Abstract
Background:
Pediatric patients with multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), are commonly treated with immunosuppressants. Understanding the impact of SARS-CoV-2 infection in patients may inform treatment decisions.
Objective:
Characterize SARS-CoV-2 infection prevalence and severity among a cohort of patients with POMS and related disorders, as well as the impact of disease-modifying therapies (DMTs).
Methods:
POMS and related disorders patients enrolled in a large, prospective registry were screened for COVID-19 during standard-of-care neurology visits. If confirmed positive of having infection, further analysis was undertaken.
Results:
Six hundred and sixty-nine patients were surveyed between March 2020 and August 2021. There were 73 confirmed COVID-19 infections. Eight of nine hospitalized patients (89%), and all patients admitted to the ICU were treated with B cell depleting therapy. The unadjusted odds ratio of hospitalization among those who tested positive of having had COVID-19 was 15.27 among those on B-cell-depleting therapy (p = 0.016).
Conclusions:
B-cell-depleting treatment was associated with a higher risk of COVID-19, higher rates of hospitalization, and ICU admission, suggesting this therapy carries a higher risk of severe infection in POMS and related disorders.
Keywords: Multiple sclerosis, disease-modifying therapies, neuromyelitis optica, demyelination, outcome measurement
Introduction
This study describes the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) infection in a multicenter cohort of pediatric patients with acquired pediatric-onset multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD) and describes the clinical characteristics in those patients with more severe COVID-19 who required hospitalization or intensive care unit (ICU) admission.
COVID-19, the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused a global pandemic beginning in late 2019.1–3 The severity of the infection has varied significantly among different populations of patients depending on factors such as age and patients’ medical conditions or comorbidities. 4 Older age, obesity, and high blood pressure emerged early-on as risk factors for more severe disease and higher risk of mortality. In children and adolescents, the effect of comorbidities and factors contributing to poor outcome with SARS-CoV-2 infection is less well understood. Pediatric demyelinating disease often is managed by therapies that induce immunosuppression. There is a significant emerging body of literature describing the impact of SARS-CoV-2 infections in adults with multiple sclerosis and other demyelinating disorders on various immunotherapies. This has shown an association of severe COVID-19 disease with older age, higher disability scores, and treatment with B-cell-depleting therapies.5–10 Conversely, a recent study evaluating the risk of COVID-19 among a smaller cohort of immunosuppressed children in Spain with neuroimmunologic conditions, indicated no difference in risk of infection between those on immunosuppression and those seen in the same clinic who were not treated with immunosuppression. No studies to date have evaluated the effect of COVID-19 specifically in children with multiple sclerosis and related disorders.
Our study addressed the following question: What is the risk of severe disease with COVID-19 infection for patients with POMS and related disorders, both generally and for those on specific disease-modifying therapies (DMTs)?
Methods
Pediatric MS and related disorders registry
This study is a multicenter, observational study utilizing a large prospective registry of pediatric MS and related demyelinating disorders. Patients are enrolled into this registry by the members of the US Network of Pediatric Multiple Sclerosis Centers (NPMSC), a consortium of 10 US pediatric multiple sclerosis (MS) centers across the United States (www.usnpmsc.org). 11 Established in 2006, this network is engaged in research to better understand the causes of MS in children and how best to treat them. Data collection includes clinical course, comorbidities, DMT use, and functional status. NPMSC members contribute this information on all patients with POMS and related disorders to a centralized database, the Pediatric Demyelinating Disease Database (PeMSDD), administered by the Data Coordinating and Analysis Center at the University of Utah to facilitate research for these rare disorders. Inclusion criteria include any patient with suspected onset of demyelinating disease of central nervous system prior to age 18. Enrollees to the database are followed up to age 24. Each center has obtained IRB approval locally to participate in this registry. Clinical data have been prospectively collected using standardized case report forms from May 2011.
