The effect of air pollution on COVID-19 severity in a sample of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS. METHODS: Data were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity. RESULTS: In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009). CONCLUSIONS: Even if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.

COVID-19 vaccine hesitancy among Italian people with multiple sclerosis.

INTRODUCTION: Vaccine hesitancy promotes the spread of infectious diseases including COVID-19 virus, limiting the herd immunity. Complications caused by COVID-19 in people with multiple sclerosis forced governments to ensure them prior access to vaccinations. Their propensity to be vaccinated needs to be assessed to promote adhesion to vaccination programs. The aim of this study was to explore the COVID-19 vaccine hesitancy rate in pwMS. METHODS: We conducted an observational study recruiting patients affected by multiple sclerosis followed at MS Clinical and Research Unit of Tor Vergata University, Rome. We invited them to fill in an online survey about their intent to get COVID-19 vaccination. Fisher's exact test and Kruskal-Wallis test were performed to explore differences in sociodemographic, clinical, and emotional variables relative to the opinions about vaccinations. An exploratory factor analysis (EFA) was performed to assess the factorial structure of the questionnaire; Pearson's correlations between the factors and Big Five personality dimensions were also calculated. RESULTS: Of 276 respondents, 90% was willing to get vaccinated, while only 1.4% was sure to refuse the vaccination. Education level, opinions on safety and efficacy of vaccines, and emotional status were found to be associated to the propensity of getting the COVID-19 vaccination (respectively: p = 0.012, p < 0.001, and p = 0.0001). Moreover, general opinions on healthcare system were related to the intention to get vaccinated. CONCLUSION: Our results reinforce the importance of a good relationship between doctor and patient and the need to adapt doctors' communication strategy to patients' personalities and beliefs.

Management of the Medico-Legal Dispute of Healthcare-Related SARS-CoV-2 Infections: Evaluation Criteria and Case Study in a Large University Hospital in Northwest Italy from 2020 to 2021.

Healthcare-related SARS-CoV-2 infection is an issue of particular concern during the pandemic. It has important repercussions on the National Health System, which represents a source of medical-legal health disputes. In the healthcare context, there are reports of negative screening at hospital admission (via nasopharyngeal swabs) and subsequent diagnosis of SARS-CoV-2 infection during hospitalization. Such cases cannot be considered a priori of healthcare-related infections but require extensive in-depth evaluation. In this study, we propose an empirical classification to frame cases of SARS-CoV-2 infection diagnosed in the hospital (first negative admission swab, with subsequent positive test during hospitalization). The classification is based on five categories: nosocomial, probably nosocomial, indeterminate, probably community, and community cases. We analyzed patients who died after testing positive for SARS-CoV-2 during hospitalization (with initial negative screening) in the largest hospital in Northwest Italy from February 2020 to 31 December 2021. A total of 383 cases were tracked and are listed as follows: 41 cases (11%) were classified as nosocomial (i.e., 3.2% of COVID-19 deaths). In contrast, 71 cases (19%) were classified as probably nosocomial, 69 (18%) were indeterminate (i.e., the clinical, radiological, and laboratory characteristics did not provide information on the genesis of the infection), 166 (43%) were classified as probably community cases, and 36 (9%) were defined as community cases. Deceased patients with nosocomial SARS-CoV-2 infection constituted the following: 3.23% (41/1266) with respect to the total number of COVID-19 deaths, 1.1% (41/3789) with respect to those who entered the hospital with a negative swab and 0.82% (41/4672) with respect to the total of deaths from any cause of death. In this paper we discuss the topic and issues of nosocomial COVID-19 in hospitalized patients and address the medicolegal implications.

Healthcare Worker Study Cohort to Determine the Level and Durability of Cellular and Humoral Immune Responses after Two Doses of SARS-CoV-2 Vaccination.

