Practical Recommendations for Exercise Training in Patients with Long COVID with or without Post-exertional Malaise: A Best Practice Proposal.

People with long COVID may suffer from a wide range of ongoing symptoms including fatigue, exertional dyspnea, reduced exercise performance, and others. In particular, impaired exercise performance is a condition that can be recovered in many people through an individualized physical exercise training program. However, clinical experience has shown that the presence of post-exertional malaise (PEM) is a significant barrier to physical exercise training in people with long COVID. Currently, there is no guideline or consensus available on how to apply exercise training in this cohort. Therefore, we conducted a literature review in the PubMed library using the following search terms: "COVID", "post-COVID", "long COVID" and "exercise" searching for studies from January 2020 to January 2024. Data from 46 trials were included. Exercise training regimes were very heterogeneous and none of these studies reported on the management of PEM in the context of an exercise training program. Based on the feedback from an additional survey that was answered by 14 international experts in the field of exercise training in long COVID, combined with the authors´ own extensive practical experience, a best practice proposal for exercise training recommendations has been developed. This proposal differentiates exercise procedures according to the presence of no, mild/moderate or severe PEM in people with long COVID. These recommendations may guide allied healthcare professionals worldwide in initiating and adjusting exercise training programs for people with long COVID, stratified according to the presence and severity of PEM.

The change of psychosocial stress factors in families with infants and toddlers during the COVID-19 pandemic. A longitudinal perspective on the CoronabaBY study from Germany.

Background: Over nearly three years, the COVID-19 pandemic has had a lasting impact on people's lives and mental health worldwide with its far-reaching restrictions and concerns about infections and other personal consequences. Families were particularly affected and showed increased stress and psychological problems. Long-term effects cannot be ruled out. So far, data on young families are sparse. The present longitudinal analysis (n = 932) of the CoronabaBY study investigated the development of parenting stress, parental affective symptoms, and child's mental health in young families with children aged 0-3 years in Germany as well as potential influencing factors. Methods: The observational study includes two measurement points over the course of the pandemic (baseline and follow-up). Data was collected by app using standardized questionnaires. Results: N = 932 participants, mainly mothers (94.7%) born in Germany (93.1%) with higher education (61.3% with at least high school diploma) and a comfortable financial situation participated in the longitudinal study. Children were on average 14.7 months old at baseline (SD: 12, range: 1-39 months). While the proportion of parents who perceived the pandemic as stressful decreased significantly from baseline (60%) to follow-up (52.3%), the proportion with parenting stress increased significantly (from 40.1% to 45.4%). Both parental and child mental health problems remained constant over time, with infants crying/feeding/sleeping problems ranging above pre-pandemic comparative data. Most predictive for high parenting stress at follow-up was high parenting stress at baseline. This was also true for parental affective symptoms (depression/anxiety) and child mental health problems. Conclusions: Despite faded pandemic restrictions, parents remained burdened. Support services do not appear to have been sufficient to help families out of their stressful situation. Our results indicate a need for action regarding low-threshold services that effectively reach affected families. Trial registration: The study was pre-registered in OSF (https://osf.io/search/?q=tksh5&page=1).

Wiskott-Aldrich Syndrome: A study on 577 patients defining the genotype as a predictive biomarker for disease severity.

WAS is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% CI 78-87) at 15 years and 70% (61-80) at 30 years of age. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hotspot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared to 71% (62-81) and 48% (34-68) in patients with any other variant (class II; p<0.0001). The cumulative incidence rates of disease-related complications such as severe bleeding (p=0.007), life-threatening infection (p<0.0001), and autoimmunity (p=0.004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (p=0.6) was not different between classes I and II. This study represents the largest cohort of WAS patients studied so far. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of variant is a biomarker to predict the outcome for WAS patients.

Long COVID in pediatrics-epidemiology, diagnosis, and management.

