Effects of CFTR-modulator triple therapy on sinunasal symptoms in children and adults with cystic fibrosis.

PURPOSE: Sinunasal symptoms and chronic rhinusinutitis are common in patients with cystic fibrosis. Cystic fibrosis transmembrane regulator (CFTR) modulators have led to dramatic improvements of respiratory symptoms and quality of life in patients with cystic fibrosis. This study aims to evaluate subjective and objective sinunasal symptoms after start of CFTR-modulator triple therapy. METHODS: 43 patients (n = 6 < 18 years), treated with highly effective CFTR-modulator therapy with elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) were included, as were 20 controls with cystic fibrosis but without CFTR-modulator therapy (n = 6 < 18 years). All assessed their sinunasal symptoms retrospectively and the intervention group at a mean of 9.3 (2-16) months after start of ELX/TEZ/IVA. RESULTS: Improvements in SNOT-22 overall score from m = 32.7 to m = 15.7 points (p < 0.0001) as well in the nasal, emotional, otologic, and sleep subdomains could be demonstrated in the intervention group. No changes were found in the control group. Children showed lower SNOT-22 scores than adults and a reduction of SNOT-22 total score from m = 9.4 to m = 2.2 (p = 0.25) was found. 8 patients were evaluated by an otorhinolaryngologist before and after start of ELX/TEZ/IVA and showed pronounced objective clinical improvement. CONCLUSIONS: Highly effective CFTR-modulator therapy has a significant positive impact on both subjective and objective sinunasal symptoms in patients with CF and some improvement could be demonstrated in children < 18 years as well.

'We just did it as a team': Learning and working on a paediatric interprofessional training ward improves interprofessional competencies in the short- and in the long-term.

PURPOSE: Interprofessional (IP) education is essential for healthcare professionals to prepare them for future IP collaboration. IP training wards (ITWs) have been established for work-based IP education. Short-term effects of ITW placements have been published but long-term results are scarce. There are no reports on ITWs in paediatrics. We established the Interprofessional Training Ward in Paediatrics (IPAPAED) for paediatric nursing trainees and medical students. The aim of the study is to evaluate both short- and long-term outcomes regarding IP competencies of IPAPAED participants. METHODS: The study was designed as a prospective, non-randomized trial, using a mixed-methods design. The Interprofessional Socialization and Valuing Scale (ISVS-9A/B) and the Interprofessional Collaboration Scale (ICS) were used for quantitative evaluation, qualitative data were gathered from structured group discussions and free-text comments. Data were collected from 68 IPAPAED participants, before and after the rotation, and 6-34 months later.Results: IPAPAED participants showed increased global scores in the ISVS 9 A/B and rated their communication competencies and their accommodation in IP teams better (ICS). Improvements in communication competency and accommodation persisted at 6-34 months.Conclusions: IP learning and working on IPAPAED had positive short-term effects on interprofessional competencies. Some of these effects persisted on a long-term.

Cystic fibrosis in disguise - the wolf in sheep's clothing, a case report.

BACKGROUND: Childhood hypoglycemia in combination with hepatomegaly is suspicious for inborn errors of metabolism. Cystic fibrosis typically presents with failure to thrive, pulmonary and gastrointestinal symptoms. Hepatic involvement and hypoglycemia can occur in a significant number of patients, although hepatomegaly is uncommon. CASE PRESENTATION: A 28 months old boy was presented with recurrent upper airways infections, progressive lethargy and weight loss. Clinically hepatomegaly was the main presenting feature and hypoglycemia (minimum 1.4 mmol/l) was noted as were elevated transaminases. The patient did not produce enough sweat to analyze it. Infectious causes for hepatitis were excluded and a broad metabolic work-up initiated. A therapy with starch was initiated to control hypoglycemia. In further course loose stools were reported and pancreatic elastase was found to be reduced. A further sweat test yielded pathological chloride concentration and genetic testing confirmed the diagnosis of cystic fibrosis. CONCLUSIONS: Cystic fibrosis is a systemic disease and less common presentations need to be considered. Even in the age of CF-newborn screening in many countries CF needs to be ruled out in typical and atypical clinical presentations and diagnostics need to be repeated if inconclusive.

Nursing staff's and physicians' acquisition of competences and attitudes to interprofessional education and interprofessional collaboration in pediatrics.