We prospectively studied immunological response against SARS-CoV-2 after vaccination among healthcare workers without (group A) and with previous infection (group B). The analyses were collected at T0 (before the BNT162b2), T1 (before the second dose), T2 and T6 (1 and 6 months after the second dose). For cellular immune response, the activation-induced cell marker assay was performed with CD4 and CD8 Spike peptide megapools expressed as Stimulation Index. For humoral immune response, we determined antibodies to Spike-1 and nucleocapsid protein. The linear mixed model compared specific times to T0. The CD4+ Spike response overall rate of change was significant at T1 (p = 0.038) and at T2 (p < 0.001), while decreasing at T6. For CD8+ Spike reactivity, the interaction between the time and group was significant (p = 0.0265), and the p value for group comparison was significant at the baseline (p = 0.0030) with higher SI in previously infected subjects. Overall, the anti-S Abs significantly increased from T1 to T6 compared to T0. The group B at T6 retained high anti-S titer (p < 0.001). At T6, in both groups we found a persistent humoral response and a high CD4+ T cell response able to cross recognize SARS-COV-2 variants including epsilon, even if not a circulating virus at that time.

The impact of PM2.5, PM10 and NO2 on Covid-19 severity in a sample of patients with multiple sclerosis: A case-control study.

BACKGROUND: Many studies investigated the association between air pollution and Covid-19 severity but the only study focusing on patients with Multiple Sclerosis (MS) exclusively evaluated exposure to PM2.5. We aim to study, in a sample of MS patients, the impact of long-term exposure to PM2.5, PM10 and NO2 on Covid-19 severity, described as occurrence of pneumonia. METHODS: A 1:2 ratio case-control study was designed, differentiating cases and controls based on Covid-19 pneumonia. Associations between pollutants and outcome were studied using logistic regression. Weighted quantile sum (WQS) logistic regression was used to identify the individual contribution of each pollutant within the mixture; Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression was performed to confirm the variable selection from WQS. All the analyses were adjusted for confounders selected a priori. RESULTS: Of the 615 eligible patients, 491 patients provided detailed place of exposure and were included in the principal analysis. Higher concentrations of air pollutants were associated with increased odds of developing Covid-19 pneumonia (PM2.5: 3rd vs 1st tercile OR(95% CI)=2.26(1.29;3.96); PM10: 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)). Pollutants were highly correlated with each other; WQS index was associated to an increased risk of pneumonia (ß=0.44; p-value=0.004) and the main contributors to this association were NO2 (41%) and PM2.5 (34%). Consistently, Lasso method selected PM2.5 and NO2. CONCLUSIONS: Higher long-term exposure to PM2.5, PM10 and NO2 increased the odds of Covid-19 pneumonia among MS patients and the most dangerous pollutants were NO2 and PM2.5.

Signs and symptoms of COVID-19 in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation. METHOD: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number. RESULTS: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p < 0.001). All cases should be referred to variants up to Delta. CONCLUSION: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

A multiparametric score for assessing the individual risk of severe Covid-19 among patients with Multiple Sclerosis.

BACKGROUND: Many risk factors for the development of severe forms of Covid-19 have been identified, some applying to the general population and others specific to Multiple Sclerosis (MS) patients. However, a score for quantifying the individual risk of severe Covid-19 in patients with MS is not available. The aim of this study was to construct such score and to evaluate its performance. METHODS: Data on patients with MS infected with Covid-19 in Italy, Turkey and South America were extracted from the Musc-19 platform. After imputation of missing values, data were separated into training data set (70%) and validation data set (30%). Univariable logistic regression models were performed in the training dataset to identify the main risk factors to be included in the multivariable logistic regression analyses. To select the most relevant variables we applied three different approaches: (1) multivariable stepwise, (2) Lasso regression, (3) Bayesian model averaging. Three scores were defined as the linear combination of the coefficients estimated in the models multiplied by the corresponding value of the variables and higher scores were associated to higher risk of severe Covid-19 course. The performances of the three scores were compared in the validation dataset based on the area under the ROC curve (AUC) and an optimal cut-off was calculated in the training dataset for the score with the best performance. The probability of showing a severe Covid-19 course was calculated based on the score with the best performance. RESULTS: 3852 patients were included in the study (2696 in the training dataset and 1156 in the validation data set). 17% of the patients required hospitalization and risk factors for severe Covid-19 course were older age, male sex, living in Turkey or South America instead of living in Italy, presence of comorbidities, progressive MS, longer disease duration, higher Expanded Disability Status Scale, Methylprednisolone use and anti-CD20 treatment. The score with the best performance was the one derived using the Lasso selection approach (AUC= 0.72) and it was built with the following variables: age, sex, country, BMI, presence of comorbidities, EDSS, methylprednisolone use, treatment. An excel spreadsheet to calculate the score and the probability of severe Covid-19 is available at the following link: https://osf.io/ac47u/?view_only=691814d57b564a34b3596e4fcdcf8580. CONCLUSIONS: The originality of this study consists in building a useful tool to quantify the individual risk for Covid-19 severity based on patient's characteristics. Due to the modest predictive ability and to the need of external validation, this tool is not ready for being fully used in clinical practice to make important decisions or interventions. However, it can be used as an additional instrument to identify high-risk patients and persuade them to take important measures to prevent Covid-19 infection (i.e. getting vaccinated against Covid-19, adhering to social distancing, and using of personal protection equipment).

