Lung Function In Early Life Research Articles

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; βz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; β = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

Air pollution exposure impairs lung function in infants.

AimTo assess associations between air pollution exposure and infant lung function.MethodsHealthy infants from Stockholm were recruited to two cohorts (n = 99 and n = 78). Infant spirometry included plethysmography and raised volume forced expiratory flows. In pooled analyses, lung function at ~6 months of age was related to time‐weighted average air pollution levels at residential addresses from birth until the lung function test. The pollutants included particulate matter with an aerodynamic diameter < 10 μm (PM10) or <2.5 μm and nitrogen dioxide.ResultsThere were significant inverse relations between air pollution exposure during infancy and forced expiratory volume at 0.5 s (FEV0.5) as well as forced vital capacity (FVC) for all pollutants. For example, the decline was 10.1 ml (95% confidence interval 1.3–18.8) and 10.3 ml (0.5–20.1) in FEV0.5 and FVC, respectively, for an interquartile increment of 5.3 μg/m3 in PM10. Corresponding associations for minute ventilation and functional residual capacity were 43.3 ml/min (−9.75–96.3) and 0.84 ml (−4.14–5.82).ConclusionsAir pollution exposure was associated with impaired infant lung function measures related to airway calibre and lung volume, suggesting that comparatively low levels of air pollution negatively affect lung function in early life.

Cord blood group 2 innate lymphoid cells are associated with lung function at 6weeks of age.

ObjectiveOffspring born to mothers with asthma in pregnancy are known to have lower lung function which tracks with age. Human group 2 innate lymphoid cells (ILC2) accumulate in foetal lungs, at 10‐fold higher levels compared to adult lungs. However, there are no data on foetal ILC2 numbers and the association with respiratory health outcomes such as lung function in early life. We aimed to investigate cord blood immune cell populations from babies born to mothers with asthma in pregnancy.MethodsCord blood from babies born to asthmatic mothers was collected, and cells were stained in whole cord blood. Analyses were done using traditional gating approaches and computational methodologies (t‐distributed stochastic neighbour embedding and PhenoGraph algorithms). At 6 weeks of age, the time to peak tidal expiratory flow as a percentage of total expiratory flow time (tPTEF/tE%) was determined as well as Lung Clearance Index (LCI), during quiet natural sleep.ResultsOf 110 eligible infants (March 2017 to November 2019), 91 were successfully immunophenotyped (82.7%). Lung function was attempted in 61 infants (67.0%), and 43 of those infants (70.5% of attempted) had technically acceptable tPTEF/tE% measurements. Thirty‐four infants (55.7% of attempted) had acceptable LCI measurements. Foetal ILC2 numbers with increased expression of chemoattractant receptor‐homologous molecule (CRTh2), characterised by two distinct analysis methodologies, were associated with poorer infant lung function at 6 weeks of age.”ConclusionFoetal immune responses may be a surrogate variable for or directly influence lung function outcomes in early life.

Impact of HIV and antiretroviral drug exposure on lung growth and function over 2 years in an African Birth Cohort.

To assess the impact of HIV and antiretroviral exposure without infection on lung growth and function over the first 2 years of life. Prospective observational study of an African birth cohort, Drakenstein Child Health Study. Infants enrolled antenatally had lung function measured at 6 weeks, 1 and 2 years. HIV-infected women received antiretroviral therapy (ART) as per local guidelines. The association between HIV and antiretroviral exposure with lung function was assessed using mixed effects modelling. Of 1143 infants born, two HIV-infected infants were excluded from analysis; 909 (80%) infants had lung function collected at 6 weeks [190 (21%) were HIV-exposed uninfected (HEU)]; 782 (69%) at 1 year and 741 (65%) at 2 years. At 6 weeks HEU infants had larger tidal volume compared with HIV-unexposed infants (1.13 ml, confidence interval: 0.02-2.23, P = 0.045). High maternal viral load was associated with a 17% lower expiratory flow over 2 years (0.17, confidence interval 0.00-0.34, P = 0.046). First-line ART initiated during pregnancy was associated with lower infant tidal volume at 6 weeks compared with those who initiated ART before pregnancy (-2.7 ml, -5.31 to -0.10, P = 0.042), and low maternal CD4 cell counts associated with lower infant tidal over 2 years (-11.1 ml, -18.58-3.58, P = 0.004). HIV exposure is associated with altered lung function in early life, with a vulnerable HEU subgroup based on maternal disease severity, immunological compromise and ART exposure. These data highlight the importance of ongoing surveillance of respiratory health in HEU children.

