Increase in acute mastoiditis at the end of the COVID-19 pandemic.

PURPOSE: Common respiratory infections were significantly reduced during the COVID-19 pandemic due to general protective and hygiene measures. The gradual withdrawal of these non-pharmaceutical interventions (NPI) was associated with a notable increase in these infections, particularly in pediatric and adult otorhinolaryngology. The aim of this retrospective monocentric study was to evaluate the impact of NPI during the COVID-19 pandemic on the incidence and severity of acute mastoiditis (AM). METHODS: Pre-pandemic clinical data of AM cases from 2011 to 2019 were compared with infection counts from January 2020 to June 2023 for seasonal periodicity, age-specific differences, pathogens, and complication rates in a German third-level hospital. RESULTS: Out of 196 patients with AM 133 were children, the majority between 1 and 5 years of age. Complications of AM, such as meningitis, brain abscess, and sinus vein thrombosis, were more common in adults (87%) than in children (17%). Morbidity and mortality rates were similar before, during and after the pandemic. Pneumococci were the most common pathogen in both age groups, with a post-pandemic cumulation of Streptococcus pyogenes infections in children. While pre-pandemic cases clustered in spring, seasonality was absent in all age groups during the main phase of the pandemic. The cessation of NPI caused a steep rise in AM cases in both age groups starting from December 2022. CONCLUSION: NPI during the COVID-19 pandemic reduced the incidence of AM. Their reversal led to a substantial increase in the incidence of AM during the post-pandemic period, which may be due to a general increase in viral respiratory infections and an insufficiently trained immune system.

Health care utilisation of asylum seekers and refugees in the South-West of Germany.

BACKGROUND: Limited evidence on utilisation of health care by recently arrived asylum seekers and refugees in high-income countries is available. This study aims to describe the implementation of an integrated care facility (ICF) in an initial reception centre and measure the utilisation of care and the influence of operational parameters. METHODS: In a retrospective cohort study design, using medical records, we followed inhabitants of a reception centre in Germany between 11.10.2015 and 30.05.2018. We assessed frequency of visits and revisits to a newly established integrated care facility (ICF), and the effects of the ICF on visits to the local emergency department (LED) in the regional tertiary hospital using survival analysis and time series regression. We also explore the influence of operational parameters on the different implementation phases; phase 1: provisional clinic with 1-2 hours of physician presence daily, phase 2: implementation of ICF with 2-4 hours of care by a team of doctors and nurses daily, phase 3: routine running of ICF with daily operational hours of 10am-2pm with care provided by an interdisciplinary team of doctors and nurses. RESULTS: 14,419 total medical visits were recorded from 1,883 persons seeking health care in the ICF. The absolute number of visits per day remained similar over the study period (19·9/day), yet the relative number of visits changed from 2·2 to 15 per 100 inhabitants from phase 2 to 3, respectively. Most visits were due to respiratory infections (612/3080, 20%), and trauma and musculoskeletal conditions (441/3080, 14%). The rate of revisits to ICF was 2·9 per person per month (95%CI 2·9-3), more for those older, female, from North Africa and those with a translator present. The ratio of visits to the LED changed from 0·3/100 inhabitants per day to 0·14/100 inhabitants after implementation of the ICF and back to 0·3/100 inhabitants during the routine running. CONCLUSIONS: Though seasonal variation and referral practices must be considered, a high rate of revisits to the ICF were recorded. While visits to the LED decreased after the implementation of the ICF, visits returned to the pre-ICF levels during the routine running of the ICF. The results show that AS&R require reliable access to health care, yet the needs of specific groups of migrants may be different, especially those with language barriers, minority groups or those from certain regions. As such, care should be migrant sensitive and adapt to the changing needs of the population. Though more research is required to better understand the differing needs of migrants, this study may help to inform guidelines surrounding migrant sensitive standards of care in Germany.

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry.

OBJECTIVE: Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). METHODS: From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. RESULTS: At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. CONCLUSION: Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.

Immune-epithelial cell cross-talk enhances antiviral responsiveness to SARS-CoV-2 in children.