This review summarizes current knowledge on post-acute sequelae of COVID-19 (PASC) and post-COVID-19 condition (PCC) in children and adolescents. A literature review was performed to synthesize information from clinical studies, expert opinions, and guidelines. PASC also termed Long COVID - at any age comprise a plethora of unspecific symptoms present later than 4 weeks after confirmed or probable infection with severe respiratory syndrome corona virus type 2 (SARS-CoV-2), without another medical explanation. PCC in children and adolescents was defined by the WHO as PASC occurring within 3 months of acute coronavirus disease 2019 (COVID-19), lasting at least 2 months, and limiting daily activities. Pediatric PASC mostly manifest after mild courses of COVID-19 and in the majority of cases remit after few months. However, symptoms can last for more than 1 year and may result in significant disability. Frequent symptoms include fatigue, exertion intolerance, and anxiety. Some patients present with postural tachycardia syndrome (PoTS), and a small number of cases fulfill the clinical criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To date, no diagnostic marker has been established, and differential diagnostics remains challenging. Therapeutic approaches include appropriate self-management as well as the palliation of symptoms by non-pharmaceutical and pharmaceutical strategies.    Conclusion: PASC in pediatrics present with heterogenous severity and duration. A stepped, interdisciplinary, and individualized approach is essential for appropriate clinical management. Current health care structures have to be adapted, and research was extended to meet the medical and psychosocial needs of young people with PASC or similar conditions. What is Known: • Post-acute sequelae of coronavirus 2019 (COVID-19) (PASC) - also termed Long COVID - in children and adolescents can lead to activity limitation and reduced quality of life. • PASC belongs to a large group of similar post-acute infection syndromes (PAIS). Specific biomarkers and causal treatment options are not yet available. What is New: • In February 2023, a case definition for post COVID-19 condition (PCC) in children and adolescents was provided by the World Health Organization (WHO), indicating PASC with duration of at least 2 months and limitation of daily activities. PCC can present as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). • Interdisciplinary collaborations are necessary and have been established worldwide to offer harmonized, multimodal approaches to diagnosis and management of PASC/PCC in children and adolescents.

Pediatric and adult patients with ME/CFS following COVID-19: A structured approach to diagnosis using the Munich Berlin Symptom Questionnaire (MBSQ).

A subset of patients with post-COVID-19 condition (PCC) fulfill the clinical criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). To establish the diagnosis of ME/CFS for clinical and research purposes, comprehensive scores have to be evaluated. We developed the Munich Berlin Symptom Questionnaires (MBSQs) and supplementary scoring sheets (SSSs) to allow for a rapid evaluation of common ME/CFS case definitions. The MBSQs were applied to young patients with chronic fatigue and post-exertional malaise (PEM) who presented to the MRI Chronic Fatigue Center for Young People (MCFC). Trials were retrospectively registered (NCT05778006, NCT05638724). Using the MBSQs and SSSs, we report on ten patients aged 11 to 25 years diagnosed with ME/CFS after asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19. Results from their MBSQs and from well-established patient-reported outcome measures indicated severe impairments of daily activities and health-related quality of life.    Conclusions: ME/CFS can follow SARS-CoV-2 infection in patients younger than 18 years, rendering structured diagnostic approaches most relevant for pediatric PCC clinics. The MBSQs and SSSs represent novel diagnostic tools that can facilitate the diagnosis of ME/CFS in children, adolescents, and adults with PCC and other post-infection or post-vaccination syndromes. What is Known: • ME/CFS is a debilitating disease with increasing prevalence due to COVID-19. For diagnosis, a differential diagnostic workup is required, including the evaluation of clinical ME/CFS criteria. • ME/CFS after COVID-19 has been reported in adults but not in pediatric patients younger than 19 years. What is New: • We present the novel Munich Berlin Symptom Questionnaires (MBSQs) as diagnostic tools to assess common ME/CFS case definitions in pediatric and adult patients with post-COVID-19 condition and beyond. • Using the MBSQs, we diagnosed ten patients aged 11 to 25 years with ME/CFS after asymptomatic SARS-CoV-2 infection or mild to moderate COVID-19.

[Interdisciplinary multimodal pain therapy in postviral syndromes and ME/CFS : Features, pitfalls and model concept]. / Interdisziplinäre multimodale Schmerztherapie bei postviralen Syndromen und ME/CFS : Besonderheiten, Fallstricke und Modellkonzept.

BACKGROUND: Multimodal pain therapy usually take place in the context of group therapy lasting several weeks and is based on a generally activating approach. Due to the specificity of stress intolerance with postexertional malaise (PEM) in patients with postviral syndromes, physical as well as psychological overload must be urgently avoided in these cases; however, these aspects can only be insufficiently considered in current medical pain therapy concepts. METHODS: Summary of the current literature and presentation of clinical characteristics as well as presentation of a model project for a multimodal pain therapy in postviral syndromes with PEM. MODEL CONCEPT: The presented model project describes a day clinic treatment setting for interdisciplinary multimodal pain therapy adapted to the individual resilience with minimization of the risk of strain-induced deterioration of the condition.

Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome - State of the art: Report of the 2nd international meeting at the Charité Fatigue Center.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating disease affecting millions of people worldwide. Due to the 2019 pandemic of coronavirus disease (COVID-19), we are facing a significant increase of ME/CFS prevalence. On May 11th to 12th, 2023, the second international ME/CFS conference of the Charité Fatigue Center was held in Berlin, Germany, focusing on pathomechanisms, diagnosis, and treatment. During the two-day conference, more than 100 researchers from various research fields met on-site and over 700 attendees participated online to discuss the state of the art and novel findings in this field. Key topics from the conference included: the role of the immune system, dysfunction of endothelial and autonomic nervous system, and viral reactivation. Furthermore, there were presentations on innovative diagnostic measures and assessments for this complex disease, cutting-edge treatment approaches, and clinical studies. Despite the increased public attention due to the COVID-19 pandemic, the subsequent rise of Long COVID-19 cases, and the rise of funding opportunities to unravel the pathomechanisms underlying ME/CFS, this severe disease remains highly underresearched. Future adequately funded research efforts are needed to further explore the disease etiology and to identify diagnostic markers and targeted therapies.

Evaluation of a Webinar to Increase Health Professionals' Knowledge about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness and patients with ME/CFS are often medically underserved in Germany and other countries. One contributing factor is health professionals' lack of knowledge about epidemiology, diagnostic criteria, and treatment of ME/CFS. Opportunities are scarce for health professionals to receive continuing medical education on ME/CFS. The current research addressed this need for further education and investigated the gain of knowledge from a webinar for German-speaking health professionals. In two studies (total sample: N = 378), participants in the intervention condition completed a knowledge test twice (before and after webinar participation). Study 2 also included a waiting-list control condition with repeated response to the knowledge test without webinar participation between measurements. Results showed that at baseline, most participants had seen patients with ME/CFS, but confidence in diagnosing and treating ME/CFS was only moderate-to-low. In the intervention condition, but not in the control condition, knowledge about ME/CFS increased between the first and the second knowledge test. These results indicate that the webinar was successful in increasing health professionals' knowledge about ME/CFS. We concluded that webinars can be a cost-efficient and effective tool in providing health professionals with large-scale continuing medical education about ME/CFS.

Fighting Post-COVID and ME/CFS - development of curative therapies.

The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as potential mechanisms. However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No curative therapies are available for ME/CFS or PCS. The mechanisms identified so far provide targets for therapeutic interventions. To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.

Changes in behavior and quality of life in German young children during the COVID-19 pandemic-results from the COVID kids bavaria study.

Introduction: The COVID-19 pandemic with its containment measures such as closures of schools and daycare facilities led to numerous restrictions in daily life, putting developmental opportunities and health-related quality of life in children at risk. However, studies show that not every family was impacted equally by the pandemic and that this exceptional health and societal situation reinforced pre-existing health inequalities among the vulnerable. Our study aimed at analyzing changes in behavior and health-related quality of life of children attending elementary schools and daycare facilities in Bavaria, Germany in spring 2021. We also sought to identify associated factors contributing to inequalities in quality of life. Methods: Data from a multi-center, open cohort study ("COVID Kids Bavaria") conducted in 101 childcare facilities and 69 elementary schools across all electoral districts of Bavaria were analyzed. Children attending these educational settings (aged 3-10 years) were eligible for participation in a survey on changes in behavior and health-related quality of life. The KINDLR questionnaire (based on children's self-report and parental report) was administered about one year after the onset of the pandemic (spring 2021). Descriptive and logistic regression analyses and comparisons to pre-pandemic KiGGS (German Health Interview and Examination Survey for Children and Adolescents) data were undertaken. Results: Among respondents, a high percentage of parents reported changes in their children's eating and sleeping behavior, sports and outdoor activities as well as altered screen time. Health-related quality of life in KINDLR analyses compared to pre-pandemic population averages were lower in all age groups (for 3-6-year-old KINDLR-total score: COVID Kids Bavaria MD 74.78 ± 10.57 vs KiGGS data 80.0 ± 8.1; 7-10 years-old KINDLR-total score: COVID Kids Bavaria MD 73.88 ± 12.03 vs KiGGS data 79.30 ± 9.0). No significant differences were detected with regard to associated factors, namely type of institution, sex of the child, migration background, household size and parental education. Conclusion: These findings suggest a relevant impact of the COVID-19 pandemic on children's behavior and health-related quality of life one year after the onset of the pandemic. Further analyses in large-scale longitudinal studies are needed to determine the effects of specific pandemic or crisis associated factors contributing to health inequalities.

