Background. Whether small airway dysfunction (SAD), which is prevalent in asthma, helps to characterize wheezing phenotypes is undetermined. The objective was to assess whether SAD parameters obtained from impedance measurement and asthma probability are linked. Methods. One hundred and thirty-nine preschool children (mean age 4.7 years, 68% boys) suffering from recurrent wheeze underwent impulse oscillometry that allowed calculating peripheral resistance and compliance of the respiratory system (markers of SAD) using the extended RIC model (central and peripheral Resistance, Inertance and peripheral Compliance of the respiratory system). Children were classified using the probability-based approach of GINA guidelines (few, some, most having asthma). A principal component analysis (PCA) that determined the dimensions of wheezing disease evaluated the links between SAD and asthma probability. Results. Forty-seven children belonged to the few, 28 to the some and 64 to the most having asthma groups. Whereas their anthropometrics and measured parameters were similar, the most having asthma group exhibited the lowest mean value of airway inertance after bronchodilator probably due to airway inhomogeneities. PCA characterized nine independent dimensions including a peripheral resistance (constituted by baseline peripheral resistance, AX, R5-20Hz, X5Hz), a central resistance (baseline central resistance, R20Hz) and an airway size dimension (post-bronchodilator inertance and central resistance). PCA showed that the SAD markers were independent from clinical dimensions (control and asthma probability were two other dimensions) and did not help to define wheezing phenotypes. Conclusions. Lung function parameters obtained from impulse oscillometry and asthma probability were belonging to independent dimensions of the wheezing disease.
Background Beta-lactams generate different allergenic determinants that induce selective or cross-reactive drug hypersensitivity reactions (DHRs). We aimed to identify the drugs involved, the selectivity of the response, the mechanism, and the value of the different diagnostic tests for establishing a diagnosis in children evaluated for DHRs to beta-lactams. Methods Prospective study evaluating children aged under 16 years reporting DHRs to beta-lactams. Reactions were classified as immediate and nonimmediate reactions. The work-up included sIgE, skin testing and drug provocation tests (DPTs) for immediate reactions and patch testing and DPTs for nonimmediate ones. Results Of the 510 included children, 133 were evaluated for immediate reactions and confirmed in 8.3%. Skin test/in vitro IgE contributed to diagnosing half of the cases. Selective reactions occurred with amoxicillin (63%), followed by common penicillin determinants (27%) and cephalosporins (0.9%). Among nonimmediate reactions (11,4% of the 377 children evaluated), most required DPTs, 52.7% of which were positive at 6–7 days of drug challenge. Selective reactions were identified with amoxicillin (80%), penicillin G (7.5%), cephalosporins (7.5%), and clavulanic acid (5%). Urticaria and maculopapular exanthema were the most frequent entities. Conclusions There were few confirmed cases of either type of reaction. Skin testing proved less valuable in nonimmediate reactions, over half of which would also have been lost in a short DPT protocol. Selective responders to amoxicillin were more likely to have nonimmediate reactions, while clavulanic acid-selectivity was exclusive to the nonimmediate typology. Over half the cases with DPTs required 6-7 days of treatment for DHR confirmation.
Background: The effects of maternal ritodrine hydrochloride administration (MRA) during pregnancy on fetuses and offspring are not entirely clear. The present study aimed to evaluate the association between MRA and childhood wheezing using data from a nationwide Japanese birth cohort study. Methods: This study retrospectively analyzed data from the Japan Environment and Children’s Study, a nationwide birth cohort study, conducted between 2011 and 2014. Data of women with singleton births after 22 weeks of gestation were analyzed. The participants were divided according to MRA status. Considering childhood factors affecting the incidence of wheezing, a logistic regression model was used to calculate adjusted odds ratios for “wheezing ever,” diagnosis of asthma in the last 12 months, and “asthma ever” in women with MRA, with women who did not receive MRA as the reference. Participants were stratified by term births, and adjusted odds ratios for outcomes were calculated using a logistic regression model. Results: A total of 68,123 participants were analyzed. The adjusted odds ratio for wheezing ever was 1.17 (95% confidence interval, 1.12–1.22). The adjusted odds ratios for the other outcomes did not significantly increase after adjusting for childhood factors. The same tendency was confirmed after excluding women with preterm births. Conclusion: MRA was associated with an increased incidence of childhood wheezing up to three years, irrespective of term births or preterm births. It is important that perinatal physicians consider both the adverse maternal side effects of MRA and its potential effects on the offspring’s childhood.
