Wheeze Phenotypes Research Articles

Impact of wheat sensitization on wheeze and T2 phenotypes in general population of children

BackgroundThe association between sensitization to specific aeroallergens and outcomes in patients with asthma is well-researched; however, the association between childhood-onset wheeze/asthma and sensitization to various aeroallergens and food allergens in the general pediatric population remains poorly understood. ObjectiveThe association between sensitization to common aeroallergens and food allergens with wheeze and type 2 (T2) inflammation in the general pediatric population was investigated. MethodsSpecific IgEs against nine aeroallergens and four food allergens were measured in the prospective Hokkaido birth cohort of 428 school-age children (approximately 10 years of age). Wheeze and other allergic symptoms were assessed using the International Study of Asthma and Allergies in Childhood questionnaire. Blood eosinophil count and fractional exhaled nitric oxide level were assessed as T2 biomarkers. The Isle of Wight (IOW) birth cohort in UK was used for replication analysis (n=1032). ResultsThe prevalence of sensitization to at least one aeroallergen and food allergen was 70.5% and 22.3%, respectively. A significant association between wheeze and sensitization to aeroallergens such as ragweed, Japanese cedar, mugwort, and pet dander, were found. However, the association between wheeze and wheat sensitization was highly significant (Hokkaido birth cohort, odds ratio [OR]: 4.67; 95% confidence interval [CI]: 1.98–11.01; IOW birth cohort, OR: 4.01, 95% CI: 1.78–9.07). Sensitization to most aeroallergens, though not any food allergens, was associated with the T2high phenotype. ConclusionSensitization to wheat may be an important risk factor for wheeze/asthma development, especially the pathogenesis of T2-non/low asthma, independent of aeroallergens, in the general pediatric population.

Vitamin D Level and Immune Modulation in Children with Recurrent Wheezing.

A direct causal relationship between vitamin D (vit D) deficiency and recurrent wheezing has not been proven. The present study investigated the role of vit D in enhancing the risk of asthma or recurrent wheezing by modifying the intensity of the inflammatory process. Forty children with wheezing presenting at the emergency service and sixteen healthy control subjects were included in the study. Children with wheezing were either in the first episode (20) or with recurrent wheezing (20). Children with chronic diseases, and other conditions that present with acute wheezing or that might influence the vit D level, were excluded. Blood samples were taken at presentation and 3-6 months later, to evaluate the serum levels of total IgE, vit D, IL-10 and IL-31. Statistical analysis was performed using the SPSS 25 program, with a significance level of p < 0.05. The vit D level was lower in patients with recurrent wheezing compared with those with a single episode and with the control group, and this increased with time. IL-10 was significantly higher in children with wheezing than in the control group, with the highest values in those with an acute episode of wheezing. IL-31 was higher in children with recurrent wheezing than in those with a first episode only at the initial point, while at the final time point it was lower. Low levels of vit D appear to be detected more frequently in recurrent wheezing than in simple wheezing. Immune modulation, as measured by Th2 status reflected by IL-10 and IL-31 levels, appears to depend on the wheezing phenotype and on the general health status.

Genetics of preschool wheeze and its progression to childhood asthma.

Wheezing is a common and heterogeneous condition in preschool children. In some countries, the prevalence can be as high as 30% and up to 50% of all children experience wheezing before the age of 6. Asthma often starts with preschool wheeze, but not all wheezing children will develop asthma at school age. At this moment, it is not possible to accurately predict which wheezing children will develop asthma. Recently, studying the genetics of wheeze and the childhood-onset of asthma have grown in interest. Childhood-onset asthma has a stronger heritability in comparison with adult-onset asthma. In early childhood asthma exacerbations, CDHR3, which encodes the receptor for Rhinovirus C, was identified, as well as IL33, and the 17q locus that includes GSDMB and ORMDL3 genes. The 17q locus is the strongest wheeze and childhood-onset asthma locus, and was shown to interact with many environmental factors, including smoking and infections. Finally, ANXA1 was recently associated with early-onset, persistent wheeze. ANXA1 may help resolve eosinophilic inflammation. Overall, despite its complexities, genetic approaches to unravel the early-onset of wheeze and asthma are promising, since these shed more light on mechanisms of childhood asthma-onset. Implicated genes point toward airway epithelium and its response to external factors, such as viral infections. However, the heterogeneity of wheeze phenotypes complicates genetic studies. It is therefore important to define accurate wheezing phenotypes and forge larger international collaborations to gain a better understanding of the pathways underlying early-onset asthma.