COVID-19 data collection
In March 2020, in the early stages of the COVID-19 pandemic, all participating centers completed an additional screening questionnaire during standard of care (SOC) visits to further evaluate patient’s COVID-19 status (Supplemental data/Appendix 1). These additional data were collected for all patients in the interval since last SOC visit. Patients with “confirmed” COVID-19 were further assessed for date of infectious symptom onset and method of positive test result; for risk factors including body mass index (BMI) and comorbid disease, tobacco use, and comorbidities; for clinical presentation including symptoms, radiological, and laboratory data; for COVID-19 treatments; and for outcomes (see Supplemental Appendix). Data collection occurred between March 2020 and 15 August 2021, for patients enrolled prior to 1 July 2021.
Patients were considered positive if they reported a positive COVID-19 test, regardless of symptoms. The type of COVID-19 test was not noted. If patients had been tested and were negative, they were categorized as “negative.” Patients with neither symptoms of infection, nor prior testing were categorized as “Never Tested.” Variables collected include disease type (MS, NMO, etc.), age at the time of COVID-19 screening, age of onset, body mass index, sex, race, ethnicity, DMT, MOG/NMO serology (when available).
Among the patients reporting positive COVID-19 infection further analysis was undertaken to describe the clinical course of illness, including whether they were hospitalized, and, if so, whether they required ICU-level care. Symptoms, comorbidities, and treatments received were noted among this population.
Statistical analysis
Data were collected and stored in a centralized database managed by the Data Coordinating Analysis Center (DCAC) at the University of Utah for patients enrolled prior to 1 July 2021, with visits occurring through 15 August 2021.
Demographic features, age at screening, BMI, disease type, DMT, and MOG and AQP-4 antibody statuses were compared between patients with positive, negative, and never tested COVID-19 statuses (see Table 1). Next, demographic features, age at COVID-19 positive, BMI, demyelinating or related disease type, DMT, antibody statuses, and use of oxygen therapy were compared between hospitalized with ICU admission, hospitalized without ICU admission, and not hospitalized COVID-19-positive patients (see Table 2). Continuous variables were summarized using the mean and standard deviation (SD). Comparisons between groups were performed using Fisher’s exact test with Monte Carlo approximation for categorical variables and Kruskal–Wallis for continuous variables.
Table 1.
Demographics of COVID-19 in pediatric MS and related disorders.
| COVID diagnosis group | p-value* | |||
|---|---|---|---|---|
| Positive (N = 73) | Negative (N = 131) | Never tested (N = 465) | ||
| Sex | 0.002 a | |||
| Male | 12 (17%) | 44 (35%) | 156 (34%) | |
| Female | 60 (83%) | 82 (65%) | 298 (66%) | |
| Race | 0.254 b | |||
| White | 50 (81%) | 88 (76%) | 270 (66%) | |
| Black | 9 (15%) | 16 (14%) | 89 (22%) | |
| Asian | 1 (2%) | 4 (3%) | 24 (6%) | |
| Other | 2 (3%) | 8 (7%) | 28 (7%) | |
| Ethnicity | 0.361 a | |||
| Hispanic or Latino | 26 (37%) | 53 (43%) | 117 (28%) | |
| Not Hispanic or Latino | 44 (63%) | 70 (57%) | 296 (72%) | |
| Age at first screening: mean (SD) | 18.4 (3.7) | 15.0 (4.1) | 16.4 (4.7) | <0.001 c |