The risk of developing severe COVID-19 rises dramatically with age. Schoolchildren are significantly less likely than older people to die from SARS-CoV-2 infection, but the molecular mechanisms underlying this age-dependence are unknown. In primary infections, innate immunity is critical due to the lack of immune memory. Children, in particular, have a significantly stronger interferon response due to a primed state of their airway epithelium. In single-cell transcriptomes of nasal turbinates, we find increased frequencies of immune cells and stronger cytokine-mediated interactions with epithelial cells, resulting in increased epithelial expression of viral sensors (RIG-I, MDA5) via IRF1. In vitro, adolescent peripheral blood mononuclear cells produce more cytokines, priming A549 cells for stronger interferon responses to SARS-CoV-2. Taken together, our findings suggest that increased numbers of immune cells in the airways of children and enhanced cytokine-based interactions with epithelial cells tune the setpoint of the epithelial antiviral system. Our findings shed light on the molecular basis of children's remarkable resistance to COVID-19 and may suggest a novel concept for immunoprophylactic treatments.

Characterization of adolescents with functional respiratory disorders and prior history of SARS-CoV-2.

BACKGROUND: The SARS-CoV-2 pandemic has caused significant pulmonary morbidity and mortality in the adult population. Children and adolescents typically show milder symptoms; however, a relevant proportion of them report persistent pulmonary symptoms even after mild SARS-CoV-2 infection. Functional respiratory disorders may be relevant differential diagnoses of persistent dyspnea. This study aims at characterizing functional respiratory disorders that may arise after SARS-CoV-2 infection regarding their clinical presentation and pulmonary function tests as well as gaining insights into the clinical course after initiation of appropriate therapy. METHODS: This study retrospectively identified all patients referred to an outpatient clinic for pediatric pulmonology with functional respiratory disorders manifesting after proven SARS-CoV-2 infection between January 1, 2022, and October 31, 2022. Clinical history, thorough clinical examination regarding breathing patterns, and pulmonary function tests (PFTs) were taken into consideration to diagnose functional respiratory disorders. RESULTS: Twenty-five patients (44% female) with mean (m) age = 12.73 years (SD ± 1.86) who showed distinctive features of functional respiratory disorders after SARS-CoV-2 infection (onset at m = 4.15 (± 4.24) weeks after infection) were identified. Eleven patients showed thoracic dominant breathing with insufficient ventilation, and 4 patients mainly had symptoms of inducible laryngeal obstruction. The rest (n = 10) showed overlap of these two etiologies. Most patients had a flattened inspiratory curve on spirometry and slightly elevated residual volume on body plethysmography, but values of PFTs were normal before and after standardized treadmill exercise testing. Patients were educated about the benign nature of the condition and were offered rebreathing training. All patients with follow-up (n = 5) showed normalization of the breathing pattern within 3 months. CONCLUSIONS: Functional respiratory disorders are important differential diagnoses in persisting post-SARS-CoV-2 dyspnea in adolescents. A combination of clinical history, detailed examination of breathing patterns, and pulmonary function tests are helpful to correctly diagnose these conditions. Reassurance and rebreathing training are the mainstay of the therapy. The clinical course is favorable.

Serum neutralizing capacity and T-cell response against the omicron BA.1 variant in seropositive children and their parents one year after SARS-CoV-2 infection.

Introduction: Durability of immune protection against reinfection with SARS-CoV-2 remains enigmatic, especially in the pediatric population and in the context of immune-evading variants of concern. Obviously, this knowledge is required for measures to contain the spread of infection and in selecting rational preventive measures. Methods: Here, we investigated the serum neutralization capacity of 36 seropositive adults and 34 children approximately one year after infection with the ancestral Wuhan strain of SARS-CoV-2 by using a pseudovirus neutralization assay. Results: We found that 88.9% of seropositive adult (32/36) and 94.1% of seropositive children (32/34) convalescents retained the neutralizing activity against the SARS-CoV-2 Wuhan strain (WT). Although, the neutralization effect against Omicron BA.1 (B.1.1.529.1) was significantly lower, 70.6% (24/34) of children and 41.7% (15/36) of adults possessed BA.1 cross-neutralizing antibodies. The spike 1 (S1)-specific T cell recall capacity using an activation-induced marker assay was analyzed in 18 adults and 16 children. All participants had detectable S1-specific CD4 T cells against WT, and 72.2% (13/18) adults and 81,3% (13/16) children had detectable S1 WT-specific CD8 T cells. CD4 cross-reactivity against BA.1 was demonstrated in all investigated adults (18/18), and 66.7% (12/18) adult participants had also detectable specific CD8 BA.1 T cells while we detected BA.1 S1 reactive CD4 and CD8 T cells in 81.3% (13/16) children. Discussion: Together, our findings demonstrate that infection with the ancestral strain of SARS-CoV-2 in children as well as in adults induces robust serological as well as T cell memory responses that persist over at least 12 months. This suggests persistent immunological memory and partial cross-reactivity against Omicron BA.1.