Severe outcomes of COVID-19 among patients with multiple sclerosis under anti-CD-20 therapies: A systematic review and meta-analysis.

BACKGROUND: COVID-19 may spread through various ways ranging from asymptomatic to severe forms, until respiratory failure, critical conditions and death occurs. There is a particular concern for patients affected by multiple sclerosis, especially for those under disease-modifying treatments. Some studies have found an association between anti-CD20 therapies (especially rituximab) and severe COVID-19. However, results were not always clear and thus a systematic review was helpful. METHODS: A systematic literature search was performed independently by two authors on the main search tools considering as key inclusion criterion the presence of data on patients under ocrelizumab or rituximab positive to COVID-19. The quality of the included studies was evaluated based on a modified version of the Dutch Cochrane center critical review checklist proposed by MOOSE and in case of missing data an email was sent to the corresponding authors asking for missing information. After excluding case-reports, a random effects meta-analysis of proportions was conducted using the continuity correction and the I2statistic was calculated to measure heterogeneity. RESULTS: 29 articles were included in the analysis and the median quality of the articles reached 4/5 after having integrated the additional details provided by the authors. The articles included 5173 patients, of whom 770 (14.8%) and 455 (8.8%) were, respectively, under ocrelizumab and rituximab. Pooled estimates of hospitalization, pneumonia and intensive care unit admission were 18.1%, 14.8% and 3.3%, respectively, while pooled estimate for death was 1.8% overall and 1.6% and 4.5%, respectively, for patients under ocrelizumab and rituximab. CONCLUSION: Patients treated with rituximab seem to be at higher risk of severe COVID-19 outcomes compared to patients under other treatments.

The MuSC-19 study: The Egyptian cohort.

OBJECTIVE: This study aimed to report the severity of COVID-19 in a cohort of Egyptian patients with multiple sclerosis (MS) with particular attention on the impact of disease modifying drugs (DMDs). METHODS AND STUDY POPULATION: We included 119 MS patients recruited from two centers, Ain-Shams university and Cairo university with confirmed or suspected COVID-19 during the period from May to September 2020 as a part of the MuSC-19 project. Univariate logistic regression was fitted to assess risk factors for severe COVID-19 (at least one outcome among hospitalization, ICU admission and death). RESULTS: Females were 77%, mean age was 34 years, mean duration of MS was 5.28 years, median EDSS was 3, most of the patients (83%) had RRMS, while 15% and 2% had respectively SPMS and PPMS. Only eleven patients (9% of study population) had a severe outcome and 3 patients (3%) died. Headache was the only symptom significantly associated with the severity of COVID-19 (OR=10.85, P = 0.001). There was no association between any of the DMDs and severe COVID-19 outcome. CONCLUSION: This study showed an acceptable safety profile of DMDs in Egyptian MS patients who developed COVID-19, as 91% of the cohort had a favorable outcome. Headache as a symptom associated with severe outcome in Egyptian patients' needs further validation.

Coronavirus disease 2019 in Latin American patients with multiple sclerosis.

Patients with multiple sclerosis (MS) who present coronavirus disease 2019 (COVID-19) are of particular interest to neurologists. These patients have a neuroimmune disease and receive immunomodulatory or immunosuppressive therapies in the long-term. We present here data from 73 patients with MS and a confirmed diagnosis of COVID-19 from five Latin American countries. Fifteen patients (20.5%) were hospitalized and two patients died. The use of anti-CD20 therapies was the only risk factor associated to hospitalization and death. Despite the small sample size, this study highlights the awareness regarding therapeutic options for MS during the pandemic.