| Body mass index: mean (SD) | 27.1 (7.8) | 25.7 (7.9) | 25.4 (8.1) | 0.041 c |
| Demyelinating disease | 0.112 b | |||
| ADEM monophasic | 26 (37%) | 53 (43%) | 117 (28%) | |
| ADEM multiphasic | 44 (63%) | 70 (57%) | 296 (72%) | |
| Clinically isolated syndrome | 18.4 (3.7) | 15.0 (4.1) | 16.4 (4.7) | |
| Neuromyelitis optica spectrum disorder | 27.1 (7.8) | 25.7 (7.9) | 25.4 (8.1) | |
| Multiple sclerosis | 26 (37%) | 53 (43%) | 117 (28%) | |
| Radiologically isolated syndrome | 44 (63%) | 70 (57%) | 296 (72%) | |
| Demyelinating disease not otherwise specified | 18.4 (3.7) | 15.0 (4.1) | 16.4 (4.7) | |
| B-cell therapy at time of screening | 0.023 a | |||
| No | 43 (59%) | 98 (75%) | 330 (71%) | |
| Yes | 30 (41%) | 33 (25%) | 135 (29%) | |
| DMT at time of screening | 0.088 b | |||
| Fingolimod | 11 (16%) | 4 (3%) | 30 (7%) | |
| Glatiramer acetate | 2 (3%) | 2 (2%) | 8 (2%) | |
| InterferonB-1a IM | 0 (0%) | 1 (1%) | 1 (0%) | |
| InterferonB-1a SC | 0 (0%) | 0 (0%) | 2 (0%) | |
| Natalizumab | 4 (6%) | 7 (6%) | 25 (6%) | |
| Azathioprine | 0 (0%) | 1 (1%) | 5 (1%) | |
| Methotrexate | 0 (0%) | 1 (1%) | 0 (0%) | |
| Mycophenolate mofetil | 1 (1%) | 8 (6%) | 16 (4%) | |
| Rituximab | 24 (34%) | 26 (21%) | 100 (23%) | |
| Dimethyl fumarate | 1 (1%) | 2 (2%) | 32 (7%) | |
| Intravenous immunoglobulins | 4 (6%) | 4 (3%) | 17 (4%) | |
| Ocrelizumab | 6 (9%) | 7 (6%) | 35 (8%) | |
| Peginterferon beta-1a | 1 (1%) | 0 (0%) | 7 (2%) | |
| Teriflunomide | 0 (0%) | 1 (1%) | 0 (0%) | |
| Tocilizumab | 0 (0%) | 1 (1%) | 3 (1%) | |
| Other | 0 (0%) | 3 (2%) | 7 (2%) | |
| No DMT listed | 16 (23%) | 57 (46%) | 152 (35%) | |
| Ever had an MOG-IgG-positive blood test | 9 (29%) | 32 (33%) | 71 (30%) | 0.827 a |
| Ever had an NMO-IgG-positive blood test | 2 (4%) | 4 (4%) | 28 (9%) | 0.761 b |
ADEM: acute disseminated encephalomyelitis; COVID: coronavirus disease; DMT: disease-modifying therapies; IM: intramuscular; MOG: myelin oligodendrocyte glycoprotein; NMO: neuromyelitis optica; SC: subcutaneous; SD: standard deviation.
Chi-squared test.
Fisher’s exact test (Monte Carlo approximation for tables larger than 2×2).
Kruskal–Wallis test.
Note that p-values were calculated as the difference between the two collapsed groups “positive” versus “negative” and “never tested.”
Table 2.
COVID-19-related hospitalizations in pediatric MS and related disorders.
| Hospitalization/ICU outcome | p-value | |||
|---|---|---|---|---|
| Hospitalized (ICU) (N = 5) | Hospitalized (No ICU) (N = 4) | Not hospitalized (N = 64) | ||
| Race | 1.000 a | |||
| White | 4 (80%) | 4 (100%) | 42 (79%) | |
| Black | 1 (20%) | 0 (0%) | 8 (15%) | |
| Asian | 0 (0%) | 0 (0%) | 1 (2%) | |
| Other | 0 (0%) | 0 (0%) | 2 (4%) | |
| Age at COVID positive: mean (SD) | 20.0 (2.9) | 20.8 (3.1) | 18.3 (3.8) | 0.292 b |
| Body mass index: mean (SD) | 34.8 (3.2) | 25.7 (5.4) | 26.7 (7.9) | 0.040 b |
| Demyelinating disease | 0.350 a | |||
| ADEM monophasic | 0 (0%) | 0 (0%) | 1 (2%) | |
| Clinically isolated syndrome | 0 (0%) | 0 (0%) | 5 (8%) | |
| Neuromyelitis optica spectrum disorder | 2 (40%) | 0 (0%) | 3 (5%) | |
| Multiple sclerosis | 3 (60%) | 4 (100%) | 45 (71%) | |
| Demyelinating disease not otherwise specified | 0 (0%) | 0 (0%) | 9 (14%) | |
| DMT at time of screening | 0.173 a | |||
| Fingolimod | 0 (0%) | 0 (0%) | 11 (18%) | |
| Glatiramer acetate | 0 (0%) | 0 (0%) | 2 (3%) | |
| Natalizumab | 0 (0%) | 0 (0%) | 4 (7%) | |
| Mycophenolate mofetil | 0 (0%) | 0 (0%) | 1 (2%) | |
