Lung function trajectories from school age to adulthood and their relationship with markers of cardiovascular disease risk.

RATIONALE: Lung function in early adulthood is associated with subsequent adverse health outcomes. OBJECTIVES: To ascertain whether stable and reproducible lung function trajectories can be derived in different populations and investigate their association with objective measures of cardiovascular structure and function. METHODS: Using latent profile modelling, we studied three population-based birth cohorts with repeat spirometry data from childhood into early adulthood to identify trajectories of forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). We used multinomial logistic regression models to investigate early-life predictors of the derived trajectories. We then ascertained the extent of the association between the derived FEV1/FVC trajectories and blood pressure and echocardiographic markers of increased cardiovascular risk and stroke in ~3200 participants at age 24 years in one of our cohorts. RESULTS: We identified four FEV1/FVC trajectories with strikingly similar latent profiles across cohorts (pooled N=6377): above average (49.5%); average (38.3%); below average (10.6%); and persistently low (1.7%). Male sex, wheeze, asthma diagnosis/medication and allergic sensitisation were associated with trajectories with diminished lung function in all cohorts. We found evidence of an increase in cardiovascular risk markers ascertained by echocardiography (including left ventricular mass indexed to height and carotid intima-media thickness) with decreasing FEV1/FVC (with p values for the mean crude effects per-trajectory ranging from 0.10 to p<0.001). In this analysis, we considered trajectories as a pseudo-continuous variable; we confirmed the assumption of linearity in all the regression models. CONCLUSIONS: Childhood lung function trajectories may serve as predictors in the development of not only future lung disease, but also the cardiovascular disease and multimorbidity in adulthood.

Obstructive and restrictive spirometry from school age to adulthood: three birth cohort studies.

Background: Spirometric obstruction and restriction are two patterns of impaired lung function which are predictive of poor health. We investigated the development of these phenotypes and their transitions through childhood to early adulthood. Methods: In this study, we analysed pooled data from three UK population-based birth cohorts established between 1989 and 1995. We applied descriptive statistics, regression modelling and data-driven modelling to data from three population-based birth cohorts with at least three spirometry measures from childhood to adulthood (mid-school: 8-10 years, n = 8404; adolescence: 15-18, n = 5764; and early adulthood: 20-26, n = 4680). Participants were assigned to normal, restrictive, and obstructive spirometry based on adjusted regression residuals. We considered two transitions: from 8-10 to 15-18 and from 15-18 to 20-26 years. Findings: Obstructive phenotype was observed in ∼10%, and restrictive in ∼9%. A substantial proportion of children with impaired lung function in school age (between one third in obstructive and a half in restricted phenotype) improved and achieved normal and stable lung function to early adulthood. Of those with normal lung function in school-age, <5% declined to adulthood. Underweight restrictive and obese obstructive participants were less likely to transit to normal. Maternal smoking during pregnancy and current asthma diagnosis increased the risk of persistent obstruction and worsening. Significant associate of worsening in restrictive phenotypes was lower BMI at the first lung function assessment. Data-driven methodologies identified similar risk factors for obstructive and restrictive clusters. Interpretation: The worsening and improvement in obstructive and restrictive spirometry were observed at all ages. Maintaining optimal weight during childhood and reducing maternal smoking during pregnancy may reduce spirometry obstruction and restriction and improve lung function. Funding: MRC Grant MR/S025340/1.

Identification of differences in CD4+ T-cell gene expression between people with asthma and healthy controls.

Functional enrichment analysis of genome-wide association study (GWAS)-summary statistics has suggested that CD4+ T-cells play an important role in asthma pathogenesis. Despite this, CD4+ T-cells are under-represented in asthma transcriptome studies. To fill the gap, 3'-RNA-Seq was used to generate gene expression data on CD4+ T-cells (isolated within 2 h from collection) from peripheral blood from participants with well-controlled asthma (n = 32) and healthy controls (n = 11). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify sets of co-expressed genes (modules) associated with the asthma phenotype. We identified three modules associated with asthma, which are strongly enriched for GWAS-identified asthma genes, antigen processing/presentation and immune response to viral infections. Through integration of publicly available eQTL and GWAS summary statistics (colocalisation), and protein-protein interaction (PPI) data, we identified PTPRC, a potential druggable target, as a putative master regulator of the asthma gene-expression profiles. Using a co-expression network approach, with integration of external genetic and PPI data, we showed that CD4+ T-cells from peripheral blood from asthmatics have different expression profiles, albeit small in magnitude, compared to healthy controls, for sets of genes involved in immune response to viral infections (upregulated) and antigen processing/presentation (downregulated).

