Early Transient Wheeze Research Articles

Maternal exposure to smoking and wheezing phenotypes in children: a cohort study of the Japan Environment and Children’s Study

BackgroundPrevious studies have shown that prenatal maternal smoking and maternal secondhand smoke exposure during pregnancy were associated with an increased risk of wheezing and asthma development. However, few studies have examined the influence of different sources of tobacco exposure in different perinatal timeframes (preconception, prenatal, and postnatal) on wheezing phenotypes in children. Using national survey data from Japan, we investigated the effects of exposure to tobacco smoke during pregnancy on wheezing phenotypes in children before the age of 3 years.MethodsPregnant women who lived in the 15 regional centers in the Japan Environment and Children’s Study were recruited. We obtained information on prenatal and postnatal exposure to active and secondhand smoke (SHS) and wheeze development up to 3 years of age. Multiple logistic regression analysis was performed to determine the association between tobacco smoke exposure and wheezing phenotypes in children.ResultsWe analyzed 73,057 singleton births and identified four longitudinal wheezing phenotypes: never wheezing; early transient wheezing (wheezing by age 1 year but not thereafter); late-onset wheezing (wheezing by age 2–3 years but not beforehand); and persistent wheezing. Maternal smoking during pregnancy was significantly associated with early transient and persistent wheezing in children compared with no maternal smoking [early transient wheezing: 1–10 cigarettes per day, adjusted odds ratio (aOR) 1.43, 95% confidence interval (CI) 1.23–1.66; ≥ 11 cigarettes per day, aOR 1.67, 95% CI 1.27–2.20; persistent wheezing: 1–10 cigarettes per day, aOR 1.64, 95% CI 1.37–1.97; ≥ 11 cigarettes per day, aOR 2.32, 95% CI 1.70–3.19]. Smoking cessation even before pregnancy was also significantly associated with increased risk of early transient wheezing, late-onset wheezing, and persistent wheezing in children. Moreover, maternal exposure to SHS during pregnancy was significantly associated with increased risk of early transient and persistent wheezing compared with no such exposure.ConclusionsMaternal smoking before and throughout pregnancy was associated with wheeze development in children up to 3 years of age. It appears that smoking is detrimental compared to never smoking, regardless of whether individuals quit smoking before or after becoming aware of the pregnancy.

Persistent Asthma at School Age: Associated Factors in Preschool Children with Asthma.

Most patients with childhood asthma present their first symptoms at preschool age. Identifying modifiable risks and protective factors at an early age may help develop asthma prevention and control strategies. This study aimed to identify factors at preschool age that are associated with persistent asthma at school age. This retrospective observational study included preschool children with asthma from 2015 to 2020 at a university hospital in Southern Thailand. In total, 189 eligible participants (70.9% boys; median age, 7.6 [6.7, 8.5] years) were included. Wheeze characteristics included early transient wheeze, persistent wheeze, and late-onset wheeze that accounted for 55%, 27.5%, and 19.5% of the patients, respectively. Approximately 20% of the participants had persistent asthma. Breastfeeding was a protective factor (odds ratio [OR] 0.4 [0.2, 0.9], p = 0.04). The modifiable risk factors were siblings living in the same household (OR 2.6 [1.1, 6.2], p = 0.02) and residence in an industrial area (OR 3.8 [1.4, 10.5], p = 0.009). Additionally, presence of allergic rhinitis was associated with an increased risk of persistent asthma at school age (OR 3.6 [1.6, 8.2], p = 0.002). Early therapeutic interventions targeting modifiable factors provide a window of opportunity to prevent persistent asthma at school age.

Comparison of parent reported physician diagnosed asthma and general practitioner registration