| Rituximab | 5 (100%) | 2 (50%) | 17 (28%) | |
| Dimethyl fumarate | 0 (0%) | 1 (25%) | 0 (0%) | |
| Intravenous immunoglobulins | 0 (0%) | 0 (0%) | 4 (7%) | |
| Ocrelizumab | 0 (0%) | 1 (25%) | 5 (8%) | |
| Peginterferon beta-1a | 0 (0%) | 0 (0%) | 1 (2%) | |
| No DMT listed | 0 (0%) | 0 (0%) | 16 (26%) | |
| Ever had an MOG-IgG-positive blood test | 0 (0%) | 0 (0%) | 9 (31%) | 1.000 a |
| Ever had an NMO-IgG-positive blood test | 1 (25%) | 0 (0%) | 1 (3%) | 0.213 a |
| Oxygen therapy | 5 (100%) | 1 (25%) | 0 (0%) | <0.001 a |
ADEM: acute disseminated encephalomyelitis; COVID: coronavirus disease; DMT: disease-modifying therapies; ICU: intensive care unit; MOG: myelin oligodendrocyte glycoprotein; NMO: neuromyelitis optica; SD: standard deviation.
Fisher’s exact test (Monte Carlo approximation for tables larger than 2×2).
Kruskal–Wallis test.
Comorbidities and COVID-19 symptoms were noted for the COVID-19-positive cases by counts and percentages.
The disability level was measured with Expanded Disability Severity Score (EDSS) at each SOC visit for all patients.
Two logistic regression models were used to estimate the relationship between B-cell therapy and COVID-19. The first model estimates the odds of testing positive given B-cell therapy use. The second model estimates the odds of being hospitalized after testing positive given B-cell therapy use (see Table 3).
Table 3.
B-cell-depleting therapy use by COVID-19 status and hospitalization.
| B-cell therapy | COVID Status | Hospitalization | ||||
|---|---|---|---|---|---|---|
| Positive | Negative or never tested | Total | No | Yes | Total | |
| No | 43 | 428 | 471 | 42 | 1 | 43 |
| Yes | 30 | 168 | 198 | 22 | 8 | 30 |
| Total | 73 | 596 | 669 | 64 | 9 | 73 |
COVID: coronavirus disease.
B-cell therapy at time of screening had 1.78 (1.08, 2.93) times the odds of being positive versus negative or never tested, p-value = 0.024.
B-cell therapy at time of screening had 15.27 (1.79, 129.96) times the odds of being hospitalized versus not hospitalized, p-value = 0.016.
p-values of less than 0.05 were considered statistically significant. Odds ratios were calculated with 95% confidence intervals. Analyses were conducted using SAS 9.4 (SAS Institute, Inc., Cary, NC).
Results
COVID-19-positive cases
Demographic data are summarized in Table 1. Of 669 surveyed patients, 440 were female (67.5%). The mean age of all surveyed patients was 16.4 years (Table 2). In this group, there were 73 confirmed COVID-19 patients. COVID-19-positive patients were older than POMS and related disorders patients (mean 18.4 years, range 8.3–25.4 years, p-value < 0.001) who were negative or never tested (15.0 and 16.4 years, respectively). 82.3% (60/72) of the COVID-19-positive patients were female versus 65.5% (380/580) of the negative and never tested patients. This is statistically significant (p-value 0.002). Among the COVID-19-positive patients, 80.7% were white, compared to 67.9% of the negative and never tested patients (p-value 0.254).
Among the COVID-19-positive patients, a greater percentage of patients had a diagnosis of POMS (71.2% (n = 52)) compared with the negative and never tested patients (51.9% (n = 309), p-value 0.002). Positive MOG-IgG antibodies were present in nine COVID-19-positive patients and NMO-IgG was positive in 2 COVID-19-positive patients.
There were 16 positive patients for whom DMT data were unavailable. None of the 16 COVID-19-positive patients without DMT data were hospitalized.