Defining the normal range of fractional exhaled nitric oxide in children: one size does not fit all.

Background: The normal range of fractional exhaled nitric oxide (F ENO) is influenced by demographic factors. However, single, fixed cut-off values are used for clinical interpretation in children despite rapid growth. We aimed to define the normal range of F ENO during childhood and evaluate its utility in a diagnostic setting. Method: F ENO percentile charts were developed using data from nonasthmatic children in a population-based birth cohort (Manchester Asthma and Allergy Study). Children were skin prick tested, F ENO measured at the ages of 8, 11, 13-16 and 18 years and clinical information collected. This chart was externally validated in the Study of Eczema and Asthma to Observe the Influence of Nutrition (SEATON) cohort before being prospectively tested in symptomatic, treatment-naïve patients with suspected asthma in a diagnostic setting (Rapid Access Diagnostics for Asthma study). Results: Height, weight, body mass index and age were predictive of F ENO in univariate analysis using 1220 F ENO measurements. Only height remained significant after adjustment in the overall, nonatopic and atopic populations, and was included in the predictive equations for 50th, 75th 90th and 98th percentiles. The proposed percentile lines corresponded to the 57th (95% CI 53rd-61st), 80th (76th-83rd), 90th (87th-92nd) and 98th (96th-99th) percentiles in the SEATON cohort (660 measurements). When tested in 73 symptomatic treatment-naïve children and young adults (median (interquartile range) age: 11 (8-14) years), an F ENO >90th percentile gave a 96% specificity and positive predictive value of 97%, identifying 59% of children who were subsequently diagnosed with asthma after extensive testing. Conclusion: We developed a height-based F ENO percentile chart which quantifies the probability of asthma in symptomatic children and merits further validation towards clinical implementation.

The role of growth and nutrition in the early origins of spirometric restriction in adult life: a longitudinal, multicohort, population-based study.