Live-virus neutralization of the omicron variant in children and adults 14 months after SARS-CoV-2 wild-type infection.

Data on cross-neutralization of the SARS-CoV-2 omicron variant more than 1 year after SARS-CoV-2 infection are urgently needed, especially in children, to predict the likelihood of reinfection and to guide vaccination strategies. In a prospective observational cohort study, we evaluated live-virus neutralization of the SARS-CoV-2 omicron (BA.1) variant in children compared with adults 14 months after mild or asymptomatic wild-type SARS-CoV-2 infection. We also evaluated immunity to reinfection conferred by previous infection plus COVID-19 mRNA vaccination. We studied 36 adults and 34 children 14 months after acute SARS-CoV-2 infection. While 94% of unvaccinated adults (16/17) and children (32/34) neutralized the delta (B.1.617.2) variant, only 1/17 (5.9%) unvaccinated adults, 0/16 (0%) adolescents and 5/18 (27.8%) children <12 years of age had neutralizing activity against omicron (BA.1). In convalescent adults, one or two doses of mRNA vaccine increased delta and omicron neutralization 32-fold, similar to a third mRNA vaccination in uninfected adults. Neutralization of omicron was 8-fold lower than that of delta in both groups. In conclusion, our data indicate that humoral immunity induced by previous SARS-CoV-2 wild-type infection more than 1 year ago is insufficient to neutralize the current immune escape omicron variant.

High antibody levels and reduced cellular response in children up to one year after SARS-CoV-2 infection.

The COVID-19 course and immunity differ in children and adults. We analyzed immune response dynamics in 28 families up to 12 months after mild or asymptomatic infection. Unlike adults, the initial response is plasmablast-driven in children. Four months after infection, children show an enhanced specific antibody response and lower but detectable spike 1 protein (S1)-specific B and T cell responses than their parents. While specific antibodies decline, neutralizing antibody activity and breadth increase in both groups. The frequencies of S1-specific B and T cell responses remain stable. However, in children, one year after infection, an increase in the S1-specific IgA class switch and the expression of CD27 on S1-specific B cells and T cell maturation are observed. These results, together with the enhanced neutralizing potential and breadth of the specific antibodies, suggest a progressive maturation of the S1-specific immune response. Hence, the immune response in children persists over 12 months but dynamically changes in quality, with progressive neutralizing, breadth, and memory maturation. This implies a benefit for booster vaccination in children to consolidate memory formation.

Intravoxel incoherent motion (IVIM) MRI in pediatric patients with synovitis of the knee joint: a prospective pilot study.