BACKGROUND: Interprofessional education (IPE) is deemed essential for interprofessional collaboration (IPC) in healthcare systems. IPC has positive effects for both patients and healthcare professionals. Especially in pediatrics, IPC is paramount for adequate care of patients and their families though there is a lack of data on the attitudes towards IPE and IPC and acquisition of respective competences in pediatric nursing and medical staff. METHODS: Frequencies of interactions and attitudes towards IPE and IPC, with a focus on acquisition of competences for IPE and IPC, of nurses (N = 79) and physicians (N = 70) in a large pediatric university hospital were evaluated with an online questionnaire. RESULTS: All participants worked as part of interprofessional teams, mostly consisting of nurses and physicians. The majority (94.9% (n = 75) of nurses and 100% (n = 70) of physicians) highly valued IPC. Medical doctors acquired most competences important for IPC during day-to-day work and reported a substantial lack of IPE. Nursing staff on the other hand did report significant interprofessional education during their training as well as ongoing interprofessional learning during day-to-day work. Nurses also appreciated IPE more. CONCLUSIONS: Even though IPC is commonly reported in nurses and physicians working at a large pediatric university hospital there is a lack of structured IPE. A focus should be on IPE for nurses and physicians to enable them to effectively collaborate together. Political and local initiatives for IPE are gaining momentum but still need to be established nationally and internationally.

Patients' and parents' percetion of care on a paediatric interprofessional training ward.

BACKGROUND: Interprofessional training wards (ITWs) have been established in different fields of adult medicine to promote interprofessional learning and interprofessional collaboration of health care profession students. High patient satisfaction rates have been reported for ITWs. No data of parents' and especially patients' evaluation of care on a paediatric ITW have been reported so far. This study aims to evaluate parents' and patients' perceptions of medical and nursing care on a paediatric ITW. METHODS: In 2017 we established and started an interprofessional training ward in the setting of a general paediatric ward (IPAPAED). Medical students and nurse trainees care for 4-6 patients under supervision of registered nurses and certified physicians. All parents and all patients older than 8 years were invited to evaluate different aspect of their care on the IPAPAED. RESULTS: Since November 2017 until February 2019 parents (n = 109) rated the overall care of their children on the IPAPAED ward with m = 1.21 (SD ± .43) (1 = "excellent", 4 = "poor"). Patients (n = 56) rated their overall care with m = 1.29 (SD ± 0.5). Other aspects of care and interprofessional collaboration were rated equally well. Analysis of the (limited) free-text commentaries revealed that perceived quality of care, friendliness and communication were especially valued by patients and parents. DISCUSSION & CONCLUSION: On a paediatric ITW, in the view of parents and patients in our sample, a high level of care is delivered and satisfaction rates are excellent. An ITW seems, from a patient and parent point of view, feasible, even in paediatrics.

Student-perceived exam difficulty may trump the effects of different quality improvement measures regarding the students' evaluation of a pediatric lecture series.

BACKGROUND: Lectures are still an important part of today's medical education at many medical schools. The pediatric lecture series at the Center for Pediatrics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Germany had been evaluated poorly in recent terms. METHODS: To improve lecture quality and possibly evaluation results a combination of measures consisting of peer lecturer coaching, use of an audience response system, in depth analysis of the end of term evaluation results and changes to the exam itself were implemented. RESULTS: Peer lecturer coaching was performed successfully and both the audience response system evaluation as well as the end of term evaluation results improved significantly in the following term. Analysis of the students' comments revealed more approval of lecture content and presentation after the organization of the lecture series was changed towards less lecturers and focus on less topics. Student-perceived high exam difficulty influenced the evaluation negatively. CONCLUSION: The student-perceived exam difficulty can supersede the effects of different measures to improve lecture quality measured via evaluation. Whether better evaluation of the lecture series after different improvement measures was due to better match of the curriculum with the exam content or that an improved curriculum led to better exam performance remains to be elucidated.

Effective Immunological Guidance of Genetic Analyses Including Exome Sequencing in Patients Evaluated for Hemophagocytic Lymphohistiocytosis.