BACKGROUND: Despite SARS-CoV-2 immunizations have started in most countries, children are not currently included in the vaccination programs, thus it remains crucial to define their anti-SARS-CoV-2 immune response in order to minimize the risk for other epidemic waves. This study seeks to provide a description of the virology ad anti-SARS-CoV-2 immunity in children with distinct symptomatology. METHODS: Between March and July 2020, we recruited 15 SARS-CoV-2 asymptomatic (AS) and 51 symptomatic children (SY), stratified according to WHO clinical classification. We measured SARS-CoV-2 viral load using ddPCR and qPCR in longitudinally collected nasopharyngeal swabs samples. To define anti-SARS-CoV-2 antibodies we measured neutralization activity and total IgG load (Diasorin). We also evaluated antigen-specific B and CD8+T-cells, using a labelled S1+S2 protein and ICAM expression, respectively. Plasma protein profiling was performed with Olink. RESULTS: Virological profiling showed that AS had lower viral load at diagnosis (p=0.004) and faster virus clearance (p=0.0002) compared to SY. Anti-SARS CoV-2 humoral and cellular response did not appear to be associated with the presence of symptoms. AS and SY showed similar titers of SARS-CoV-2 IgG, levels of neutralizing activity, and frequency of Ag-specific B and CD8+T-cells. Whereas pro-inflammatory plasma protein profile was associated to symptomatology. CONCLUSION: We demonstrated the development of anti-SARS-CoV-2 humoral and cellular response with any regards to symptomatology, suggesting the ability of both SY and AS to contribute towards herd immunity. The virological profiling of AS suggested that they have lower virus load associated with faster virus clearance.
1 Conflicts of interestESC has received research support from DBV Technologies; has been a member of advisory boards for Pfizer, Pediapharm, Leo Pharma, Kaleo, DBV, AllerGenis, Sanofi Genzyme, Bausch Health, Avir Pharma; is a member of the healthcare advisory board for Food Allergy Canada; was an expert panel and coordinating committee member of the National Institute of Allergy and Infectious Diseases (NIAID)-sponsored Guidelines for Peanut Allergy Prevention; and was co-lead of the CSACI oral immunotherapy guidelines.SJ has been on speaker’s bureaus for Aralez, Novartis, Astra Zeneca, and Sanofi, and on the advisory board for Sanofi.MH has provided speaker services for Pfizer, Pediapharm, and has been part of an advisory board for ALK and provides privately funded OIT.VC has been a participant on advisory boards for Sanofi Genzyme, Bausch Health, and ALK, speaker services for Aralez Pharmaceuticals and CSL Behring.DM has provided consultation and speaker services for Pfizer, Aimmune, Kaleo, Merck, Covis and Pediapharm, and has been part of an advisory board for Pfizer and Bausch Health. He sits on the editorial board for the Journal of Food Allergy.EA Section Head of Anaphylaxis/Food Allergy for the Canadian Society of Allergy and Clinical Immunology; sits on steering committee for Canada’s National Food Allergy Action Plan; moderator/speaker fees from Novartis, GSK, Sanofi, AstraZeneca.LS NoneTW speaking engagements for Pfizer and Stallergenes Greer, Advisory Board member for ALK and Leo PharmaJP is the Section Head of Allied Health for the Canadian Society of Allergy and Clinical Immunology; and sits on the steering committee for Canada’s National Food Allergy Action Plan
Background: Cystic fibrosis (CF) is reported to be a risk factor for drug hypersensitivity. However, there is conflicting data about true prevalence of drug allergy in children with CF. Methods: The suspicious drug hypersensitivity reactions (DHR) of children with CF were enquired by European Network for Drug Allergy (ENDA) questionnaire and skin tests and/or drug provocation tests were performed according to established guidelines. Results: Two hundred and nineteen children (48.9% boys; median [IQR] age, 8.4 years [4.8-12.4 years]) with cystic fibrosis were included in the study, from whom 22 patients with 24 suspected DHRs were evaluated. Most of the suspected DHRs were non-immediate (n=16, 66.6%) type and the offending drugs were amoxicillin clavulanic acid (n=7), macrolides (n=4), trimethoprim sulfamethoxazole (TMP/SMX) (n=2), piperacillin tazobactam (n=1), pancrelipase (n=1) and ursodeoxycholic acid (n=1). Eight (33.3%) of the DHRs were classified as immediate [ceftriaxone (n=2), ceftazidim (n=2), meropenem (n=1), ambisome (n=2), vancomycin (n=1)]. The main presenting clinical presentations were maculopapular eruption (41.6%) and urticaria (37.5%), accompanied by angioedema (8.3%), flushing (12.5%) and vomiting (8.3%). Nine skin tests (with beta-lactam protocol in 6 patients) and 24 DPTs were performed and none of the skin tests revealed a positive result, however 2 DPTs with TMP/SMX were positive. Conclusion: Actual drug allergy was demonstrated in 2 of 219 patients (0.9%) with nonbeta-lactam antibiotics. These results conflict with previous researches that showed higher drug allergy rates but were consistent with some recent studies. Numerous and long-term use of multiple drugs during management of cystic fibrosis may contribute to tolerance development.