BACKGROUND: Diagnosing synovial inflammation by administration of gadolinium-based contrast agents is limited by invasiveness and possible side effects, especially in children and adolescents. PURPOSE: We investigated diagnostic accuracy of diffusion-weighted (DWI) MRI with intravoxel incoherent motion (IVIM) imaging compared to contrast-enhanced MRI for detecting synovitis of the knee in a population of pediatrics and young adults. In addition we compared quantitative measures of synovial diffusion and perfusion to a group of healthy volunteers. METHODS: In this prospective study, 8 pediatric patients with 10 symptomatic knees (6 girls and 2 boys, mean age 13 years) with known or suspected synovitis underwent pre- and post-contrast 3.0 T MRI of the knee joint and additional DWI sequences between October 2016 and July 2019. For comparison we enrolled 5 healthy young adults (2 women and 3 men, median age 27 years) with contrast-free MRI of both knees. Post-contrast T1w images and DWI images at b = 1000s/mm2 with apparent diffusion coefficient (ADC) maps of patients were separately rated by two independent and blinded readers with different levels of experience for the presence or absence and degree of synovitis along with the level of confidence. We measured signal intensity on DWI of synovium, joint effusion and muscle with regions of interests and calculated the IVIM-parameters tissue diffusion coefficient (D) and perfusion fraction (f) for patients and volunteers. RESULTS: All patients showed at least some synovial contrast enhancement, 8 (80%) children knees were diagnosed with synovitis on contrast-enhanced (= ce)-T1w, the diagnostic standard. Ratings by the first and second reader on ce-T1w and DWI showed full agreement (kappa = 1) in diagnosing synovitis and substantial agreement (k = 0,655) for the degree of synovial enhancement. Interobserver agreement on DWI showed fair agreement (k = 0,220) between both readers. Diagnostic confidence was lower on DWI. Mean D- and f-values of muscle was comparable between patients and volunteers. Effusion mean D was higher, mean f was lower, synovial mean D was lower, mean f higher in patients than in volunteers. All differences were statistically significant (p < 0.001). CONCLUSIONS: Diffusion-weighted MRI with IVIM imaging remains a promising, though reader-dependent alternative to i.v. contrast-enhanced imaging in pediatric patients to reliably diagnose, or rule out, synovitis of the knee joint. We detected significantly restricted synovial diffusion and increased perfusion in patients compared to healthy volunteers. TRIAL REGISTRATION: Ethical Comitee University Hospital Ulm, Nr. 320/16.

Long COVID symptoms in exposed and infected children, adolescents and their parents one year after SARS-CoV-2 infection: A prospective observational cohort study.

BACKGROUND: Long COVID in children and adolescents remains poorly understood due to a lack of well-controlled studies with long-term follow-up. In particular, the impact of the family context on persistent symptoms following SARS-CoV-2 infection remains unknown. We examined long COVID symptoms in a cohort of infected children, adolescents, and adults and their exposed but non-infected household members approximately 1 year after infection and investigated clustering of persistent symptoms within households. METHODS: 1267 members of 341 households (404 children aged <14 years, 140 adolescents aged 14-18 years and 723 adults) were categorized as having had either a SARS-CoV-2 infection or household exposure to SARS-CoV-2 without infection, based on three serological assays and history of laboratory-confirmed infection. Participants completed questionnaires assessing the presence of long COVID symptoms 11-12 months after infection in the household using online questionnaires. FINDINGS: The prevalence of moderate or severe persistent symptoms was statistically significantly higher in infected than in exposed women (36.4% [95% CI: 30.7-42.4%] vs 14.2% [95% CI: 8.7-21.5%]), infected men (22.9% [95% CI: 17.9-28.5%] vs 10.3% [95% CI: 5.8-16.9%]) and infected adolescent girls (32.1% 95% CI: 17.2-50.5%] vs 8.9% [95%CI: 3.1-19.8%]). However, moderate or severe persistent symptoms were not statistically more common in infected adolescent boys aged 14-18 (9.7% [95% CI: 2.8-23.6%] or in infected children <14 years (girls: 4.3% [95% CI: 1.2-11.0%]; boys: 3.7% [95% CI: 1.1-9.6%]) than in their exposed counterparts (adolescent boys: 0.0% [95% CI: 0.0-6.7%]; girls < 14 years: 2.3% [95% CI: 0·7-6·1%]; boys < 14 years: 0.0% [95% CI: 0.0-2.0%]). The number of persistent symptoms reported by individuals was associated with the number of persistent symptoms reported by their household members (IRR=1·11, p=·005, 95% CI [1.03-1.20]). INTERPRETATION: In this controlled, multi-centre study, infected men, women and adolescent girls were at increased risk of negative outcomes 11-12 months after SARS-CoV-2 infection. Amongst non-infected adults, prevalence of negative outcomes was also high. Prolonged symptoms tended to cluster within families, suggesting family-level interventions for long COVID could prove useful. FUNDING: Ministry of Science, Research and the Arts, Baden-Württemberg, Germany.

Pulmonary Function and Persistent Clinical Symptoms in Children and Their Parents 12 Months After Mild SARS-CoV-2 Infection.

