The impact of air pollution on COVID-19 severity among infected individuals in a population of italian MS patients

Introduction: Studies have found associations between air pollution and pneumonia and air pollution is an established risk factors for common COVID-19 complications including pneumonia. Additionally, air pollutants have been identified as possible risk factors for MS onset and relapses. To our knowledge, only one study explored the impact of air pollution on Covid-19 severity specifically among MS patients but has only focused on PM2.5 exposures. Aim(s): We aim to evaluate the association between long-term exposure to air pollution and COVID-19 severity, described as developing pneumonia in a population of COVID-19-positive MS patients. Method(s): Data on COVID-19 infection among MS patients were extracted from an Italian web-based platform (Musc-19). A casecontrol study was designed including patients with and without pneumonia at a case-control ratio of 1:2 and 615 patients were included. The included patients were asked to provide information on the geographical area where they had spent most time in the previous 5 years. When this information was missing, the address of the MS center was used as a proxy and evaluated in sensitivity analysis. Air quality was assessed as annual average particulate matter (PM2.5 and PM10) and Nitrogen Dioxide (NO2) ground-level concentrations derived from air quality model results as provided by the 'Copernicus Atmospheric Monitoring Service', and evaluated as categorical exposures (terciles). The association between pollutants and COVID-19 pneumonia was studied using logistic regression models, also adjusting for confounders (age, sex, BMI, comorbidities, EDSS, MS type, duration and treatments). Result(s): Detailed exposure was obtained for 491 patients, of whom 34% had pneumonia. Higher concentrations of air pollutants were associated with increased odds of developing COVID-19 pneumonia in both unadjusted and adjusted models (Adjusted models estimates: PM2.5: 2nd vs 1st tercile OR(95% CI)=2.09 (1.20;3.65), 3rd vs 1st tercile OR(95% CI)=2.26(1.29;3.96);PM10: 2nd vs 1st tercile OR(95% CI)=1.83(1.05;3.20), 3rd vs 1st tercile OR(95% CI)=2.12(1.22;3.68);NO2: 3rd vs 1st tercile OR(95% CI)=2.12(1.21;3.69)). Results remained consistent in the sensitivity analysis. Conclusion(s): Higher long-term concentrations of PM2.5, PM10 and NO2 were associated with COVID-19 pneumonia among MS patients. Urgent measures to reduce air pollution should be adopted especially to protect the most vulnerable population.

Risk of inflammatory reactivation following SARS-CoV-2 vaccine in a large cohort of Multiple Sclerosis patients

Background: Whether vaccines play a role triggering or reactivating inflammation in Multiple Sclerosis (MS) has been long debated. There are few reports suggesting that Sars-Cov2 vaccines, as well as COVID-19 infection, may exacerbate relapses in MS. Studies on large cohorts are needed to establish the safety of Sars-Cov2 vaccines in the MS population. Aim(s): To assess the risk of clinical and radiological reactivation following Sars-Cov2 vaccines in patients with MS. Method(s): Patients with MS with known date of SarsCov2 vaccination were identified among those followed up at the Multiple Sclerosis Center of the Tor Vergata University Hospital. Data on clinical relapses and radiological activity (Gadolinium enhancing and new T2 lesions) in the 12 months before and after vaccination were extracted from clinical charts. Result(s): We enrolled 751 patients (64,7% female, mean age 45.9 +/- 11.63 years, 89.9% relapsing-remitting, 5.5% secondary progressive and 4.7% primary progressive, disease duration 11.2 +/- 8.11 years, median EDSS 2.0 [1.0 - 4.0], 12.1% untreated, 41.1% treated with first line immunomodulators and 46.7% with second line high efficacy treatments). Among them, 96.7% received mRNABNT162b2 (Pfizer), 2% mRNA-1273 (Moderna) and 1.3% other COVID-19 vaccines. In the whole cohort we did not find a significant increase of the rate of patients with relapse in the 12 months after vaccines (2.3%) compared to the 12 months before (2,9%, McNemar test, p=0.5), as well as of the rate of patients with radiological activity (both 11.5%, McNemar test, p=0.13). Similar findings were obtained separately analysing untreated patients, patients treated with first line and treated with second line drugs at the time of vaccination. Conclusion(s): Our preliminary results in a large monocentric cohort of MS patients suggest that vaccination with Sars-Cov2 vaccines does not induce disease reactivation. Further analyses are needed to confirm these findings.