BACKGROUND: Spirometric restriction, defined as a reduced forced vital capacity (FVC) with a preserved FEV1/FVC ratio, is associated with increased respiratory and non-respiratory comorbidities and all-cause mortality in adulthood. Little is known about the early origins of this condition. We sought to identify early-life risk factors for spirometric restriction in adult life. METHODS: In this longitudinal, multicohort, population-based study, we used data from the Tucson Children's Respiratory Study (TCRS), which recruited 1246 healthy infants at birth between April 1980, and October 1984, in Tucson, AZ, USA. Questionnaires were answered by the primary caregiver at enrolment, immediately after the child's birth, and multiple follow-up questionnaires were completed through childhood and adulthood. At the age of 22, 26, 32, and 36 years, lung function was measured with spirometry. At each survey, three mutually exclusive spirometric patterns were defined: (1) normal (FEV1/FVC ≥10th percentile and FVC ≥10th percentile); (2) restrictive (FEV1/FVC ≥10th percentile and FVC <10th percentile); and (3) obstructive (FEV1/FVC <10th percentile, independent of FVC). Data on demographic features and parental health factors were collected from questionnaires; pregnancy and perinatal data (including nutritional problems) and birth measurements were obtained from medical records; and weight, height, and body-mass index (BMI) during childhood (age 6-16 years) were measured by study nurses. The associations between early-life risk factors and spirometric patterns were assessed by multivariate multinomial logistic regression analysis, adjusted for survey year, sex, and race-ethnicity. Significant risk factors were further tested for replication in the Swedish Child (Barn), Allergy, Milieu, Stockholm, Epidemiological (BAMSE; n=1817; spirometry surveys were done at age 24 years) survey and the UK Manchester Asthma and Allergy Study (MAAS; n=411; spirometry surveys were done at age 18 years) birth cohorts, and fixed-effect meta-analyses of relative risk ratios (RRRs) from multinomial logistic regression models were done to generate a pooled estimate of the effect across the three cohorts. Measurements of body composition (MAAS; n=365) and total lung capacity (TCRS; n=173 and MAAS; n=407) were also available for a subset of participants. FINDINGS: Of 1246 healthy infants included in TCRS, for the present study we included data for 652 participants who had at least one set of spirometry data, contributing up to 1668 observations. In the TCRS cohort, results from the multivariate models showed that maternal nutritional problems during pregnancy (RRR 2·48 [95% CI 1·30-4·76]; p=0·0062), being born small for gestational age (birthweight <10th percentile; 3·26 [1·34-7·93]; p=0·0093), and being underweight in childhood (BMI-for-age <5th percentile; 3·54 [1·35-9·26]; p=0·010) were independent predictors of spirometric restriction in adult life. Associations between being small for gestational age (p=0·0028) and underweight in childhood (p<0·0001) with adult spirometric restriction were supported by the results of meta-analysis of data from all three cohorts. In the MAAS cohort, having a low lean BMI (ie, <10th percentile) at age 11 years predicted adult (age 18 years) spirometric restriction (RRR 3·66 [1·48-9·02]; p=0·0048). These associations of spirometric restriction with small for gestational age, childhood underweight, and low lean BMI in childhood were verified in participants with spirometric restriction who had diminished total lung capacity, indicating that these factors specifically increase the risk of lung restriction. INTERPRETATION: Poor growth and nutritional deficits in utero and throughout childhood precede and predict the development of spirometric restriction in adult life. Strategies to improve prenatal and childhood growth trajectories could help to prevent spirometric restriction and its associated morbidity and mortality burden. FUNDING: National Institutes of Health.

Spirometric phenotypes from early childhood to young adulthood: a Chronic Airway Disease Early Stratification study.

BACKGROUND: The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts. METHODS: We studied 49 334 participants from 14 population-based cohorts in different age groups (≤10, >10-15, >15-20, >20-25 years, and overall, 5-25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV1/FVC z-score ≥LLN, and FVC z-score

Diagnosis of asthma in symptomatic children based on measures of lung function: an analysis of data from a population-based birth cohort study.

BACKGROUND: Concerns have been expressed about asthma overdiagnosis. The UK National Institute of Health and Care Excellence (NICE) proposed a new diagnostic algorithm applying four lung function measures sequentially (ratio of forced expiratory volume in 1 s [FEV1] to forced vital capacity [FVC] <70%, bronchodilator reversibility ≥12%, fractional exhaled nitric oxide [FeNO] ≥35 parts per billion, and peak expiratory flow variability >20%). We aimed to assess the diagnostic value of three of the tests individually, and then test the proposed algorithm in symptomatic children. METHODS: We used follow-up data at age 13-16 years from the Manchester Asthma and Allergy Study, a prospective, population-based, birth cohort study. We initially present results for the whole population, then by subgroup of disease. To simulate the situation in primary care, we included participants reporting symptoms of wheeze, cough, or breathlessness in the previous 12 months and who were not on regular inhaled corticosteroids. We used an epidemiological definition of current asthma, defined as all three of physician-diagnosed asthma, current wheeze, and current use of asthma treatment, reported by parents in a validated questionnaire. We assigned children with negative answers to all three questions as non-asthmatic controls. We also measured spirometry, bronchodilator reversibility, and FeNO at follow-up; data for peak expiratory flow variability were not available. We calculated the proportion of participants with a current positive lung function test at each step of the algorithm, and recorded the number of participants that met our definition of asthma. FINDINGS: Of 1184 children born into the cohort, 772 attended follow-up at age 13-16 years between July 22, 2011, and Nov 11, 2014. Among 630 children who completed spirometry, FEV1:FVC was less than 70% in ten (2%) children, of whom only two (20%) had current asthma. Bronchodilator reversibility was positive in 54 (9%) of 624 children, of whom only 12 (22%) had current asthma. FeNO was 35 or more parts per billion in 115 (24%) of 485 children, of whom 29 (25%) had current asthma. Only four of 56 children with current asthma had positive results for all three tests (spirometry, bronchodilator reversibility, and FeNO). Conversely, 24 (43%) of the 56 children with current asthma were negative on all three tests. FEV1:fvc (p=0·0075) and FeNO (p<0·0001), but not bronchodilator reversibility (p=0·97), were independently associated with asthma in multivariable logistic regression models. Among children who reported recent symptoms, the diagnostic accuracy of the algorithm was poor. INTERPRETATION: Our findings challenge the proposed cutoff values for spirometry, the order in which the lung function tests are done, and the position of bronchodilator reversibility within the algorithm sequence. Until better evidence is available, the proposed NICE algorithm on asthma diagnosis should not be implemented in children. FUNDING: UK Medical Research Council.