Background: Pulmonary involvement is the leading cause of morbidity and mortality after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Long-term impairment has been reported in adults with severe infection. However, most infections cause only mild symptoms or are even asymptomatic, especially in children. There is insufficient evidence regarding pulmonary outcome measures in mild SARS-CoV-2. The objectives of this study were to determine spirometry parameters after SARS-CoV-2 infection and correlate those with reported persisting symptoms in children, adolescents, and adults. Methods: Data on clinical symptoms during acute infection as well as SARS-CoV-2 serology results were recorded. Twelve months after infection, spirometry was performed and information on persisting symptoms was collected using a structured questionnaire. 182 participants (108 SARS-CoV-2 positive) from 48 families were included; 53 children (< 14 years), 34 adolescents and young adults (14-25 years), and 95 adults. Results: Spirometry values did not significantly differ between the particular subgroups of the cohort (adults, adolescents, children; infected and non-infected individuals). Adults reported more symptoms during acute infection as well more persisting fatigue (29.7% of participants), reduced physical resilience (34.4%), and dyspnea (25.0%) 12 months after infection than adolescents (fatigue 26.7%, reduced physical resilience 20%, and 0% dyspnea) and children (4%, 0%, 0%, respectively). There was no correlation between persistent subjective symptoms and spirometry results. Discussion: Children and adolescents are less affected than adults by acute SARS-CoV-2 as well as by post-infection persistent symptoms. Spirometry was not able to demonstrate any differences between healthy individuals and participants who had suffered from mild SARS-CoV-2 12 months after the infection.

[Updated recommendations on the treatment of infectious diseases in refugees in childhood and adolescence in Germany (situation as of 30 March 2022), registered as S1 guidelines (AWMF-Register Nr. 048-017)]. / Aktualisierte Empfehlungen zur infektiologischen Versorgung von Flüchtlingen im Kindes- und Jugendalter in Deutschland (Stand 30. März 2022), angemeldet als S1-Leitlinie (AWMF-Register Nr. 048-017): Stellungnahme der Deutschen Gesellschaft für Pädiatrische Infektiologie e. V. (DGPI), der Gesellschaft für Tropenpädiatrie und Internationale Kindergesundheit e. V. (GTP), des Berufsverbandes der Kinder- und Jugendärzte e. V. (BVKJ) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin e. V. (DGKJ), unter Mitarbeit des Berufsverbands der Ärztinnen und Ärzte des Öffentlichen Gesundheitsdienstes e. V. (BVÖGD), der Deutschen Gesellschaft für Kinderchirurgie e. V. (DGKCH), der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe e. V. (DGGG), Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin (DEGAM), des Bündnis Kinder- und Jugendgesundheit e. V. (früher Deutsche Akademie für Kinder- und Jugendmedizin, DAKJ), der Deutschen Gesellschaft für Tropenmedizin, Reisemedizin und Globale Gesundheit e. V. (DTG), der Deutschen Gesellschaft für Globale und Tropenchirurgie e. V. (DTC) und der Pädiatrisch Infektiologischen Gruppe Schweiz (PIGS).

Background: Based on 190,000 applications for asylum, Germany remains a top destination for refugees and asylum seekers in Europe. The updated recommendations are considered evidence-based and targeted guidelines for the diagnosis and prevention of infectious diseases in underage refugees and asylum seekers. Objective: The objective of these recommendations is to guide medical staff in the care of minor refugees, in particular to:1. assure early recognition and completion of incomplete vaccination status,2. diagnose and treat common infectious diseases,3. recognize and treat imported infectious diseases that are considered uncommon to the German healthcare system. Material and methods: The recommendations have been formally written to be published as AWMF S1 guidelines.This includes a representative expert panel appointed by several professional societies, and formal adoption of the recommendations by the board of directors of all societies concerned. Results: Recommendations are given for the medical evaluation of minor refugees, including medical history and physical examination. A blood count as well as screening for tuberculosis and hepatitis B should be offered to all minor refugees. In addition, screening for other infectious diseases like hepatitis C, HIV or schistosomiasis should be considered depending on age and country of origin. Vaccinations are recommended based on both age and country of origin. Conclusion: As thousands of minor refugees continue to seek shelter in Germany every year, professional health care with adequate financial support needs to be established to ensure an appropriate medical treatment of this particularly vulnerable population.

Role of ABO Blood Group in SARS-CoV-2 Infection in Households.