Impaired interferon response in plasmacytoid dendritic cells from children with persistent wheeze

Impaired interferon response and allergic sensitization may contribute to virus-induced wheeze and asthma development in young children. Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity as critical producers of type I interferons. pDCs also express the high-affinity IgE receptor through which type I interferon production may be negatively regulated. Whether antiviral function of pDCs is associated with recurrent episodes of wheeze in young children is not well understood. We sought to evaluate the phenotype and function of circulating pDCs in children with a longitudinally defined wheezing phenotype. We performed multiparameter flow cytometry on PBMCs from 38 children presenting to the emergency department with an acute episode of respiratory wheeze and 19 controls. RNA sequencing on isolated pDCs from the same individuals was also performed. For each subject, their longitudinal exacerbation phenotype was determined using the Western Australia public hospital database. We observed a significant depletion of circulating pDCs inyoung children with a persistent phenotype of wheeze. The same individuals also displayed upregulation of the FcεRI on their pDCs. Based on transcriptomic analysis, pDCs from these individuals didnot mount a robust systemic antiviral response as observed inchildren who displayed a nonrecurrent wheezing phenotype. Our data suggest that circulating pDC phenotype and function are altered in young children with a persistent longitudinal exacerbation phenotype. Expression of high-affinity IgE receptor is increased and their function as major interferon producers is impaired during acute exacerbations of wheeze.

Understanding progression from pre-school wheezing to school-age asthma: Can modern data approaches help?

Preschool wheezing and childhood asthma create a heavy disease burden which is only exacerbated by the complexity of the conditions. Preschool wheezing exhibits both "curricular" and "aetiological" heterogeneity: that is, heterogeneity across patients both in the time-course of its development and in its underpinning pathological mechanisms. Since these are not fully understood, but clinical presentations across patients may nonetheless be similar, current diagnostic labels are imprecise-not mapping cleanly onto underlying disease mechanisms-and prognoses uncertain. These uncertainties also make a identifying new targets for therapeutic intervention difficult. In the past few decades, carefully designed birth cohort studies have collected "big data" on a large scale, incorporating not only a wealth of longitudinal clinical data, but also detailed information from modalities as varied as imaging, multiomics, and blood biomarkers. The profusion of big data has seen the proliferation of what we term "modern data approaches" (MDAs)-grouping together machine learning, artificial intelligence, and data science-to make sense and make use of this data. In this review, we survey applications of MDAs (with an emphasis on machine learning) in childhood wheeze and asthma, highlighting the extent of their successes in providing tools for prognosis, unpicking the curricular heterogeneity of these conditions, clarifying the limitations of current diagnostic criteria, and indicating directions of research for uncovering the etiology of the diseases underlying these conditions. Specifically, we focus on the trajectories of childhood wheeze phenotypes. Further, we provide an explainer of the nature and potential use of MDAs and emphasize the scope of what we can hope to achieve with them.

Periconceptional maternal diet quality and offspring wheeze trajectories: Japan Environment and Children's Study.

The role of prenatal diet on childhood wheezing and subsequent risk of asthma is inconclusive, which may be partly due to the heterogeneity in wheezing phenotypes. We aimed to identify wheeze trajectories in early childhood and to examine their associations with periconceptional maternal diet quality. Data from 70,530 mother-child pairs of liveborn singletons from the Japan Environment and Children's Study were analysed. Wheezing was reported by caregivers using a modified International Study of Asthma and Allergies in Childhood questionnaire yearly from 1 to 4 years of age, from which trajectories were derived using group-based trajectory modelling. Maternal diet in the year preceding the first trimester of pregnancy was assessed using a validated food frequency questionnaire; overall diet quality was determined using the balanced diet score based on the Japanese Food Guide Spinning Top. Bayesian inference of multinomial logistic regression models was performed to examine the association between maternal diet quality and wheeze trajectory in early childhood. We identified four wheeze trajectories: 'never/infrequent' (69.1%; reference group), 'early-childhood onset' (6.2%), 'transient early' (16.5%) and 'persistent' (8.2%). After adjustment for confounders, a higher quartile of maternal balanced diet score was associated with a lower risk of belonging to the 'transient early' and 'persistent' wheeze trajectories compared with the 'never/infrequent' wheeze trajectory by 10% of both. Maternal balanced diet score was not associated with belonging to the 'early-childhood onset' wheeze trajectory. Improving maternal diet quality prior to conception may reduce certain wheeze phenotypes in early childhood.