Determinants of early-life lung function in African infants.

BackgroundLow lung function in early life is associated with later respiratory illness. There is limited data on lung function in African infants despite a high prevalence of respiratory disease.AimTo assess the determinants of early lung function in African infants.MethodInfants enrolled in a South African birth cohort, the Drakenstein child health study, had lung function measured at 6–10 weeks of age. Measurements, made with the infant breathing via a facemask during natural sleep, included tidal breathing, sulfur hexafluoride multiple breath washout and the forced oscillation technique. Information on antenatal and early postnatal exposures was collected using questionnaires and urine cotinine. Household benzene exposure was measured antenatally.ResultsSuccessful tests were obtained in 645/675 (95%) infants, median (IQR) age of 51 (46–58) days. Infant size, age and male gender were associated with larger tidal volume. Infants whose mothers smoked had lower tidal volumes (−1.6 mL (95% CI −3.0 to −0.1), p=0.04) and higher lung clearance index (0.1 turnovers (95% CI 0.01 to 0.3), p=0.03) compared with infants unexposed to tobacco smoke. Infants exposed to alcohol in utero or household benzene had lower time to peak tidal expiratory flow over total expiratory time ratios, 10% (95% CI −15.4% to −3.7%), p=0.002) and 3.0% (95% CI −5.2% to −0.7%, p=0.01) lower respectively compared with unexposed infants. HIV-exposed infants had higher tidal volumes (1.7 mL (95% CI 0.06 to 3.3) p=0.04) compared with infants whose mothers were HIV negative.ConclusionWe identified several factors including infant size, sex, maternal smoking, maternal alcohol, maternal HIV and household benzene associated with altered early lung function, many of which are factors amenable to public health interventions. Long-term study of lung function and respiratory disease in these children is a priority to develop strategies to strengthen child health.

Maternal body mass index, neonatal lung function and respiratory symptoms in childhood.

Recent studies have shown that maternal obesity is associated with increased risk of wheezing in the offspring. We assessed whether impaired neonatal lung function could explain this association. We measured neonatal lung function in 2606 children of our prospective birth cohort. Information about daily symptoms of wheezing was obtained using questionnaires. Consultations and prescriptions for wheezing illnesses were derived from general practitioner patient files. Higher maternal body mass index (BMI) was associated with increased risk of wheezing in the first year of life and more consultations and prescriptions for wheezing illnesses until the age of 5 years. Lung function could partially explain the association with wheezing in the first year of life. Adding respiratory resistance to the model decreased the incidence rate ratio from 1.023 (95% CI 1.008-1.039) to 1.015 (95% CI 0.998-1.032). Anthropometrics of the 5-year-olds largely explained the association with consultations. Intermediates or confounders could not explain the association with prescriptions. There is an association between higher maternal BMI and increased risk of wheezing illnesses. In the first year of life, it is largely explained by an impaired lung function in early life, especially in children of nonatopic mothers. At the age of 5 years, infant lung function is of minor influence in this association.

Early treatment in preschool children: an evidence-based approach.