Objective To compare parent reported physician diagnosed asthma from questionnaires for epidemiological purposes, to general practitioner (GP) recorded childhood asthma. Methods This study was embedded in the KOALA Birth Cohort Study with regular follow-up by ISAAC core questions on asthma in 2834 children in two different recruitment groups, with ‘conventional’ lifestyles or ‘alternative’ lifestyles. At age 11–13 years these data were linked to data extracted from GP records. We compared parent reported physician diagnosed asthma, asthma medication use, and current asthma with GP recorded asthma diagnosis and medication. Two different combinations of questions were used to define current asthma (i.e. ISAAC and MeDALL based definition). Results Among 958 children with information provided both by the parents and GPs, 98 children (10.2%) had parent reported physician diagnosed asthma, 115 children (12.0%) had a GP recorded asthma diagnosis (Cohen’s kappa 0.49; 95% CI 0.40 to 0.57). Discrepant cases showed that asthma symptoms at an early age led to different labeling between parents and GP. The agreement between ISAAC based definition and MeDALL based definition was excellent (Cohen’s kappa 0.82; 95% CI 0.74 to 0.88). Conclusion Parent reported physician diagnosed asthma and GP recorded childhood asthma had only moderate agreement, and is possibly influenced by labeling early transient wheeze as asthma diagnosis. It is important that parent reported physician diagnosed asthma is combined with additional questions such as current asthma symptoms and asthma medication use, as used in ISAAC or MeDALL based current asthma, in order to obtain reliable information for epidemiological research.

Prevalence and Determinants of Wheezing and Bronchodilatation in Children With Cystic Fibrosis: A Retrospective Cohort Study.

BackgroundMany patients with cystic fibrosis (CF) wheeze, and are dubbed as having CF-asthma. Understanding the determinants of such wheezing may avoid unnecessary treatments and open newer treatment avenues.ObjectivesMain: To evaluate the prevalence and characteristics of wheezing and a positive bronchodilatory response (BDR) in children with CF. Secondary: To identify the predictive markers and the impact of current wheezing a positive BDR.MethodsA retrospective single-center study in children with CF. We determined the characteristics of physician-reported wheeze in patients <6 years, and a BDR in patients aged 6–17 years. Anthropometric, lung function, laboratory, genetic and microbiological data were recorded in all groups. Variables were compared using the Chi2 and Student t-tests, and ANOVA.Results125 preschool and 69 school-aged children and adolescents with CF were included in the study. 71.2% of patients <6 years of age had had at least one episode of wheezing: 26.3% of patients were Transient Early Wheezers, 12.6% Late Onset Wheezers and 37.9% were Persistent Wheezers. The prevalence of a positive BDR was 73.5, 48.5, and 52.9% in the 6–8 years, 10–12 years, and 15–17 years age groups, respectively. Allergic factors were not predictive of wheezing in preschoolers. In the 6–8 years age group, the sum of wheal diameters of allergic skin prick tests (SPT, house dust mite + cat + dog dander) was greater in those with a BDR vs. no BDR (4 [2.0–8.8] vs. 1 [0–7.0] mm, p = 0.01). The presence of Pseudomonas aeruginosa in the bronchial secretions before 3 years of age was not significantly associated with either the presence of wheezing at the age of 6 years or a BDR in school-aged children and adolescents. The proportion of homozygous p.F508del patients was significantly lower in the group of patients who had wheezed by 6 years of age (60% vs. 72.7%, p = 0.009), but higher in the 6–8 years old group with a BDR vs. no BDR (64% vs. 36%, p = 0.04). Current wheezers at 6 years had a lower mean FEV1 vs. the non-current wheezers (91.5 ± 4.4% vs. 100.9 ± 2.4%; p = 0.047). Similarly, forced vital capacity (FVC) was significantly lower in the 6–8 years old group with BDR vs. no BDR (85 ± 19 vs. 101 ± 21%, p = 0.015).ConclusionWheezing and BDR are very frequent findings in children with CF. Current wheeze at the age of 6 years was associated with worse lung function. Labeling wheezing in CF as “CF-Asthma” is misleading since the determinants are different, and may lead to inappropriate prescriptions of inhaled steroids.

Transient low IgG4 levels cause recurrent wheezing requiring multiple hospitalizations in infancy.