We report our experience in using flow cytometry-based immunological screening prospectively as a decision tool for the use of genetic studies in the diagnostic approach to patients with hemophagocytic lymphohistiocytosis (HLH). We restricted genetic analysis largely to patients with abnormal immunological screening, but included whole exome sequencing (WES) for those with normal findings upon Sanger sequencing. Among 290 children with suspected HLH analyzed between 2010 and 2014 (including 17 affected, but asymptomatic siblings), 87/162 patients with "full" HLH and 79/111 patients with "incomplete/atypical" HLH had normal immunological screening results. In 10 patients, degranulation could not be tested. Among the 166 patients with normal screening, genetic analysis was not performed in 107 (all with uneventful follow-up), while 154 single gene tests by Sanger sequencing in the remaining 59 patients only identified a single atypical CHS patient. Flow cytometry correctly predicted all 29 patients with FHL-2, XLP1 or 2. Among 85 patients with defective NK degranulation (including 13 asymptomatic siblings), 70 were Sanger sequenced resulting in a genetic diagnosis in 55 (79%). Eight patients underwent WES, revealing mutations in two known and one unknown cytotoxicity genes and one metabolic disease. FHL3 was the most frequent genetic diagnosis. Immunological screening provided an excellent decision tool for the need and depth of genetic analysis of HLH patients and provided functionally relevant information for rapid patient classification, contributing to a significant reduction in the time from diagnosis to transplantation in recent years.

Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents.

Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M-HLH) in 21 patients, most of whom had T- (n = 12) or B-cell neoplasms (n = 7), with Epstein-Barr virus as a co-trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch-HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M- and Ch-HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M-HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch-HLH patients had evidence of active HLH. To overcome HLH, malignancy- and HLH-directed treatments were administered in the M-HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch-HLH, treatment ranged from postponement of chemotherapy to the use of etoposide-containing regimens.

The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2.

Genetic disorders of lymphocyte cytotoxicity predispose patients to hemophagocytic lymphohistiocytosis (HLH). Reduced lymphocyte cytotoxicity has been demonstrated in Hermansky-Pudlak syndrome type 2 (HPS2), but only a single patient was reported who developed HLH. Because that patient also carried a potentially contributing heterozygous RAB27A mutation, the risk for HLH in HPS2 remains unclear. We analyzed susceptibility to HLH in the pearl mouse model of HPS2. After infection with lymphocytic choriomeningitis virus, pearl mice developed all key features of HLH, linked to impaired virus control caused by a moderate defect in CTL cytotoxicity in vivo. However, in contrast to perforin-deficient mice, the disease was transient, and all mice fully recovered and controlled the infection. An additional heterozygous Rab27a mutation did not aggravate the cytotoxicity defect or disease parameters. In the largest survey of 22 HPS2 patients covering 234 patient years, we identified only 1 additional patient with HLH and 2 with incomplete transient HLH-like episodes, although cytotoxicity or degranulation was impaired in all 16 patients tested. HPS2 confers a risk for HLH that is lower than in Griscelli or Chediak-Higashi syndrome, probably because of a milder defect in cytotoxicity. Preemptive hematopoietic stem cell transplantation does not appear justified in HPS2.

Hemophagocytic lymphohistiocytosis in imported pediatric visceral leishmaniasis in a nonendemic area.

OBJECTIVES: To describe characteristics of visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (HLH) with focus on diagnostic clues and pitfalls, including the frequency of central nervous system (CNS) involvement, and to determine the efficacy of liposomal amphotericin B (L-AmB). STUDY DESIGN: We retrospectively analyzed clinical and laboratory features, diagnostic procedures, and treatment of 13 patients with HLH with imported visceral leishmaniasis, reported to the German HLH reference center (1999-2012). RESULTS: The spectrum of presentations was indistinguishable from patients with hereditary HLH or with acquired HLH because of infections with other pathogens. In 8 patients, disease onset occurred before the age of 2 years, coinciding with the typical age of manifestation of primary HLH. Two patients had mild nonspecific CNS findings. Misleading antiviral IgM (n = 6) and autoantibodies (n = 2) led to inaccurate interpretation of the etiology of HLH, sometimes with inappropriate therapeutic consequences. False negative results for Leishmania were obtained by initial bone marrow microscopy in 6/13, serology in 1/12, bone marrow culture in 2/5, and polymerase chain reaction of peripheral blood in 1/3 patients, and all bone marrow samples tested were Leishmania-positive by polymerase chain reaction (n = 7). L-AmB was administered to 12 patients, 5 of whom had no prior HLH-directed immunosuppressive therapy; sodium stibogluconate was administered to 1 patient. Persistent remission was achieved in 11 cases. Two patients required repeated or prolonged L-AmB therapy. CONCLUSIONS: Awareness of diagnostic pitfalls may save patients from unnecessary toxic treatment. CNS involvement is rare. L-AmB shows efficacy in visceral leishmaniasis-associated HLH.

Challenges and opportunities of evaluating work based interprofessional learning: insights from a pediatric interprofessional training ward.