Wheezing is a common symptom in early childhood but only some of these children will experience continued wheezing symptoms in later childhood making the diagnosis and treatment of these children challenging. This review covers recent findings regarding the epidemiology, diagnosis, evaluation, and treatment of preschool-aged children with asthma. Key characteristics that distinguish the childhood asthma-predictive phenotype include male sex, history of wheezing with lower respiratory tract infections, history of parental asthma, history of atopic dermatitis, eosinophilia, early sensitization to food or aeroallergens, or lower lung function in early life. The preschool-aged asthma population tends to be characterized as exacerbation prone with relatively limited impairment. The diagnosis of asthma in preschool-aged children is often based on symptom patterns, presence of risk factors, and therapeutic responses. Asthma management includes intermittent and daily inhaled corticosteroids, daily leukotriene-receptor antagonists, and, in rare cases, combination therapies. The diagnosis of asthma in preschool-aged children is based on symptom patterns and the presence of risk factors, and the goals of asthma management are achieved through a partnership between the family and the healthcare team using regular assessment of symptom control and response to daily controller therapy.

Childhood Asthma-Predictive Phenotype

Wheezing is a fairly common symptom in early childhood, but only some of these toddlers will experience continued wheezing symptoms in later childhood. The definition of the asthma-predictive phenotype is in children with frequent, recurrent wheezing in early life who have risk factors associated with the continuation of asthma symptoms in later life. Several asthma-predictive phenotypes were developed retrospectively based on large, longitudinal cohort studies; however, it can be difficult to differentiate these phenotypes clinically as the expression of symptoms, and risk factors can change with time. Genetic, environmental, developmental, and host factors and their interactions may contribute to the development, severity, and persistence of the asthma phenotype over time. Key characteristics that distinguish the childhood asthma-predictive phenotype include the following: male sex; a history of wheezing, with lower respiratory tract infections; history of parental asthma; history of atopic dermatitis; eosinophilia; early sensitization to food or aeroallergens; or lower lung function in early life.

Chorioamnionitis and Subsequent Lung Function in Preterm Infants

ObjectiveTo explore the relationship between prematurity, gender and chorioamnionitis as determinants of early life lung function in premature infants.MethodsPlacenta and membranes were collected from preterm deliveries (<37 weeks gestational age) and evaluated for histological chorioamnionitis (HCA). Patients were followed and lung function was performed in the first year of life by Raised Volume-Rapid Thoracic Compression Technique.ResultsNinety-five infants (43 males) born prematurely (median gestational age 34.2 weeks) were recruited. HCA was detected in 66 (69%) of the placentas, and of these 55(58%) were scored HCA Grade 1, and 11(12%) HCA Grade 2. Infants exposed to HCA Grade 1 and Grade 2, when compared to those not exposed, presented significantly lower gestational ages, higher prevalence of RDS, clinical early-onset sepsis, and the use of supplemental oxygen more than 28 days. Infants exposed to HCA also had significantly lower maximal flows. There was a significant negative trend for z-scores of lung function in relation to levels of HCA; infants had lower maximal expiratory flows with increasing level of HCA. (p = 0.012 for FEF50, p = 0.014 for FEF25–75 and p = 0.32 for FEV0.5). Two-way ANOVA adjusted for length and gestational age indicated a significant interaction between sex and HCA in determining expiratory flows (p<0.01 for FEF50, FEF25–75 and p<0.05 for FEV0.5). Post-hoc comparisons revealed that female preterm infants exposed to HCA Grade 1 and Grade 2 had significant lower lung function than those not exposed, and this effect was not observed among males.ConclusionsOur findings show a sex-specific negative effect of prenatal inflammation on lung function of female preterm infants. This study confirms and expands knowledge upon the known association between chorioamnionitis and early life chronic lung disease.

Reduced Infant Lung Function, Active Smoking, and Wheeze in 18-Year-Old Individuals

D Mullane, SW Turner, DW Cox, J Goldblatt, LI Landau, PN le Souef. JAMA Pediatr. 2013;167(4):368–373 To test the hypothesis that reduced lung function in early life is associated with increased risk of persistent wheeze at age 18 years. A total of 253 subjects were originally recruited at age 1 month. Maximal flow at functional residual capacity (VmaxFRC) was measured in 1-month-old infants who were then followed up at ages 6, 12, and 18 years. On the basis of symptoms reported, the subjects …

Reduced Infant Lung Function, Active Smoking, and Wheeze in 18-Year-Old Individuals

