Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cei.13495

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.

Abstract The objective of this systematic review and meta-analyses is to estimate the prevalence of long-COVID in children and adolescents and to present the full spectrum of symptoms present after acute COVID-19. We have used PubMed and Embase to identify observational studies published before February 10th, 2022 that included a minimum of 30 patients with ages ranging from 0 to 18 years that met the National Institute for Healthcare Excellence (NICE) definition of long-COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 (≥ 12 weeks) symptoms. Random-effects meta-analyses were performed using the MetaXL software to estimate the pooled prevalence with a 95% confidence interval (CI). Heterogeneity was assessed using I 2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed (registration PROSPERO CRD42021275408). The literature search yielded 8373 publications, of which 21 studies met the inclusion criteria, and a total of 80,071 children and adolescents were included. The prevalence of long-COVID was 25.24%, and the most prevalent clinical manifestations were mood symptoms (16.50%), fatigue (9.66%), and sleep disorders (8.42%). Children infected by SARS-CoV-2 had a higher risk of persistent dyspnea, anosmia/ageusia, and/or fever compared to controls. Limitations of the studies analyzed include lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and a high level of heterogeneity. 

/pdf/long-covid-in-children-and-adolescents-a-systematic-review-1qmcrlxo.pdf

Long-COVID in children and adolescents: a systematic review and meta-analyses

Most children have a mild course of acute COVID-19. Only few mainly non-controlled studies with small sample size have evaluated long-term recovery from SARS-CoV-2 infection in children. The aim of this study was to evaluate symptoms and duration of 'long COVID' in children. A nationwide cohort study of 37,522 children aged 0-17 years with RT-PCR verified SARS-CoV-2 infection (response rate 44.9%) and a control group of 78,037 children (response rate 21.3%). An electronic questionnaire was sent to all children from March 24th until May 9th, 2021. Symptoms lasting > 4 weeks were common among both SARS-CoV-2 children and controls. However, SARS-CoV-2 children aged 6-17 years reported symptoms more frequently than the control group (percent difference 0.8%). The most reported symptoms among pre-school children were fatigue Risk Difference (RD) 0.05 (CI 0.04-0.06), loss of smell RD 0.01 (CI 0.01-0.01), loss of taste RD 0.01 (CI 0.01-0.02) and muscle weakness RD 0.01 (CI 0.00-0.01). Among school children the most significant symptoms were loss of smell RD 0.12 (CI 0.12-0.13), loss of taste RD 0.10 (CI 0.09-0.10), fatigue RD 0.05 (CI 0.05-0.06), respiratory problems RD 0.03 (CI 0.03-0.04), dizziness RD 0.02 (CI 0.02-0.03), muscle weakness RD 0.02 (CI 0.01-0.02) and chest pain RD 0.01 (CI 0.01-0.01). Children in the control group experienced significantly more concentration difficulties, headache, muscle and joint pain, cough, nausea, diarrhea and fever than SARS-CoV-2 infected. In most children 'long COVID' symptoms resolved within 1-5 months.Long COVID in children is rare and mainly of short duration.• There are increasing reports on 'long COVID' in adults. • Only few studies have evaluated the long-term recovery from COVID-19 in children, and common for all studies is a small sample size (median number of children included 330), and most lack a control group.• 0.8% of SARS-CoV-2 positive children reported symptoms lasting >4 weeks ('long COVID'), when compared to a control group. • The most common 'long COVID' symptoms were fatigue, loss of smell and loss of taste, dizziness, muscle weakness, chest pain and respiratory problems. • These 'long COVID' symptoms cannot be assigned to psychological sequelae of social restrictions. • Symptoms such as concentration difficulties, headache, muscle- and joint pain as well as nausea are not 'long COVID' symptoms. • In most cases 'long COVID' symptoms resolve within 1-5 months. 

