134-136 please re-write the paragraph as listed below:

Furthermore, we compared the prevalence of COVID-19 in patients with MS based on the type of DMT, and our results showed no significant difference in the prevalence of COVID-19 based on the kind of DMT taken by the patients.

Keep R as upper case for reference throughout the tables. This needs to be done for all tables.

Discussion:

Line 177-179: Please add a little discussion here about the effects of CD 20 and COVID-19 severity in your patient population and how it affected the vaccine efficacy in your patient population?

Conclusion:

Line 197-199 Please re-write paragraph as listed below:

We found that the prevalence of COVID-19 in the patients with MS was higher than in the other studies, which could be an alarm for patients with chronic and immunosuppressive diseases in the healthcare system in Iran.

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PLoS One. 2023 Mar 23;18(3):e0283538. doi: 10.1371/journal.pone.0283538.r006

Author response to Decision Letter 2

9 Mar 2023

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Thank you for your note. The reference list has been checked and corrected.

Additional Editor Comments:

Results:

Line 134-136 please re-write the paragraph as listed below:

Furthermore, we compared the prevalence of COVID-19 in patients with MS based on the type of DMT, and our results showed no significant difference in the prevalence of COVID-19 based on the kind of DMT taken by the patients.

It was corrected in the manuscript.

Keep R as upper case for reference throughout the tables. This needs to be done for all tables.

Discussion:

Line 177-179: Please add a little discussion here about the effects of CD 20 and COVID-19 severity in your patient population and how it affected the vaccine efficacy in your patient population?

It was added in the discussion.

Conclusion:

Line 197-199 Please re-write paragraph as listed below:

We found that the prevalence of COVID-19 in the patients with MS was higher than in the other studies, which could be an alarm for patients with chronic and immunosuppressive diseases in the healthcare system in Iran.

It was corrected in the manuscript.

Attachment

Submitted filename: response3.docx

Click here for additional data file. (17KB, docx)

Decision Letter 3

Anza Bilal Memon

12 Mar 2023

Multiple sclerosis and covid-19: a retrospective study in Iran

PONE-D-22-22791R3

Dear Dr., Jafari, 

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter, and your manuscript will be scheduled for publication.

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Kind regards,

Anza Bilal Memon, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Anza Bilal Memon

16 Mar 2023

PONE-D-22-22791R3

Multiple sclerosis and COVID-19: a retrospective study in Iran

Dear Dr. Jafari:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Anza Bilal Memon

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: response to reviewers.docx

    Click here for additional data file. (27.2KB, docx)
    Attachment

    Submitted filename: response to reviewers2.docx

    Click here for additional data file. (20.1KB, docx)
    Attachment

    Submitted filename: response3.docx

    Click here for additional data file. (17KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

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