Trajectories of lung function during childhood.

RATIONALE: Developmental patterns of lung function during childhood may have major implications for our understanding of the pathogenesis of respiratory disease throughout life. OBJECTIVES: To explore longitudinal trajectories of lung function during childhood and factors associated with lung function decline. METHODS: In a population-based birth cohort, specific airway resistance (sRaw) was assessed at age 3 (n = 560), 5 (n = 829), 8 (n = 786), and 11 years (n = 644). Based on prospective data (questionnaires, skin tests, IgE), children were assigned to wheeze phenotypes (no wheezing, transient, late-onset, and persistent) and atopy phenotypes (no atopy, dust mite, non-dust mite, multiple early, and multiple late). We used longitudinal linear mixed models to determine predictors of change in sRaw over time. MEASUREMENTS AND MAIN RESULTS: Contrary to the assumption that sRaw is independent of age and sex, boys had higher sRaw than girls (mean difference, 0.080; 95% confidence interval [CI], 0.049-0.111; P < 0.001) and a higher rate of increase over time. For girls, sRaw increased by 0.017 kPa ⋅ s(-1) per year (95% CI, 0.011-0.023). In boys this increase was significantly greater (P = 0.012; mean between-sex difference, 0.011 kPa ⋅ s(-1); 95% CI, 0.003-0.019). Children with persistent wheeze (but not other wheeze phenotypes) had a significantly greater rate of deterioration in sRaw over time compared with never wheezers (P = 0.009). Similarly, children with multiple early, but not other atopy phenotypes had significantly poorer lung function than those without atopy (mean difference, 0.116 kPa ⋅ s(-1); 95% CI, 0.065-0.168; P < 0.001). sRaw increased progressively with the increasing number of asthma exacerbations. CONCLUSIONS: Children with persistent wheeze, frequent asthma exacerbations, and multiple early atopy have diminished lung function throughout childhood, and are at risk of a progressive loss of lung function from age 3 to 11 years. These effects are more marked in boys.

Differing associations of BMI and body fat with asthma and lung function in children.

BACKGROUND: Current evidence suggests that in children there is a significant, albeit weak, association between asthma and obesity. Studies generally use body mass index (BMI) in evaluating body adiposity, but there are limitations to its use. METHOD: Children from a population-based study attending follow-up (age 11 years) were weighed, measured and had percent body (PBF) and truncal (PTF) fat assessed using bioelectrical impedance. They were skin prick tested and completed spirometry. Parents completed a validated respiratory questionnaire. Children were defined as normal or overweight according to BMI and PBF cut-offs. We tested the association between these adiposity markers with wheeze, asthma, atopy, and lung-function. RESULTS: Six hundred forty-six children (339 male) completed follow-up. BMI z-score, PBF, and PTF were all positively associated with current wheeze (odds ratio [95% CI]: 1.27 [1.03, 1.57], P = 0.03; 1.05 [1.00, 1.09], P = 0.03; 1.04 [1.00, 1.08], P = 0.04, respectively). Similar trends were seen with asthma. However, when examining girls and boys separately, significant positive associations were found with PBF and PTF and asthma but only in girls (gender interaction P = 0.06 and 0.04, respectively). Associations between being overweight and wheezing and asthma were stronger when overweight was defined by PBF (P = 0.007, 0.03) than BMI (P > 0.05). Higher BMI was significantly associated with an increase in FEV(1) and FVC, but only in girls. Conversely, increasing body fat (PBF and PTF) was associated with reduced FEV(1) and FVC, but only in boys. No associations between adiposity and atopy were found. CONCLUSION: All adiposity measures were associated with wheeze, asthma, and lung function. However, BMI and PBF did not have the same effects and girls and boys appear to be affected differently.