IMPORTANCE This is the first study to link reduced lung function in early life, before the development of symptoms, to wheeze in 18-year-olds. Additionally, the study gives insight into factors other than reduced lung function that are also associated with persistent wheeze in young adults. To test the hypothesis that reduced lung function in early life is associated with increased risk for persistent wheeze at age 18 years. Birth cohort study. Perth, Western Australia. Individuals followed up from age 1 month to 18 years. Maximal flow at functional residual capacity (V'maxFRC) was measured in 1-month-old infants who were followed up at ages 6, 12, and 18 years. Based on reported symptoms, individuals were categorized as having remittent wheeze, later-onset wheeze, persistent wheeze, and no wheeze. Smoking status was noted at age 18 years. Of the 253 individuals originally recruited, 150 were followed up at age 18 years; 37 of the 150 had recent wheeze. Compared with the no-wheeze group (n = 96), persistent wheeze (n = 13) was independently associated with reduced percentage of predicted V'maxFRC (mean reduction, 43%; 95% CI, 13-74). Compared with the no-wheeze group, persistent wheeze was also associated with atopy in infancy (odds ratio = 7.1; 95% CI, 1.5-34.5), maternal asthma (odds ratio = 6.8; 95% CI, 1.4-32.3), and active smoking (odds ratio = 4.8; 95% CI, 1.0-21.3). When only wheeze at age 18 years was considered, reduced percentage of predicted V'maxFRC was associated with wheeze at age 18 years only among current smokers (P = .04). Wheeze persisting from ages 6 to 18 years is associated with multiple factors, including reduced infant lung function, infant-onset atopy, maternal asthma, and active smoking. Wheeze at age 18 years (regardless of previous wheeze status) is associated with active smoking, but only among those with reduced lung function in infancy. These findings give unique insight into the cause of obstructive airways disease in 18-year-olds, and follow-up of this cohort might be expected to further extend our understanding.

P1-56 Understanding the natural progression in FEV1 decline in patients with lung disease

IntroductionWe outline a novel approach for longitudinal modelling of lung function with long-term follow-up in which within-patient variation over time is described by a stationary (mean-reverting) stochastic process, and apply...

Smoke exposure interacts with ADAM33 polymorphisms in the development of lung function and hyperresponsiveness

ADAM33 is the first identified asthma gene by positional cloning, especially asthma combined with bronchial hyperresponsiveness (BHR). Moreover, ADAM33 is associated with early-life lung function and decline of forced expiratory volume in 1 s (FEV(1)) in the general population. In utero and postnatal cigarette smoke exposure (CSE) are associated with reduced lung function, and development of BHR and asthma. We hypothesized that this may occur via interaction with ADAM33. To replicate the role of ADAM33 in childhood lung function and development of BHR and asthma. Furthermore, we investigated gene-environment interaction of ADAM33 with in utero and postnatal CSE in the Dutch PIAMA cohort. Six ADAM33 single-nucleotide polymorphisms (SNPs) were genotyped. Rint was measured at age 4 and 8 years, FEV(1) and BHR at age 8 years; asthma was based on questionnaire data at age 8. In the total cohort, the rs511898 A, rs528557 C, and rs2280090 A alleles increased the risk to develop asthma (+BHR). There existed interaction between in utero but not postnatal CSE and the rs528557 and rs3918396 SNPs with respect to development of BHR, the rs3918396 SNP with Rint at age 8 and the rs528557 SNP with FEV(1)% predicted. We confirm associations between ADAM33 and the development of asthma (+BHR). This is the first study suggesting that interaction of in utero CSE with ADAM33 results in reduced lung function and the development of BHR, which needs further confirmation.

Early Detection of Lung Disease in Children with Cystic Fibrosis Using Lung Function

Measurement of lung function is routine in older children and adults with cystic fibrosis (CF) but not in infants and preschool children. Pulmonary infection, neutrophil-dominated inflammation and clinical exacerbations in young children similar to those seen in older subjects have been identified and highlight the urgent need to evaluate lung function in early life. Mounting evidence suggests lung function techniques sensitive to changes in peripheral lung function may be required to detect the early functional abnormalities in infants and preschool children with CF. In addition, the majority of studies in young children with CF have not reported longitudinal data and therefore the prognostic potential of existing lung function methods to track disease progression is poorly understood. This review aims to describe recent research findings in infants and preschool children and to outline currently available lung function techniques, issues around their standardization and their relative advantages and disadvantages in young children with CF.

