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Background: Self‐reported exercise‐induced dyspnea (EID) is common among adolescents. Possible underlying pathologies are exercise‐induced bronchoconstriction (EIB) and laryngeal obstruction (EILO). The forced oscillation technique (FOT) may evaluate exercise‐induced changes in airway caliber. Aim: To investigate in adolescents the relationship between EID, EIB (post‐exercise fall in forced expiratory volume in 1s (FEV1)≥10%), EILO, and post‐exercise challenge changes in FOT parameters. Methods: One hundred and forty‐three subjects (97 with EID) of 13–15 years old underwent a standardized exercise challenge with FOT measurement and spirometry repeatedly performed between 2 and 30 min post‐exercise. EILO was studied in a subset of 123 adolescents. Subjects showing greater changes than the healthy subgroup in the modulus of the inspiratory impedance were considered FOT responders. Results: EID‐nonEIB subjects presented similar post‐exercise changes in all FOT parameters to nonEID‐nonEIB adolescents. Changes in all FOT parameters correlated with FEV1 fall. 45 of 97 EID subjects responded neither by FEV1 nor FOT to exercise. 19 and 18 subjects responded only by FEV1 (onlyFEV1responders) or FOT (onlyFOTresponders), respectively. Only a lower baseline forced vital capacity (FVC)%predicted and a higher FEV1/FVC distinguished the onlyFEV1responders from onlyFOTresponders. FOT parameters did not present specific post‐exercise patterns in EILO subjects. Conclusion: FOT can be used to identify post‐exercise changes in lower airway function. However, EID has a modest relation with both FEV1 and FOT responses, highlighting the need for objective testing. More research is needed to understand whether onlyFEV1responders and onlyFOTresponders represent different endotypes. [ABSTRACT FROM AUTHOR]

Immune responses of neonates differ markedly to those of adults, with skewed cytokine phenotypes, reduced inflammatory properties and drastically diminished memory function. Recent research efforts have started to unravel the role of cellular metabolism in determining immune cell fate and function. For studies in humans, much of the work on metabolic mechanisms underpinning innate and adaptive immune responses by different haematopoietic cell types is in adults. Studies investigating the contribution of metabolic adaptation in the unique setting of early life are just emerging, and much more work is needed to elucidate the contribution of metabolism to neonatal immune responses. Here, we discuss our current understanding of neonatal immune responses, examine some of the latest developments in neonatal immunometabolism and consider the possible role of altered metabolism to the distinctive immune phenotype of the neonate. Understanding the role of metabolism in regulating immune function at this critical stage in life has direct benefit for the child by affording opportunities to maximize immediate and long‐term health. Additionally, gaining insight into the diversity of human immune function and naturally evolved immunometabolic strategies that modulate immune function could be harnessed for a wide range of opportunities including new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Dysregulation of eicosanoids is associated with asthma and a composite of oxylipins, including exhaled leukotriene B4 (LTB4), characterizes childhood asthma. While fractional exhaled nitric oxide (FeNO) has been used as the standard for monitoring steroid responsiveness, the potential utility of eicosanoids in monitoring the therapeutic outcomes remains unclear. We aimed to examine the levels of major eicosanoids representing different metabolic pathways in exhaled breath condensates (EBCs) of children with asthma during exacerbation and after treatment. Methods: Levels of 6 exhaled eicosanoid species in asthmatic children and healthy subjects were evaluated using ELISA. Results: In addition to those previously reported, including LTB4, the levels of exhaled 15‐hydroxyeicosatetraenoic acid (15‐HETE), but not thromboxane B2 (TXB2), showed significant difference between asthmatics (N = 318) and healthy controls (N = 97), particularly the severe group showed the lowest levels of exhaled 15‐HETE. Receiver operating characteristic (ROC) curve analyses revealed similar distinguishing power for the levels of 15‐HETE, FEV1 (forced expiratory volume in the first second), and FeNO, while the 15‐HETE/LTB4 ratio was significantly lower in subjects with asthma as compared to that of healthy controls (p < 0.0001). Analysis of asthmatics (N = 75) during exacerbation and convalescence showed significant improvement in lung function (FEV1, p <.001), but not FeNO, concomitant with significantly increased levels of 15‐HETE (p <.001) and reduced levels of TXB2 (p <.05) at convalescence, particularly for those who at the top 30% level during exacerbation. Further, decreased LTB4 and lipoxin A4 (LXA4) at convalescence were noted only in those at the top 30 percentile during exacerbation. Conclusion: The exhaled 15‐HETE was found to discriminate childhood asthma while decreased levels of exhaled TXB2 and increased levels of 15‐HETE were prominent at convalescence. [ABSTRACT FROM AUTHOR]

Background: Chemokines are important mediators in immune cell recruitment, contributing to allergy development. However, extensive studies of chemokines in the circulation in relation to the presence and development of allergic diseases remain scarce. Our aim was to investigate associations of circulating allergy‐related chemokines with the development of asthma and sensitization cross‐sectionally and longitudinally in a population‐based cohort. Methods: The chemokines CCL17, CCL22, CXCL10, CXCL11 and CCL18 were measured in plasma samples from children in the Manchester Asthma and Allergy Study. Samples were available from cord blood at birth (n = 376), age 1 (n = 195) and age 8 (n = 334). Cross‐sectional and longitudinal association analyses were performed in relation to asthma and allergic sensitization, as well as allergic phenotype clusters previously derived using machine learning in the same study population. Results: In children with asthma and/or allergic sensitization, CCL18 levels were consistently elevated at 1 and/or 8 years of ages. In a longitudinal model including information on asthma from 4 time points (5, 8, 11 and 16 years of ages), we observed a significant association between increasing CCL18 levels at age 1 and a higher risk of asthma from early school age to adolescence (OR = 2.9, 95% CI 1.1–7.6, p =.028). We observed similar associations in longitudinal models for allergic sensitization. Asthma later in life was preceded by increased CXCL10 levels after birth and decreased CXCL11 levels at birth. Conclusion: Elevated CCL18 levels throughout childhood precede the development of asthma and allergic sensitization. The Th1‐associated chemokines CXCL10 and CXCL11 also associated with the development of both outcomes, with differential temporal effects. [ABSTRACT FROM AUTHOR]