A greater percentage of COVID-19-positive patients were on B-cell-depleting therapy (either rituximab or ocrelizumab) than the remainder of the cohort (41.1% vs 28.2% respectively, p-value 0.023).
Among the COVID-19-positive patients, chronic lung disease (1), diabetes (3), hypertension (1), immunodeficiency disease (1), morbid obesity (2), and other (8) comorbidities were noted.
The COVID-19-positive patients had an overall lower disability level than the negative or never-tested group. An EDSS score of 3 (moderate disability) and higher was present in four of 66 positive patients (6%) and 71 of 574 negative or never tested patients (12.4%). A score above 6 (assistance required to walk and work) was present in one of 66 COVID-19-positive patients (1.5%) and 16 of 574 negative or never-tested patients (2.8%).
Hospitalized or ICU cases
Nine of the COVID-19-positive patients were hospitalized. Of the hospitalized patients, eight of nine (89%) were treated with B-cell-depleting therapy, and one patient was treated with dimethyl fumarate. Of those on B-cell therapy who were COVID-19-positive, 27% (8/30) required hospitalization and 17.2% (5/29) required ICU-level care (see Table 3).
Five of the nine hospitalized patients required ICU-level care. All five patients in the ICU (100%) were on B-cell-depleting therapy. Three of these ICU patients were diagnosed with MS, while the other two were diagnosed with NMOSD (one NMO-IgG-positive, one seronegative). All the ICU patients required oxygen therapy. All nine patients survived their ICU and hospital course. Limited data were available for one of the subjects who received care out of the NPMSC network. The duration of the B-cell-depleting therapy for COVID-19-positive, hospitalized patients was a mean of 3.43 years (median 3.00 years, range 0.07–9.31 years). For COVID-19-positive, nonhospitalized patients, the duration of B-cell-depleting therapy was a mean 2.51 years (median 1.77 years, range 0.04–8.02 years).
BMI was above 32 (i.e. in the obese range) in all four of the ICU cases with available BMI data. Obesity is a known risk factor for severe COVID-19 in both adults and children.10,12 Pediatric patients in our study with confirmed COVID-19 had higher mean BMIs when compared to the negative and never tested groups (p = 0.041).
A logistic regression analysis of all patients in the cohort showed that those on B-cell therapy at the time of screening had 1.78 times the odds of being positive compared to those not on B-cell therapy (95% confidence interval 1.08, 2.93, p = 0.024). A logistic regression analysis showed that, among those on B-cell-depleting therapy who tested positive for COVID-19, the unadjusted odds ratio of hospitalization was 15.27 (95% confidence interval 1.79, 129.96, p = 0.016).
Discussion
Our study finds that of the pediatric patients hospitalized with COVID-19, 8/9 were on B-cell-depleting therapy and the overall percentage of COVID-19-positive patients on B-cell-depleting therapy was higher than in the overall cohort.
Several prior studies have evaluated COVID-19 outcomes in adult patients with multiple sclerosis. One recent study found risk factors for COVID-19 in MS were younger patients, COVID-19 contacts, work on site, lower education, and lower SES. 13 In the COVIsep registry, 7 a multicenter, registry-based, retrospective, observational cohort study, adult patients with MS were followed between March and May 2020, and of 347 patients included, 73 (21%) were hospitalized and 12 (3.5%) died of COVID-19. Another study 14 suggested hypothetical risks of COVID-19 associated with different DMTs based on mechanisms of action and typical lab abnormalities associated. Intermediate- or high-risk patients were those considered on fingolimod, anti-CD20 therapies, cladribine, and alemtuzumab. None of our patients were on the latter two treatment options. The patients with moderate- or high-risk DMT groups had a higher COVID-19 severity than those in the low-risk or no-risk groups. In terms of the sickest patients, 12 died, with most of those having progressive MS and high EDSS. Four patients were admitted to the ICU; two were on ocrelizumab and had obesity as a comorbidity including one relatively young patient; one was on rituximab; and one was not on DMT. On multivariate analysis, only higher baseline EDSS, age, and obesity were independently associated with higher COVID-19 severity (hospitalization or higher severity).