To investigate whether the immunoglobulin G (IgG4) subclass is associated with recurrent wheezing and/or asthma in infants. From April 2015 to March 2016, 77 infants under 3 years old who attended our hospital were enrolled in four groups (Group 1, controls; Group 2, infants with recurrent wheezing and multiple hospitalizations despite starting inhaled corticosteroids [ICS]; Group 3, infants with recurrent wheezing and without hospitalization after starting ICS; Group 4, allergic infants without wheezing). The relationship between IgG subclasses, especially IgG4, and recurrent wheezing resistant to ICS and requiring multiple hospitalizations in infants was examined. The serum IgG, IgM, IgA, IgG1, IgG2, and IgG3 levels did not differ significantly among the four groups. The IgG4 level in Group 2 infants (3.1 ± 0.2 mg/dl) was significantly lower than in Groups 1,3, and 4 (9.9 ± 8.0, 8.4 ± 6.1, and 23.4 ± 18.0 mg/dl). Of the 16 infants in Group 2, 10 could be followed to age 6 years. Nine of them had no recurrent wheezing at 6 years without medication. In addition, their IgG4 levels at age 6 years (16.1 ± 7.1 mg/dl) were significantly increased from those in infancy (3.0 ± 0.1 mg/dl). A transient low IgG4 level in infancy might cause recurrent wheezing and/or asthmatic symptoms in infants, and it may be one of the types of early transient wheezing.

Dietary strategies for the prevention of asthma in children.

This review summarizes information relating to dietary intake during pregnancy, lactation and early life that may prevent childhood asthma. This review also summarizes how future studies may be improved. Recent findings from observational studies suggest that eating according to certain dietary patterns during pregnancy, such as the dietary inflammatory index, Mediterranean diet and Maternal diet index, may reduce asthma and or wheeze in the child. Vitamin D supplementation with higher doses than recommended during pregnancy may be associated with reduced early transient childhood wheezing in the offspring. Higher levels of omega-3 fatty acids in breast milk may be protective against childhood asthma. Breastfeeding infants has been shown to offer many benefits to mother and child but a direct relationship between breastfeeding and the development of asthma has not been established. During childhood, infants and children may need to reduce their intake of advanced glycation end products, increase their food intake according to the traditional Mediterranean diet and increase the diversity of foods eaten. Current evidence provides limited suggestions regarding dietary changes for preventing early transient childhood wheezing. In order to harmonize methods for future data collection and reporting, it is important to harmonize relevant definitions and other important factors. The aim of the considerations described here is to enable a better comparison of future studies and provide better guidance to patients and families.

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.

Low gestational vitamin D level and childhood asthma are related to impaired lung function in high-risk children

Lung function impairment in early life often persists into adulthood. Therefore, identifying risk factors for low childhood lung function is crucial. We examined the effect of 25-hydroxyvitamin D (25[OH]D) level and childhood asthma phenotype on childhood lung function in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). The 25(OH)D level was measured at set time points in mothers during pregnancy and in children during early life. On the basis of parental reports, children were categorized into 3 clinical phenotypes: asymptomatic/infrequent wheeze, early transient wheeze, and asthma at age 6 years. Lung function was assessed with impulse oscillometry at ages 4, 5, and 6 years and with spirometry at ages 5 and 6 years. A total of 570 mother-child pairs were included in this post hoc analysis. Mean gestational 25(OH)D-level quartiles were negatively associated with child respiratory resistance at 5 Hz (R5) from age 4 to 6 years (β, -0.021 kPa/L/s; 95% CI, -0.035 to -0.007; P= .003) and positively associated with FEV1 (β, 0.018 L; 95% CI, 0.005-0.031; P= .008) and forced vital capacity (β, 0.022 L; 95% CI, 0.009-0.036; P= .002) from age 5 to 6 years. Children with asthma at age 6 years had lower lung function from age 4 to 6 years than the asymptomatic/infrequent wheeze group (β, 0.065 kPa/L/s; 95% CI, 0.028 to 0.102; P< .001 for R5 and β, -0.063 L; 95% CI, -0.099 to -0.028; P< .001 for FEV1). Low gestational 25(OH)D level and childhood asthma are important risk factors for decreased lung function in early childhood.

Variations of interleukin-1 receptor-associated kinase-4 encoding gene were not associated with post-bronchiolitis lung function.

Interleukin-1 receptor associated kinase-4 (IRAK4) encoded by the IRAK4 gene mediates signals of innate immunity. Single nucleotide polymorphisms (SNP) of the IRAK4 rs4251513 and rs4251520 were associated with an increased risk of early transient wheezing, when 94 SNPs were studied in 2007 Dutch and 7242 French children prospectively followed-up for eight years from birth (1).

Childhood wheeze trajectory-specific risk factors: A systematic review and meta-analysis.