Background: Exhaled breath condensate (EBC) pH is a promising biomarker of airway inflammation. Lack of method standardization and interstudy variability precludes its use in clinical practice. While endogenous determinants have been described, underlying mechanisms for variability are mostly unknown. Thus, we aimed to assess the association between asthma and EBC pH in children, while studying potential environmental factors for interstudy variability. Methods: A cross‐sectional analysis of exhaled breath condensates from 613 children, aged 7–12 years, was conducted. Assessments included lung function and airway reversibility, exhaled nitric oxide, allergic sensitization, and body mass index (BMI). Indoor air quality (IAQ) was assessed in children's classrooms during 5 school days. Post‐deaeration EBC pH showed a bimodal distribution, and the sample was split into acidic and alkaline groups. Regression models were constructed to assess the effects of asthma and asthma adjusted to IAQ parameters on EBC pH. Results: Following adjustment to gender and BMI, asthma was significantly associated with a lower EBC pH in the acidic group. The effect of asthma on EBC pH was independent of IAQ, in both groups. In the acidic group, EBC pH was significantly affected by temperature [β = −0.09 (−0.15, −0.02)] and PM 2.5 concentration [β = −0.16 (−0.32, −0.01)], and in the alkaline group by relative humidity [β = 0.07 (0.02, 0.13)] and concentration of endotoxins [β = −0.06 (−0.1, −0.01)]. Conclusion: Our study shows that in addition to individual determinants such as asthma, environmental factors may influence and should be taken into consideration when interpreting EBC pH level in children. [ABSTRACT FROM AUTHOR]

Additionally, children with asthma had worse COVID-19 severity scores indicating that asthma may be a risk factor for more severe forms of COVID-19 among children seeking ER care. Asthma/recurrent wheezing and prematurity were associated with LRT involvement and worse COVID-19 severity scores among children seeking ER care. In multivariate analysis, LRT involvement was significantly associated with prematurity and asthma, whereas a more severe COVID-19 score was associated with asthma, prematurity, neurological disease, and age <2 years of age. Asthma is associated with lower respiratory tract involvement and worse clinical score in children with COVID-19. [Extracted from the article]

Problematic severe asthma remains a significant challenge to manage, accounting for the majority of healthcare utilization among children with asthma. The heterogeneity is recognized and the clinical phenotypes of "difficult‐to‐treat" asthma (DA) and "severe therapy‐resistant asthma" (STRA) help to guide management. Recent evidence supports molecular distinctions between these phenotypes and shows poor correlations between peripheral and airway markers of inflammation, especially in STRA. Airway neutrophils in the context of childhood severe asthma have been explored, but their role in disease causation, protection, or as bystanders remain unknown, and thus, treatment implications are unclear. Several novel management strategies, including once‐daily maintenance therapy, single‐device maintenance and reliever therapy, and novel biological treatments are being increasingly used for DA and STRA. However, pediatric data for efficacy of novel treatments is scarce, and when available, is restricted to adolescents. The aim of this review is to highlight recent advances in objective biomarkers that aid stratification and management of childhood severe asthma and to highlight gaps in pediatric evidence. Specifically, the urgent need for efficacy studies to improve the management of problematic severe asthma in children younger than 12 years. [ABSTRACT FROM AUTHOR]

Background: The Mediterranean diet (MD) has known health benefits, but its specific impact on allergy development is unclear. As part of the PARIS birth cohort follow‐up, we aimed to investigate the adherence of 8‐year‐old children to the MD and its association with allergic/respiratory morbidity at school age. Methods: Diet was assessed using a food frequency questionnaire completed by the parents. Adherence to the MD was assessed based on two scores: the KIDMED index and the Mediterranean Diet Score (MDS). Current allergic diseases (asthma, rhinitis, eczema), lung function indices (FEV1 and FVC), FeNO and specific IgE levels were determined during a health check‐up at 8 years. Associations between levels of adherence to the MD and respiratory/allergic morbidity were studied using multivariable logistic and linear regression models adjusted for potential confounders. Results: A total of 975 children were included in the present study, 35.6% with low adherence to the MD, 55.7% with moderate adherence and 8.7% with high adherence according to the KIDMED index. High family socioeconomic status, any breastfeeding at 6 months and consumption of organic food were associated with higher adherence to the MD. Compared with low adherence, high adherence was associated with lower risk of asthma and sensitization at 8 years, as well as higher FEV1 and FVC. Conclusion: This study suggests a protective effect of high adherence to the MD on allergic and respiratory morbidity at school age. These results need to be confirmed by further longitudinal analyses. A healthy diet may prevent allergic and respiratory morbidity in school‐aged children. [ABSTRACT FROM AUTHOR]

Severe asthma (SA) affects less than 5% of the pediatric asthma population but is considered to account for approximately half of total pediatric asthma healthcare costs. For children with allergic SA not requiring omalizumab, the economic burden of allergic comorbidities was €174.50 representing 17.8% of direct SA costs and 15.8% of global SA costs (Figure S1). Allergic comorbidities, including food allergies (FA) and allergic rhinitis (AR), are frequent in children with SA.1 The presence of FA and AR increases asthma severity 1-6 and medication use.4-6 Treating AR improves asthma symptoms.3 However, the economic burden of allergic comorbidities in children with SA has been poorly studied. The mean overall cost of SA was €3,982.00 over the six-month study period.7 For children with allergic SA, the mean cost attributed to allergic comorbidities was €2,803.00 representing 48.1% of the direct SA costs and 45.8% of the global SA costs (Figure S1). [Extracted from the article]

Background: Exposure to indoor moisture damage and visible mold has been found to be associated with asthma and respiratory symptoms in several questionnaire‐based studies by self‐report. We aimed to define the prospective association between the early life exposure to residential moisture damage or mold and fractional exhaled nitric oxide (FeNO) and lung function parameters as objective markers for airway inflammation and asthma in 6‐year‐old children. Methods: Home inspections were performed in children's homes when infants were on average 5 months old. At age 6 years, data on FeNO (n = 322) as well as lung function (n = 216) measurements were collected. Logistic regression and generalized additive models were used for statistical analyses. Results: Early age major moisture damage and moisture damage or mold in the child's main living areas were significantly associated with increased FeNO levels (>75th percentile) at the age of 6 years (adjusted odds ratios, 95% confidence intervals, aOR (95% CI): 3.10 (1.35‐7.07) and 3.16 (1.43‐6.98), respectively. Effects were more pronounced in those who did not change residential address throughout the study period. For lung function, major structural damage within the whole home was associated with reduced FEV1 and FVC, but not with FEV1/FVC. No association with lung function was observed with early moisture damage or mold in the child's main living areas. Conclusion: These results underline the importance of prevention and remediation efforts of moisture and mold‐damaged buildings in order to avoid harmful effects within the vulnerable phase of the infants and children's immunologic development. [ABSTRACT FROM AUTHOR]