Introduction: Interprofessional collaboration among healthcare professionals is fostered through interprofessional education (IPE). Work-based IPE has demonstrated effectiveness within interprofessional training wards. We developed the Interprofessional Training Ward in Pediatrics (IPAPED) and employ a combination of established assessment tools and a newly created IPAPED questionnaire, directed at to assess both students' learning experiences and program structure. This paper presents the development and analysis of the psychometric properties of the IPAPED questionnaire. Methods: Nursing trainees and medical students participated in IPAPED. The IPAPED questionnaire was developed to complement established instruments, based on IPE frameworks. Interprofessional collaboration and communication were represented in subscales in part 1 of the questionnaire. Part 2 focused on the IPAPED program itself. Statistical analyses included calculation of internal consistency for part 1 and exploratory factor analyses for part 2. Results: All IPAPED participants between November 2017 and November 2022 completed the questionnaire (n = 105). 94 of 105 questionnaires were analyzed. Internal consistency for part 1 was low (Cronbach's α <0.58). Exploratory factor analyses revealed three distinct factors: teaching and learning material, interprofessional learning facilitation and professional guidance by nurses on the ward. Discussion: Our results illustrate the challenge of performing high quality, theory based evaluation in a work-based setting. However, exploratory factor analyses highlighted the opportunity of focusing on both learning facilitators and staff on the wards to ensure a maximum learning output for participants. Developing program-specific questionnaires to gain insight into local structures has the potential to improve work-based IPE formats.

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.

Short-term effects of a novel bronchial drainage device: A pilot cohort study in subjects with cystic fibrosis.

Background and Aims: In cystic fibrosis (CF) airways, impaired airway mucociliary clearance and mucus accumulation due to cystic fibrosis transmembrane conductance regulator defects contribute to inflammation, progressive structural lung damage, and decline of lung function. Physiotherapy is essential to promote mucus mobilization and removal in CF and is a key element of rehabilitation measures, but conventional techniques may be suboptimal to mobilize viscous mucus. This study aimed to test the specific effects of a novel bronchial drainage device (BDD) (Simeox®; PhysioAssist) in subjects with CF and evaluate lung function, diaphragm mobility, and sputum properties. Methods: This prospective monocentric clinical cohort study in the setting of outpatient physiotherapy of CF patients (n = 21) with stable CF lung disease collected pulmonary lung function tests (PFT), diaphragm mobility, and sputum properties before and after two physiotherapy sessions using the novel BDD. PFT was assessed using spirometry and diaphragm mobility using m-mode ultrasound analysis. Spontaneous sputum samples were collected before and after using the BDD and analyzed for microstructure and DNA concentrations. Results: PFT parameters (FEV1, FVC, MEF25/50/75) were not affected by the use of the BDD. Ultrasound analysis of diaphragm mobility revealed an increase in maximum diaphragm excursion upon the intervention. Mucus analysis demonstrated altered microstructure and higher DNA concentrations collected after using the BDD compared to samples collected before. Pearson correlation analysis showed significant correlations between changes in mucus properties and DNA levels in respective mucus samples. Conclusion: Our results demonstrate that the novel BDD improves diaphragm mobility and alters sputum properties in subjects with CF. The novel BDD with unique properties may be further studied as a device in CF-specific physiotherapy to facilitate sputum mobilization of CF patients.

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.

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.

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.

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.

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.

Pulmonary granulomatosis of genetic origin.

Granulomatous inflammation of the lung can be a manifestation of different conditions and can be caused by endogenous inflammation or external triggers. A multitude of different genetic mutations can either predispose patients to infections with granuloma-forming pathogens or cause autoinflammatory disorders, both leading to the phenotype of pulmonary granulomatosis. Based on a detailed patient history, physical examination and a diagnostic approach including laboratory workup, pulmonary function tests (PFTs), computed tomography (CT) scans, bronchoscopy with bronchoalveolar lavage (BAL), lung biopsies and specialised microbiological and immunological diagnostics, a correct diagnosis of an underlying cause of pulmonary granulomatosis of genetic origin can be made and appropriate therapy can be initiated. Depending on the underlying disorder, treatment approaches can include antimicrobial therapy, immunosuppression and even haematopoietic stem cell transplantation (HSCT). Patients with immunodeficiencies and autoinflammatory conditions are at the highest risk of developing pulmonary granulomatosis of genetic origin. Here we provide a review on these disorders and discuss pathogenesis, clinical presentation, diagnostic approach and treatment.