Correction: The Evaluation of Health Care Services for Children and Adolescents With Post-COVID-19 Condition: Protocol for a Prospective Longitudinal Study.

[This corrects the article DOI: 10.2196/41010.].

The Evaluation of Health Care Services for Children and Adolescents With Post-COVID-19 Condition: Protocol for a Prospective Longitudinal Study.

BACKGROUND: Some children and adolescents suffer from late effects of a SARS-CoV-2 infection despite a frequently mild course of the disease. Nevertheless, extensive care for post-COVID-19 condition, also known as post-COVID-19 syndrome, in children and young people is not yet available. A comprehensive care network, Post-COVID Kids Bavaria (PoCo), for children and adolescents with post-COVID-19 condition has been set up as a model project in Bavaria, Germany. OBJECTIVE: The aim of this study is to evaluate the health care services provided within this network structure of care for children and adolescents with post-COVID-19 condition in a pre-post study design. METHODS: We have already recruited 117 children and adolescents aged up to 17 years with post-COVID-19 condition who were diagnosed and treated in 16 participating outpatient clinics. Health care use, treatment satisfaction, patient-reported outcomes related to health-related quality of life (the primary endpoint), fatigue, postexertional malaise, and mental health are being assessed at different time points (at baseline and after 4 weeks, 3 months, and 6 months) using routine data, interviews, and self-report questionnaires. RESULTS: The study recruitment process ran from April 2022 until December 2022. Interim analyses will be carried out. A full analysis of the data will be conducted after follow-up assessment is completed, and the results will be published. CONCLUSIONS: The results will contribute to the evaluation of therapeutic services provided for post-COVID-19 condition in children and adolescents, and avenues for optimizing care may be identified. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41010.

Comparing SARS-CoV-2 variants among children and adolescents in Germany: relative risk of COVID-19-related hospitalization, ICU admission and mortality.

PURPOSE: SARS-CoV-2 infections cause COVID-19 and have a wide spectrum of morbidity. Severe disease courses among children are rare. To date, data on the variability of morbidity in relation to variant of concern (VOC) in children has been sparse and inconclusive. We compare the clinical severity of SARS-CoV-2 infection among children and adolescents in Germany during the Wildtype and Alpha combined, Delta and Omicron phases of the COVID-19 pandemic. METHODS: Comparing risk of COVID-19-related hospitalization, intensive care unit (ICU) admission and death due to COVID-19 in children and adolescents, we used: (1) a multi-center seroprevalence study (SARS-CoV-2-KIDS study); (2) a nationwide registry of pediatric patients hospitalized with SARS-CoV-2 infections; and (3) compulsory national reporting for RT-PCR-confirmed SARS-CoV-2 infections in Germany. RESULTS: During the Delta predominant phase, risk of COVID-19-related hospitalization among all SARS-CoV-2 seropositive children was 3.35, ICU admission 1.19 and fatality 0.09 per 10,000; hence about halved for hospitalization and ICU admission and unchanged for deaths as compared to the Wildtype- and Alpha-dominant period. The relative risk for COVID-19-related hospitalization and ICU admission compared to the alpha period decreased during Delta [0.60 (95% CI 0.54; 0.67) and 0.51 (95% CI 0.42; 0.61)] and Omicron [0.27 (95% CI 0.24; 0.30) and 0.06 (95% CI 0.05; 0.08)] period except for the < 5-year-olds. The rate of case fatalities decreased slightly during Delta, and substantially during Omicron phase. CONCLUSION: Morbidity caused by SARS-CoV-2 infections among children and adolescents in Germany decreased over the course of the COVID-19 pandemic, as different VOCs) emerged.

Post-COVID Syndrome.