The immunopathology of respiratory syncytial virus (RSV) infection varies considerably, severe disease occurring only in a minority of the affected children. The variability of the clinical presentation is in part explained by viral and environmental factors but, in infants and young children, disease severity is certainly linked to the physiologic immaturity of the innate and adaptive immune system. There is evidence that the maturation of the host immune response is positively influenced by the composition of the nasopharyngeal microbiome that, promoting an efficient reaction, can counteract the predisposition to develop viral respiratory infections and lower the risk of disease severity. However, interaction between the nasopharyngeal microbiota and respiratory viruses can be bidirectional since microbial dysbiosis may also represent a reflection of the disease‐induced alterations of the local milieu. Moreover, viruses like RSV can also increase the virulence of potential pathogens in nasopharynx, a main reservoir of bacteria, and therefore promote their spread to the lower airways causing superinfection. Moreover, if negative changes in microbial community composition in early life may constitute a heightened risk toward severe RSV respiratory infection, on the contrary specific groups of microorganisms seem to be associated with protection. A better understanding into the potential negative and positive role of the different nasopharyngeal bacterial species on RSV infection may improve primary prevention and possibly care of this highly contagious disorder. [ABSTRACT FROM AUTHOR]

Asthma has now become one of the most common atopic disorders not only in developed countries but also in many developing countries. The etiology is likely due to a complex interaction between genetic and environmental factors. In many Asian countries, the prevalence of asthma has also been documented by validated instruments to be increasing rapidly over the past two decades. However, studies in rural areas in Asia with a traditional farming environment revealed markedly lower asthma prevalence when compared with residents in nearby cities despite having similar genetic background. Among the environmental factors implicated in the pathogenesis of asthma, air pollution, dietary patterns, viral infections, and early microbial exposure have been studied extensively around the world. Asia provides many opportunities to study these potential factors as there are many ethnic groups living in distinctly different environments. The understanding of the roles of these factors in affecting the early immune system and subsequent development of asthma will enable us to develop potential primary preventive strategies against a disease which affects millions worldwide. [ABSTRACT FROM AUTHOR]

Overall, children below 3 years of age incurred 3.6 times higher asthma costs and in particular 9.3 times higher asthma-related hospitalization costs than those aged 4 and older. The substantially higher costs in the first 3 years of life reflect the challenge of managing asthma in young children because, despite the early diagnosis, they were frequently hospitalized for asthma and other respiratory conditions. Right panel, direct medical costs related to other respiratory conditions, total and by components gl Figures S3 and S4 respectively present the sex- and SES-stratified age trends of costs related to asthma and other respiratory conditions. Between 4 and 18 years of age, per child-year asthma-related costs steadily declined, but at a slower rate of -14.1%, while hospitalization costs declined by -30.0% every year. [Extracted from the article]

Background: It is unclear in which periods of life lung function deficits develop, and whether these are affected by risk factors such as asthma, bronchial hyper‐responsiveness (BHR) and allergic comorbidity. The goal of this systematic review was to identify temporal associations of asthma, BHR and allergic comorbidity with large and small lung function development from birth until peak function in early adulthood. Methods: We searched MEDLINE, EMBASE, Web of Science and CINAHL for papers published before 01.01.2020 on risk factors and lung function measurements of large and small airways. Studies were required to report lung function at any time point or interval from birth until peak lung function (age 21‐26) and include at least one candidate risk factor. Results: Of the 45 papers identified, 44 investigated cohorts and one was a clinical trial with follow‐up. Asthma, wheezing, BHR and allergic sensitization early in life and to multiple allergens were associated with a lower lung function growth of large and small airways during early childhood compared with the control populations. Lung function development after childhood in subjects with asthma or persistent wheeze, although continuing to grow at a lower level, largely tracked parallel to non‐affected individuals until peak function was attained. Clinical implications and future research: Deficits in lung function growth develop in early childhood, and children with asthma, BHR and early‐life IgE (poly)sensitization are at risk. This period is possibly a critical window of opportunity to identify at‐risk subjects and provide treatment aimed at preventing long‐term sequelae of lung function. [ABSTRACT FROM AUTHOR]

Background: There are limited data describing lung function changes in children after an asthma exacerbation. Our hypothesis was that lung function does not fully recover in children in the months following an asthma exacerbation. Methods: We used a data set of children with asthma where lung function (including FEV1, FEV1/FVC ratio and FEF25‐75) was measured at 3‐month intervals over a year. Mixed‐level models compared spirometry measured on two occasions 3 months apart before a single exacerbation (assessments 1 and 2) with measurements made on two occasions after the exacerbation (assessments 3 and 4), with adjustment for covariates. Changes in spirometry over a year were also analysed across those with exacerbations in no, one or more than one 3‐month periods. Results: For the 113 children who had a single exacerbation, spirometry measured at assessments 1 or 2 did not differ from measurements at assessments 3 or 4 when the whole population was considered. When stratified into tertiles by change in %FEV1 between assessments 2 and 3, those with the greater reduction were more likely to be treated with long‐acting beta‐agonist, but in this category, %FEV1 at assessment 4 had returned to the value at assessment 1. %FEV1 did not change over a 12‐month period within and between the three exacerbation categories (n = 809). Conclusion: One or more asthma exacerbation was not associated with a fall in lung function for the whole population. In a subset of individuals, lung function does fall after an exacerbation but returns to pre‐exacerbation values after a period of months. [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that a child's risk of developing atopic disease is impacted by both genetic and environmental factors. Because small children spend the majority of their time in their homes, exposure to microbial factors in their home environment may be protective or risk factors for development of atopic diseases, such as atopic dermatitis. Methods: Dust samples from the homes of 86 Black South African children 12 to 36 months old were collected for analysis of the bacterial microbiome. This case‐control study design included children with and without atopic dermatitis from rural and urban environments. Results: Significant differences in bacterial composition and diversity were found when comparing children with and without atopic dermatitis. Furthermore, house dust microbiota was significantly different in rural and urban areas. Differences were best accounted for by higher relative abundance of Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae families in rural compared with urban houses. Levels of Ruminococcaceae were also found to be significantly depleted in the house dust of rural children with atopic dermatitis as compared to control children. Conclusions: House dust composition may be an important risk factor for the development of atopic disease, and this association may be driven in part by the gut microbiome. Low levels of the Ruminococcaceae family from Clostridia class in particular may explain the association between urban living and atopy. However, further research is needed to elucidate these links. [ABSTRACT FROM AUTHOR]