There is growing interest in the use of latent trajectory methodology to identify wheeze patterns in heterogeneous populations of children. This study systematically reviewed and meta-analyzed childhood wheeze trajectory studies to identify childhood wheeze trajectory group-specific risk factors among children from birth through to adolescence. We included studies that used latent trajectory methodology to identify wheeze trajectories and associated risk factors. We searched PubMed, EMBASE, and Google Scholar from 2000 through September 30, 2019, for relevant studies. The study was conducted according to the PRISMA recommendations. Thirteen cohort studies conducted in eleven high-income countries were included in our meta-analysis with the length of follow-up ranging from 3 to 18 years. Five distinct latent wheeze trajectory groups were identified: Never/Infrequent, Early-Transient, Early-Persistent, Intermediate-Onset, and Late-Onset. We found moderate-to-strong evidence that family history of asthma predicted persistent childhood wheezing among male children but with lower risk among first-born children. There was weak-to-moderate evidence for childhood atopy, male sex, short duration of breastfeeding, tobacco exposure, daycare attendance, and having siblings as risk factors for Early-Transient wheezing; except for breastfeeding, these factors were also associated with intermediate and Late-Onset wheezing with varying effect sizes in high-risk vs general population cohorts. Our findings confirm the consistency of wheeze trajectory groups defined by onset, peak prevalence, and duration; we also suggest a common nomenclature for future trajectory studies. With the exception of the relationship between a family history of asthma and persistent childhood wheezing, commonly suspected wheeze risk factors (childhood atopy, male sex, short duration of breastfeeding, tobacco exposure, daycare attendance, and having siblings) are not trajectory-specific and have varying effects in high-risk vs general population cohorts. Delineation of time-varying risk factor effects may be critical to the specificity of wheeze trajectory group prediction to better inform prognosis and targeted early preventive intervention among at-risk children.

Quantitative and semiquantitative estimates of mold exposure in infancy and childhood respiratory health.

Previous epidemiologic studies of dampness and mold relied on metrics that did not fully assess exposure-response relationships. Our objective was to examine quantitative metrics of dampness and mold during infancy and respiratory health outcomes during childhood. In-home visits were conducted before age 1 for children in the Cincinnati Childhood Allergy and Air Pollution Study. Respiratory outcomes included age 3 wheeze and age 7 asthma and wheeze. The associations between home exposure and respiratory outcomes were evaluated for 779 children using logistic regression adjusting for household income, neighborhood socioeconomic status, and the presence of pests. Children residing in homes with ≥0.29 m2 of moisture damage were significantly more likely to have wheezing at age 3 and persistent wheeze through age 7 (adjusted odds ratio [aOR] = 2.2; 95% confidence interval [CI] = 1.0, 4.3 and aOR = 3.2; CI = 1.3, 7.5, respectively). Additionally, homes having ≥0.19 m2 of mold damage were associated with wheezing at age 3 and early transient wheeze assessed at age 7 (aOR = 2.9; CI = 1.3, 6.4 and aOR = 3.5; CI = 1.5, 8.2, respectively). Mold damage <0.19 m2 and moisture damage <0.29 m2 were not associated with health outcomes. Mold and moisture damage were also not associated with asthma. Our data indicate that only the highest categories analyzed for mold (≥0.19 m2) and moisture damage (≥0.29 m2) in homes at age 1 were significantly associated with wheeze at ages 3 and 7; however, data below these levels were too sparse to assess the shape of the relationship or explore potential health-relevant thresholds.

Transient childhood wheeze is associated with less atopy in adolescence.