Long-term exposure to PM10 and NO2 in association with lung volume and airway resistance in the MAAS birth cohort.

BACKGROUND: Findings from previous studies on the effects of air pollution exposure on lung function during childhood have been inconsistent. A common limitation has been the quality of exposure data used, and few studies have modeled exposure longitudinally throughout early life. OBJECTIVES: We sought to study the long-term effects of exposure to particulate matter with an aerodynamic diameter ≤ 10 µm (PM10) and to nitrogen dioxide (NO2) on specific airway resistance (sR(aw)) and forced expiratory volume in 1 sec (FEV1) before and after bronchodilator treatment. Subjects were from the Manchester Asthma and Allergy Study (MAAS) birth cohort (n = 1,185). METHODS: Spirometry was performed during clinic visits at ages 3, 5, 8, and 11 years. Individual-level PM10 and NO2 exposures were estimated from birth to 11 years of age through a microenvironmental exposure model. Longitudinal and cross-sectional associations were estimated using generalized estimating equations and multivariable linear regression models. RESULTS: Lifetime exposure to PM10 and NO2 was associated with significantly less growth in FEV1 (percent predicted) over time, both before (-1.37%; 95% CI: -2.52, -0.23 for a 1-unit increase in PM10 and -0.83%; 95% CI: -1.39, -0.28 for a 1-unit increase in NO2) and after bronchodilator treatment (-3.59%; 95% CI: -5.36, -1.83 and -1.20%; 95% CI: -1.97, -0.43, respectively). We found no association between lifetime exposure and sR(aw) over time. Cross-sectional analyses of detailed exposure estimates for the summer and winter before 11 years of age and lung function at 11 years indicated no significant associations. CONCLUSIONS: Long-term PM10 and NO2 exposures were associated with small but statistically significant reductions in lung volume growth in children of elementary-school age.

Effect of addition of salmeterol versus doubling the dose of fluticasone propionate on specific airway resistance in children with asthma.

Based primarily on extrapolation from adult studies, current pediatric asthma guidelines advise the addition of long-acting beta2-agonists for children symptomatic on low/moderate-dose inhaled corticosteroids before increasing the corticosteroid dose. This study was designed to compare the effect of combination salmeterol/fluticasone propionate (SFC) with doubling the dose of fluticasone propionate (FP) on specific airway resistance (sR(aw)) in moderate/severe persistent asthmatic children. A double-blind, randomized, controlled study was performed; children with asthma (4-11 years old; sR(aw) > 1.3 kPa·s) were randomized after a 2-week run-in (FP, 100 µg, b.i.d.) to either SFC (50 µg/100 µg b.i.d.) or FP (200 µg b.i.d.) via Diskus (GlaxoSmithKline, Stockley Park, U.K.) for 6 weeks. Lung function (sR(aw)-plethysmography and forced expiratory volume in 1 second [FEV1]) was measured before run-in, at randomization, after 3 weeks, at the end of 6-week treatment, and after 48-hour washout. Symptom scores and rescue medication use were recorded throughout. Thirty-five children entered run-in and 24 were randomized (mean age, 7.3 ± 2.2 years; 50% boys). All children showed an improvement in sR(aw). After adjusting for age, gender, and baseline sR(aw,) children receiving SFC had a significantly greater improvement in sR(aw) compared with those receiving FP (adjusted means ratio [95% confidence interval {CI}], 0.81 [0.68-0.97]; p = 0.021). There was a significant interaction between treatment and gender (sR(aw), adjusted geometric mean [95% CI ]kPa·s, SFC versus FP: boys, 1.25 [1.10-1.41] [n = 7] versus 1.87 [1.61-2.17] [n = 5]; girls, 1.29 [1.10-1.52] [n = 5] versus 1.29 [1.13-1.47] [n = 7]; p = 0.008). There were no differences in FEV1, symptoms, or rescue medication use between the groups. Addition of salmeterol provides greater improvement in sR(aw) than doubling the dose of FP in children with moderate/severe persistent asthma.

