Late-onset Wheeze Research Articles

Age-specific influence of wheezing phenotypes on pre-adolescent and adolescent health-related quality of life.

Asthma is associated with diminished health-related quality of life (HRQoL). Particularly in adolescence, asthma may be under-diagnosed and undertreated or poorly managed. Therefore, we aimed to determine the association between childhood wheezing phenotypes rather than asthma and adolescent HRQoL in children aged 10-17 yr. We analyzed the data from two prospective population-based cohort studies (n = 604 and n = 1804) conducted in southern Germany with baseline assessments in 2000 and 2006 and follow-ups at frequent intervals. Parent-reported wheeze was categorized into never, early transient, persistent, and late-onset wheeze. We assessed child-reported HRQoL in seven scales using the validated KINDL-R. Multivariate linear regression models were computed. Participants with late-onset wheeze had significantly lower values in all HRQoL scales, but physical well-being compared to never wheezers. Early transient wheeze was negatively associated with three HRQoL scales only (family, school, and total). These effects were confined to the oldest age group (≥13.5 yr) in one study. Persistent wheeze was not associated with HRQoL. In teenagers, late-onset wheezers seem to be particularly vulnerable for impairments in psychosocial aspects of health-related quality of life. They may therefore require particular attention with regard to education about asthma management and potentially family-based psychosocial intervention.

Association of IL33–IL-1 receptor–like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood

Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway. In 2 birth cohorts, the Prevalence and Incidence of Asthma and Mite Allergy (PIAMA) study and Avon Longitudinal Study of Parents and Children (ALSPAC), we analyzed associations of longitudinal wheezing phenotypes and asthma with single nucleotide polymorphisms (SNPs) of 8 genes encoding IL-33, IL1RL1, its coreceptor IL1RAcP, its adaptors myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-11 receptor domain containing adaptor protein (TIRAP), and the downstream IL-1 receptor-associated kinase 1, IL-1 receptor-associated kinase 4, and TNF receptor-associated factor 6 (TRAF6). Furthermore, we investigated whether SNPs in this pathway show replicable evidence of gene-gene interaction. Ninety-four SNPs were investigated in 2007 children in the PIAMA study and 7247 children in ALSPAC. Associations with wheezing phenotypes and asthma at 8 years of age were analyzed in each cohort and subsequently meta-analyzed. Gene-gene interactions were assessed through model-based multifactor dimensionality reduction in the PIAMA study, and gene-gene interactions of 10 SNP pairs were further evaluated. Intermediate-onset wheeze was associated with SNPs in several genes in the IL33-IL1RL1 pathway after applying multiple testing correction in the meta-analysis: 2 IL33 SNPs (rs4742170 and rs7037276), 1 IL-1 receptor accessory protein (IL1RAP) SNP (rs10513854), and 1 TRAF6 SNP (rs5030411). Late-onset wheeze was associated with 2 IL1RL1 SNPs (rs10208293 and rs13424006), and persistent wheeze was associated with 1 IL33 SNP (rs1342326) and 1 IL1RAP SNP (rs9290936). IL33 and IL1RL1 SNPs were nominally associated with asthma. Three SNP pairs showed interaction for asthma in the PIAMA study but not in ALSPAC. IL33-IL1RL1 pathway polymorphisms are associated with asthma and specific wheezing phenotypes; that is, most SNPs are associated with intermediate-onset wheeze, a phenotype closely associated with sensitization. We speculate that IL33-IL1RL1 pathway polymorphisms affect development of wheeze and subsequent asthma through sensitization in early childhood.

The Birth of Mankind

<h3>Background:</h3> Patterns of wheezing during early childhood may indicate differences in aetiology and prognosis of respiratory illnesses. Improved characterisation of wheezing phenotypes could lead to the identification of environmental influences...

Perinatal risk factors for wheezing phenotypes in the first 8 years of life

A novel data-driven approach was used to identify wheezing phenotypes in pre-schoolchildren aged 0-8years, in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort. Five phenotypes were identified: never/infrequent wheeze, transient early wheeze, intermediate onset wheeze, persistent wheeze and late onset wheeze. It is unknown which perinatal risk factors drive development of these phenotypes. The objective of the study was to assess associations of perinatal factors with wheezing phenotypes and to identify possible targets for prevention. In the PIAMA study (n=3963), perinatal factors were collected at 3months, and wheezing was assessed annually until the age of 8years. Associations between perinatal risk factors and the five wheezing phenotypes were assessed using weighted multinomial logistic regression models. Odds ratios were adjusted for confounding variables and calculated with 'never/infrequent wheeze' as reference category. Complete data were available for 2728 children. Risk factors for transient early wheeze (n=455) were male gender, maternal and paternal allergy, low maternal age, high maternal body mass index, short pregnancy duration, smoking during pregnancy, presence of older siblings and day-care attendance. Risk factors for persistent wheeze (n=83) were male gender, maternal and paternal allergy, and not receiving breastfeeding for at least 12weeks. Intermediate onset wheeze (n=98) was associated with a lower birth weight and late onset wheeze (n=45) with maternal allergy. We identified different risk factors for specific childhood wheezing phenotypes. Some of these are modifiable, such as maternal age and body mass index, smoking, day-care attendance and breastfeeding, and may be important targets for prevention programmes.