Recurrent wheezing phenotypes after severe bronchiolitis and progression to asthma

Recurrent wheezing, a common diagnosis after severe bronchiolitis, has multiple phenotypes of uncertain relation to childhood asthma. Among infants hospitalized for bronchiolitis, we investigated the relation of three 2020 recurrent wheezing phenotypes by age 4 years to asthma by age 6 years. In a 17-center cohort study of infants hospitalized with bronchiolitis, we investigated the National Heart, Lung, and Blood Institute (NHLBI) 2020-defined recurrent wheezing phenotype and 2 additional phenotypes based on this definition: multitrigger and severe. As a sensitivity analysis, we examined the NHLBI 2007 recurrent wheezing phenotype. We calculated the proportion of study subjects who developed asthma by age 6 years and used multivariable logistic regression to examine characteristics associated with the highest-risk 2020 phenotype. Of 921 infants, 632 (69%) developed NHLBI 2020 recurrent wheezing, 734 (80%) developed multitrigger wheezing, and 165 (18%) developed severe wheezing by age 4 years; in addition, 296 (32%) developed NHLBI 2007-defined recurrent wheezing by age 3 years. Of 862 children with sufficient data (94%), 239 (28%) developed asthma by age 6 years. The proportions of children who progressed to asthma were as follows: 33% of those with NHLBI 2020-defined wheezing, 33% of those with multitrigger wheezing, 54% of those with severe wheezing, and 52% of those with NHLBI 2007-defined recurrent wheezing. The children with the severe phenotype who developed asthma had the associated characteristics preterm birth, child eczema, maternal asthma, and non-respiratory syncytial virus infection. Most infants with severe bronchiolitis developed the NHLBI 2020-defined recurrent wheezing phenotype by age 4 years. Depending on the phenotype, 33% to 54% will develop asthma by age 6 years. Future research will examine whether earlier treatment of high-risk phenotypes will improve wheezing symptoms and potentially prevent childhood asthma. (J Allergy Clin Immunol Global 2023;2:84-7.).

Prematurity-associated wheeze: current knowledge and opportunities for further investigation.

Prematurity-associated wheeze is a common complication of preterm birth, with significant impact on the health and healthcare utilization of former preterm infants. This wheezing phenotype remains poorly understood and difficult to predict. This review will discuss the current state of the literature on prematurity-associated wheeze. We will discuss etiology and pathophysiology, and offer two conceptual models for the pathogenesis of this complex condition. This review will also identify current methods of ascertainment, and discuss the strengths and limitations of each. We will explore research-backed approaches to prevention and management, and finally suggest both pre-clinical and clinical avenues for investigation. An in-depth understanding of prematurity-associated wheeze will aid clinicians in its diagnosis and management, and inspire scientists to pursue much-needed further study into causes and prevention of this common and impactful condition. IMPACT: There is no recent, concise review on the current state of research on prematurity-associated wheeze, which is a rapidly evolving area of study. This article highlights causal models of wheeze, methods of ascertainment, management strategies for the clinician, and opportunities for further research for the physician scientist.