/pdf/long-covid-symptoms-and-duration-in-sars-cov-2-positive-3rwalxi1.pdf

Long COVID symptoms and duration in SARS-CoV-2 positive children — a nationwide cohort study

The Role of TH17 Cells in Multiple Sclerosis: Therapeutic Implications

Persistent symptoms following SARS-CoV-2 infection among children and young people: a meta-analysis of controlled and uncontrolled studies.

Post-COVID19 complications such as pediatric inflammatory multisystem syndrome (PIMS) and Long-COVID19 move increasingly into focus, potentially causing more harm in young adolescents than the acute infection. To better understand the symptoms of long-term mental health outcomes in adolescents and distinguish infection-associated symptoms from pandemic-associated symptoms, we conducted a 12 question Long-COVID19 survey. Using this survey, we compared the responses on neurocognitive, general pain and mood symptoms from seropositive and seronegative adolescents in a cross-sectional study design. Since May 2020, students grade 8-12 in fourteen secondary schools in Eastern Saxony were enrolled in the SchoolCovid19 study. Serostatus was assessed regularly in all participants. In March/April 2021, 1560 students with a median age of 15 years participated at the regular study visit after re-opening of the schools in mid-March and responded to our Long-COVID19 survey as part of this visit. 1365 (88%) students were seronegative, 188 (12%) were seropositive. Each symptom asked in the Long-COVID19 survey was present in at least 35% of the students within the last seven days before the survey. With the exception of seropositive students being less sad, there was no significant difference comparing the reported symptoms between seropositive students and seronegative students. The lack of differences comparing the reported symptoms between seropositive and seronegative students suggests that Long-COVID19 might be less common than previously thought and emphasizes on the impact of pandemic-associated symptoms regarding the well-being and mental health of young adolescents.Clinical Trial Registration: SchoolCoviDD19: Prospektive Erfassung der SARS-CoV-2 Seropositivität bei Schulkindern nach Ende der unterrichtsfreien Zeit aufgrund der Corona-Schutz-Verordnung (COVID-19), DRKS00022455, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022455. 

/pdf/comparison-of-mental-health-outcomes-in-seropositive-and-2n3rivoj.pdf

Comparison of mental health outcomes in seropositive and seronegative adolescents during the COVID19 pandemic

Lower household transmission rates of SARS-CoV-2 from children compared to adults.

BackroundPost-COVID19 complications such as pediatric inflammatory multisystem syndrome (PIMS) and Long-COVID19 move increasingly into focus, potentially causing more harm in this age group than the acute infection. To better understand the symptoms of long-COVID19 in adolescents and to distinguish infection-associated symptoms from pandemic-associated symptoms, we conducted a Long-COVID19 survey, comparing responses from seropositive and seronegative adolescents. To our knowledge, data of Long-COVID19 surveys with seronegative control groups have not been published yet. MethodsSince May 2020 students grade 8-12 in fourteen secondary schools in Eastern Saxony were enrolled in the SchoolCovid19 study. Seroprevalence was assessed via serial SARS-CoV-2 antibody testing in all participants. Furthermore, during the March/April 2021 study visit all participants were asked to complete a 12 question Long-COVID19 survey regarding the occurrence and frequency of difficulties concentrating, memory loss, listlessness, headache, abdominal pain, myalgia/ arthralgia, fatigue, insomnia and mood (sadness, anger, happiness and tenseness). Findings1560 students with a median age of 15 years participated in this study. 1365 (88%) were seronegative, 188 (12%) were seropositive. Each symptom was present in at least 35% of the students within the last seven days before the survey. However, there was no statistical difference comparing the reported symptoms between seropositive students and seronegative students. Whether the infection was known or unknown to the participant did not influence the prevalence of symptoms. InterpretationThe lack of differences comparing the reported symptoms between seropositive and seronegative students suggests that Long-COVID19 might be less common than previously thought and emphasizing the impact of pandemic-associated symptoms regarding the well-being and mental health of young adolescents. FundingThis study was supported by a grant by the Federal State of Saxony. M.K.W. was supported by the Else Kroner-Fresenius Center for Digital Health (EKFZ), TU Dresden, Germany.