Third dose of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies

Introduction: In patients with Multiple Sclerosis (pwMS) treated with anti-CD20 treatment or fingolimod it was observed a reduced humoral response after the second dose of mRNA-based SARS-CoV-2 vaccines.It is important to evaluate the effect of the third dose in these groups of patients. Aim(s): To describe the demographical and clinical characteristics of pwMS which received the third dose of Covid-19 vaccine and compare within patients the antibody levels measured just before the third dose with the same assessment executed one month after the third dose. Method(s): The CovaXiMS study is a prospective study for the evaluation of immunogenicity of anti-SARS-CoV2 vaccines in pwMS. Adult pwMS who have performed a third dose of SARSCoVv- 2 vaccination were included in the study. The main endpoint is the change in the antibody levels from six months after the second dose vs one month following the third dose, by considering actual DMTs. Result(s): Out of 1881 enrolled pwMS, 318 (16.9%) received the third dose (83.6% mRNA BNT162b2 and 16.4%mRNA-1273) with a complete assessment of antibody levels before and after the injection. Of them, 236 (74.2%) were females, with a mean age of 48.1 (SD:12.43). Median EDSS was 2.0 [IQR: 1.0-3.5], 8 (2.5%) pwMS recorded at least one relapse in the three months before enrollment, 271 (85.2%) were RRMS, 27 (8.5%) SPMS, and 20 (6.3%) PPMS. Fifty-six (17.6%) pwMS were on fingolimond, 52 (16.4%) on anti-CD20, and 210 (66.0%) on other drugs. Median antibody level (BAU/ml) measured just before the third dose was: 0.0 for pwMS treated with anti-CD20, 35.7 for pwMS on fingolimod and 680.9 for pwMS with other therapies. One month after the third dose the median change in the antidoby levels (BAU/ml) was: +0.6 for pwMS on anti-CD20, +694.6 for pwMS on fingolimod and +13879.4 BAU/ml for pwMS on other DMTs (p<0.001). Considering 659 BAU/mL as the best cut-off indicating a protective antibody level, as suggested by previous literature, 98% of pwMS on other DMTs showed a value above this value, 55% of pwMS on fingolimod, and 23% of pwMS on anti-CD20 (p<0.001). Conclusion(s): After the third dose, a significant increase in antidoby levels was detected in patients with MS. Patients in fingolimod and anti-CD20 had an increase significantly lower than patients in other drugs, but 55% of patients on fingolimod reached an antibody level considered as protective.

Impact of COVID-19 on pregnancy and fetal outcomes in women with multiple sclerosis

Introduction: In the general population, maternal SARS-CoV-2 infection during pregnancy is associated with an increased risk of several adverse maternal and fetal outcomes. In patients with Multiple Sclerosis (PwMS) an increased risk of severe COVID- 19 was reported after treatment with antiCD20 or corticosteroid close to COVID-19 onset. However, no data are currently available about maternal and fetal outcomes in pregnant women with MS who contracted COVID-19 during gestation. Objective(s): To evaluate maternal and fetal outcomes and their predictors in a population of pregnant women with MS with COVID-19 diagnosis selected from two large national registries and compared with matched control pregnancies extracted from a historical Italian MS cohort. Method(s): We recruited pregnant pwMS who contracted SARSCoV- 2 infection after conception and were prospectively followed- up in Italian and Turkish MS Centres, in the period 2020-2022. All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders, including disease modifying treatments. A historical matched control group was extracted from a previous Italian multicenter cohort. Data on pregnancy outcomes were compared using logistic and linear multivariable regression analyses, when appropriate. Result(s): So far clinical characteristics and data on COVID-19 outcomes are available for 85 pregnant MS women (mean age 35.2+/-6.4 years, 83 relapsing remitting (RR), mean disease duration 8.3+/-6.86 years, median Expanded Disability Status Scale (EDSS) 1.0 (IQR 1.0-2.5), body mass index 24.5+5.8, current smokers 10.6%, occasional or regular alcohol consumption 28.3%). As for COVID-19 course, 8 women (9.4%) were hospitalized;no one required transfer to intensive care. The historical control group consists of 232 women with RRMS (mean age 34.6+/-3.1 years, mean disease duration 8.8+/-4.8 years, median EDSS 1.5 (IQR 1.0-2.0). The collection of information on maternal and fetal outcomes is ongoing: eclampsia, maternal mortality and admission to intensive care unit, spontaneous abortion, stillbirths, congenital abnormalities, preterm delivery, child weight and length at birth, admission to neonatal intensive care unit. Conclusion(s): Our preliminary data show no increased risk of severe COVID-19 in MS patients who contracted the infection during pregnancy. The analysis on pregnancy-related maternal and fetal outcomes is ongoing.