Background: Childhood allergic rhinitis (AR) is clinically highly heterogeneous. We aimed to identify distinct subgroups amongst children with AR, and to ascertain their association with patterns of symptoms, allergic sensitization and concomitant physician-diagnosed asthma. Methods: We recruited 510 children with physician-diagnosed AR, of whom 205 (40%) had asthma. Latent class analysis (LCA) was performed to identify latent structure within the data set using 17 variables (allergic conjunctivitis, eczema, asthma, family history of asthma, family history of allergic rhinitis, skin sensitization to 8 common allergens, tonsillectomy, adenoidectomy). Results: A four−class solution was selected as the optimal model based on statistical fit. We labeled AR latent classes as: (1) AR with grass mono-sensitization and conjunctivitis (n=361, 70.8%); (2) AR with house dust mite sensitization and asthma (n=75, 14.7%); (3) AR with pet and grass polysensitization and conjunctivitis (n=35, 6.9%) and (4) AR among children with tonsils and adenoids removed (n=39, 7.6%). Perennial AR was significantly more common among children in Class 2 (OR 5.83, 95%CI 3.42−9.94, p<0.001) and Class 3 (OR 2.88, 95%CI 1.36−6.13, p=0.006). Mild and intermittent AR symptoms were significantly more common in children in Class 3 compared to those in Class 1. AR was more severe in Class 1, compared to other 3 classes, indicating that upper respiratory symptoms are more severe among children with isolated seasonal rhinitis, than in those with rhinitis and coexisting asthma. Conclusion: We have identified 4 phenotypes in school-age children with AR, which were associated with different patterns of clinical symptoms and comorbidities.
Background: Enterovirus (EV) infections, being among the most prevalent viruses worldwide, have been associated with reduced risk of allergic diseases. We sought to determine the association of EVs with allergic sensitization and disease in early childhood. Methods: The study was carried out in a nested case-control setting within a prospective birth cohort in Finland. We included 138 case children who had specific IgE (s-IgE) sensitization at the age of 5 years and 138 control children without s-IgE sensitization. Allergic disease was recorded at study visits and asked with ISAAC questionary. We screened for the presence of serotype specific antibodies against 41 EVs at 1 to 5 years of age and assessed their association with allergic sensitization and disease. Results: The overall number of EV infections did not differ between s-IgE-sensitized children and non-sensitized control children. However, there was a tendency of case children with an allergic disease having less EV infections than their controls. This observation was statistically significant for species A EVs in case children with atopic dermatitis vs. control children: OR 0.6 (95 % CI 0.36-0.99), P = 0.048. Conclusion: This study supports the evidence that EV exposure and development of allergic disease are inversely associated. Interestingly, the inverse association was not observed for bare atopic IgE sensitization, but for IgE sensitization coupled with clinical atopic disease. This suggests that environmental factors influencing IgE sensitization may differ from those influencing progression to clinical allergic disease.
BACKGROUND: Exercise-induced respiratory symptoms are frequently reported by asthmatics and exercise-induced bronchospasm (EIB) is a frequent cause that requires objective testing for diagnosis. Eucapnic voluntary hyperventilation (EVH) is recommended as an exercise surrogate stimulus for this purpose, but its short-term reproducibility is not yet established in young asthmatics. OBJECTIVE: To evaluate the short-term test-retest agreement and reproducibility of FEV1 changes after EVH in young asthmatics. METHODS: Asthmatics aged between 10 and 20 years underwent EVH for EIB diagnosis on two occasions 2-4 days apart at a specialized university clinic. FEV1 was measured 5, 15 and 30 minutes after EVH with a target ventilation rate 21 times baseline FEV1. EIB was diagnosed as a decrease >10% in FEV1 from baseline. RESULTS: Twenty-six of 62 recruited individuals tested positive for EIB on both visits (positive group) and 17 on one visit only (divergent group); and 19 tested negative on both visits (negative group). The overall agreement was 72.5% (95%CI 61.6%, 83.6%) and positive and negative agreement was 41.9% and 30.6% respectively. Despite overall low bias in FEV1 response between test days (0.87%), the limits of agreement were wide (+20.72%). There were no differences in pre-challenge FEV1 or achieved ventilation rate, between visits either between groups (p=0.097 and p=0.461) or within groups, (p=0.828 and p=0.780). No test was interrupted by symptoms and there were no safety issues. CONCLUSIONS: More than one EVH test should be performed in young asthmatics with a negative test to exclude EIB and minimize misdiagnosis and mistreatment.