Early-Life Risk Factors for Childhood Wheeze Phenotypes in a High-Risk Birth Cohort

To define longitudinal childhood wheeze phenotypes and identify their early-life risk factors. Current wheeze was recorded 23 times up to age 7 years in a birth cohort at high risk for allergy (n = 620). Latent class analysis of wheeze responses identified 5 classes. Multinomial logistic regression estimated associations of probability-weighted wheezing classes with early-life factors. All phenotypes were compared with never/infrequent wheezers. Lower respiratory tract infection (LRTI) by 1 year (relative risk [RR], 3.00; 95% CI, 1.58-5.70), childcare by 1 year (RR, 1.51; 95% CI, 1.02-2.22), and higher body mass index (RR, 2.51; 95% CI, 1.09-5.81) were associated with increased risk of early transient wheeze, whereas breastfeeding was protective (RR, 0.54; 95% CI, 0.32-0.90). LRTI (RR, 6.54; 95% CI, 2.55-16.76) and aeroallergen sensitization (RR, 4.95; 95% CI, 1.74-14.02) increased the risk of early persistent wheeze. LRTI (RR, 5.31; 95% CI, 2.71-10.41), eczema (RR, 2.77; 95% CI, 1.78-4.31), aeroallergen sensitization (RR, 5.60; 95% CI, 2.86-10.9), and food sensitization (RR, 2.77; 95% CI, 1.56-4.94) increased the risk of intermediate-onset wheeze, whereas dog exposure at baseline (RR, 0.52; 95% CI, 0.32-0.84) and first-born status (RR, 0.49; 95% CI, 0.32-0.76) were protective. Heavy parental smoking at birth (RR, 3.18; 95% CI, 1.02-9.88) increased the risk of late-onset wheeze, whereas breastfeeding reduced it (RR, 0.34; 95% CI, 0.12-0.96). All wheeze classes except early transient had greater risk of wheeze at age 12 years compared with never/infrequent wheezers. We found distinct early-life risk factor profiles for each wheeze phenotype. These findings provide insight into possible wheeze mechanisms and have implications for identifying preventive strategies and addressing clinical management of early-life wheeze.

Joint modeling of parentally reported and physician-confirmed wheeze identifies children with persistent troublesome wheezing

Previous studies have suggested the presence of different childhood wheeze phenotypes through statistical modeling based on parentally reported wheezing. We sought to investigate whether joint modeling of observations from both medical records and parental reports helps to more accurately define wheezing disorders during childhood and whether incorporating information from medical records better characterizes severity. In a population-based birth cohort (n = 1184), we analyzed data from 2 sources (parentally reported current wheeze at 4 follow-ups and physician-confirmed wheeze from medical records in each year from birth to age 8 years) to determine classes of children who differ in wheeze trajectories. We tested the validity of these classes by examining their relationships with objective outcomes (lung function, airway hyperreactivity, and atopy), asthma medication, and severe exacerbations. Longitudinal latent class modeling identified a 5-class model that best described the data. We assigned classes as follows: no wheezing (53.3%), transient early wheeze (13.7%), late-onset wheeze (16.7%), persistent controlled wheeze (13.1%), and persistent troublesome wheeze (PTW; 3.2%). Longitudinal trajectories of atopy and lung function differed significantly between classes. Patients in the PTW class had diminished lung function and more hyperreactive airways compared with all other classes. We observed striking differences in exacerbations, hospitalizations, and unscheduled visits, all of which were markedly higher in patients in the PTW class compared with those in the other classes. For example, the risk of exacerbation was much higher in patients in the PTW class compared with patients with persistent controlled wheeze (odds ratio [OR], 3.58; 95% CI, 1.27-10.09), late-onset wheeze (OR, 15.92; 95% CI, 5.61-45.15), and transient early wheeze (OR, 12.24; 95% CI, 4.28-35.03). We identified a novel group of children with persistent troublesome wheezing, who have markedly different outcomes compared with persistent wheezers with controlled disease.

Validation of novel wheeze phenotypes using longitudinal airway function and atopic sensitization data in the first 6 years of life: Evidence from the Southampton Women's survey