Background: Cardio‐metabolic risk factors might have an adverse effect on respiratory outcomes, but associations in children are unknown. We aimed to study the longitudinal associations of cardio‐metabolic risk factors with lung function and asthma at school age. We also examined whether any association was explained by child's body mass index (BMI). Methods: In a population‐based cohort study among 4988 children, cardio‐metabolic risk factors were measured at 6 and 10 years and included blood pressure, cholesterol, triglycerides, insulin, and C‐reactive protein (CRP) concentrations. At age 10 years, lung function was measured by spirometry and current physician‐diagnosed asthma was assessed by questionnaire. Results: After adjustment for confounders, child's BMI, and multiple testing, we observed that a higher diastolic blood pressure at the age of 6 years was associated with a higher forced vital capacity (FVC) at the age of 10 years (Z‐score difference (95% CI): 0.05 (0.01, 0.08), per SDS increase in diastolic blood pressure). Also, child's CRP concentrations above the 75th percentile at both ages 6 and 10 years were related to a lower FVC as compared to CRP concentrations below the 75th percentile at both ages (Z‐score difference (95% CI) −0.21 (−0.36, −0.06)). No consistent associations of other cardio‐metabolic risk factors with respiratory outcomes were observed. Conclusion: Blood pressure and CRP, but not lipids and insulin, were associated with lower lung function but not with asthma. The underlying mechanisms and long‐term effects of these associations require further investigation. [ABSTRACT FROM AUTHOR]

As breastfeeding is of utmost importance for child development and survival, identifying whether breast milk is a route of transmission for human viruses is critical. Based on the principle of Koch's postulate, we propose an analytical framework to determine the plausibility of viral transmission by breast milk. This framework is based on five criteria: viral infection in children receiving breast milk from infected mothers; the presence of virus, viral antigen, or viral genome in the breast milk of infected mothers; the evidence for the virus in breast milk being infectious; the attempts to rule out other transmission modalities; and the reproduction of viral transmission by oral inoculation in an animal model. We searched for evidence in published reports to determine whether the 5 criteria are fulfilled for 16 human viruses that are suspected to be transmissible by breast milk. We considered breast milk transmission is proven if all 5 criteria are fulfilled, as probable if 4 of the 5 criteria are met, as possible if 3 of the 5 criteria are fulfilled, and as unlikely if less than 3 criteria are met. Only five viruses have proven transmission through breast milk: human T‐cell lymphotropic virus 1, human immunodeficiency virus, human cytomegalovirus, dengue virus, and Zika virus. The other 11 viruses fulfilled some but not all criteria and were categorized accordingly. Our framework analysis is useful for guiding public health recommendations and for identifying knowledge gaps amenable to original experiments. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the role of body mass index with regard to exercise performance, exercise‐induced bronchoconstriction (EIB), and respiratory symptoms in 7‐ to 16‐year‐old children. Methods: A total of 1120 outdoor running exercise challenge test results of 7‐ to 16‐year‐old children were retrospectively reviewed. Lung function was evaluated with spirometry, and exercise performance was assessed by calculating distance per 6 minutes from the running time and distance. Respiratory symptoms in the exercise challenge test were recorded, and body mass index modified for children (ISO‐BMI) was calculated for each child from height, weight, age, and gender according to the national growth references. Results: Greater ISO‐BMI and overweight were associated with poorer exercise performance (P <.001). In addition, greater ISO‐BMI was independently associated with cough (P =.002) and shortness of breath (P =.012) in the exercise challenge. However, there was no association between ISO‐BMI and EIB or with wheeze during the exercise challenge. Conclusion: Greater ISO‐BMI may have a role in poorer exercise performance and appearance of respiratory symptoms during exercise, but not in EIB in 7‐ to 16‐year‐old children. [ABSTRACT FROM AUTHOR]

Background: Environmental exposures are involved in the pathogenesis of the allergic phenotype and in determining which individual triggers a person becomes sensitized to. Atopic dermatitis (AD) may modulate these effects through increased penetration through the skin modifying the immune system and AD may be triggered or intensified by environmental exposures. These exposures and immune‐modulating factors may differ in urban and rural environments. Objectives: To compare house dust composition in urban and rural settings and correlate them with AD outcomes. Methods: Dust samples were collected from the beds of 156 children aged 6 months to 3 years. 42% of participants had atopic dermatitis. Samples were analyzed for bacterial endotoxin, fungal (β‐1,3‐glucan) levels, and house dust mite, cockroach, dog, cat, mouse, and peanut allergen. Exposures were compared in urban and rural environments and in participants with and without AD. Results: Endotoxin but not fungal β‐glucan exposure is higher in the environment of healthy controls than children with AD in both urban and rural settings. House dust mite allergen exposure is high in urban and rural settings with Dermatophagoides detected in 100% of samples. Cat and dog allergen exposure mirrors pet ownership patterns which differ slightly between groups and environments. Mouse allergen exposure is higher in urban homes. Conclusion: Environmental endotoxin may be protective against AD in both urban and rural settings. There are marked differences in allergen exposure in urban and rural settings, but these are unlikely to be important protective or risk factors. [ABSTRACT FROM AUTHOR]