An association between certain ABO/Rh blood groups and susceptibility to SARS-CoV-2 infection has been proposed for adults, although this remains controversial. In children and adolescents, the relationship is unclear due to a lack of robust data. Here, we investigated the association of ABO/Rh blood groups and SARS-CoV-2 in a multi-center study comprising 163 households with 281 children and 355 adults and at least one SARS-CoV-2 seropositive individual as determined by three independent assays as a proxy for previous infection. In line with previous findings, we found a higher frequency of blood group A (+ 6%) and a lower frequency of blood group O (-6%) among the SARS-CoV-2 seropositive adults compared to the seronegative ones. This trend was not seen in children. In contrast, SARS-CoV-2 seropositive children had a significantly lower frequency of Rh-positive blood groups. ABO compatibility did not seem to play a role in SARS-CoV-2 transmission within the families. A correction for family clusters was performed and estimated fixed effects of the blood group on the risk of SARS-CoV-2 seropositivity and symptomatic infection were determined. Although we found a different distribution of blood groups in seropositive individuals compared to the reference population, the risk of SARS-CoV-2 seropositivity or symptomatic infection was not increased in children or in adults with blood group A or AB versus O or B. Increasing age was the only parameter positively correlating with the risk of SARS-CoV-2 infection. In conclusion, specific ABO/Rh blood groups and ABO compatibility appear not to predispose for SARS-CoV-2 susceptibility in children.

Low Prevalence of Anti-DFS70 Antibodies in Children With ANA-Associated Autoimmune Disease.

Introduction: Anti-DFS70 antibodies occur in healthy individuals with various medical conditions. Unlike other anti-nuclear autoantibodies (ANA), they are not associated with systemic autoimmune disease in adult patients. To date, only a few studies have addressed the prevalence and/or clinical relevance of anti-DFS70 autoantibodies in children with and without autoimmune disease. Methods: Included in this retrospective cross-sectional mono-centric study were 308 pediatric patients with suspected or known autoimmune conditions who had a positive ANA in indirect immune fluorescence (IIF) screening and who were screened for anti-DFS70 antibodies by extractable nuclear antigen antibodies (ENA) immunoblot. Patients were assigned to four different diagnostic categories according to their diagnosis in the corresponding medical record: (a) absence of autoimmune or rheumatic disease (noARD, n = 116); (b) suspected autoimmunity without definitive diagnosis (sAI, n = 48); (c) other rheumatic disease (ORD) (n = 115); and (d) ANA-associated autoimmune disease (AARD, n = 29). Results: The prevalence of anti-DFS70 antibodies in the overall cohort was 33.8%. Among children without ARD (46.6%, 54/116), prevalence was significantly higher than among children with ORD (23.7%, 27/115, p = 0.0003) or AARD (17.2%, 5/29, p = 0.0054). Among all of the anti-DFS70 positive patients with AARD, other autoantibodies were found in the ENA immunoblot. In contrast, among anti-DFS70 positive patients with ORD (11.5%, 4/27), sAI (33.3%, 6/18) and noARD (16.7%, 9/54), other autoantibodies infrequently were detected (p = 0.0005). Patients with uveitis rarely were positive for anti-DFS70 antibodies (7.7%, 1/13). No association was found between anti-DFS70 antibodies and a history of allergic conditions (p = 0.51). The concordance between a typical DFS pattern in IIF and the detection of anti-DFS70 antibodies by immunoblot was 59.3%. Conclusion: As with adults, the higher prevalence of anti-DFS70 among children without autoimmune disease confirms the mutual exclusion for this autoantibody in the pathogenesis of ARD. Among ANA-positive children, monospecific anti-DFS70 antibodies may help to discriminate between AARD and not-AARD-related conditions.

Robust and durable serological response following pediatric SARS-CoV-2 infection.