IMPACT of COVID-19 TREATMENTS on PERIPHERAL CAPILLARY DENSITY EVALUATED by NAILFOLD VIDEOCAPILLAROSCOPY

Background: Human SARS-CoV-2 infection can induce a wide spectrum of organ dysfunctions, including microvascular impairment [1]. S1 subunit of viral receptor-binding domain binds to the angiotensin-converting enzyme 2 receptor on endothelium and S2 subunit allows the virus to enter endothelial cells. The resulting breakdown of barrier integrity drives a cascade of infammatory and thrombotic events, that aggravate the course of COVID-19 together with other risk factors [2-4]. Up to date, a lower capillary density has been reported in several distinct body districts, using sublingual video microscopy, ocular optical coherence tomography angiography, skin functional laser Doppler perfusion imaging and nailfold videocapillaroscopy (NVC) [5-8]. NVC examination has been performed in adult COVID-19 patients, however, without a control group [8]. Objectives: To confrm the statistical signifcance of the reduction in capillary density per linear millimeter evaluated by NVC in comparison with primary Ray-naud's phenomenon (PRP) patients and control subjects (CNT) and to evaluate the impact of an aggressive therapy against COVID-19 on the sparing in the number of capillaries. Methods: Sixty-one COVID-19 survivors, thirty-one PRP patients and thirty CNT age and sex-matched underwent NVC analysis. Demographic and clinical data of COVID-19 survivors were collected with special regard to concomitant therapies, that included antivirals, antibiotics, anticoagulants and anti-infamma-tory/immunomodulant drugs (glucocorticoids, hydroxychloroquine, IL-6 receptor antagonist). COVID-19 survivors were divided in two subgroups according to the severity of the active infection: thirty-four survivors with past mild-moderate disease (either unneedy for oxygen supplementation or need for Venturi mask) and twenty-seven survivors with past severe disease (need for Continuous Positive Airways Pressure and/or mechanical ventilation). The same Rheumatologist performed NVC evaluations in all patients and controls, using an optical probe, equipped with a 200x magnifcation lens and connected to a picture analysis software (Videocap, DS Medica, Milan, Italy). Absolute capillary number per linear millimeter was counted. Results: COVID-19 survivors underwent NVC examination after a mean period of 126±53 days from the disease onset. Multivariate analysis showed differences in absolute capillary number per linear millimeter (p<0.001) after adjusting for age, sex, body mass index, comorbidities and concomitant drugs. The mean (± standard deviation) absolute nailfold capillary number per linear millimeter was signifcantly lower in severe (8.2±1.15) and mild-moderate (8.4±0.75) COVID-19 survivors than in both PRP (8.7±0.68) and CNT subjects (9.3±0.53) (p<0.001). The analysis of the impact of treatments on capillary density in the severe COVID-19 patients showed a positive trend (preservation of the capillary number) with antivirals (no: 7.8±1.53;yes: 8.5±0.64;p=0.35) and anti-IL-6 receptor antagonist administration (no: 7.8±1.36;yes: 8.6±0.74;p=0.16), while none of the other drugs was shown to be effective (glucocorticoids p = 0.46;antibiotics = 0.52;anticoagulants not evaluable as they were used in all COVID-19 patients). Conclusion: SARS-CoV-2 infection seems associated to a signifcant capillary loss as distinctive NVC feature and data concerning the comparison of capillary density pre COVID-19 and post COVID-19 are desirable to reinforce this observation. The positive trend in saving the number of capillaries induced by aggressive anti-infammatory therapies in COVID-19 survivors needs larger cohorts of patients.

Effect of SARS-CoV-2 mRNA vaccination in multiple sclerosis patients treated with disease modifying therapies

Introduction: In patients with Multiple Sclerosis (pwMS) disease- modifying therapies (DMTs) are known to affect immune response to antigens and possibly to SARS-CoV2 vaccine. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. Objectives and aims: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARSCov- 2 vaccination with mRNA vaccines (BNT162b2, Pfizer/ BioNTech, Inc or mRNA-1273, Moderna Tx, Inc) to evaluate their effect on SARS-CoV-2 antibody response. Methods: A blood collection for the measure of SARS-CoV-2 antibody before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized and blinded serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche Diagnostics). Results: Preliminary data were collected on 780 pwMS (76% BNT162b2 and 24% mRNA-1273) who had pre- and 4-week post-vaccination blood assessments. 87 (11.2%) were untreated, 154 (19.7%) on ocrelizumab, 25 (3.2%) on rituximab, 85 (10.9%) on fingolimod, 25 (3.2%) on cladribine and 404 (51.7%) on other DMTs. 677 patients (86.8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariate analysis, the antibody levels of patients on ocrelizumab (178-fold decrease, p<0.001), fingolimod (26-fold decrease, p<0.001) and rituximab (17-fold decrease, p<0.001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3.5-fold higher antibody level than with the BNT162b2 vaccine (p<0.001). Interpretation: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3.5-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those that will be produced by studying the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. At the time of the ECTRIMS presentation data on the full sample (about 2000 subjects) will be presented.