Background: While infant bronchiolitis contributes to substantial acute (eg, severity) and chronic (eg, asthma development) morbidities, its pathobiology remains uncertain. We examined the integrated relationships of local (nasopharyngeal) and systemic (serum) responses with bronchiolitis morbidities. Methods: In a multicenter prospective cohort study of infants hospitalized for bronchiolitis, we applied a network analysis approach to identify distinct networks (modules)—clusters of densely interconnected metabolites—of the nasopharyngeal and serum metabolome. We examined their individual and integrated relationships with acute severity (defined by positive pressure ventilation [PPV] use) and asthma development by age 5 years. Results: In 140 infants, we identified 285 nasopharyngeal and 639 serum metabolites. Network analysis revealed 7 nasopharyngeal and 8 serum modules. At the individual module level, nasopharyngeal‐amino acid, tricarboxylic acid (TCA) cycle, and carnitine modules were associated with higher risk of PPV use (r >.20; P <.001), while serum‐carnitine, amino acid, and glycerophosphorylcholine (GPC)/glycerophosphorylethanolamine (GPE) modules were associated with lower risk (all r < −.20; P <.05). The integrated analysis for PPV use revealed consistent findings—for example, nasopharyngeal‐TCA (adjOR: 2.87, 95% CI: 1.68‐12.2) and serum‐GPC/GPE (adjOR: 0.54, 95% CI: 0.38‐0.80) modules—and an additional module—serum‐glucose‐alanine cycle module (adjOR: 0.69, 95% CI: 0.56‐0.86). With asthma risk, there were no individual associations, but there were integrated associations (eg, nasopharyngeal‐carnitine module; adjOR: 1.48, 95% CI: 1.11‐1.99). Conclusion: In infants with bronchiolitis, we found integrated relationships of local and systemic metabolome networks with acute and chronic morbidity. Our findings advance research into the complex interplay among respiratory viruses, local and systemic response, and disease pathobiology in infants with bronchiolitis. [ABSTRACT FROM AUTHOR]

Background: Much of our knowledge of childhood asthma comes from questionnaire‐based studies. Our main aim was to assess the agreement between parental‐reported data at 12 years of age and data from two national Swedish registers. Methods: Data were obtained from the prospective, longitudinal, population‐based Children of Western Sweden cohort, which focused on children born in 2003. The parents answered questionnaires at six months and one, four, eight and 12 years of age. Personal identity numbers linked 3634 children to the Swedish Prescribed Drug Register (SPDR) and the National Patient Register (NPR). Results: At 12 years of age, there was substantial overall agreement between the asthma medication reported by the parents in the questionnaire and the SPDR for any asthma medication (94.8%, kappa 0.71) and maintenance treatment (95.3%, kappa 0.68). In contrast, the agreement between the outpatient asthma diagnoses in the NPR and the questionnaire‐based asthma was 30.5% and it was 32.8% between the NPR and the dispensed asthma medication in the SPDR. Hospitalization was rare for obstructive diseases after early childhood, and 38.2% of the 12‐year‐old children only received a short‐acting beta agonist, with no maintenance treatment. Conclusion: There was good agreement between the questionnaire‐based data on asthma medication and the national drug register, but the National Patient Register provided incomplete information on asthma diagnoses, probably because it did not include primary care diagnoses. The results show that well‐constructed parental questionnaires can provide reliable data on childhood asthma. [ABSTRACT FROM AUTHOR]

Background: A diet rich in fruits and vegetables has been suggested to counteract the oxidative stress and inflammation that characterize asthma. We aimed to assess the association between vegetable and fruit diversity consumption and asthma and its related outcomes in school‐aged children. Methods: Participants included 647 children (49% females, aged 7‐12 years) recruited from 20 public schools across the city of Porto, in Portugal. Vegetable intake and fruit intake were ascertained using a single self‐reported 24‐hour recall questionnaire. A diversity score was built taking into account the different number of individual vegetables and fruits consumed and categorized into two groups based on the total reported median consumption, which was rounded to the nearest whole number (≤3 and >3, for vegetables; and ≤1 and >1, for fruits). A questionnaire was used to enquire about self‐reported medical diagnosis of asthma and respiratory symptoms. Airway inflammation was assessed measuring exhaled fractional nitric oxide concentration (eNO) and was categorized into two groups (<35 and ≥35 ppb). The association between fruit and vegetable diversity and respiratory outcomes was examined using logistic regression models, adjusting for confounders. Results: A higher vegetable diversity consumption per day was negatively associated with having self‐reported asthma (OR = 0.67; 95% CI 0.47, 0.95), while having a vegetable diversity consumption superior to 3 items per day was negatively associated with levels of eNO ≥ 35 ppb (OR = 0.38; 95% CI 0.16, 0.88) and breathing difficulties (OR = 0.39; 95% CI 0.16, 0.97). Conclusion: Eating a greater variety of vegetables was associated with a lower chance of airway inflammation and prevalence of self‐reported asthma in school children. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the association of serum periostin levels with clinical features in children with asthma. Methods: Children with physician‐diagnosed asthma who attended regularly to an outpatient pediatric allergy and asthma center were enrolled in the study along with control subjects. Asthma severity and control status of the patients were evaluated according to the recent GINA guidelines. Results: A total of 158 children (125 with asthma and 33 age‐ and sex‐matched control subjects) with a median age of 10.2 years (range 5.9‐17.0) were enrolled. Asthma severity was mild in 41 (32.8%), moderate in 63 (50.4%), and severe in 21 (16.8%) children. Children with asthma had significantly higher periostin levels than controls (53.1 ± 13.1 vs 43.0 ± 11.2 ng/mL, P <.001). The mean serum periostin levels in children with severe asthma (63.8 ± 10.8) were significantly higher than in children with moderate asthma (53.3 ± 12.7) and mild asthma (47.4 ± 11.1) (P <.001). Results of multivariable logistic regression analysis demonstrated an association between serum periostin levels and asthma severity in children (OR, 1.10; 95% CI, 1.04‐1.15, P <.001). When analyzed for the best cut‐off value with the highest combined sensitivity and specificity, a cut‐off value of 52 ng/mL for serum periostin level was obtained with sensitivity, specificity, PPV, and NPV of 100%, 50%, 29%, and 100%, respectively. Conclusion: Although serum periostin levels are higher in children with asthma, its diagnostic role in identifying children with severe asthma is limited. [ABSTRACT FROM AUTHOR]