An observational study of 67 adult and 9 pediatric patients with MS and related disorders who had confirmed or highly suspected COVID-19, showed that those who were critically ill (8) or died (18) were age 42 or older (two in their 40s, one age 50, four in their 60s and one in their 70s). Those who were hospitalized were more likely to be older, have comorbidities, have progressive disease, and be non-ambulatory. Of note, the authors did not find an association between type of DMT and risk of hospitalization. This was echoed in the recent Spanish article 15 showing no association between immunosuppression and COVID-19 disease incidence. Notably, this study was smaller, included patients with other neuroimmunologic diseases and had a minority of patients on B-cell-depleting therapy. There remains a lack of evidence regarding how COVID-19 affects patients with POMS including the factors that might be associated with severe infection with COVID-19.
In our study, the majority of those who required hospitalization were on B-cell-depleting therapy, and all of those who required ICU admission (three with MS, two with NMOSD) were on B-cell-depleting therapy. B-cell-depleting therapy was the most notable commonality in those patients who were hospitalized (8/9) and requiring ICU admission (5/5), suggesting that B-cell-depleting therapy may carry a higher risk of hospitalization. Several studies have reported B-cell-depleting therapies as a risk factor for severe COVID-19 disease in adult patients, and our study demonstrates that this treatment class is a risk factor in this pediatric population as well.16,17
To show that severity of COVID-19 illness and hospitalization was not a result of steroid use, we analyzed the time from most recent steroid use to the onset of COVID-19 symptoms. When the cohort was evaluated for time from the most recent steroid treatment to the time of COVID-19 onset, the mean was 2.88 years with a range of 0.01 to 7.32 years, standard deviation 1.91 years. One patient received steroids shortly after the onset of COVID-19 symptoms. We also evaluated the time from the most recent relapse to the onset of COVID-19 symptoms. There was a mean of 3.54 years since last relapse, with a range of 0–9.68 years, standard deviation of 2.37 years. Neither recent steroid use nor recent neurologic relapse was felt to significantly contribute to our findings.
The patients in the ICU for whom we have BMI data were obese. We have previously shown that obesity is overrepresented in patients with POMS. 18 While obesity may have played a role in admission to the ICU, larger studies are required to evaluate its role as an independent risk factor in children on immunotherapies.
As of 26 August 2021 (coincident with our database lock for this study) as reported by the American Academy of Pediatrics, there were 4.8 million cases of COVID-19 in children in the United States. 19 Overall, children represented 14.8% of total COVID-19 cases. 20 However, children have disproportionately fewer hospitalizations, representing only 1.6%–3.6% of total hospitalizations. Notably, for the states for which we have data on hospitalization rates, only 0.1%–1.9% of all children with confirmed COVID-19 required hospitalization.
In contrast, ours is a relatively small sample size (669 total patients, 73 (11%) had confirmed COVID-19. Nine (12%) of our patients with confirmed COVID-19) required hospitalization. There may be confounding factors such as the relatively older age of our patients and the risk-taking behaviors of this population, compared to pediatric patients with COVID-19. Overall, this suggests that patients with POMS and related disorders may be a unique population who are more likely to have a severe illness requiring hospitalization compared to the general pediatric population. 21 Immunosuppression with B-cell-depleting therapy may be one factor that puts some of these patients at higher risk.
Strengths of our study are the inclusion of a wide range of geographically located centers in the United States and the use of a pre-existing registry focused on pediatric MS and related disorders allowing for a large sample size of these patients with rare disorders from which to screen, and detailed demographic and clinical data records.
Limitations of our study include the following:
Relatively small sample size of COVID-19-positive patients and a low number of hospitalized patients limiting further statistical analysis.
Potential reporting bias. Although most patients with MS continue follow-up care through the dedicated MS centers, some may have underreported milder courses, have gone undetected, or have been lost to follow up. There are other possible factors that may have influenced COVID-19 risk. For example, it is possible that a disproportionate number of our patients reside in urban areas with increased transmission rates.
Both our patient data and the pediatric data we have for comparison to the larger US population are pre both Delta and Omicron variants. Because our data are from pre-Omicron and Delta, we used the AAP data we had from before these variants as the virulence, transmission rates, demographics of those infected and hospitalized, and other factors were likely different for these variants, particularly Omicron.