An analysis of main symptoms of COVID-19 in MS patients and related risk factors

Introduction: MS patients affected by SARS-CoV-2 disease may present with a wide pattern of symptoms, not always suggestive of the severity of infection. A recent study has shown that main symptoms of Covid-19 can be grouped in seven different clusters. Risk and protective factors for their occurrence in MS patients has never been investigated. Objectives: To identify the most common symptoms of Covid-19 that are part of specific clusters in MS patients and evaluate all factors associated with their manifestation. Methods: As part of the MuSC-19 Italian project, all data were extracted from a dedicated web-based platform that allows researchers to evaluate the impact of Covid-19 on people affected by MS. After having tested the degree of agreement between different types of symptoms (Cohen's k), univariate and multivariate logistic regression models were applied to identify predicting factors for each group. Results: 1554 MS patients with confirmed Covid-19 and presenting at least one symptom referred to a specific cluster were analyzed. Patients presented nearly three groups of symptoms (mean: 2.8). The most common include fever/chills/rigor/fatigue/ cough (87%), followed by ageusia/anosmia (46%). Smoking habit was the most confirmed risk factor for developing a wide range of symptoms: common cold-like symptoms (OR:1.6, 95%CI:1.3- 2.1;p<0.001), joint and muscle pain (OR:1.3, 95%CI:1.1-1.7;p=0.037), gastrointestinal problems (OR:1.3, 95%CI: 1.1-1.7;p = 0.029), and loss of smell/taste (OR:1.4, 95%CI: 1.07-1.72;p=0.013). Smoking was confirmed also as risk factor for increasing the number of symptoms (OR:1.5, 95%CI:1.2-1.8;p<0.001), together with alcohol use (OR:1.25, 95%CI:1.1-1.5;p=0.021) and with assumption of anti-CD20 therapies (OR:1.7, 95%CI:1.2-2.5;p=0.004). Males have a lower risk for developing a major number of symptoms (OR:0.8, 95%CI:0.6 - 0.9;p=0.006). Finally, a lower EDSS was associated to a slight increment of symptoms, probably due to an already underlying presence of some common symptoms in most critical MS patients, which consequently were not reported (OR:0.9, 95%CI:0.8-0.9;p=0.005). Conclusions: Knowing possible risk factors and modifying some lifestyle behaviors might minimize the occurrence of Covid-19 symptoms. Anyway, further studies are needed for confirming these findings, and an additional follow up study on the presence of persistent symptoms after apparent Covid-19 resolution may help to better understand all possible risk factors.

The impact of PM2.5 on COVID-19 severity among Italian MS patients

Introduction: Studies have pointed out that air pollution longterm exposure may play a role in the severity and prognosis of SARS-CoV-2 infections. Additionally, air pollution has been associated to MS prevalence and course. However, the role of air pollution in COVID-19 severity has never been explored specifically among MS patients. Aims: To explore the association between air pollution assessed by PM2.5 levels and COVID-19 severity among MS patients. Methods: Demographic and clinical characteristics as well as data about Covid-19 severity were extracted from an Italian webbased platform (Musc-19 project) containing clinician-reported data from 118 Italian MS centers. PM2.5 ground-level concentrations were derived from air quality model results, as provided by the 'Copernicus Atmospheric Monitoring Service' (CAMS). Ordered logistic regression models were used to assess the association between PM2.5 (continuous and in tertiles) and Covid-19 prognosis (defined on three levels as mild course, hospitalization, and intensive care unit (ICU) admission or death) while controlling for possible confounders. Results: PM2.5 concentrations were available for 1517 MS patients, of whom 1321(87%) were classified as mild Covid-19 cases, 172(11%) were hospitalized and 24(2%) were admitted to ICU or died. Higher concentrations of PM2.5 were associated with increased odds of developing a worst Covid-19 prognosis (10-unit increase in PM2.5: OR(95% CI)=1.76(1.16-2.67) p-value=0.008;3rd vs 1st tertile: OR(95% CI)=1.74(1.17-2.59) p-value=0.006). Results remained consistent when we included only the Covid-19 cases confirmed by a nasopharyngeal swab (N=1087). Conclusions: Higher concentrations of PM2.5 are associated with Covid-19 severity among MS patients. Further studies are needed to evaluate the impact of other air pollutants, but urgent measures to reduce air pollution must be surely adopted.