Day-care attendance, position in sibship, and early childhood wheezing: a population-based birth cohort study.

BACKGROUND: There are conflicting data on the effect of day-care attendance and position in sibship on the development of wheezing. OBJECTIVE: To investigate the relationship between day-care attendance and position in sibship with early childhood wheeze. METHODS: Prospective population-based birth cohort. At age 5 years, we collected information on parentally reported symptoms (n = 922); lung function was ascertained using plethysmography (n = 745) and allergic sensitization by skin testing (n = 815). Participants were assigned into categories according to the age of entry to day-care (0-6, 6-12, >12 mo) and number of older siblings (0, 1, 2, >2). RESULTS: Current wheeze was reported by 203 participants (22%); 224 (28%) were sensitized. In the multivariate model, sensitization (odds ratio, 2.47; 95% CI, 1.66-3.67), male sex (1.49, 1.01-2.20), maternal asthma (1.72, 1.10-2.68), and maternal smoking during pregnancy (2.15, 1.26-3.66) significantly increased the risk of wheezing. Entering day-care between 6 and 12 or after 12 months of age was significantly and inversely associated with current wheeze (0.25, 0.11-0.60; and 0.65, 0.44-0.98, respectively). Entry into nursery between 6 and 12 months reduced the risk of persistent wheezing (P = .04). We found no association between day-care attendance and lung function. Entering nursery in the first 6 months of life was associated with increased risk of atopy (2.47, 1.23-4.95). Having older siblings was associated only with rhinoconjunctivitis (0.72, 0.54-0.97). CONCLUSION: Day-care attendance was associated with a reduced risk of current wheezing in 5-year-old children. The protective effect appeared strongest for children who entered day-care between the ages of 6 and 12 months.

Staphylococcus aureus sensitization and allergic disease in early childhood: population-based birth cohort study.

BACKGROUND: Staphylococcus aureus-secreted enterotoxins (SEs) may be involved in the pathophysiology of atopic diseases. OBJECTIVE: We investigated the role of SEs in allergic diseases during early childhood (using the mixture of SE-specific IgEs [SE-mix] as a marker). METHODS: Children (N = 510) were followed from birth to age 5 years (repeated questionnaires, IgE to inhalant and food allergens, lung function [spirometry, plethysmography], airway reactivity [dry air challenge]). We measured SE-mix specific IgE (SE-A, SE-C, toxic shock syndrome toxin 1) by using fluorescence immunoassay. RESULTS: We found no association between rhinitis and SE-mix sensitization. Children with eczema were more frequently SE-mix-sensitized than children without (17.4% vs 8.3%; P = .02). SE-mix sensitization rate increased significantly with increasing eczema severity (no eczema, mild, moderate/severe: 8.3%, 14.8%, 42.9%; P = .003) and remained independently associated with eczema in a multivariate model adjusting for total IgE (adjusted odds ratio, 2.19; 95% CI, 1.05-4.56; P = .04). SE-mix sensitization was associated with current wheeze in the univariate but not the multivariate model. Among wheeze phenotypes, persistent wheezers were most commonly sensitized to SE-mix (never, transient, late-onset, persistent: 8.5%, 3.8%, 7.7%, 17.6%; P = .05). Among wheezers, those SE-mix-sensitized had significantly higher airway reactivity compared with those nonsensitized (mean FEV(1) change, mL [95% CI]: -59 [-121, 3] vs 19 [-10.2, 48.9]; P = .04), with little difference after adjusting for atopy. CONCLUSION: We found differences in SE-mix IgE antibodies between healthy 5-year-old children and children with eczema and wheeze. The proportion of patients sensitized to SE-mix increases with increasing disease severity. CLINICAL IMPLICATIONS: Staphylococcal enterotoxins are potential modifiers of childhood wheeze and eczema.