BACKGROUND: As defined by the WHO, the term post-COVID syndrome (PCS) embraces a group of symptoms that can occur following the acute phase of a SARS-CoV-2 infection and as a consequence thereof. PCS is found mainly in adults, less frequently in children and adolescents. It can develop both in patients who initially had only mild symptoms or none at all and in those who had a severe course of coronavirus disease 2019 (COVID-19). METHODS: The data presented here were derived from a systematic literature review. RESULTS: PCS occurs in up to 15% of unvaccinated adults infected with SARS-CoV-2. The prevalence has decreased in the most recent phase of the pandemic and is lower after vaccination. The pathogenesis of PCS has not yet been fully elucidated. Virustriggered inflammation, autoimmunity, endothelial damage (to blood vessels), and persistence of virus are thought to be causative. Owing to the broad viral tropism, different organs are involved and the symptoms vary. To date, there are hardly any evidence-based recommendations for definitive diagnosis of PCS or its treatment. CONCLUSION: The gaps in our knowledge mean that better documentation of the prevalence of PCS is necessary to compile the data on which early detection, diagnosis, and treatment can be based. To ensure the best possible care of patients with PCS, regional PCS centers and networks embracing existing structures from all healthcare system sectors and providers should be set up and structured diagnosis and treatment algorithms should be established. Given the sometimes serious consequences of PCS for those affected, it seems advisable to keep the number of SARS-CoV-2 infections low by protective measures tailored to the prevailing pandemic situation.

Post-COVID-19 condition in the German working population: A cross-sectional study of 200,000 registered stem cell donors.

BACKGROUND: The SARS-CoV-2 pandemic has strained health systems worldwide, and infection numbers continue to rise. While previous data have already shown that many patients suffer from symptoms for months after an acute infection, data on risk factors and long-term outcomes are incomplete, particularly for the working population. OBJECTIVES: We aimed to provide information on the prevalence of post-COVID-19 conditions in a subset of the German working-age population (18-61 years old) and to analyze risk factors. METHODS: We conducted an online survey with a health questionnaire among registered potential stem cell donors with or without a self-reported history of polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. Logistic regression models were used to examine the risks of severity of acute infection, sex, age, body mass index, diabetes mellitus, and arterial hypertension medication on post-COVID-19 symptoms. RESULTS: A total of 199,377 donors reported evaluable survey questionnaires-12,609 cases had a history of SARS-CoV-2 infection and 186,768 controls had none. Overall, cases reported physical, cognitive, and psychological complaints more frequently compared to controls. Increased rates of complaints persisted throughout 15 months postinfection, for example, 28.4%/19.3% of cases/controls reported fatigue (p <0.0001) and 9.5%/3.6% of cases/controls reported loss of concentration (p <0.0001). No significant differences were observed in the frequency of reported symptoms between 3 and 15 months postinfection. Multivariate analysis revealed a strong influence of the severity of the acute SARS-CoV-2 infection episode and age on the risk for post-COVID-19 conditions. CONCLUSION: We report the prevalence of post-COVID-19 conditions in mainly unvaccinated individuals with SARS-CoV-2 infections between February 2020 and August 2021. The severity of the acute course and age were major risk factors. Vaccinations may reduce the risk of post-COVID-19 conditions by reducing the risk of severe infections.

One-year follow-up of young people with ME/CFS following infectious mononucleosis by Epstein-Barr virus.

Background: Infectious mononucleosis after primary infection with Epstein-Barr virus (EBV-IM) has been linked to the development of myalgic encephalomyelitis/chronic fatigue-syndrome (ME/CFS) in children, adolescents, and young adults. Here, we present clinical phenotypes and follow-up data from a first German cohort of young people with ME/CFS following EBV-IM. Methods: 12 adolescents and 13 young adults were diagnosed with IM-triggered ME/CFS at our specialized tertiary outpatient service by clinical criteria requiring post-exertional malaise (PEM) and a history of confirmed EBV primary infection as triggering event. Demographic information, laboratory findings, frequency and severity of symptoms, physical functioning, and health-related quality of life (HRQoL) were assessed and re-evaluated 6 and 12 months later. Results: Young adults displayed more severe symptoms as well as worsening of fatigue, physical and mental functioning, and HRQoL throughout the study, compared to adolescents. After one year, 6/12 (54%) adolescents no longer met the diagnostic criteria for ME/CFS while all young adults continued to fulfill the Canadian consensus criteria. Improvement in adolescents was evident in physical functioning, symptom frequency and severity, and HRQoL, while young adults showed little improvement. EBV serology and EBV DNA load did not correlate with distinct clinical features of ME/CFS, and clinical chemistry showed no evidence of inflammation. Remarkably, the median time from symptom onset to ME/CFS diagnosis was 13.8 (IQR: 9.1-34.9) months. Conclusions: ME/CFS following EBV-IM is a severely debilitating disease often diagnosed late and with limited responses to conventional medical care, especially in adults. Although adolescents may have a better prognosis, their condition can fluctuate and significantly impact their HRQoL. Our data emphasize that biomarkers and effective therapeutic options are also urgently needed to improve medical care and pave the way to recovery.