Early childhood wheezing phenotypes and determinants in a South African birth cohort: longitudinal analysis of the Drakenstein Child Health Study

Developmental trajectories of childhood wheezing in low-income and middle-income countries (LMICs) have not been well described. We aimed to derive longitudinal wheeze phenotypes from birth to 5 years in a South African birth cohort and compare those with phenotypes derived from a UK cohort. We used data from the Drakenstein Child Health Study (DCHS), a longitudinal birth cohort study in a peri-urban area outside Cape Town, South Africa. Pregnant women (aged ≥18 years) were enrolled during their second trimester at two public health clinics. We followed up children from birth to 5 years to derive six multidimensional indicators of wheezing (including duration, temporal sequencing, persistence, and recurrence) and applied Partition Around Medoids clustering to derive wheeze phenotypes. We compared phenotypes with a UK cohort (the Avon Longitudinal Study of Parents and Children [ALSPAC]). We investigated associations of phenotypes with early-life exposures, including all-cause lower respiratory tract infection (LRTI) and virus-specific LRTI (respiratory syncytial virus, rhinovirus, adenovirus, influenza, and parainfluenza virus) up to age 5 years. We investigated the association of phenotypes with lung function at 6 weeks and 5 years. Between March 5, 2012, and March 31, 2015, we enrolled 1137 mothers and there were 1143 livebirths. Four wheeze phenotypes were identified among 950 children with complete data: never (480 children [50%]), early transient (215 children [23%]), late onset (104 children [11%]), and recurrent (151 children [16%]). Multivariate adjusted analysis indicated that LRTI and respiratory syncytial virus-LRTI, but not other respiratory viruses, were associated with increased risk of recurrent wheeze (odds ratio [OR] 2·79 [95% CI 2·05-3·81] for all LTRIs; OR 2·59 [1·30-5·15] for respiratory syncytial virus-LRTIs). Maternal smoking (1·88 [1·12-3·02]), higher socioeconomic status (2·46 [1·23-4·91]), intimate partner violence (2·01 [1·23-3·29]), and male sex (2·47 [1·50-4·04]) were also associated with recurrent wheeze. LRTI and respiratory syncytial virus-LRTI were also associated with early transient and late onset clusters. Wheezing illness architecture differed between DCHS and ALSPAC; children included in ALSPAC in the early transient cluster wheezed for a longer period before remission and late-onset wheezing started at an older age, and no persistent phenotype was identified in DCHS. At 5 years, airway resistance was higher in children with early or recurrent wheeze compared with children who had never wheezed. Airway resistance increased from 6 weeks to 5 years among children with recurrent wheeze. Effective strategies to reduce maternal smoking and psychosocial stressors and new preventive interventions for respiratory syncytial virus are urgently needed to optimise child health in LMICs. UK Medical Research Council; The Bill & Melinda Gates Foundation; National Institutes of Health Human Heredity and Health in Africa; South African Medical Research Council; Wellcome Trust.

Early-life residential exposure to moisture damage is associated with persistent wheezing in a Finnish birth cohort.

Moisture damage increases the risk for respiratory disorders in childhood. Our aim was to determine whether early age residential exposure to inspector-observed moisture damage or mold is associated with different wheezing phenotypes later in childhood. Building inspections were performed by civil engineers, in a standardized manner, in the children's homes-mostly single family and row houses (N=344)-in the first year of life. The children were followed up with repeated questionnaires until the age of 6 years and wheezing phenotypes-never/infrequent, transient, intermediate, late onset, and persistent-were defined using latent class analyses. The multinomial logistic regression model was used for statistical analysis. A total of 63% (n=218) had infrequent or no wheeze, 23% (n=80) had transient and 9.6% (n=21) had a persistent wheeze. Due to the low prevalence, results for intermediate (3.8%, n=13) and late-onset wheeze (3.5%, n=12) were not further evaluated. Most consistent associations were observed with the persistent wheeze phenotype with an adjusted odds ratio (95% confidence intervals) 2.04 (0.67-6.18) for minor moisture damage with or without mold spots (present in 23.8% of homes) and 3.68 (1.04-13.05) for major damage or any moisture damage with visible mold in a child's main living areas (present in 13.4% of homes). Early-age moisture damage or mold in the kitchen was associated with transient wheezing. At an early age, residential exposure to moisture damage or mold, can be dose-dependently associated especially with persistent wheezing phenotype later in childhood.

Mannose-binding lectin genotype is associated with respiratory disease in young children: A multicenter cohort study.