Exhaled breath condensate pH and childhood asthma: unselected birth cohort study.

RATIONALE: Exhaled breath condensate pH (EBC-pH) may be useful noninvasive marker for evaluation of patients with asthma. OBJECTIVES: To investigate the relationship between EBC-pH and symptoms suggestive of childhood asthma in an epidemiologic setting and examine its relation to lung function, airway hyperresponsiveness (AHR), and airway inflammation. METHODS: Within the context of a prospective population-based birth cohort, EBC was collected from 630 children at age 8 yr using the RTube (pH measured after deaeration with argon). Lung function was measured by spirometry (FEV1; n = 521) and plethysmography (sRaw; n = 567), and AHR by methacholine challenge (n = 498). Airway inflammation was assessed using exhaled nitric oxide (eNO; n = 305). RESULTS: EBC-pH values ranged widely (4.40-8.29), and did not differ between 54 children with parentally reported asthma and 562 nonasthmatic subjects (median [interquartile range]: 7.75 [7.45-7.85] vs. 7.77 [7.59-7.87]; p = 0.35). There was a trend for lower EBC-pH among current wheezers (n = 98; 7.72 [7.50-7.83]) compared with nonwheezers (n = 532; 7.77 [7.60-7.87]; p = 0.07). Wheeze frequency, severity, and use of antiasthma medication were not associated with EBC-pH. There was no consistent association between EBC-pH and lung function, airway reactivity, and airway inflammation (FEV1, sRaw, PD20 methacholine, or eNO). There was no significant difference in EBC-pH between current wheezers receiving asthma medication who had positive methacholine challenge compared with children without any of these features. CONCLUSIONS: In the epidemiologic setting, EBC-pH does not differ between children with and without parentally reported symptoms suggestive of asthma. We found no consistent association between EBC-pH and lung function, AHR, and airway inflammation in this sample from the general population.

Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function.

RATIONALE: Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood. OBJECTIVES: 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. METHODS: 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. MAIN RESULTS: 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. CONCLUSIONS: Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5' end of the gene.

Wheeze phenotypes and lung function in preschool children.

Distinct phenotypes can be identified in childhood wheezing illness. Within the context of a birth cohort study, we investigated the association between preschool lung function and phenotypes of wheeze. From parentally reported history of wheeze (interviewer-administered questionnaire, age 3 and 5 years), children were classified as never wheezers, transient early wheezers, late-onset wheezers, or persistent wheezers. Lung function (specific airway resistance [sRaw]; kPa/second) was assessed at age 3 (n = 463) and 5 years (n = 690). Persistent wheezers had markedly poorer lung function compared with other groups. In children who had wheezed by age 3, the risk of persistent wheeze increased with increased sRaw (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.3-22.0; p = 0.02). In a multivariate model, increasing sRaw (OR 5.5, 95% CI 1.2-25.9; p = 0.03) and the child's sensitization (OR 2.8, 95% CI 1.3-5.8; p = 0.008) were significant independent predictors of persistent wheezing. We found no association between lung function at age 3 and late-onset wheeze in children who had not wheezed previously (OR 0.6, 95% CI 0.07-5.3; p = 0.64). In conclusion, poor lung function at age 3 predicted the subsequent persistence of symptoms in children who had wheezed within the first 3 years, but was not associated with the onset of wheeze after age 3 in children who had not wheezed previously.

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

OBJECTIVE: To investigate the effect of pet ownership and exposure to indoor allergens on lung function in 3-year-old children. DESIGN: Birth cohort study. SETTING: Community. PARTICIPANTS: Children recruited prenatally and followed prospectively to age 3 years. MAIN OUTCOME MEASURES: 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). RESULTS: 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. CONCLUSIONS: 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.

Early life environmental control: effect on symptoms, sensitization, and lung function at age 3 years.