Background: Randomized controlled trials (RCTs) suggest a protective effect of high‐dose vitamin D supplementation in pregnancy on offspring risk of persistent wheeze, but only in some individuals, which might be explained by variations in vitamin D pathway genes. This study aimed to investigate the effect of vitamin D supplementation by maternal and offspring vitamin D receptor (VDR) genotype and GC genotype, encoding vitamin D binding protein (VDBP), in two RCTs. Methods: In the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) RCT, we analyzed the effect of high‐dose vitamin D during pregnancy on the risk of persistent wheeze age 0‐3 years by variants in single nucleotide polymorphisms (SNPs) in VDR (rs1544410, rs2228570, rs7975128, rs7975232) and GC (rs4588, rs7041). Replication was sought in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Results: In COPSAC2010, VDR SNP rs1544410 influenced the effect of high‐dose vitamin D: maternal Pinteraction =.049 and child Pinteraction =.001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10‐0.68), P =.006, and no effect among CT or CC genotypes: 0.85 (0.48‐1.51), P =.58 and 0.94 (0.47‐1.89), P =.87, respectively. However, these findings were not replicated in VDAART. There was no significant effect modification from maternal or offspring GC genotype in either COPSAC2010 or VDAART: all Pinteraction ≥.17. Conclusions: We found that the effect of high‐dose vitamin D supplementation during pregnancy on offspring risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC2010 RCT, but not VDAART, which may be due to population differences. [ABSTRACT FROM AUTHOR]

Rhinitis—and especially allergic rhinitis (AR)—remains the most frequent hypersensitivity condition, affecting up to a quarter of the population and impacting the quality of life of individual patients and the health economy. Data, especially with respect to underlying pathophysiologic mechanisms, mainly derive from studies on adults and are subsequently extrapolated to the pediatric population. Therapeutic algorithms for children with rhinitis are long based on the same principles as in adults. We explore and describe novel aspects of rhinitis, ranging from mechanisms to disease classification, phenotypes, diagnostic and monitoring tools, and the use of treatments, with a focus on the traits of pediatric age groups. [ABSTRACT FROM AUTHOR]

Between April and July 2020, we performed peripheral B lymphocyte immunophenotype in five patients with positive specific IgG against SARS-CoV2, who satisfied WHO preliminary case definition criteria for MIS-C,1 and compared them with eight children affected by COVID-19 and 15 age-matched healthy donors (HD). Immunophenotype studies in COVID-19 patients have demonstrated a peculiar B-cell response with increased plasmablast (PB) frequency.4 Interestingly, the increase in PB is not associated with an augmentation in spike protein-specific IgG titer. Since April 2020, an increasing number of authors have reported a new clinical syndrome related to SARS-COV2 infection in children, characterized by rapidly progressive systemic inflammation with multi-organ dysfunction. [Extracted from the article]

Background: Over the last few decades, the level of pollen from birch and homologous trees has increased in parts of Europe. Sensitization to birch pollen allergens (principally Bet v 1) has been associated with food cross‐reactivity called pollen food allergy syndrome (PFAS). Objective: To evaluate changes in allergic diseases due to IgE sensitization over 25 years in asthmatic children. Methods: This was a cross‐sectional retrospective study conducted in Paris. We analyzed two cohorts of asthmatic children with similar characteristics explored between 1993‐1999 (old cohort = OC) and 2012‐2018 (recent cohort = RC). Results: 121 children were in the OC and 120 in the RC. An increase in sensitization to tree pollens was found especially for birch pollen, which was 11.6% in the OC and 31% in the RC (P =.0002). Allergic rhinitis prevalence was significantly higher in the RC than in the OC (96% vs 52%, respectively, P <.0001). IgE‐mediated food allergy increased from 6% to 16% in the OC and RC, respectively, (P =.01) mainly due to PFAS. In the RC, a higher mean Bet v 1‐specific IgE level was observed in children with PFAS compared to children without (105.7 KU/L ± 17.8 and 48.9 kU/L ± 15.7, respectively, P <.05). Conclusion: Allergic rhinitis and food allergy with tree pollen sensitization have increased in Paris over 25 years mainly due to PFAS. Environmental factors could be responsible for these modifications as described in the literature. [ABSTRACT FROM AUTHOR]

Background: A high dose of folic acid during pregnancy may increase the risk of asthma, wheezing, and respiratory disease in childhood. Folate acid can modify inflammation and immune susceptibility of offspring with some epigenetic differentiation, including DNA methylation. This study evaluated associations between maternal folate levels during pregnancy and childhood wheezing; furthermore, the study assessed whether maternal folate‐modified DNA methylation is related to asthma. Methods Participants in the current study were 6651 mother‐child pairs who had complete data on characteristics and who had completed at least one of the International Study of Asthma and Allergies in Childhood questionnaires when the child was 1, 2, 4, and 7 years of age. Moreover, a case‐control study to assess DNA methylation at 7 years of age was conducted among 136 children who experienced wheezing and a control group of 139 children with no history of allergies. Results The median of maternal serum was 16.76 nmol/L, assayed by chemiluminescent immunoassay. We found significantly increased adjusted odds ratios of childhood wheezing at 2 years age according to maternal folate levels, compared with the lowest folate quartile (odds ratio [95% confidence interval] = highest; 1.27 [1.03, 1.56], and second, 1.27 [1.05, 1.55]); however, no changes were observed at 1, 4, and 7 years of age. In a case‐control study, no association of maternal folate levels with DNA methylation was observed. Conclusion Our results suggest that maternal folate did not affect persistent wheezing in school‐aged children, or DNA methylation of gasdermin B, orosomucoid‐like 3, and Ikaros family zinc finger 3 at 7 years of age. [ABSTRACT FROM AUTHOR]