Mannose-binding lectin (MBL) is an important component of the innate immune system. Polymorphisms in the MBL2 gene and promoter region are directly associated with MBL-deficiency. We sought to determine the association between MBL genotype on the frequency of common childhood respiratory infections, respiratory symptoms, and atopic outcomes in early childhood. MBL2 gene variants were analyzed in newborns recruited to the GO-CHILD multicenter prospective cohort study. Follow-up for respiratory infection and atopy diagnoses and symptoms, healthcare utilization, and medication prescription were conducted by postal questionnaires at 12 and 24 months. Genotyping and follow-up were completed in 1004 children. Genotypes associated with MBL-deficiency were associated with an increased risk of bronchiolitis (relative risk [RR] 1.95, 95% confidence interval [CI] 1.33-2.85) and pneumonia (RR 2.46, 95%CI 1.16-5.22). MBL-deficient genotypes were associated with an increased risk of wheeze with shortness of breath episodes (RR 1.22, 95%CI 1.04-1.43), emergency department attendance (RR 1.90 95%CI 1.13-3.19), and hospital admission (RR 2.01, 95%CI 1.04-3.89) for wheeze. MBL-deficient genotypes were associated with a reduced risk of developing atopic dermatitis (RR 0.72, 95%CI 0.53-0.98). The positive association between MBL-deficient genotypes and bronchiolitis and pneumonia, as well as a severe wheeze phenotype in some young children, supports the hypothesis that MBL is an important component of innate immunity in the vulnerable period before the maturation of the adaptive immune system. Identification of disease-modifying genotypes may help target preventative strategies in high-risk infants.

Early-life predictors and risk factors of peanut allergy, and its association with asthma in later-life: Population-based birth cohort study.

BackgroundUnderstanding risk factors for peanut allergy (PA) is essential to develop effective preventive measures.ObjectiveThe objective was to ascertain associates and predictors of PA, and the relationship between PA and asthma severity.MethodsIn a population‐based birth cohort, we investigated the association between objectively confirmed PA with early‐life environmental exposures, filaggrin (FLG)‐loss‐of‐function mutations and other atopic disease. We then examined the association of PA with longitudinal trajectories of sensitization, wheeze and allergic comorbidities, which were previously derived using machine learning. Finally, we ascertained the relationship between PA and asthma severity.ResultsPA was confirmed in 30/959 participants with evaluable data. In the multivariate analysis, eczema in infancy (OR = 4.4, 95% CI 1.5–13.2, p = 0.007), egg sensitization at age 3 years (OR = 9.7, 95% CI 3.3–29.9, p < 0.001) and early‐life cat ownership (OR = 3.0, 95% CI 1.1–8.4, p = 0.04) were independent associates of PA. In the stratified analysis among 700 participants with genetic information, in children with early‐life eczema there was no difference in FLG mutations between children with and without PA (3/18 [16.7%] vs. 42/220 [19.1%], p = 1.00). In contrast, among children without eczema, those with PA were almost eight times more likely to have FLG mutations (2/6 [33.3%] vs. 27/456 [5.9%], p = 0.049). We observed associations between PA and multiple allergic sensitization profiles derived using machine learning, with ~60‐fold increase in risk among individuals assigned to multiple early sensitization. PA was significantly associated with persistent wheeze (but not other wheeze phenotypes), and with trajectories of atopic disease characterized by co‐morbid persistent eczema and wheeze (but not with transient phenotypes). Children with PA were more likely to have asthma, but among asthmatics we found no evidence of an association between PA and asthma severity.ConclusionsPeanut allergy is associated with multiple IgE sensitization and early‐onset persistent eczema and wheeze. FLG loss‐of‐function mutations were associated with peanut allergy in children without eczema.

Current strategies for phenotyping and managing asthma in preschool children.