Background: Rural communities who consume unpasteurized and traditional fermented milk products on a regular basis, have a low prevalence of allergic diseases. Lactic acid producing bacteria present within these products, is postulated to have an allergy protective role against atopy. Objective: To characterize and compare the bacterial microbiota of fresh unpasteurised cow’s milk and to explore the effect of milk fermentation (commercially and traditionally fermented) on the bovine milk microbiota. Methods: Raw, unpasteurized cow’s milk was collected from urban and rural farms. Another sample, collected from a rural farm, was left to ferment naturally. Three different brands of commercially fermented milk samples were also analysed. The V3 and V4 regions of the 16S rRNA gene were amplified to assess microbiota composition. Results: Urban and rural fresh milk had the highest microbiota alpha diversity, and commercially bought fermented milk products, the least. Commercially fermented milk was consistently dominated by lactic acid producing bacteria, belonging to the phylum Firmicutes, while homemade fermented milk comprised of approximately 50% Firmicutes and 50% Proteobacteria. The relative abundance of several organisms differed between fermented and unfermented milk. Lactococcus lactis dominated all milk products, however its relative abundance was lower in fresh milk compared with fermented milk. Lactobacillus paracasei and Streptococcus infantis were abundant in traditionally fermented milk, but absent in commercially fermented products. Potential pathogens were demonstrated in fresh and home fermented milk. Conclusion: Commercially fermented milk can be promoted as a safe and possible allergy protective complementary feed from 1 year of age.
Background The maturation of innate immune responses in health and atopy is still incompletely understood. Methods We aimed to evaluate age-related trajectories of the TLR3 and TLR7/8 pathways across the lifespan and whether these differ between healthy and atopic individuals. Peripheral blood mononuclear cells (PBMCs) were isolated from 39 otherwise healthy atopic and 39 non-atopic subjects, aged 0-45 years. Selected cytokines involved in antiviral responses were measured by Luminex in culture supernatants of poly(I:C)- and R848-stimulated PBMCs. The non-parametric correlation between age and cytokine expression and differences in developmental trajectories between healthy and atopic were estimated. Patterns of cytokine development were identified with principal component analysis. Results Normal innate immune maturation entails significant and progressive age-related changes in the production of IL-1β, TNF-α, MIP-1β, MCP-3, IP-10, IL-10, IL-12p70 and IFN-γ upon TLR3 and/or TLR7/8 stimulation. Individual cytokines made small contributions to the observed variability; chemokines MCP-3 and IP-10 were key contributors. The development of these pathways deviated in atopic subjects with significant differences observed in the trajectories of IL-1β, MIP-1β and IL-10 synthesis. Conclusion TLR3 and TLR7/8 pathways mature during childhood, while atopy is associated with an abnormal maturation pattern. Suboptimal responses in Th1, inflammatory cytokine and chemokine production may be implicated in poor antiviral immunity in atopics, while deficient maturation of IL-10 producing capacity in the breaking of tolerance.
Background: Although atopic dermatitis (AD) is associated with certain gene variants, the rapidly increasing incidence of AD suggests that environmental factors contribute to disease development. In this study, we investigated the association of AD incidence and phenotype with antibiotic exposure within 6 months of age, considering the dose administered and genetic risk. Methods: This study included 1,637 children from the COCOA birth cohort. Pediatric allergists assessed the presence of AD at each visit and obtained information about antibiotic exposure for more than 3 days. IL-13 (rs20541) polymorphism was genotyped by the TaqMan method. We stratified the AD phenotypes into 4 groups and used multinomial logistic regression models for analysis. Results: Antibiotic exposure within 6 months of age was found to increase the risk of AD within 3 years of life (aOR=1.40, 95%, CI 1.09–1.81) in dose-dependent manner. Antibiotic exposure more than twice increased the risk of the early-persistent AD phenotype (aOR=2.50, 95% CI 1.35–4.63). There was a weak interaction between genetic polymorphisms and environmental factors on the development of AD (p for interaction=0.06). Children with the IL-13 (rs20541) GA+ AA genotype have a higher risk of the early-persistent AD phenotype when exposed to antibiotics more than twice than those with the IL-13 (rs20541) GG genotype and without exposure to antibiotics (aOR=4.73, 2.01–11.14). Conclusion: Antibiotic exposure within 6 months was related to the incidence of early-persistent AD and a dose-dependent increase in the incidence of AD in childhood, whose effect was modified by the IL-13 (rs20541) genotype.