Different disease modifying therapies can increase or decrease Covid-19 severity in Multiple Sclerosis

Objective: To describe the effect of disease modifying therapies (DMT) on Covid-19 severity in a large cohort of Italian patients with Covid-19 and multiple sclerosis (MS). Background: We previously presented data from a nationwide study of persons with MS with suspected or confirmed Covid-19, collected from March 2020. In June we started collecting also asymptomatic patients, when serological tests started to be routinely done. Design/Methods: This was a retrospective multi-center observational study. We defined Covid-19 severity as a 4-level variable: Level 1=asymptomatic, level 2=symptomatic without signs of pneumonia, level 3=radiologically defined pneumonia or hospitalization, level 4=intensive care unit (ICU) or death. We analysed the impact of baseline variables on this outcome by a multivariable ordinal logistic model quantifying the association by Odds Ratio (OR). Results: On October 12, we enrolled 902 MS patients, 298 (33%) with confirmed and 604 (67%) with suspected Covid-19;37 (4%) were asymptomatic. The number of ICU/deaths were 8/95 (8%) among those treated with anti-CD20 therapies (mean age=41 years), 0/84 (0%) among those treated with Interferon (mean age=47 years) and 37/723 (5%) among those treated with other drugs (mean age=43 years). Among the 37 asymptomatic patients, 7/84 (8.3%) were in Interferon, 1/95 (1.1%) was on anti-CD20 and 29/723 (4%) were on other drugs. At multivariable analysis, independent risk factors for a severe Covid-19 were age (OR=1.05, p<0.001), EDSS(OR=1.13, p=0.02), Male sex(OR=1.44, p=0.057) and DMT used: Treatment with anti-CD20 (Ocrelizumab or Rituximab) increased the risk (OR=1.99, p=0.035) and treatment with Interferon reduced the risk (OR=0.48, p=0.05) of severe Covid-19 as compared to treatment with DMF, used as the reference DMT. Conclusions: This analysis confirms on a larger population the increase of risk of severe Covid-19 of anti-CD20 therapies and highlights the protective role of Interferon. Data on asymptomatic patients are rapidly accumulating and will provide useful information about this.

The outcome of a national MS-Covid-19 study: What the Turkish MS cohort reveals?

BACKGROUND: The pandemic of the new type of corona virus infection 2019 [Covid-19] also affect people with Multiple Sclerosis (pwMS). Currently, the accumulating information on the effects of the infection regarding the demographic and clinical characteristics of the disease, as well as outcomes within different DMTs¸ enable us to have better practices on the management of the Covid-19 infection in pwMS. OBJECTIVE: To investigate the incidence of coronavirus disease 2019 (Covid-19) and to reveal the relationship between the demographic-clinical and therapeutic features and the outcome of Covid-19 infection in a multi-center national cohort of pwMS. METHODS: The Turkish Neurological Society-MS Study Group in association with the Italian MuSC-19 Study Group initiated this study. A web-based electronic Case Report Form (eCRF) of Study-MuSC-19 were used to collect the data. The demographic data and MS histories of the patients were obtained from the file tracking forms of the relevant clinics. RESULTS: 309 MS patients with confirmed Covid-19 infection were included in this study. Two hundred nineteen (219) were females (70.9%). The mean age was 36.9, ranging from 18 to 66, 194 of them (62.8%) were under 40. The clinical phenotype was relapsing-remitting in 277 (89.6%) and progressive in 32 (10.4%). Disease duration ranged from 0.2 years to 31.4 years. The median EDSS was 1.5, ranging from 0 to 8.5. The EDSS score was<= 1 in 134 (43%) of the patients. 91.6% of the patients were on a DMT, Fingolimod was the most frequently used drug (22.0%), followed by Interferon (20.1%). The comorbidity rate is 11.7%. We were not able to detect any significant association of DMTs with Covid-19 severity. CONCLUSION: The Turkish MS-Covid-19 cohort had confirmed that pwMS are not at risk of having a more severe COVID-19 outcome irrespective of the DMT that they are treated. In addition, due to being a younger population with less comorbidities most had a mild disease further highlight that the only associated risk factors for having a moderate to severe COVID-19 course are similar with the general population such as having comorbid conditions and being older.