Half of all children will experience an episode of wheezing by 6 years. Recurrent preschool wheezing is associated with early lung function loss and has a lifelong impact on airway health, so deciding which children should be treated to prevent exacerbations while also avoiding irreversible health consequences is crucial. The purpose of this review is to provide a practical approach to the pediatric patient under 5 years of age with asthma, with particular attention to the recent enhanced identification of wheeze phenotypes. Here, we note the difficulty of defining 'asthma' for this age group and advocate that it be determined by the set of respiratory symptoms presented, without assumptions about the underlying mechanisms of the disease. In addition, we propose a forward-looking approach, what treatment to apply to particular phenotypes, which child should be treated, and, if so, which treatment strategy to choose. No clear recommendation exists for the management of nonallergic preschool wheezing, a substantial clinical and research gap. We recommend an empathetic approach to parent anxiety and considering objective markers: timing, severity, and frequency of symptoms, along with an assessment of other biomarkers, including viral etiology, aeroallergen sensitization, and blood eosinophils, that contribute to successful decision-making.

Modeling Wheezing Spells Identifies Phenotypes with Different Outcomes and Genetic Associates.

Rationale: Longitudinal modeling of current wheezing identified similar phenotypes, but their characteristics often differ between studies. Objectives: We propose that a more comprehensive description of wheeze may better describe trajectories than binary information on the presence/absence of wheezing. Methods: We derived six multidimensional variables of wheezing spells from birth to adolescence (including duration, temporal sequencing, and the extent of persistence/recurrence). We applied partition-around-medoids clustering on these variables to derive phenotypes in five birth cohorts. We investigated within- and between-phenotype differences compared with binary latent class analysis models and ascertained associations of these phenotypes with asthma and lung function and with polymorphisms in asthma loci 17q12-21 and CDHR3 (cadherin-related family member 3). Measurements and Main Results: Analysis among 7,719 participants with complete data identified five spell-based wheeze phenotypes with a high degree of certainty: never (54.1%), early-transient (ETW) (23.7%), late-onset (LOW) (6.9%), persistent (PEW) (8.3%), and a novel phenotype, intermittent wheeze (INT) (6.9%). FEV1/FVC was lower in PEW and INT compared with ETW and LOW and declined from age 8 years to adulthood in INT. 17q12-21 and CDHR3 polymorphisms were associated with higher odds of PEW and INT, but not ETW or LOW. Latent class analysis- and spell-based phenotypes appeared similar, but within-phenotype individual trajectories and phenotype allocation differed substantially. The spell-based approach was much more robust in dealing with missing data, and the derived clusters were more stable and internally homogeneous. Conclusions: Modeling of spell variables identified a novel intermittent wheeze phenotype associated with lung function decline to early adulthood. Using multidimensional spell variables may better capture wheeze development and provide a more robust input for phenotype derivation.

Wheeze trajectories: Determinants and outcomes in the CHILD Cohort Study

Wheezing in early life is associated with asthma in adulthood; however, the determinants of wheezing trajectories and their associations with asthma and lung function in childhood remain poorly understood. In the CHILD Cohort Study, we aimed to identify wheezing trajectories and examine the associations between these trajectories, risk factors, and clinical outcomes at age 5 years. Wheeze data were collected at 8 time points from 3 months to 5 years of age. We used group-based trajectory models to derive wheeze trajectories among 3154 children. Associations with risk factors and clinical outcomes were analyzed by weighted regression models. We identified 4 trajectories: a never/infrequent trajectory, transient wheeze, intermediate-onset (preschool) wheeze, and persistent wheeze. Higher body mass index was a common risk factor for all wheeze trajectories compared with that in the never/infrequent group. The unique predictors for specific wheeze trajectories included male sex, lower respiratory tract infections, and day care attendance for transient wheeze; paternal history of asthma, atopic sensitization, and child genetic risk score of asthma for intermediate wheeze; and maternal asthma for persistent wheeze. Blood eosinophil counts were higher in children with the intermediate wheeze trajectory than in those children with the other trajectories at the ages of 1 and 5 years. All wheeze trajectories were associated with decreased lung function and increased risk of asthma at age 5 years. We identified 4 distinct trajectories in children from 3 months to 5 years of age, reflecting different phenotypes of early childhood wheeze. These trajectories were characterized by different biologic and physiologic traits and risk factors.

Potential sex differences in human milk leptin and their association with asthma and wheeze phenotypes: Results of the Ulm Birth Cohorts.