The relationships between childhood wheeze phenotypes and subsequent allergic conditions other than asthma, including hay fever, eczema and sensitization, have not been widely reported. We aimed to investigate this relationship up to late adolescence. Using five childhood wheeze phenotypes defined from 620 children in a high-atopy risk birth cohort (Melbourne Atopy Cohort Study), we investigated their relationships with sensitization, eczema, hay fever and fractional exhaled nitric oxide (FeNO) at ages 12 and/or 18years using logistic and linear regression models. 'Early Persistent wheeze' was associated with the increased risk of eczema (odds ratio: 3.69; 95% CI: 1.23, 11.12) and sensitization (4.52; 1.50, 13.64) at 12years. 'Intermediate Onset wheeze' was associated with the increased risk of eczema at 12years (2.57; 1.11, 5.97), hay fever at 12 (2.87; 1.44, 5.74) and 18years (2.19; 1.20, 4.02), sensitization at 12 (2.25; 1.17, 4.34) and 18years (2.46; 1.18, 5.12), and raised FeNO at 18years. 'Late Onset wheeze' was associated with the increased risk of hay fever at 12 (5.18; 1.11, 24.20) and 18years (4.20; 1.03, 17.11) and sensitization at 12years (3.27; 0.81, 13.27). In contrast, 'Early Transient wheeze' was associated with the reduced risk of eczema (0.44; 0.20, 0.96), hay fever (0.57; 0.33, 0.99) and sensitization (0.59; 0.35, 0.99) at 18years and a lower FeNO compared with 'Never/Infrequent wheezers'. Persistent wheeze phenotypes were associated with allergic outcomes up to 18years with 'Intermediate Onset wheeze' being the most atopic group. In contrast, 'Early Transient wheezers' had less risk of allergic outcomes at 18years. This protective effect may reassure parents of wheezy infants and young children.

A modern approach to identifying and characterizing child asthma and wheeze phenotypes based on clinical data.

‘Asthma’ is a complex disease that encapsulates a heterogeneous group of phenotypes and endotypes. Research to understand these phenotypes has previously been based on longitudinal wheeze patterns or hypothesis-driven observational criteria. The aim of this study was to use data-driven machine learning to identify asthma and wheeze phenotypes in children based on symptom and symptom history data, and, to further characterize these phenotypes. The study population included an asthma-rich population of twins in Sweden aged 9–15 years (n = 752). Latent class analysis using current and historical clinical symptom data generated asthma and wheeze phenotypes. Characterization was then performed with regression analyses using diagnostic data: lung function and immunological biomarkers, parent-reported medication use and risk-factors. The latent class analysis identified four asthma/wheeze phenotypes: early transient wheeze (15%); current wheeze/asthma (5%); mild asthma (9%), moderate asthma (10%) and a healthy phenotype (61%). All wheeze and asthma phenotypes were associated with reduced lung function and risk of hayfever compared to healthy. Children with mild and moderate asthma phenotypes were also more likely to have eczema, allergic sensitization and a family history of asthma. Furthermore, those with moderate asthma phenotype had a higher eosinophil concentration (β 0.21, 95%CI 0.12, 0.30) compared to healthy and used short-term relievers at a higher rate than children with mild asthma phenotype (RR 2.4, 95%CI 1.2–4.9). In conclusion, using a data driven approach we identified four wheeze/asthma phenotypes which were validated with further characterization as unique from one another and which can be adapted for use by the clinician or researcher.

Characterization of longitudinal wheeze phenotypes from infancy to adolescence in Project Viva, a prebirth cohort study

Using data from infancy to adolescence, our analysis of longitudinal wheeze phenotypes allowed us to visualize four longitudinal wheeze trajectories (never/infrequent wheeze, mid-childhood onset wheeze, early transient wheeze, and persistent wheeze).

Wheezing in children: Approaches to diagnosis and management.

Wheezing in children: Approaches to diagnosis and management.

Unsupervised trajectories of respiratory/allergic symptoms throughout childhood in the PARIS cohort.

Natural course and co-occurrence of asthma, eczema, and allergic rhinitis through childhood are still not fully documented. We aim to identify and characterize profiles based on the time course, severity, and apparent triggers of respiratory/allergy symptoms in school-aged children. Data on occurrence, severity, and triggers of asthma, rhinitis, and dermatitis symptoms were collected annually during the follow-up of the PARIS birth cohort. Children with similar symptom trajectories until 8-9years were grouped into profiles using multidimensional (all symptoms considered simultaneously) cluster analysis. Associations between profiles and different health outcomes were analyzed using logistic or linear regression models. Six distinct symptomatic profiles were identified. A profile was defined by persistent dermatitis symptoms, associated with sensitization to food and aeroallergens. Two profiles were characterized by wheezing: one with early transient wheezing and the other with persistent wheezing related to doctor-diagnosed asthma, airway obstruction, and perennial aeroallergen sensitization. Three profiles were characterized by rhinitis symptoms: one non-allergic and two allergic, either with persistent rhinitis symptoms related to allergic multimorbidity and sensitization to perennial aeroallergens, or with late-onset symptoms, related to both pollen and perennial aeroallergens sensitization as well as low lung function. This study brings further insights into the developmental profiles of respiratory/allergic outcomes from birth to school age. The identified profiles clearly differed regarding objective features such as diagnosed morbidity, sensitization, or lung function measurements, thus highlighting their biologic and clinical relevance. Allergic rhinitis profiles deserve particular attention, since they were likely to be involved in multimorbidity patterns.