In terms of severity of illness, hospitalization, and the role of vaccination, a large percentage of our data was accumulated after COVID-19 vaccination was available for individuals 16 and over (original EUA for Pfizer-BioNTech vaccine for those 16 and over; 11 December 2020; EUA for Moderna vaccine for those 18 and over; 18 December 2020; and EUA for Jansen vaccine for those 18 and over; 27 February 2021). Most of the study period was before EUA for the Pfizer-BioNTech vaccine was expanded to include those 12 and older (10 May 2021), and the entirety of the study was before EUA for Pfizer-BioNTech was expanded to those ages 5–11 (29 October 2021). We do not have data on the vaccination status of our cohort. Future directions include evaluating potential associations between COVID-19 and disease relapses, lymphocyte counts on disease-modifying treatments and disability scores in POMS and related disorders, and the role of vaccinations in transmission and illness severity, including hospitalization, in this population.
Conclusion
B-cell depletion is a highly effective DMT for pediatric MS and some related disorders but carries an increased risk of infection. Our study suggests that COVID-19 infection carries an increased risk of hospitalization among pediatric patients treated with these drugs. As the potential benefit of these DMTs is weighed against the risks, risk of hospitalization with COVID-19 should be included. 22 Our results suggest that the patients treated with these immunomodulatory therapies should maintain a higher degree of vigilance with respect to social distancing and mask-wearing. Further studies are needed to evaluate the efficacy of SARS-CoV2 vaccinations23,24 in the pediatric MS and related disorders population, as well as strategies to introduce early and effective COVID-19 monoclonal antibodies and antiviral therapies to infected pediatric patients.
Supplemental Material
Supplemental material, sj-docx-1-msj-10.1177_13524585231151948 for Characteristics of pediatric patients with multiple sclerosis and related disorders infected with SARS-CoV-2 by Teri Schreiner, Molly Wilson-Murphy, Jan Mendelt-Tillema, Michael Waltz, Rachel Codden, Leslie Benson, Mark Gorman, Manu Goyal, Lauren Krupp, Tim Lotze, Soe Mar, Jayne Ness, Mary Rensel, Shelly Roalstad, Moses Rodriguez, John Rose, Nikita Shukla, Emmanuelle Waubant, Yolanda Wheeler, T Charles Casper and Tanuja Chitnis in Multiple Sclerosis Journal
Footnotes
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.B. received funding from NIH, Harvard Medical School Shore grant, ROHHAD Fight, Inc. She received honoraria from Novartis. She participated in clinical trials with Biogen, Alexion, and Genentech/Roche. She is a consultant to the National Vaccine Injury Compensation Program and the Massachusetts Department of Public Health. T.C.C. receives research funding from Hoffman-La Roche, Ltd. T.C. has served as a consultant for Biogen, Novartis, Genentech-Roche, and Tiziana Life Sciences; clinical trial advisory boards and/or clinical trial participation: Novartis, Sanofi, and Genentech-Roche; received research support from Bristol Myers Squibb, Octave Bioscience, Novartis, Sanofi, and Tiziana Life Sciences. M.G. received research funding from Pfizer and Roche. L.K., over the last 3 years, has received research or programmatic funding, or has received compensation for consulting, speaking, travel and meal allowances, or serving on dSMB committees from Biogen, Novartis, Eisai, Roche, Gerson Lehrman, Janssen, Medscape, NeuroLive, Peer View, WebMD, Bristol Myers Squibb, CME Outfitters, General Dynamics Information, At the Limits, Cambridge Medical Technologies, and Medergy Marketing. She is also a non-compensated consultant and/or advisory board member with Novartis and Celgene. L.K. receives royalties for use of the Fatigue Severity Scale by various biopharmaceutical entities. M.R. disclosures include the following: Advisory Board or panel: Serono, Biogen, Horizon, TG, Novartis; Board Member: Chagrin Falls Educational Foundation, Ohio