Multiple Sclerosis and the Risk of Infection: A Consensus Guideline

Multiple sclerosis (MS) is an inflammatory condition affecting the central nervous system. Infection is a major consideration in the MS population due to its relevance to several stages of the disease process: (i) it has been suggested that infective processes may be 'triggering' or aetiological factors for MS, (ii) concurrent infection is known to exacerbate symptoms in MS, (iii) people with MS are at higher risk of infection when compared to the general population, and this risk is exaggerated in those receiving disease modifying therapies (DMTs). This guidance document was developed by specialists in the field of MS, Immunology, Infectious Disease and Pharmacy. A modified Delphi approach was used to develop clinically relevant, evidence-based consensus guidelines to help physicians navigate the complex interaction between DMTs and infectious diseases. We focus on specific risks predisposing people with MS to infection and how to manage these risks. We also provide recommendations on how to screen for, prevent, and manage infection in this population, in particular tuberculosis, progressive multifocal leukoencephalopathy, hepatitis B, human papillomavirus, herpetic and other opportunistic infections. We also discuss vaccination and the COVID-19 pandemic in people on DMTs.

Did the UK's public health shielding policy protect the clinically extremely vulnerable during the COVID-19 pandemic in Wales? Results of EVITE Immunity, a linked data retrospective study.

INTRODUCTION: The UK shielding policy intended to protect people at the highest risk of harm from COVID-19 infection. We aimed to describe intervention effects in Wales at 1 year. METHODS: Retrospective comparison of linked demographic and clinical data for cohorts comprising people identified for shielding from 23 March to 21 May 2020; and the rest of the population. Health records were extracted with event dates between 23 March 2020 and 22 March 2021 for the comparator cohort and from the date of inclusion until 1 year later for the shielded cohort. RESULTS: The shielded cohort included 117,415 people, with 3,086,385 in the comparator cohort. The largest clinical categories in the shielded cohort were severe respiratory condition (35.5%), immunosuppressive therapy (25.9%) and cancer (18.6%). People in the shielded cohort were more likely to be female, aged ≥50 years, living in relatively deprived areas, care home residents and frail. The proportion of people tested for COVID-19 was higher in the shielded cohort (odds ratio [OR] 1.616; 95% confidence interval [CI] 1.597-1.637), with lower positivity rate incident rate ratios 0.716 (95% CI 0.697-0.736). The known infection rate was higher in the shielded cohort (5.9% vs 5.7%). People in the shielded cohort were more likely to die (OR 3.683; 95% CI: 3.583-3.786), have a critical care admission (OR 3.339; 95% CI: 3.111-3.583), hospital emergency admission (OR 2.883; 95% CI: 2.837-2.930), emergency department attendance (OR 1.893; 95% CI: 1.867-1.919) and common mental disorder (OR 1.762; 95% CI: 1.735-1.789). CONCLUSION: Deaths and healthcare utilisation were higher amongst shielded people than the general population, as would be expected in the sicker population. Differences in testing rates, deprivation and pre-existing health are potential confounders; however, lack of clear impact on infection rates raises questions about the success of shielding and indicates that further research is required to fully evaluate this national policy intervention.

Humoral and T- cell response to multiple COVID-19 booster vaccinations in people with MS

Introduction: People with multiple sclerosis (PwMS) treated with anti-CD20 therapies and fingolimod are less likely to successfully produce a humoral response to COVID-19 vaccines 1 and 2. Objective(s): To measure the humoral and/or cellular response to COVID-19 booster vaccinations in a cohort of PwMS who were previously seronegative after their initial COVID vaccine course. Aim(s): To determine whether there is a benefit of COVID-19 booster vaccinations for people with MS who are known to have had an attenuated response to initial vaccines. Method(s): We studied a cohort of PwMS all of whom were seronegative for anti-SARS-CoV-2 spike protein IgG after the 1st and 2nd COVID-19 vaccines, including PwMS treated with ocrelizumab (n=53), fingolimod (n=15), other DMTs (n=9) and no DMT (n=2). Dried blood spot +/- whole blood samples were obtained from participants at 2-8 weeks after their 3rd (n=79) and 4th (n=40) COVID-19 vaccines. Samples were used to measure anti-SARS-CoV-2 spike protein IgG (ELISA) and T-cell response (IFN-g release assay measured on whole blood). Result(s): Overall 27/79 (34%) who were seronegative after COVID vaccine 2 seroconverted after vaccine 3. Seroconversion rates were 17% for PwMS treated with ocrelizumab, 47% for fingolimod and 100% for other DMTs. A further 2/30 (7%) of those who remained seronegative after vaccine 3 seroconverted after vaccine 4. Anti-SARS-CoV-2 T-cell responses were measurable in 26/40 (65%) after vaccine 3 and 13/19 (68%) after vaccine 4 but were conspicuously absent in people treated with fingolimod. Overall, 75% of participants showed either humoral or cellular response after receiving 4 COVID vaccinations. PwMS with laboratory evidence of prior COVID-19 infection had higher measurable T-cell responses. Conclusion(s): Booster vaccinations for COVID-19 are associated with incremental benefits in measurable immunity in those with attenuated responses to the initial vaccine course. Overall, three quarters of those who were seronegative after COVID vaccines 1 & 2 had a measurable immune response after COVID vaccine 4. This data supports the use of booster vaccinations in pwMS at risk of attenuated vaccine response.