The quality and persistence of children's humoral immune response following SARS-CoV-2 infection remains largely unknown but will be crucial to guide pediatric SARS-CoV-2 vaccination programs. Here, we examine 548 children and 717 adults within 328 households with at least one member with a previous laboratory-confirmed SARS-CoV-2 infection. We assess serological response at 3-4 months and 11-12 months after infection using a bead-based multiplex immunoassay for 23 human coronavirus antigens including SARS-CoV-2 and its Variants of Concern (VOC) and endemic human coronaviruses (HCoVs), and additionally by three commercial SARS-CoV-2 antibody assays. Neutralization against wild type SARS-CoV-2 and the Delta VOC are analysed in a pseudotyped virus assay. Children, compared to adults, are five times more likely to be asymptomatic, and have higher specific antibody levels which persist longer (96.2% versus 82.9% still seropositive 11-12 months post infection). Of note, symptomatic and asymptomatic infections induce similar humoral responses in all age groups. SARS-CoV-2 infection occurs independent of HCoV serostatus. Neutralization responses of children and adults are similar, although neutralization is reduced for both against the Delta VOC. Overall, the long-term humoral immune response to SARS-CoV-2 infection in children is of longer duration than in adults even after asymptomatic infection.

Early-onset pulmonary and cutaneous vasculitis driven by constitutively active SRC-family kinase HCK.

BACKGROUND: Inborn errors of immunity are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity, or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of inborn errors of immunity, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. OBJECTIVE: We sought to report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515∗, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis. METHODS: Whole-exome sequencing, Sanger sequencing, mass spectrometry, and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines. RESULTS: Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α, and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in inflammatory lung disease. CONCLUSIONS: We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of inborn errors of immunity.

A Novel Case of Homozygous Interferon Alpha/Beta Receptor Alpha Chain (IFNAR1) Deficiency With Hemophagocytic Lymphohistiocytosis.

We present a case of complete deficiency of the interferon alpha/beta receptor alpha chain (IFNAR1) in a child with fatal systemic hyperinflammation, apparently provoked by live-attenuated viral vaccination. Such pathologic hyperinflammation, fulfilling criteria for hemophagocytic lymphohistiocytosis, is an emerging phenotype accompanying inborn errors of type I interferon immunity.

Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 in Households with Children, Southwest Germany, May-August 2020.

Resolving the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in households with members from different generations is crucial for containing the current pandemic. We conducted a large-scale, multicenter, cross-sectional seroepidemiologic household transmission study in southwest Germany during May 11-August 1, 2020. We included 1,625 study participants from 405 households that each had ≥1 child and 1 reverse transcription PCR-confirmed SARS-CoV-2-infected index case-patient. The overall secondary attack rate was 31.6% and was significantly higher in exposed adults (37.5%) than in children (24.6%-29.2%; p = <0.015); the rate was also significantly higher when the index case-patient was >60 years of age (72.9%; p = 0.039). Other risk factors for infectiousness of the index case-patient were SARS-CoV-2-seropositivity (odds ratio [OR] 27.8, 95% CI 8.26-93.5), fever (OR 1.93, 95% CI 1.14-3.31), and cough (OR 2.07, 95% CI 1.21-3.53). Secondary infections in household contacts generate a substantial disease burden.

Case Report: Lymphohistiocytic Myocarditis With Severe Cardiogenic Shock Requiring Mechanical Cardiocirculatory Support in Multisystem Inflammatory Syndrome Following SARS-CoV-2 Infection.

Multisystem Inflammatory Syndrome (MIS) is a novel hyperinflammatory syndrome associated with SARS-CoV-2 infection. It predominantly affects children (MIS-C) a few weeks after a usually asymptomatic SARS-CoV-2 infection and is only rarely seen in adults above 21 years (MIS-A). Only scarce data on histological findings in both pediatric and adult patients has been published so far. An 18-year-old male patient was admitted to hospital in a febrile state, which progressed to severe cardiogenic shock and multi-organ failure requiring extracorporeal life support. Myocardial biopsy revealed small vessel-associated immune cell infiltrates. Diagnosis of MIS-C was made after ruling out all potential differential diagnosis. Use of immunosuppressive treatment with steroids, interleukin-1 blockade and high-dose intravenous immunoglobulins resulted in the patient's full recovery. Multisystem Inflammatory Syndrome (MIS) is a new differential diagnosis of cardiac dysfunction in pediatric and adult patients. The lack of myocardial necrosis differentiates the disease from other viral myocarditis and offers an explanation for the fast response to immunomodulatory therapy and the favorable prognosis. The preceding SARS-CoV-2 infection might only have been mildly symptomatic or even asymptomatic.