Patient's point of view on the use of telemedicine in multiple sclerosis: a web-based survey.

Restrictions in the access to healthcare facilities during COVID-19 pandemic have raised the need for remote monitoring of chronic medical conditions, including multiple sclerosis (MS). In order to enable the continuity of care in these circumstances, many telemedicine applications are currently tested. While physicians' preferences are commonly investigated, data regarding the patients' point of view are still lacking. We built a 37 items web-based survey exploring patients' propensity, awareness, and opinions on telemedicine with the aim to evaluate the sustainability of this approach in MS. Analysing 613 questionnaires out of 1093 that were sent to persons with MS followed at the Multiple Sclerosis Center of Tor Vergata University, Rome, we found that more than half of respondents (54%) were open to having a televisit. Propensity toward telemedicine significantly depended on having a higher income (p = 0.037), living farther from the center (p = 0.038), using computer and tablet (p = 0.010) and using the Internet for other remote activities (p < 0.001), conversely it was not influenced by any specific disease characteristics (i.e. degree of disability). The main advantages and disadvantages of televisit reported by participants were respectively saving time (70%) and impossibility to measure physical parameters (71%). Although the majority of respondents are in favour of televisit, so far this approach is restricted to those displaying better socioeconomic conditions and higher familiarity with technology. Implications of the study are that telemedicine platforms should be better tailored to patients' demands in order to spread the use of telemedicine, to enhance usability and to increase patients' adherence.

Adherence to social distancing and use of personal protective equipment and the risk of SARS-CoV-2 infection in a cohort of patients with multiple sclerosis.

Background Aiming to safeguard its population from COVID19 infection, Italian government provided specific advices, especially to fragile individuals such those affected by Multiple Sclerosis (MS), to respect social distancing, to arrange remote work and to use personal protective equipment (PPE). The aim of this study is to investigate real adherence to these measures among MS patients and to evaluate its impact on exposure to infection. Methods MS patients followed at the MS center of Tor Vergata University hospital, Rome, Italy were asked to complete an anonymous 35-items web-survey exploring demographics, residency, employment, social distancing habits, use of PPE, MS features and COVID19 infection data, including self-reported information about contacts with SARS-CoV-2 positive/presumed positive persons. In order to estimate adherence to social distancing and use of PPE, an overall 'Lockdown Score' (LS) on 0-10 scale was created analyzing four main domains (Working (0 - 4), Social distancing and PPE use (0 - 4), Assistance for shopping needs (0 - 2), Residency (-2 - 0)). Mean scores for several pre-defined subgroups of patients were compared using both univariable and multivariable analyses. Accuracy of the score in discriminating subjects at higher risk of coming in contact with SARS-CoV-2 positive/presumed positive individuals was calculated as the area under the receiver-operator characteristic curve (AUC). The optimal cut-off was identified and used to dichotomize LS (high/ low). Logistic regression model was applied to estimate individuals' characteristics associated with high/low LS and odds ratio of coming in contact with SARS-CoV-2 positive/presumed positive persons based on continous and dichotomised LS. Results Respondents (N = 551) had a mean(±SD) overall LS of 6.52±2.11 (Working 3.16±1.19, Social distancing and PPE use 2.69±1.33, Assistance 0.66± 0.62, Residency penalty applied in 4 cases). Female, disabled and unemployed individuals had significantly higher mean LS (p<0.05). The AUC of the LS was 0.68 (95% CI, 0.59-0.77) and the optimal LS cut-off for discrimination was 6.0. Consistently, female, disabled and unemployed individuals had higher odd of getting a high LS (≥ 6) compared to male, independent and employed (p<0.05). Odd of coming in contact with SARS-CoV-2 positive/presumed positive individuals was significantly reduced for one-unit increase in LS (0.74 (95% CI: 0.64-0.85)) and among individuals with high LS (0.37 (95% CI: 0.19-0.72)). Only one subject among respondents declared to have been diagnosed with COVID19. Conclusions MS patients, especially those with social unfavorable conditions, demonstrated good adherence to social distancing and use of protection equipment. Implementing domains, such as social assistance, may improve protection from infection. LS score is potentially able to identify subjects with behaviors at greater risk of infection, although it needs to be validated against MS population living in higher incidence areas.