NMSS, IConquer MS; Consultant: Biogen, Genentech, Improve Consulting, Kijia, Novartis, BMS; Grants/Research support: she has received commercial research support from Medimmune, Novartis, Biogen (MS Paths), Roche-Genentech, and CBF Foundation. She has received foundation/society research support from the National Multiple Sclerosis Society. She has received educational grants from Genzyme and CBJ Foundation. Speaker’s Bureau: Genzyme, Biogen, and Multiple Sclerosis Association of America; IDMC member: Biogen; Owner: Brain Fresh (Professional development educational support) and Brain Ops Group (Joint Venture with Healthy Hostess DBA Kijia for Professional development through brain-based tools). J.R. received research funding from NMSS, GJCF, NIH, Biogen, and VA. T.S. participates in research funded by Roche and National MS Society. She is on the Data Safety Monitoring board for Biogen studies of pediatric MS. She has received speakers’ fees from Roche and Cycle Pharmaceuticals. E.W. has participated in multicenter clinical trials funded by Genentech, Alexion, and Biogen. She has current support from the NIH, NMSS, PCORI, CMSC, and Race to Erase MS. She has received honoraria for a talk for CMSC and for consulting for Emerald Pharmaceuticals. R.C., S.M., N.S., M.R., J.-M.T., M.W., M.W.-M., and Y.W. declare no conflicts of interest.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Network of Pediatric Multiple Sclerosis Centers (www.usnpmsc.org) is funded by a grant from the National MS Society who had no role in the data collection, analysis, or drafting of this manuscript.
ORCID iDs: Teri Schreiner 
https://orcid.org/0000-0002-3816-812X
Lauren Krupp https://orcid.org/0000-0001-7003-807X
Mary Rensel https://orcid.org/0000-0001-9613-8394
Tanuja Chitnis https://orcid.org/0000-0002-9897-4422
Supplemental material: Supplemental material for this article is available online.
Contributor Information
Teri Schreiner, Department of Pediatrics and Neurology, Children’s Hospital of Colorado, University of Colorado, Aurora, CO, USA.
Molly Wilson-Murphy, Boston Children’s Pediatric MS Center, Boston, MA, USA.
Jan Mendelt-Tillema, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Michael Waltz, University of Utah, Salt Lake City, UT, USA.
Rachel Codden, George E. Wahlen Department of Veterans Affairs Medical Center, University of Utah, Salt Lake City, UT, USA.
Leslie Benson, Boston Children’s Pediatric MS Center, Boston, MA, USA.
Mark Gorman, Boston Children’s Pediatric MS Center, Boston, MA, USA.
Manu Goyal, Washington University, St. Louis, MO, USA.
Lauren Krupp, NYU Langone, New York, NY, USA.
Tim Lotze, Baylor College of Medicine, Houston, TX, USA.
Soe Mar, Washington University, St. Louis, MO, USA.
Jayne Ness, University of Alabama at Birmingham, Birmingham, AL, USA.
Mary Rensel, Cleveland Clinic, Cleveland, OH, USA.
Shelly Roalstad, University of Utah, Salt Lake City, UT, USA.
Moses Rodriguez, Department of Neurology, Mayo Clinic, Rochester, MN, USA.
John Rose, George E. Wahlen Department of Veterans Affairs Medical Center, University of Utah, Salt Lake City, UT, USA.
Nikita Shukla, Baylor College of Medicine, Houston, TX, USA.
Emmanuelle Waubant, UCSF, San Francisco, CA, USA.
Yolanda Wheeler, University of Alabama at Birmingham, Birmingham, AL, USA.
T Charles Casper, University of Utah, Salt Lake City, UT, USA.
Tanuja Chitnis, Brigham and Women’s Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Associated Data
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Supplementary Materials
Supplemental material, sj-docx-1-msj-10.1177_13524585231151948 for Characteristics of pediatric patients with multiple sclerosis and related disorders infected with SARS-CoV-2 by Teri Schreiner, Molly Wilson-Murphy, Jan Mendelt-Tillema, Michael Waltz, Rachel Codden, Leslie Benson, Mark Gorman, Manu Goyal, Lauren Krupp, Tim Lotze, Soe Mar, Jayne Ness, Mary Rensel, Shelly Roalstad, Moses Rodriguez, John Rose, Nikita Shukla, Emmanuelle Waubant, Yolanda Wheeler, T Charles Casper and Tanuja Chitnis in Multiple Sclerosis Journal