Pathologic Analysis of Twenty-one Appendices From Children With Multisystem Inflammatory Syndrome Compared to Specimens of Acute Appendicitis: A Cross-sectional Study.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is a rare, severe complication of coronavirus disease 2019, commonly involving the gastrointestinal tract. Some children with MIS-C undergo appendectomy before the final diagnosis. There are several hypotheses explaining the pathomechanism of MIS-C, including the central role of the viral antigen persistence in the gut, associated with lymphocyte exhaustion. We aimed to examine appendectomy specimens from MIS-C patients and assess their pathologic features, as well as the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens. METHODS: In this cross-sectional study we included 21 children with MIS-C who underwent appendectomy. The control group included 21 sex- and age-matched children with acute appendicitis (AA) unrelated to SARS-CoV-2 infection. Histologic evaluation of appendiceal specimens included hematoxylin and eosin staining and immunohistochemical identification of lymphocyte subpopulations, programmed cell death protein-1 (PD-1) and SARS-CoV-2 nucleocapsid antigen. RESULTS: Appendices of MIS-C patients lacked neutrophilic infiltrate of muscularis propria typical for AA (14% vs. 95%, P < 0.001). The proportion of CD20+ to CD5+ cells was higher in patients with MIS-C (P = 0.04), as was the proportion of CD4+ to CD8+ (P < 0.001). We found no proof of SARS-CoV-2 antigen presence, nor lymphocyte exhaustion, in the appendices of MIS-C patients. CONCLUSIONS: The appendiceal muscularis of patients with MIS-C lack edema and neutrophilic infiltration typical for AA. SARS-CoV-2 antigens and PD-1 are absent in the appendices of children with MIS-C. These findings argue against the central role of SARS-CoV-2 persistence in the gut and lymphocyte exhaustion as the major triggers of MIS-C.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

A survey study on antibiotic prescription practices for acute asthma exacerbations: An European academy of allergy and clinical immunology task force report.

INTRODUCTION: Guidelines recommend treating asthma exacerbations (AAEs) with bronchodilators combined with inhaled and/or systemic corticosteroids. Indications for antibiotic prescriptions for AAEs are usually not incorporated although the literature shows antibiotics are frequently prescribed. AIM: To investigate the antibiotic prescription rates in AAEs and explore the possible determining factors of those practices. METHODS: A digital survey was created to determine the antibiotic prescription rates in AAEs and the influencing factors for the prescription practices. The survey was distributed among European academy of allergy and clinical immunology (EAACI) members by mass emailing and through regional/national societies in the Netherlands, Italy, Greece, and Poland. Furthermore, we retrieved local antibiotic prescription rates. RESULTS: In total, 252 participants completed the survey. Respondents stated that there is a lack of guidelines to prescribe antibiotics in AAEs. The median antibiotic prescription rate in this study was 19% [IQR: 0%-40%] and was significantly different between 4 professions: paediatrics 0% [IQR: 0%-37%], pulmonologists 25% [IQR: 10%-50%], general practitioners 25% [IQR: 0%-50%], and allergologists 17% [IQR: 0%-33%]) (p = 0.046). Additional diagnostic tests were performed in 71.4% of patients before prescription and the most common antibiotic classes prescribed were macrolides (46.0%) and penicillin (42.9%). Important clinical factors for health care providers to prescribe antibiotics were colorised/purulent sputum, abnormal lung sounds during auscultation, fever, and presence of comorbidities. CONCLUSION: In 19% of patients with AAEs, antibiotics were prescribed in various classes with a broad range among different subspecialities. This study stresses the urgency to compose evidence-based guidelines to aim for more rational antibiotic prescriptions for AAE.

A systematic review and meta-analysis on absolute eosinophil counts and the risk of asthma in preschool children with wheezing: An EAACI Task Force Report.