Background: Food allergy is a major health problem that significantly impacts quality of life (QoL). There is growing focus to evaluate food allergy related QoL and treatment value beyond the clinical effectiveness perspective by engaging patients and caregivers. We aimed to identify and prioritize outcomes important to food allergy parents of children and patients allergic to milk, egg, and/or peanut, to guide comparative effectiveness research (CER) that focuses on evaluating food allergy treatment decisions. Methods: We conducted a modified 3-round Delphi study to identify and derive consensus on priority treatment outcomes for parents of children and adult patients with diagnosed allergies to at least one of three major allergenic foods (milk, egg, and peanut) from across the United States. Results: Round 1 yielded 44 statements for round 2, and 39 statements reached the agreement level for round 3 ranking. Statements were organized under 4 sections: 1) food allergy problems, 2) treatment experiences, 3) important treatment outcomes, and 4) value of different treatment options. Conclusion: Food allergy parents and patients face several social, psychological, medical, healthcare, financial, food selection, and awareness challenges. The areas of consensus on important treatment outcomes revealed shared priority for reducing the risk of potentially fatal allergic reactions and having reliable treatments. The most valued treatment options reflect hope for permanent cure and fear of serious allergic reactions.
Background: Safely liberalizing the diet to include an allergenic food may accelerate resolution of food allergy. The outcome of liberalization, however, varies among patients. Methods: We conducted a prospective observational study to identify factors associated with outcome for egg allergy 1 year after oral food challenge (OFC). We enrolled children < 72 months-old who had egg allergy and underwent OFC for determination of the safe intake quantity of egg allergen. At enrollment, each child’s clinical background was recorded. The Food Allergy Quality of Life Questionnaire–Parent Form (FAQLQ–PF) was administered to the caregivers to assess their children’s QoL. Dietary advice based on the OFC result was then provided to support safe consumption of eggs. At 1 year after OFC, the quantity of egg each child safely consumed in daily life was surveyed. We classified the egg allergy outcome as Outgrowing (Group O) if the quantity increased during the 1 year, or as Non-outgrowing (Group N) if it did not. Factors associated with the outcome were investigated by multivariate logistic regression analysis. Results: A total of 93 children were enrolled, and after 1 year 57 finished in Group O and 36 in Group N. The mean FAQLQ-PF score at baseline was significantly lower (i.e., better QoL) in group O than in group N. Multivariate logistic regression analysis identified comorbid asthma, comorbid atopic dermatitis and a poor QoL as factors predicting an unfavorable outcome. Conclusion: QoL may affect food allergy outcome. Intervention focusing on QoL may promote outgrowing food allergies.
Background: Mutations in the filaggrin gene (FLG) affect epidermal barrier function and increase the risk of atopic dermatitis (AD). We hypothesized that FLG mutations affect immune cell composition in a general pediatric population. Therefore, we investigated if school-aged children with and without FLG mutations have differences in immune cell numbers. Methods: This study was embedded in a population-based prospective cohort study, the Generation R Study, and included 523 children of European genetic ancestry aged 10 years. The most common FLG mutations in the European population (R501X, S1085CfsX36, R2447X and S3247X) were genotyped. Additionally, 11-color flow cytometry was performed on peripheral blood samples to determine helper T (Th), regulatory T (Treg) and CD27+ and CD27- memory B cells. Sensitivity analysis was performed in 102 AD cases, assessed by parental questionnaires. Results: FLG mutations were observed in 8.4% of the total population and in 15.7% of the AD cases. Children with any FLG mutation had higher Th22 cell numbers compared to FLG wild-type children. Children with and without FLG mutations had no difference in Th1, Th2, Th17, Treg or memory B cell numbers. Furthermore, in children with AD, FLG mutation carriership was not associated with differences in T- and B-cells or their subsets. Conclusions: School-aged children with FLG mutations have higher Th22 cell, which might suggest an immunological defense mechanism to an altered skin barrier function. No associations between Th or Treg cells and FLG mutations suggests that FLG mutations do not otherwise affect immune composition in a general pediatric population.
Background: Periostin has emerged as a novel biomarker in the pathogenesis of T helper 2-type allergic diseases in the last years. 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 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 < 0.001). The mean serum periostin levels of 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 < 0.001). Serum periostin levels were found to be significantly correlated with asthma severity (Spearman’s rho [r]=0.41, p < 0.001). 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 <0.001) Conclusion: Serum periostin levels may serve clinicians in identifying children with severe asthma.