The influence of maternal respiratory infections during pregnancy on infant lung function

We studied whether maternal respiratory infections during pregnancy adversely influence lung growth and development of the offspring, resulting in poor early life lung function. Infants were participants of the Wheezing Illnesses Study Leidsche Rijn (WHISTLER). Lung function measurements (single occlusion technique) were performed during natural sleep. Questionnaire data were used to obtain information on maternal respiratory infections during pregnancy. Multivariate analysis was conducted to assess the relationship between maternal respiratory infections during pregnancy and resistance and compliance of the respiratory system, adjusting for potential confounding variables. Lower values of compliance (Crs) were found in infants of mothers with respiratory infections during pregnancy; Crs fell by 5.5% (P = 0.031). The difference in Crs between infants of mothers with and without respiratory infections during pregnancy remained unchanged and statistically significant after adjusting for potential confounding variables. The more respiratory infections the mother experienced during pregnancy, the lower the value of Crs was in her offspring (P for trend = 0.016). Using Crs corrected for body weight the relationship with maternal infections was non-significant, however still showing a trend. The results of this study may indicate that mothers who experience respiratory infections during pregnancy have newborns with lower compliance of the respiratory system.

Effect of Inhaled Steroids on Lung Function in Young Children: A Cohort Study

Devulapalli CS, Haaland G, Pettersen M, Carlsen KH, Lodrup Carlsen KC. Eur Respir J. 2004;23:869–875To determine the use of inhaled corticosteroids (ICSs) for treating recurrent bronchial obstruction in young children up to 2 years of age and to assess possible modifying effects of ICSs on lung function in young children with recurrent bronchial obstruction.Observational, noninterventional birth cohort of 3754 newborn children (3697 with complete questionnaire data by 2 years of age); 306 children with documented recurrent bronchial obstruction by 2 years old were identified along with 306 matched controls.Two tidal-flow/volume measurements were taken (1 at presentation of disease [children were steroid naive] and 1 at 2 years of age [mean ages: 11.2 and 25.6 months, respectively]) from 21 subjects who subsequently received ICS (ICS+), 33 who did not receive ICS (ICS−), and 15 controls. The mean ± SD duration of ICS treatment was 10.3 ± 6.5 months. The main outcomes were treatment with ICS and baseline ratio of time to peak expiratory flow otal expiratory time (tPTEF/tE).From the entire cohort, 77 children (2.1%) and 64 of 306 children (21%) with recurrent bronchial obstruction had received ICS by 2 years of age. Baseline tPTEF/tE was significantly lower at the first visit in ICS+ subjects, as compared with ICS− subjects, as well as in ICS+ and ICS− subjects as compared with controls. The mean difference in baseline tPTEF/tE from the first to second visit was borderline statistically significant in the ICS+ group only and correlated significantly with the duration of ICS treatment.The present observational cohort study demonstrated that one fifth of young children with recurrent bronchial obstruction had received ICSs. Early ICS treatment improved lung function by the age of 2 years, mostly in those with the longest duration of treatment.There is little information available concerning how often inhaled steroids are used during the first 2 years of life in the treatment of obstructive airway disease and limited information on the modifying effects of ICSs on the development of lung function in early life. As expected, infants with recurrent bronchial obstruction and lower lung function were treated more often with ICS compared with matched controls. Improvement in lung function in these children increased with increasing duration of treatment. This study suggests that the choice of medical therapy is often determined by the clinical state of the child, and once started, it may be a factor that can influence later outcome. More studies such as this are desirable to fully understand the role of ICSs in early life.