An Analysis of Serological Response and Infection Outcomes Following Oxford Astra-Zeneca (azd1222) and Pfizer-Biontech (mRNA BNT162b2) SARS-CoV-2 Vaccines in Kidney and Pancreas Transplant Patients

Purpose: SARS-CoV-2 is associated with high mortality among transplant recipients. This study aims to compare the humoral responses between the Oxford-Astra- Zeneca(AZ) and BNT162b2(Pfizer-BioNTech) vaccines in transplant recipients Methods: We recruited 920 kidney and SPK transplant patients receiving at least one dose of SARS-CoV-2 vaccine excluding patients with virus pre-exposure. Serological status was determined using the COVID-SeroKlir ELISA (Kantaro-EKF). Patients with corrected antibody level less than 0.7AU/mL were considered seronegative. Result(s): 495 AZ and 141 Pfizer patients had a sample post-first and 593 post-second dose (346 AZ vs 247 Pfizer) analysed. Following the 1st dose 25.7% of patients seroconverted (26.6% AZ and 22.8% Pfizer). Post-second dose 42.8% of AZ patients seroconverted (148/346) compared to 52.6% of Pfizer (130/247, p=0.02, HR 1.48, CI 1.07-2.06). When negative responders were excluded, Pfizer patients were shown to have a significantly higher response than AZ patients (median 2.6 vs 1.78AU/ mL, Mann-Whitney p=0.005), still lower than the one observed in general population. Patients on mycophenolate had a reduced seroconversion rate (42.2% vs 61.4%, p=0.001, HR 2.17) and reduced antibody levels (0.47 vs. 1.22 AU/mL, p=0.001) and this effect was dose dependent (p=0.05). Prednisolone reduced the seroconversion rate from 58.2% to 43.6% (p=0.03,HR 1.8) among Pfizer but not AZ recipients. This result was internally validated in two time points. Regression analysis has shown that antibody levels were reduced by older age (p=0.002), mycophenolate (p=0.001), AZ vaccine (vs Pfizer) (p=0.001) and male gender (p=0.02). There was no difference on infection rate post 2nd dose among the two vaccines but 14/15 serious post-vaccine infections leading to admission occurred to patients who did not seroconvert. Conclusion(s): Both seroconversion and antibody levels are lower following AZ compared to Pfizer vaccinated transplant patients following two vaccine doses. Mycophenolate, older age, male gender are also factors affecting the antibody response. Serious post vaccine infections are limited to patients without antibody response. Transplant patients remain at serious risk of SARS-CoV-2 infection.

Effects of COVID-19 on a Complex Behavioral Intervention to Improve the Diagnosis and Management of UTI in Nursing Homes

Background. Half of all urinary tract infections (UTI) are probably unnecessary. We conducted a cluster-randomized trial in which a toolkit to enhance the diagnosis and treatment of UTIs was introduced in study NHs via usual implementation versus an enhanced implementation approach based on external facilitation and peer comparison reporting. Methods. Thirty Wisconsin NHs were randomized to each treatment arm in a 1.5:1 ratio. NHs used an online portal to report urine culture and antibiotic treatment data over a 6-month pre-intervention period (Jan-June 2019), a pre-COVID 8-month post intervention period (July 2019-Feb 2020) and an 8-month post-COVID intervention period (Mar-Oct 2020). Study outcomes included urine culture (UC), antibiotic start (AS), and antibiotic days of therapy (DOT) rates per 1,000 resident days. A generalized estimating equation model for panel data was used to assess differences in study outcomes between treatment arms before and after onset of the COVID-19 pandemic. STATA 16.1 was used for all analyses. Results. A total of 802 UCs (457 pre-COVID, 345 post-COVID), 724 AS (401 pre-COVID, 323 post-COVID), and 6,454 DOT (3553 pre-COVID and 2901 post-COVID) were reported over the 16-month intervention period. No significant differences in the study outcomes were observed during the pre-COVID intervention period, however, UC rates in NHs assigned to the usual care arm of the study increased while those in the enhanced arm declined following onset of COVID-19 (Figure 1). AS and DOT rates followed a similar pattern although the differences between the study arms were not statistically significant. Conclusion. Our findings suggest that NHs assigned to usual implementation regressed in their diagnosis and treatment of UTIs during the COVID-19 pandemic while those receiving external facilitation and peer comparison reports were more resilient to the effects of COVID-19.