The hormone leptin has been suggested to play a role in the respiratory and immune systems. Evidence on sex-specific concentrations of leptin in human milk and sex-specific associations with the development of asthma and wheeze has been put forward but is still scarce. To investigate whether male and female infants receive different levels of leptin through human milk and whether leptin is implicated in the development of asthma and wheeze in a sex-dependent manner using data from the two Ulm Birth Cohort studies. Leptin data were available from human milk samples collected at 6weeks (Ulm Birth Cohort Study [UBCS, n=678; Ulm SPATZ Health Study, n=587]), and, in SPATZ only, at 6months (n=377) and 12months (n=66) of lactation. Sex-specific associations with doctor-diagnosed asthma and wheeze phenotypes were assessed in crude and adjusted models using logistic regression. Adjustments were made for maternal allergy, exclusive breastfeeding, infant age at the time of milk sampling, and child BMI z-score. At 6weeks, leptin levels (median [min, max], in ng/L) were higher in the milk for girls (197 [0.100, 4120]) than in milk for boys (159 [1.02, 3280], p=.045) in UBCS. No significant sex differences were observed in SPATZ (p=.152). There were no significant associations of leptin with asthma or wheeze in both studies, even in a sex-dependent manner (p>.05). It remains unclear whether male and female infants receive different levels of leptin through human milk. However, leptin in human milk may not be associated with history and development of asthma and wheeze in a sex-specific manner.

Childhood wheezing phenotypes and their association to perinatal factors: a longitudinal study.

Multiple gestational and early life factors have been described as the variables that increase the risk for each phenotype of infantile wheezing. Our objective was to study the evolution of wheezing in a cohort of children followed up to 9-10 years of age and its relationship with different perinatal risk factors. A longitudinal study was made on the evolution of wheezing, over time, in 1164 children from Salamanca (Spain) included in the International Study of Wheezing in Infants, when the children were 12 months old. They were classified into three phenotypes: transient early wheezing (last episode before 3 years of age), early persistent wheezing (start before 3 years age and persisting thereafter), and late-onset wheezing (first episode after 3 years of age). Univariate and multivariable analyses were performed to establish associations between the different phenotypes and perinatal factors. Data were obtained corresponding to a total of 531 children. Of these, 169 (31.8%) had experienced transient early wheezing, 100 (18.8%) early persistent wheezing, 28 (5.3%) late-onset wheezing, and 234 (44.1%) had never experienced wheezing. Cesarean delivery, early exposure to infections, the presence of atopic eczema, and a smoking father were associated with transient early wheezing. Early persistent wheezing was associated with a family history of allergy, smoking, and obstetric diseases. Exclusive breastfeeding was identified as a protective factor in both transient and persistent early wheezing. Late-onset wheezing was associated with the male gender and with maternal history of rhinitis and eczema. Wheezing phenotypes were associated with different risk perinatal factors. Knowledge in the field is essential in order to influence the modifiable factors.

Identifying wheezing phenotypes in a pediatric Turkish cohort

Objective Characterization of wheezing phenotypes in children might help to identify the underlying mechanisms through which asthma occurs. In our study, we aimed to describe wheezing phenotypes in Turkish children and to identify risk factors according to phenotypes. Methods 651 wheezy children were evaluated and 5 wheezing phenotypes were described according to age of onset, atopy and persistence at 6 years of age and risk factors were identified. Results Distribution of wheezing phenotypes was transient early wheeze (TEW)(34.9%) non-atopic wheeze (NAW) (18%), atopic wheeze (AW) (22.3%), intermediate onset wheeze (IOW) (11.1%), late onset wheeze (LOW) (11.7%). LOW, AW, and IOW were associated with, father’s, sibling’s and family’s atopy (p:0.001) whereas LOW and AW were associated with mother’s asthma and atopy as well as family’s asthma (p < 0.05). Atopic dermatitis and allergic rhinitis were common of patients with LOW, AW, and IOW (p < 0.05). İnfection was the major trigger for TEW and NAW whereas multiple triggers were common of AW, LOW, and IOW. Allergens were mostly associated with AW, IOW and LOW. Aeroallergen-specific IgE positivity was mostly with AW, IOW, and LOW phenotype. Skin prick tests showed multiple allergen sensitivity in IOW, LOW groups and mostly single allergen in AW phenotype. Modified asthma predictive index (mAPI) positivity was high in all groups except TEW and NAW. Conclusions With this study we classified five wheeze phenotypes and found that atopy and family’s atopy history, maternal asthma were strongly associated with AW, LOW, and IOW phenotypes which were usually effected by allergens or multiple triggers.