ADAM33: a newly identified protease involved in airway remodelling

Asthma is a complex disorder in which major genetic and environmental factors interact to both initiate the disease and modify its progression. While asthma is recognised as a disorder of the conducting airways characterised by Th2-directed inflammation, it is being increasingly apparent that alteration of the structural cells of the airways (airway remodelling) is also fundamental to disease chronicity and severity. The gene ADAM33, encoding a novel member of a identified as an asthma susceptibility gene as the result of a positional cloning effort in a cohort of families recruited form the UK and USA. Subsequent genetic studies have now provided evidence that ADAM33 may be involved in determining lung function throughout life, associated with early life lung function as well as increased decline therapeutic intervention in asthma and future work will focus on the mechanisms by which it alters lung function and bronchial hyperresponsiveness.

Polymorphisms in A Disintegrin and Metalloprotease 33 (ADAM33) Predict Impaired Early-Life Lung Function

Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood. Within the context of a prospective birth cohort study, we investigated the association between single nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene and early-life lung function. Children were genotyped for 17 SNPs in ADAM33. Lung function at age 3 (n = 285) and 5 years (n = 470) was assessed using plethysmographic measurement of specific airway resistance (sRaw). At age 5, we also measured FEV(1). SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium mapping to identify the causal locus. Carriers of the rare allele of F+1 SNP had reduced lung function at age 3 years (p = 0.003). When the recessive model was considered, four SNPs (F+1, S1, ST+5, V4) showed association with sRaw at age 5 years (p < 0.04). Using linkage disequilibrium mapping, we found evidence of a significant causal location between BC+1 and F1 SNPs, at the 5' end of the gene. Four SNPs were associated with lower FEV(1) (F+1, M+1, T1, and T2; p < or = 0.04). The risk of transient early wheezing more than doubled among children homozygous for the A allele of F+1 (odds ratio, 2.39; 95% confidence intervals, 1.18-4.86; p = 0.02), but there was no association between any SNP and allergic sensitization or physician-diagnosed asthma. Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5' end of the gene.

Lung function at age 3 years: effect of pet ownership and exposure to indoor allergens.

To investigate the effect of pet ownership and exposure to indoor allergens on lung function in 3-year-old children. Birth cohort study. Community. Children recruited prenatally and followed prospectively to age 3 years. Specific airway resistance (sRaw) (measured with body plethysmograph) at age 3 years; skin-prick tests; data on cat and dog ownership collected prospectively; allergen levels measured in dust collected from homes (high exposure defined as mite allergens >2 microg/g in mattress, and dog >10 microg/g and cat >8 microg/g allergens on the living room floor). There was no effect of cat or dog ownership at birth or age 3 years on lung function, and no association between lung function and mite, dog, or cat allergen exposure. Sensitized children exposed to high levels of sensitizing allergen had significantly poorer lung function (n = 49, sRaw kiloPascal per second [kPa/s]; geometric mean [GM], 1.20; 95% confidence interval [CI], 1.13-1.28) than children who were not sensitized and not exposed (n = 114; GM, 1.08; 95% CI, 1.04-1.12); not sensitized, but exposed (n = 282; GM, 1.07; 95% CI, 1.05-1.10); or sensitized and not exposed (n = 53; GM, 1.12; 95% CI, 1.06-1.18; P = .005). In a multivariate model, independent significant associates of lung function were maternal and paternal asthma, and the combination of sensitization and exposure to sensitizing allergen, with significant interaction between them. Lung function was substantially worse in sensitized and highly exposed children with both asthmatic parents (GM, 2.23; 95% CI, 1.68-2.97), compared with those with neither (GM, 1.09; 95% CI, 1.04-1.16) or just 1 of these features. Pet ownership, sensitization without exposure, or exposure in nonsensitized individuals have no effect on lung function. However, the combination of specific sensitization and exposure to sensitizing allergen is associated with significantly poorer lung function in early life.

Reported versus confirmed wheeze and lung function in early life

Aims: To investigate the relation between parentally reported wheeze (unconfirmed), physician confirmed wheeze, and subsequent lung function. Methods: Children at risk of allergic disease (one parent atopic) were recruited antenatally...