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Mental Health of Adolescents in the Pandemic: Long-COVID-19 or Long-Pandemic Syndrome?

cONtEXt: Alemtuzumab, a humanized monoclonal antibody against cD52, is effective in the treatment of early relapsing-remitting multiple sclerosis (Ms). common adverse effects include an acute-phase reaction, infections and autoimmune diseases, including thyroid disorders. sEttING: Patients from two phase 3 trials (cArE Ms 1 and 2, n=15) were studied in a clinical research center. PAtIENts: Five out of fifteen patients developed severe Graves’ disease after a mean of 32 months following the first alemtuzumab treatment. MAIN OUtcOME MEAsUrEs: thyroid function tests and thyroid antibodies were assessed. In addition, endocrine tests and measurement of antibodies indicative of autoimmunity were performed. rEsULts: Of the five patients developing Graves’ disease, four patients were initially treated with antithyroid drugs, whereas the fifth patient had mild and self-limiting hyperthyroidism. Of the four patients treated with antithyroid drugs, one is currently under medical treatment in a dose-reducing regimen, whereas three patients underwent near-total thyroidectomy 2, 12 and 16 months later. two patients developed endocrine ophthalmopathy. Pituitary, adrenal and gonadal hormones were normal in all patients. While four out of five patients were positive for several other autoantibodies, none developed other autoimmune diseases. cONcLUsION: since autoimmune thyroid disease is common after alemtuzumab treatment for Ms, pretreatment screening and careful follow-up may allow for early diagnosis and treatment.

/pdf/graves-disease-after-treatment-with-alemtuzumab-for-multiple-1e3o561bsq.pdf

Graves' disease after treatment with alemtuzumab for multiple sclerosis.

Background: Alemtuzumab is a highly effective drug for the treatment of multiple sclerosis (MS), characterized by specific patterns of depletion and repopulation. As an induction-like treatment concept, two mandatory infusion courses can inhibit long-term disease activity in the majority of patients, and additional courses can successfully manage subsequent re-emergence of disease activity. Currently, there are no biomarkers to identify patients with re-emergent disease activity requiring retreatment. Methods: In this study, we systematically characterized 16 MS patients commencing alemtuzumab. Clinical parameters, MRI and detailed immunoprofiling were conducted every 3 months for up to 84 months. Results: Alemtuzumab led to significant decrease in clinical disease activity in all evaluated patients. Nine out of 16 patients presented with no evidence of disease activity (NEDA)-3 up to 84 months ("complete-responder"), while 7 patients demonstrated clinical or/and subclinical MRI disease activity and received alemutzumab retreatment ("partial-responder"). In both response categories, all T- and B-cell subsets were markedly depleted after alemtuzumab therapy. In particular, absolute numbers of Th1 and Th17 cells were markedly decreased and remained stable below baseline levels-this effect was particularly pronounced in complete-responders. While mean cell numbers did not differ significantly between groups, analysis of event-driven immunoprofiling demonstrated that absolute numbers of Th1 and Th17 cells showed a reproducible increase starting 6 months before relapse activity. This change appears to predict emergent disease activity when compared with stable disease. Conclusion: Studies with larger patient populations are needed to confirm that frequent immunoprofiling may assist in evaluating clinical decision-making of alemtuzumab retreatment.

Judith Blankenburg

Papers

Comparison of mental health outcomes in seropositive and seronegative adolescents during the COVID19 pandemic

Lower household transmission rates of SARS-CoV-2 from children compared to adults.

Mental Health of Adolescents in the Pandemic: Long-COVID-19 or Long-Pandemic Syndrome?

Graves' disease after treatment with alemtuzumab for multiple sclerosis.

Event-Driven Immunoprofiling Predicts Return of Disease Activity in Alemtuzumab-Treated Multiple Sclerosis.