Preschool children with wheezing disorders pose diagnostic and therapeutic challenges and consume substantial healthcare resources. Peripheral eosinophil blood count (EBC) has been proposed as a potential indicator for future asthma development. This review by the European Academy of Allergy and Clinical Immunology (EAACI) Preschool Wheeze Task Force aimed to provide systematic evidence for the association between increased EBC and the risk of future asthma, as well as to identify potential cutoff values. In February 2023, a search of PubMed, EMBASE, and Cochrane Library databases was conducted to identify studies comparing EBCs in preschool children with wheezing who continued to wheeze later in life and those who did not. Included observational studies focused on children aged <6 years with a wheezing disorder, assessment of their EBCs, and subsequent asthma status. No language or publication date restrictions were applied. Among the initial 3394 studies screened, 10 were included in the final analysis, involving 1225 patients. The data from these studies demonstrated that high EBC in preschool children with wheezing is associated with future asthma development, with odds ratios of 1.90 (95% CI: 0.45-7.98, p = .38), 2.87 (95% CI: 1.38-5.95, p < .05), and 3.38 (95% CI: 1.72-6.64, p < .05) for cutoff values in the <300, 300-449, and ≥450 cells/µL ranges, respectively. Defining a specific cutoff point for an elevated EBC lacks consistency, but children with EBC >300 cells/µL are at increased risk of asthma. However, further research is needed due to the limitations of the included studies. Future investigations are necessary to fully elucidate the discussed association.

Intravenous magnesium sulfate for asthma exacerbations in children: Systematic review with meta-analysis.

BACKGROUND: Asthma is the most prevalent chronic disease in children and constitutes a significant healthcare burden. First-line therapy for acute asthma exacerbations is well established. However, secondary treatments, including intravenous magnesium sulfate (IV-MgSO4), remain variable due to scarcity of data on its efficacy and safety. OBJECTIVE: To assess the effectiveness and safety of IV-MgSO4 as a second line of treatment in managing children with asthma exacerbations. METHODS: We searched five databases from inception until April 2023 on randomized clinical trials of IV-MgSO4 in children with acute asthma exacerbations. The primary outcomes were hospitalization rate and length, and change in the severity score. Secondary outcomes included percentage increase in peak expiratory flow rate (PEFR), hospital re-admission rate, need and length for pediatric intensive care unit (PICU) treatment, and adverse effects. Meta-analysis was performed for three outcomes with estimated odds ratios (ORs) or mean differences (MDs) and 95% confidence intervals (CIs). RESULTS: Eleven studies met the final criteria. In comparison to control, administration of IV-MgSO4 was associated with a reduced hospitalization risk (OR 0.15; 95%CI: 0.03, 0.73) in four studies, and improvement of lung function (MD 26.77% PEFR; 95%CI: 18.41, 54.79) in two studies. There were no significant differences in the length of stay between groups. Due to heterogeneity, a narrative synthesis of other outcomes was performed. CONCLUSION: The use of IV-MgSO4 demonstrated a reduction in the hospitalization rate and PEFR improvement in children with asthma exacerbations. Adverse effects were rare. Further well-designed studies are needed to better determine the efficacy and safety profile of IV-MgSO4.

IP-10 for the Diagnosis and Treatment Monitoring of Tuberculosis in Children.

PURPOSE: To determine the utility of interferon-gamma-inducible protein 10 (IP-10) for identifying active tuberculosis (TB) and TB infection (TBI) in children in BCG-vaccinated populations, establish its diagnostic performance characteristics, and evaluate changes in IP-10 level during anti-TB chemotherapy. METHODS: Concentrations of IP-10 and IFN-γ were measured in QuantiFERON-TB Gold (QFT) supernatants in children with suspected TB or due to recent TB contact. A total of 225 children were investigated: 33 with active TB, 48 with TBI, 83 TB contacts, 20 with suspected TB but other final diagnoses, and 41 controls. In 60 children, cytokine responses were evaluated at a follow-up visit after 2 months of anti-TB treatment. RESULTS: IP-10 expression was significantly higher in infected children (active TB and TBI cases) than in uninfected individuals. IP-10 proved effective in identifying TB infection at its optimal cut-off (>1084.5 pg/mL) but was incapable of differentiating between children with active TB and TBI. Combining IP-10 and IFN-γ increased the QFT sensitivity. IP-10 but not IFN-γ decreased significantly during anti-TB treatment in children with active TB (p = 0.003). CONCLUSION: IP-10 identifies TB infection and declines during anti-TB chemotherapy in children. Incorporating IP-10 into new immunodiagnostic assays could improve TB diagnosis and allow for treatment monitoring.