Association of SARS-CoV-2 Seropositivity With Myalgic Encephalomyelitis and/or Chronic Fatigue Syndrome Among Children and Adolescents in Germany.

Importance: During the COVID-19 pandemic, a reduction in quality of life and physical and mental health among children and adolescents has been reported that may be associated with SARS-CoV-2 infection and/or containment measures. Objective: To assess the association of SARS-CoV-2 seropositivity with symptoms that may be related to myalgic encephalomyelitis and/or chronic fatigue syndrome (ME/CFS) among children and adolescents. Design, Setting, and Participants: This substudy of the cross-sectional SARS-CoV-2 seroprevalence surveys in Germany (SARS-CoV-2 KIDS) was performed in 9 pediatric hospitals from May 1 to October 31, 2021. Pediatric patients were recruited during an inpatient or outpatient visit regardless of the purpose of the visit. Parental questionnaires and serum samples were collected during clinically indicated blood draws. The parental questionnaire on demographic and clinical information was extended by items according to the DePaul Symptom Questionnaire, a pediatric screening tool for ME/CFS in epidemiological studies in patients aged 5 to 17 years. Exposures: Seropositivity was determined by SARS-CoV-2 IgG antibodies in serum samples using enzyme-linked immunosorbent assays. Main Outcomes and Measures: Key symptoms of ME/CFS were evaluated separately or as clustered ME/CFS symptoms according to the DePaul Symptom Questionnaire, including fatigue. Results: Among 634 participants (294 male [46.4%] and 340 female [53.6%]; median age, 11.5 [IQR, 8-14] years), 198 (31.2%) reported clustered ME/CFS symptoms, including 40 of 100 SARS-CoV-2-seropositive (40.0%) and 158 of 534 SARS-CoV-2-seronegative (29.6%) children and adolescents. After adjustment for sex, age group, and preexisting disease, the risk ratio for reporting clustered ME/CFS symptoms decreased from 1.35 (95% CI, 1.03-1.78) to 1.18 (95% CI, 0.90-1.53) and for substantial fatigue from 2.45 (95% CI, 1.24-4.84) to 2.08 (95% CI, 1.05-4.13). Confinement to children and adolescents with unknown previous SARS-CoV-2 infection status (n = 610) yielded lower adjusted risks for all symptoms except joint pain ME/CFS-related symptoms. The adjusted risk ratio was 1.08 (95% CI, 0.80-1.46) for reporting clustered ME/CFS symptoms and 1.43 (95% CI, 0.63-3.23) for fatigue. Conclusions and Relevance: These findings suggest that the risk of ME/CFS in children and adolescents owing to SARS-CoV-2 infection may be very small. Recall bias may contribute to risk estimates of long COVID-19 symptoms in children. Extensive lockdowns must be considered as an alternative explanation for complex unspecific symptoms during the COVID-19 pandemic.

Association between IgG responses against the nucleocapsid proteins of alphacoronaviruses and COVID-19 severity.

Understanding immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to contain the COVID-19 pandemic. Using a multiplex approach, serum IgG responses against the whole SARS-CoV-2 proteome and the nucleocapsid proteins of endemic human coronaviruses (HCoVs) were measured in SARS-CoV-2-infected donors and healthy controls. COVID-19 severity strongly correlated with IgG responses against the nucleocapsid (N) of SARS-CoV-2 and possibly with the number of viral antigens targeted. Furthermore, a strong correlation between COVID-19 severity and serum responses against N of endemic alpha- but not betacoronaviruses was detected. This correlation was neither caused by cross-reactivity of antibodies, nor by a general boosting effect of SARS-CoV-2 infection on pre-existing humoral immunity. These findings raise the prospect of a potential disease progression marker for COVID-19 severity that allows for early stratification of infected individuals.