Novel Treatment-Refractory Preschool Wheeze Phenotypes Identified by Cluster Analysis of Lung Lavage Constituents

Preschool children with treatment-refractory wheeze often require unscheduled acute care. Current guidelines advise treatment of persistent wheeze with inhaled corticosteroids. Alternative treatments targeting structural abnormalities and specific inflammatory patterns could be more effective. To apply unsupervised analysis of lung lavage (bronchoalveolar lavage [BAL]) variables to identify clusters of preschool children with treatment-refractory wheeze. A total of 155 children 6 years or younger underwent bronchoscopy with BAL for evaluation of airway structure, inflammatory markers, and pathogens. Variables were screened with factor analysis and sorted into clusters by Ward's method, and membership was confirmed by discriminant analysis. The model was repeatable in a 48-case validation sample and accurately classified 86% of cases. Cluster 1 (n= 60) had early-onset wheeze, 85% with structural abnormalities, mostly tracheamalacia, with low total IgE and agranulocytic BAL. Cluster 2 (n= 42) had later-onset wheeze, the highest prevalence of gastroesophageal reflux, little atopy, and two-third had increased BAL lipid-laden macrophages. Cluster 3 (n= 46) had mid-onset wheeze, low total IgE, and two-third had BAL viral transcripts, predominately human rhinovirus, with BAL neutrophilia. Cluster 4 (n= 7) was older, with high total IgE, blood eosinophilia, and mixed BAL eosinophils and neutrophils. Preschool children with recurrent wheeze refractory to inhaled corticosteroid treatment include 4 clusters: airway malacia, gastroesophageal reflux, indolent human rhinovirus bronchoalveolitis, and type-2high inflammation. The results support the risk and cost of invasive bronchoscopy to diagnose causes of treatment-refractory wheeze and develop novel therapies targeting airway malacia, human rhinovirus infection, and BAL neutrophilia in preschool children.

A model of perinatal stress and childhood wheezing: ELSPAC-CZ cohort.

Prenatal origins of wheezing are not fully understood. This study develops a model of mechanisms linking perinatal stress exposure to wheeze phenotypes in children. Data were obtained from 1880 mother-child dyads participating in ELSPAC-CZ birth cohort. Wheeze phenotypes assessed between birth and age 7 years included "never wheeze," "early-onset transient (EOT) wheeze," "early-onset persistent (EOP) wheeze," and "late-onset (LO) wheeze." Prenatal and postnatal stress exposures were assessed in mid-pregnancy and 6 months after delivery, respectively, using an inventory of 42 life events. In adjusted models, children in the highest tercile (high) versus lowest tercile (low) for prenatal life events had a 38% higher risk of EOT wheeze (relative risk ratio [RRR] = 1.38; 95% confidence interval [CI] = 1.01-1.88; p = .041) and 50% higher risk of LO wheeze (RRR = 1.50; 95% CI = 1.00-2.25; p = .047). High versus low exposure to postnatal life events predicted a 60% increase in relative risk of EOT wheeze (RRR = 1.60; 95% CI = 1.17-2.19; p = .003) and medium versus low exposure was related to an 85% increase in relative risk of EOP wheeze (RRR = 1.85; 95% CI = 1.16-2.95; p = .010). Lower respiratory tract infections and postpartum depression partially mediated between postnatal life events and any wheeze (indirect effects 1.06, 95% CI = 1.02-1.09, p = .003 and odds ratio [OR] = 1.08, 95% CI = 1.02-1.15, p = .012, respectively), while postnatal events mediate for prenatal events (indirect effect OR = 1.11; 95% CI = 1.03-1.18; p = .005). Exposures to prenatal and postnatal life events are risk factors for the development of wheezing. Prenatal stress contributes to wheeze directly and also through postnatal life events, respiratory infections, and maternal depression.