Association of respiratory virus types with clinical features in bronchiolitis: Implications for virus testing strategies. A systematic review and meta-analysis.

BACKGROUND: Bronchiolitis is a leading cause of infant hospitalization, linked to respiratory syncytial virus (RSV) and rhinovirus (RV). Guidelines lack specific viral testing for bronchiolitis management. To establish effective management strategies, it is crucial to assess whether specific respiratory virus types are correlated with distinct examination features. METHODS: Through a systematic search of three databases, 21 studies were qualitatively analyzed, with 18 used for meta-analysis. Various outcomes like wheezing on auscultation, fever, atopic traits, and infection severity were evaluated. RESULTS: RSV-positive bronchiolitis was associated with a higher need for oxygen supplementation (OR 1.78, 95% CI 1.04-3.02) in 5 studies, while RV-positive bronchiolitis was more frequently linked to personal history of eczema (OR 0.60, 95% CI 0.41-0.88) in 6 studies. No significant differences were observed in the other outcomes examined. CONCLUSIONS: Bronchiolitis caused by RSV or RV presents with similar clinical features. Despite the associations between RSV-positive bronchiolitis and need for oxygen supplementation, and RV-positive bronchiolitis and a history of eczema, our study shows that viral etiology of bronchiolitis cannot be determined solely based on clinical presentation. Tailored management strategies, informed by accurate viral testing, seem crucial in clinical practice for enhancing patient outcomes in severe bronchiolitis.

Severe bronchiolitis profiling as the first step towards prevention of asthma.

Bronchiolitis is the most common respiratory infection leading to hospitalization and constitutes a significant healthcare burden. The two main viral agents causing bronchiolitis, respiratory syncytial virus (RSV) and rhinovirus (RV), have distinct cytopathic, immune response, and clinical characteristics. Different approaches have been suggested for subtyping bronchiolitis based on viral etiology, atopic status, transcriptome profiles in blood, airway metabolome, lipidomic data, and airway microbiota. The highest risk of asthma at school age has been in a subgroup of bronchiolitis characterized by older age, high prevalence of RV infection, previous breathing problems, and/or eczema. Regarding solely viral etiology, RV-bronchiolitis in infancy has been linked to a nearly three times higher risk of developing asthma than RSV-bronchiolitis. Although treatment with betamimetics and systemic corticosteroids has been found ineffective in bronchiolitis overall, it can be beneficial for infants with severe RV bronchiolitis. Thus, there is a need to develop a more individualized therapeutic approach for bronchiolitis and follow-up strategies for infants at higher risk of asthma in the future perspective.

Severe bronchiolitis profiling as the first step towards prevention of asthma

Bronchiolitis is the most common respiratory infection leading to hospitalization and constitutes a significant healthcare burden. The two main viral agents causing bronchiolitis, respiratory syncytial virus (RSV) and rhinovirus (RV), have distinct cytopathic, immune response, and clinical characteristics. Different approaches have been suggested for subtyping bronchiolitis based on viral etiology, atopic status, transcriptome profiles in blood, airway metabolome, lipidomic data, and airway microbiota. The highest risk of asthma at school age has been in a subgroup of bronchiolitis characterized by older age, high prevalence of RV infection, previous breathing problems, and/or eczema. Regarding solely viral etiology, RV-bronchiolitis in infancy has been linked to a nearly three times higher risk of developing asthma than RSV-bronchiolitis. Although treatment with betamimetics and systemic corticosteroids has been found ineffective in bronchiolitis overall, it can be beneficial for infants with severe RV bronchiolitis. Thus, there is a need to develop a more individualized therapeutic approach for bronchiolitis and follow-up strategies for infants at higher risk of asthma in the future perspective (AU)

Association of low physical activity with higher respiratory tract infections frequency among pre-school children.