Prenatal 25-hydroxyvitamin D deficiency affects development of atopic dermatitis via DNA methylation

Prenatal 25-hydroxyvitamin D deficiency affects development of atopic dermatitis via DNA methylation

Developmental regulation of type 1 and type 3 interferon production and risk for infant infections and asthma development

Virus-associated febrile lower respiratory tract infections (fLRIs) during infancy have been identified as risk factors for persistent wheeze development. We hypothesized that variations in innate immune defense capacity during this period, as exemplified by production of type 1 and 3 interferons (T1/3IFNs), might be an underlying determinant of risk. We sought to investigate relationships between postnatal development of innate interferon response capacity and susceptibility to early infections and persistent wheeze. We studied a subset of subjects from a birth cohort at high risk for asthma/allergy and determined the capacity of cord blood cells (n=151) to produce any of a panel of 17 T1/3IFNs in response to the viral mimic polyinosinic-polycytidylic acid using a sensitive PCR assay. We investigated relationships between neonatal interferon responses and lower respiratory tract infection history during infancy, wheezing history to 5 age years, and ensuing maturation of innate immune capacity by age 4years (n=160) and 10years (n=125). Although cohort subjects produced an average of 2.6±0.3 of the 17 innate interferons tested at birth, 24% showed no T1/3IFN production. This nonproducer subgroup showed increased risk for infant fLRIs (odds ratio, 2.62; 95% CI, 1.14-6.06; P=.024) and persistent wheeze (odds ratio, 4.24; 95% CI, 1.60-11.24; P=.004) at age 5years relative to those producing 1 or more T1/3IFNs, whereas risk for infant wheezy lower respiratory tract infections or "transient early wheeze" was unaffected. Moreover, infants who experienced fLRIs subsequently demonstrated accelerated development of T1/3IFN response capacity between 1 and 4years of age. T1/3IFN response capacity appears strongly developmentally constrained at birth. Infants in whom this negative regulation is strongest manifest increased risk for severe respiratory tract infections during infancy and subsequent persistent wheeze.

Wheeze trajectories are modifiable through early-lifeintervention and predict asthma in adolescence.

The objectives of this study were to identify developmental trajectories of wheezing using data-driven methodology, and to examine whether trajectory membership differentially impacts the effectiveness of primary preventive efforts that target modifiable asthma risk factors. Secondary analysis of the Canadian Asthma Primary Prevention Study (CAPPS), a multifaceted prenatal intervention among children at high risk of asthma, followed from birth to 15years. Wheezing trajectories were identified by latent class growth analysis. Predictors, intervention effects, and asthma diagnoses were examined between and within trajectory groups. Among 525 children, 3 wheeze trajectory groups were identified: Low-Progressive (365, 69%), Early-Transient (52, 10%), and Early-Persistent (108, 21%). The study intervention was associated with lower odds of Early-Transient and Early-Persistent wheezing (P<.01). Other predictors of wheeze trajectories included, maternal asthma, maternal education, city of residence, breastfeeding, household pets, infant sex and atopy at 12months. The odds of an asthma diagnosis were three-fold to six-fold higher in the Early-Persistent vs Low-Progressive group at all follow-up assessments (P=.03), whereas Early-Transient wheezing (limited to the first year) was not associated with asthma. In the Early-Persistent group, the odds of wheezing were lower among intervention than control children (adjusted odds ratio: 0.67; 95% CI: 0.48; 0.93) at 7years. Using data-driven methodology, children can be classified into clinically meaningful wheeze trajectory groups that appear to be programmed by modifiable and non-modifiable factors, and are useful for predicting asthma risk. Early-life interventions can alter some wheeze trajectories (ie, Early-Persistent) in infancy and reduce wheezing prevalence in mid-childhood.