We investigated whether environmental control during pregnancy and early life affects sensitization and lung function at the age of 3 years. High-risk children (n = 251) were prenatally randomized to stringent environmental control (active) or no intervention (control). Questionnaires, skin testing, IgE, and specific airway resistance (sRaw) measurement were completed at the age of 3 years. Children in the active group were significantly more frequently sensitized compared with control subjects (at least one allergen by skin tests: risk ratio, 1.61; 95% confidence interval [CI], 1.02-2.55; p = 0.04; mite by IgE: risk ratio, 2.85; 95% CI, 1.02-7.97; p = 0.05). However, sRaw was significantly better in the active group (kiloPascal/second, geometric mean [95% CI]: 1.05 [1.01-1.10] vs. 1.19 [1.13-1.25], p < 0.0001, active vs. control). Maximal flow at functional residual capacity was measured using rapid thoracic compression at the age of 4 weeks in a subgroup. Prospective lung function data (at infancy and 3 years) were obtained in 32 children (14 active and 18 control). There was no difference in infant lung function between the groups, but at 3 years, sRaw was significantly lower in the active compared with control children (p = 0.003). Stringent environmental control was associated with increased risk of mite sensitization but better results for some measurements of lung function in high-risk children at the age of 3 years.

Childhood asthma.

The prevalence of asthma and wheezing illness in children has increased substantially over recent decades and places a large burden on health care resources. Despite increasing evidence that both genetic and environmental factors have significant effects on airway development and function in early life, our understanding of the natural history of the disease is limited. Several phenotypes of wheeze have been described and many risk factors identified for the development of asthma. A thorough knowledge of early life lung physiology will enable us to identify children at risk for developing persistent disease. The development of objective outcome measures that can be applied in early life will aid in distinguishing between children with transient early wheeze and those who will progress to persistent disease, enabling effective, targeted therapy.

Urinary eosinophilic protein X, atopy, and symptoms suggestive of allergic disease at 3 years of age.

BACKGROUND: Urinary eosinophilic protein X (U-EPX) measurement is easy to perform in children. However, its use for prediction, diagnosis, and monitoring of asthma and atopy is unclear. OBJECTIVE: We sought to investigate the relationship between U-EPX and clinical phenotypes suggestive of allergic diseases. METHODS: U-EPX measurement (RIA), respiratory questionnaires, and skin testing were completed at age 3 years in 903 children followed prospectively from birth. Specific airway resistance was measured in 503 currently asymptomatic children by using whole-body plethysmography during tidal breathing. RESULTS: Nonatopic children with wheezing or eczema had slightly increased U-EPX levels compared with nonatopic asymptomatic children. U-EPX levels (geometric mean EPX/creatinine ratio) were as follows: nonatopic asymptomatic children (n = 313), 61.3 microg/mmol (95% CI, 56.4-66.6 microg/mmol); nonatopic children with wheezing (n = 148), 71.2 microg/mmol (95% CI, 63.2-80.1 microg/mmol); nonatopic children with eczema (n = 90), 65.7 microg/mmol (95% CI, 56.7-76.2 microg/mmol); and nonatopic children with wheezing and eczema (n= 86), 79.7 microg/mmol (95% CI, 67.4-94.3 microg/mmol). Children who had persistent atopy early in life had significantly higher U-EPX levels at age 3 years (nonatopic at 1 and 3 years [n = 263], 63.4 microg/mmol [95% CI, 58.4-69.0 microg/mmol]; atopic at 1 but not 3 years [n = 24], 65.1 microg/mmol [95% CI, 43.8-96.7 microg/mmol]; nonatopic at 1 year and atopic at 3 years [n = 62], 90.0 microg/mmol [95% CI, 74.6-108.4 microg/mmol]; atopic at 1 and 3 years [n = 35], 111.5 microg/mmol [95% CI, 89.2-139.3 microg/mmol]; P <.002). Atopy alone and with wheezing, eczema, or both was associated with significantly increased U-EPX levels (P <.0001). Wheezing appeared to be associated with higher U-EPX levels compared with eczema in both atopic and nonatopic children. The highest U-EPX level was found in atopic children with a history of wheezing and eczema (P <.0001). There was no relationship between U-EPX level and lung function. CONCLUSION: U-EPX level reflects the presence of atopy and associated symptoms and might be useful for monitoring the progression of allergic disease.