BACKGROUND: There is no consensus on the benefits of physical activity (PA) regarding upper respiratory tract infections (URTIs) among children. This study aimed to determine an association between the PA level and URTIs in preschoolers. METHODS: In 4-7-year-old participants, URTI symptoms were monitored using the Polish version of the Wisconsin Upper Respiratory System Survey for Kids. The daily number of steps, PA intensity, and sleep duration were measured with a Garmin-vivofit pedometer. The lag effect between the initial level of daily PA and the frequency of infections was evaluated. RESULTS: The average daily step count from healthy days was a significant determinant of the total number of days with the URTI symptoms, and it accounted for 44% (p < 0.001) of this variable variance. A low level of baseline PA (initial 14-day "run-in" observation period) was associated with an increased risk of URTI. In the non-sport group, the severity of the URTI symptoms depended on the number of daily steps. No significant correlation was found between sleep duration and the number of URTI days. CONCLUSION: Low levels of PA in preschoolers result in increased susceptibility to respiratory infections. Parents should encourage children to engage in PA to prevent URTIs. IMPACT: In pre-school children, higher physical activity (PA) is associated with fewer days of upper respiratory tract infection symptoms (URTIS). Children with a higher average daily step count have fewer days with URTIS over a long-term observation period. A change in the average number of steps per day by 1000 changed the number of days with symptoms of URTI by 4 days. The severity of URTIS was inversely related to the degree of PA. Children who participate in sports 3 or more hours per week have fewer URTIS than those who do not engage in sports regularly.

Pathogenesis, immunology, and immune-targeted management of the multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome (PIMS): EAACI Position Paper.

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately 4 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

Prevalence of major food allergens in skincare products for atopic dermatitis.

Introduction: Food allergy is a common concomitant disease in patients with atopic dermatitis. Sensitisation and subsequent development of food allergy might result from the application of skincare products containing food allergens, particularly when the skin barrier is impaired and inflamed. Emollients are the mainstay of the management of atopic dermatitis; however, the prevalence of food allergens in skincare products used for atopic dermatitis is unknown. Aim: To analyse the prevalence of major food allergens in skincare products for atopic dermatitis. Material and methods: Three major online cosmetic retailers in Poland were screened for atopic skincare products. The major food allergens under the mandatory allergen labelling regulation of the European Union were searched for using the INCI nomenclature of cosmetics ingredients. Results: We screened 396 skincare products, out of which 127 (32.1%) products contained at least one derivative of a major food allergen. The most common allergens were almonds, macadamia nuts, soya and cereals, followed by sesame and milk. There was no significant difference in the presence of food derivatives between leave-on and rinse-off skincare products, as well as between those intended for use by infants and children, and adults only. Conclusions: Our analysis revealed that major food allergens are prevalent in skincare products for eczema. Applying skincare products containing food derivatives on affected and inflamed skin can promote percutaneous sensitisation. Therefore, clinicians and patients with atopic dermatitis must be careful of products used for treating eczema that may contain derivatives of a major food allergen.

Can bacterial lysates be useful in prevention of viral respiratory infections in childhood? The results of experimental OM-85 studies.

Respiratory tract infections (RTI) are mainly viral in origin and among the leading cause of childhood morbidity globally. Associated wheezing illness and asthma are still a clear unmet medical need. Despite the continuous progress in understanding the processes involved in their pathogenesis, preventive measures and treatments failed to demonstrate any significant disease-modifying effect. However, in the last decades it was understood that early-life exposure to microbes, may reduce the risk of infectious and allergic disorders, increasing the immune response efficacy. These results suggested that treatment with bacterial lysates (BLs) acting on gut microbiota, could promote a heterologous immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. This hypothesis has been supported by clinical and experimental studies showing the reduction of RTI frequency and severity in childhood after oral BL prophylaxis and elucidating the involved mechanisms. OM-85 is the product whose anti-viral effects have been most extensively studied in vitro, animal, and human cell studies and in translational animal infection/disease models. The results of the latter studies, describing the potential immune training-based activities of such BL, leading to the protection against respiratory viruses, will be reported. In response to human rhinovirus, influenza virus, respiratory syncytial virus and severe acute respiratory coronavirus-2, OM-85 was effective in modulating the structure and the functions of a large numbers of airways epithelial and immune cells, when administered both orally and intranasally.