Background: Children with severe respiratory syncytial virus (RSV) bronchiolitis in infancy have increased risks of asthma and reduced lung function in later life. There are limited studies on the longitudinal changes of lung function and bronchial hyperreactivity from early to late childhood in infants hospitalized for RSV bronchiolitis. Methods: In a prospective cohort of 206 children with their first episode of RSV‐confirmed bronchiolitis in the first year of life, 122 had spirometry performed at least twice between 5‐16 years of age. Methacholine bronchoprovocation was available in 127 and 79 children at 7 and 12 years of age, respectively. Longitudinal changes in FEV1, FVC, and FEV1/FVC z‐scores and methacholine PC20 were analyzed. Results: 55% of the study cohort (N = 122) were male, and 55% were Caucasian. During follow‐up, longitudinal changes in z‐scores for pre‐ and post‐bronchodilator FEV1 (P <.0001) FVC (P <.0001) and FEV1/FVC (P <.0001 for pre‐ and 0.007 for post‐bronchodilator) from age 5 to 10‐16 years were observed. Declined lung function in late childhood was significantly associated with gender, physician diagnosis of asthma, and allergic sensitization. PC20 geometric mean increased from 0.28 mg/mL at 7 years to 0.53 mg/mL at 12 years of age, and the frequency of abnormal bronchial hyperreactivity decreased from 96% to 78% (P =.0003). Conclusions: Following severe RSV bronchiolitis, there appear to be significant longitudinal changes in pre‐ and post‐bronchodilator lung function during childhood. The study has several limitations including significant dropouts and the lack of a control group and post‐bronchodilator measurements. Bronchial hyperreactivity is common in children following severe RSV bronchiolitis; however, it appears to decrease as they enter late childhood. [ABSTRACT FROM AUTHOR]

Background: Evidence about the association of high blood eosinophil count with asthma exacerbation is inconsistent and unclear. The objective of this meta‐analysis was to determine whether elevated blood eosinophil count predicts asthma exacerbation. Methods: We searched MEDLINE, EMBASE, and additional databases, without any language restriction. We also checked the reference lists of the included studies and of relevant systematic reviews. The main outcome was the occurrence of asthma exacerbation. We calculated global pooled odds ratios (ORs) and their 95% confidence intervals (CIs) and performed predefined subgroup analyses. We appraised the quality of the studies using Newcastle‐Ottawa Scale, examined the heterogeneity between studies, assessed publication bias, and carried out sensitivity analyses. Results: Among 1567 retrieved publications, 23 observational studies comprising 155,772 participants met the inclusion criteria. High blood eosinophil count was associated with higher odds of asthma exacerbation [OR: 1.31 (95% CI: 1.16, 1.49)], specifically with asthma‐related outpatient visits [OR: 1.46 (95% CI: 1.25, 1.70)] and emergency department visits [OR: 1.63 (95% CI: 1.29, 2.07)]. A significant association was observed starting from an eosinophils' cutoff value of 200 cells/μl. The association was observed for cohort studies [OR: 1.30 (95%CI: 1.13, 1.49)], North American studies [OR: 1.43 (95%CI: 1.31, 1.57)], Asian populations [OR: 1.67 (95%CI: 1.34, 2.08)], children [OR: 1.38 (95%CI: 1.22, 1.56)], and studies that adjusted for inhaled corticosteroids therapy [OR: 1.42 (95%CI: 1.28, 1.56)]. Conclusions: Blood eosinophil counts ≥ 200 cells/µL are associated with asthma exacerbation. Blood eosinophil count is a modifiable factor that could be addressed in asthma management strategies. [ABSTRACT FROM AUTHOR]

Background: To date, there is no comprehensive study examining how asthma diagnosed in childhood or adolescence is associated with diagnoses of subsequent non‐communicable diseases (NCDs) during adulthood. Our study aimed to examine the associations between pediatric asthma and several adult NCDs, with temporality and long interval times between asthma and NCD diagnoses. Methods: We used RAND Indonesian Family Life Survey Fifth Wave (IFLS5) fielded in 2014‐2015, to study whether being diagnosed with pediatric asthma at 0‐19 years of age was associated with increased risks of hypertension, diabetes, rheumatoid arthritis, stomach diseases, kidney diseases, and heart diseases or stroke diagnosed in adulthood. We used the weighted Poisson regression adjusting for age, sex, urbanicity, and insurance status to estimate risk ratios. Subgroup analyses were performed by sex and age of asthma and other NCD diagnoses. Results: Pediatric asthma significantly increased risks of hypertension, diabetes, and stomach diseases diagnosed at 20 years of age or above. Males with pediatric asthma diagnosed at 0‐10 years of age had significantly higher risk of hypertension, while females with pediatric asthma diagnosed at 0‐10 years of age had significantly higher risks of diabetes and stomach diseases. Females with pediatric asthma diagnosed at 11‐19 years of age had significantly higher risks of diabetes, arthritis, stomach diseases, and kidney diseases. We also found varying associations by age of NCD diagnosis. Conclusion: Our results suggest pediatric asthma is associated with increased risks of several adult NCDs, and these associations may vary by sex and age of asthma and other NCD diagnoses. [ABSTRACT FROM AUTHOR]

Background: The asthma syndrome is influenced by hereditary and environmental factors. With the example of farm exposure, we study whether genetic and environmental factors interact for asthma. Methods: Statistical learning approaches based on penalized regression and decision trees were used to predict asthma in the GABRIELA study with 850 cases (9% farm children) and 857 controls (14% farm children). Single‐nucleotide polymorphisms (SNPs) were selected from a genome‐wide dataset based on a literature search or by statistical selection techniques. Prediction was assessed by receiver operating characteristics (ROC) curves and validated in the PASTURE cohort. Results: Prediction by family history of asthma and atopy yielded an area under the ROC curve (AUC) of 0.62 [0.57‐0.66] in the random forest machine learning approach. By adding information on demographics (sex and age) and 26 environmental exposure variables, the quality of prediction significantly improved (AUC = 0.65 [0.61‐0.70]). In farm children, however, environmental variables did not improve prediction quality. Rather SNPs related to IL33 and RAD50 contributed significantly to the prediction of asthma (AUC = 0.70 [0.62‐0.78]). Conclusions: Asthma in farm children is more likely predicted by other factors as compared to non‐farm children though in both forms, family history may integrate environmental exposure, genotype and degree of penetrance. [ABSTRACT FROM AUTHOR]