"Liquid biopsy" - extracellular vesicles as potential novel players towards precision medicine in asthma.

Extracellular vesicles (EVs) have emerged as vital mediators in intracellular communication in the lung microenvironment. Environmental exposure to various triggers (e.g., viruses, allergens) stimulates the EV-mediated cascade of pro-inflammatory responses that play a key role in the asthma pathomechanism. This complex EV-mediated crosstalk in the asthmatic lung microenvironment occurs between different cell types, including airway epithelial cells and immune cells. The cargo composition of EVs mirrors hereby the type and activation status of the parent cell. Therefore, EVs collected in a noninvasive way (e.g., in nasal lavage, serum) could inform on the disease status as a "liquid biopsy", which is particularly important in the pediatric population. As a heterogeneous disease, asthma with its distinct endotypes and phenotypes requires more investigation to develop novel diagnostics and personalized case management. Filling these knowledge gaps may be facilitated by further EV research. Here, we summarize the contribution of EVs in the lung microenvironment as potential novel players towards precision medicine in the development of asthma. Although rapidly evolving, the EV field is still in its infancy. However, it is expected that a better understanding of the role of EVs in the asthma pathomechanism will open up new horizons for precision medicine diagnostic and therapeutic solutions.

Respiratory virus type to guide predictive enrichment approaches in the management of the first episode of bronchiolitis: A systematic review.

It has become clear that severe bronchiolitis is a heterogeneous disease; even so, current bronchiolitis management guidelines rely on the one-size-fits-all approach regarding achieving both short-term and chronic outcomes. It has been speculated that the use of molecular markers could guide more effective pharmacological management and achieve the prevention of chronic respiratory sequelae. Existing data suggest that asthma-like treatment (systemic corticosteroids and beta2-agonists) in infants with rhinovirus-induced bronchiolitis is associated with improved short-term and chronic outcomes, but robust data is still lacking. We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane's Library to identify eligible randomized controlled trials to determine the efficacy of a personalized, virus-dependent application of systemic corticosteroids in children with severe bronchiolitis. Twelve studies with heterogeneous methodology were included. The analysis of the available results comparing the respiratory syncytial virus (RSV)-positive and RSV-negative children did not reveal significant differences in the associatons between systemic corticosteroid use in acute episode and duration of hospitalization (short-term outcome). However, this systematic review identified a trend of the positive association between the use of systematic corticosteroids and duration of hospitalization in RSV-negative infants hospitalized with the first episode of bronchiolitis (two studies). This evidence is not conclusive. Taken together, we suggest the design for future studies to assess the respiratory virus type in guiding predictive enrichment approaches in infants presenting with the first episode of bronchiolitis. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020173686.

Fungal exposome, human health, and unmet needs: A 2022 update with special focus on allergy.

Humans inhale, ingest, and touch thousands of fungi each day. The ubiquity and diversity of the fungal kingdom, reflected by its complex taxonomy, are in sharp contrast with our scarce knowledge about its distribution, pathogenic effects, and effective interventions at the environmental and individual levels. Here, we present an overview of salient features of fungi as permanent players of the human exposome and key determinants of human health, through the lens of fungal allergy and other fungal hypersensitivity reactions. Improved understanding of the fungal exposome sheds new light on the epidemiology of fungal-related hypersensitivity diseases, their immunological substratum, the currently available methods, and biomarkers for environmental and medical fungi. Unmet needs are described and potential approaches are highlighted as perspectives.