Background: Previous research suggests that children who experience asthma may be less physically active; however, results have been inconclusive. This study aimed to investigate whether the presence of asthma or wheeze is associated with lower physical activity levels in children, and whether sex, body mass index or earlier asthma or wheeze status modifies the association. Methods: This study was conducted in 391 HealthNuts participants in Melbourne, Australia. Asthma and wheeze data were collected via questionnaire at age 4 and 6, and physical activity was measured through accelerometry. Using adjusted linear regression models, the cross‐sectional and longitudinal associations were investigated. Results: There was no evidence of a difference in time spent in moderate‐to‐vigorous physical activity (MVPA) at age 6 years between children with and without asthma at age 4; children with asthma spent 8.3 minutes more time physically active per day (95% CI: −5.6, 22.1, P =.24) than children without asthma. Similar results were seen for children with current wheeze (5.8 minutes per day more, 95% CI: −5.9, 17.5, P =.33) or ever wheeze or asthma (7.7 minutes per day more, 95% CI: −4.8, 20.2, P =.23) at age 4 years. Comparable null results were observed in the cross‐sectional analyses. Interaction with BMI could not be assessed; however, previous asthma or wheeze status and sex were not found to modify these associations. Conclusion: This analysis found no evidence of asthma hindering physical activity in these young children. These results are encouraging, as they indicate that the Australian asthma and physical activity public health campaigns are being effectively communicated and adopted by the public. [ABSTRACT FROM AUTHOR]

Objective: The prevalence of childhood asthma has been increasing in recent years. This study aims to investigate the involvement of the key molecules of IL‐1 (interleukin‐1) signaling pathways in pediatric patients with asthma. Methods: Differentially expressed genes (DEGs) associated with IL‐1 signaling pathways were identified with RNA‐seq from peripheral blood samples collected from asthmatic or healthy children and were further verified in clinical peripheral blood samples. Cellular models and asthmatic mice were subsequently developed to validate the identified asthmatic markers. Results: Among the DEGs identified by RNA‐seq, eight signal transducers associated with the IL‐1 signaling network, namely IL‐1RN, IL‐1β, IL‐1RAP, IRAK3, IL‐1R1, MYD88, IRAK2, and PELI1, were found to be substantially upregulated in children with asthma. Interestingly, a significant serially increased expression of four genes (IL‐1RN, IL‐1RAP, IRAK3, and PELI1) was observed in healthy subjects, patients with chronic persistent asthma and patients with acute exacerbation asthma. In particular, these four genes were continuously overexpressed in recurrent patients. A significant induction of the above four genes was then observed in house dust mite (HDM)–stimulated peripheral blood mononuclear cells (PBMCs) and ovalbumin (OVA)–induced asthmatic mice. In addition, a time‐dependent induction of IL‐1RAP and PELI1 was also detected in HDM‐treated THP‐1 cells, an acute monocytic leukemia cell line. Conclusions: These results demonstrate that IL‐1RN, IL‐1RAP, IRAK3, and PELI1, which are signal transducers of the IL‐1 signaling pathway, could serve as biomarkers for the pathogenesis of childhood asthma and for potential therapeutic targets of asthma. [ABSTRACT FROM AUTHOR]

Background: We sought to evaluate whether elective caesarean section is associated with subsequent hospitalization for bronchiolitis. Methods: This is a retrospective cohort study that used the electronic medical record database of Clalit Health Services, the largest healthcare fund in Israel, serving over 4.5 million members and over half of the total population. The primary outcome was bronchiolitis admission in the first 2 years of life. We performed logistic regression analyses to identify independent associations. We repeated the analysis using boosted decision tree machine learning techniques to confirm our findings. Results: There were 124 553 infants enrolled between 2008 and 2010, and 5168 (4.1%) were hospitalized for bronchiolitis in the first 2 years of life. In logistic regression models stratified by seasons, elective caesarean section birth was associated with 15% increased odds (95% CI: 1.02‐1.30) for infants born in the fall season, 28% increased odds (95% CI: 1.11, 1.47) for those born in the winter, 35% increased odds (95% CI: 1.12‐1.62) for those born in the spring and 37% increased odds (95% CI: 1.18‐1.60) for those born in the summer. In the boosted gradient decision tree analysis, the area under the curve for risk of bronchiolitis admission was 0.663 (95% CI: 0.652, 0.674) with timing of birth as the most important feature. Conclusion: Elective caesarean section, a potentially modifiable risk factor, is associated with increased odds of hospitalization for bronchiolitis in the first 2 years of life. These data should be considered when scheduling elective caesarean sections especially for infants born in spring and summer months. [ABSTRACT FROM AUTHOR]

Background: Asthmatic children on corticosteroids can develop hypothalamic‐pituitary‐adrenal axis suppression (HPAS). Single nucleotide polymorphisms (SNPs) rs242941 and rs1876828 of the corticotrophin‐releasing hormone receptor 1 (CRHR1) gene were associated with lower stimulated cortisol (F) levels, whereas rs41423247 of the glucocorticoid receptor (NR3C1) gene was associated with higher basal F levels. The objective of the current study was to confirm whether these three SNPs are associated with HPAS in asthmatic children. Methods: DNA was extracted from saliva obtained from 95 asthmatic children, who had previously undergone basal F and metyrapone testing. Thirty‐six children were classified as suppressed. Non‐suppressed children were subclassified according to their post‐metyrapone adrenocorticotropin (PMTP ACTH) level into a middle (106‐319 pg/mL) and a high (>319 pg/mL) ACTH response group. TaqMan® polymerase chain reaction assays were utilized. Results: Only rs41423247 was inversely associated with HPAS (OR = 0.27 [95% CI 0.06‐0.90]). Its GC genotype was inversely associated with HPAS (log odds = −1.28, P =.021). √PMTP ACTH was associated with CC (effect size = 10.85, P =.005) and GC genotypes (effect size = 4.06, P =.023). The C allele is inherited as a dominant trait (effect size = −1.31 (95% CI −2.39‐−0.33; P =.012). In the high ACTH response group, both genotypes affected the PMTP ACTH (effect sizes 1.41 and 15.46; P‐values.023 and <2 × 10−26 for GC and CC, respectively). Conclusions: The C allele of rs41423247 was found to be protective against HPAS. CC genotype is associated with the highest PMTP ACTH response. [ABSTRACT FROM AUTHOR]

To the Editor Inhaled corticosteroid (ICS) therapy is recommended for most children with asthma irrespective of severity. Given the established role of ICS in treating asthma, it would not be ethical to enroll patients with moderate-severe asthma into a study where they may be randomized to non-ICS therapy. Therefore, much of the data characterizing the growth-suppressive effects of ICS come from children with mild-moderate asthma. [Extracted from the article]