In 1995 the Tucson Children's Respiratory Study (TCRS) identified clinically distinct phenotypes amongst early wheezers; the Avon Longitudinal Study of Parents And Children (ALSPAC) has recently re-examined these. To validate statistically derived ALSPAC phenotypes in the Southampton Women's Survey (SWS) using infant and 6-year lung function, and allergic sensitization at 1, 3, and 6 years, comparing these with TCRS phenotypes. Complete 6-year follow-up data were available for 926 children, selected from 1,973 infants born to 12,579 women characterized pre-conception. Ninety-five children had V'maxFRC and FEV0.4 measured age 5-14 weeks using rapid compression/raised volume techniques. At 6 years we performed spirometry (n = 791), fractional exhaled nitric oxide (FeNO, n = 589) and methacholine challenge (n = 234). Skin prick testing was performed at 12m, 3 and 6 years (n = 1,494, 1,255, 699, respectively). Using wheeze status questionnaire data at 6m, 12m, 2, 3 and 6 years we classified children into TCRS (never, transient early, persistent, late-onset) and ALSPAC based groups (never, early, transient, intermediate-onset, late-onset, persistent). Amongst ALSPAC groups, persistent and late-onset wheeze were associated with atopy at 3 and 6 years, whilst intermediate-onset wheeze showed earlier atopic association at 1 year; all three were associated with FeNO at 6 years. Persistent wheezers had lower infant (V'maxFRC P < 0.05) and 6-year lung function (FEV1, FEV1/FVC, and FEF(25-75), P < 0.05), whilst late and intermediate-onset wheezers showed no lung function deficits. Transient wheezers were non-atopic but showed persistent lung function deficits (V'maxFRC in infancy, FEV1 and FEF(25-75) at 6 years, all P < 0.05). Those who wheezed only in the first year (early phenotype) showed no lung function deficits. No associations were seen with 6 years bronchial hyper-responsiveness or infancy FEV0.4. SWS cohort data validates the statistically derived ALSPAC six-class model. In particular, lung function and atopy successfully differentiate persistent, late-onset and intermediate-onset wheeze, whilst the Tucson "transient early" wheeze phenotype can be sub-classified into groups that reflect early lung function. Since the 4-class model fails to adequately differentiate phenotypes based on lung function and atopy, we propose that strong consideration be given to using the 6-class paradigm for longitudinal outcome work in wheezing with onset in early life.

S32 Childhood Wheeze Phenotypes Can Be Usefully Sub-Classified Using Longitudinal Lung Function and Atopic Sensitisation Data. Evidence from the Southampton Women’s Survey

BackgroundEpidemiological phenotypes for childhood wheeze were first proposed by the Tucson Children’s Respiratory Study (TCRS), describing four distinct phenotypes. A new, six phenotype, characterisation has recently been proposed by the...

Reduced neonatal lung function and wheezing illnesses during the first 5 years of life

Studies of reduced neonatal lung function and wheezing illnesses during childhood show conflicting results. The aim of our study was to assess the association between resistance (Rrs) and compliance (Crs) of the respiratory system by using the single occlusion technique (SOT) and prospectively collected wheezing illnesses during the first 5 years of life in a large birth cohort. SOT was performed during natural sleep before the age of 2 months. Information about wheezing illnesses was collected from the electronic patient file. 549 infants had a successful SOT measurement and complete medical records. Every kPa·L(-1)·s(-1) increase in Rrs was associated with 10% more consultations in the first 3 years of life. Every 10 mL·kPa(-1) increase in Crs was associated with a 14% reduction in consultations in the first 3 years of life, 27% in the fourth to fifth years of life, and a lower probability of having asthma at the age of 5 years (OR 0.66). Children with late-onset or persistent wheezing had significant lower Crs values than their peers. An increased neonatal resistance is associated with more wheezing illnesses during infancy, while a reduced neonatal compliance is associated with more wheezing illnesses during the first 5 years of life, a late-onset or persistent wheezing phenotype, and asthma.

Maternal obesity, gestational weight gain, and risk of asthma and atopic disease in offspring: A study within the Danish National Birth Cohort

High pre-pregnancy body mass index (BMI) and excessive gestational weight gain (GWG) are suggested to influence risk of asthma and atopic disease in offspring. We examined the effect of BMI and GWG on risk of asthma, wheezing, atopic eczema (AE), and hay fever in children during the first 7 years of life. This was a cohort study of 38,874 mother-child pairs from the Danish National Birth Cohort (enrollment 1996-2002) with information from the 16th week of pregnancy and at age 6 months, 18 months, and 7 years of the child. Odds ratios (ORs) with 95% CIs were calculated by logistic regression with adjustment for potential confounders. During the first 7 years of life, 10.4% of children developed doctor-diagnosed asthma, 25.8% AE, and 4.6% hay fever. Maternal BMI and to a lesser extent GWG were associated with doctor-diagnosed asthma ever. In particular, BMI≥35 (adjusted OR, 1.87; 95% CI, 0.95-3.68) and GWG≥25 kg (adjusted OR, 1.97; 95% CI, 1.38-2.83) were associated with current severe asthma at age 7 years. Maternal BMI was also associated with wheezing in offspring, with the strongest association observed between BMI≥35 and late-onset wheezing (adjusted OR, 1.87; 95% CI, 1.28-2.73). Maternal BMI and GWG were not associated with AE or hay fever. Maternal obesity during pregnancy was associated with increased risk of asthma and wheezing in offspring but not with AE and hay fever, suggesting that pathways may be nonallergic.

Childhood wheezing phenotypes and FeNO in atopic children at age 8

Fractional exhaled Nitric Oxide (FeNO) is a surrogate biomarker of the degree of eosinophilic airway inflammation. Using longitudinal latent class analysis, five wheezing phenotypes have been identified, characterized by different ages of onset and prognosis. To assess FeNO measured at 4 and 8years in children with different phenotypes of wheeze and atopy. Children participated in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) study, a prospective birth cohort in the Netherlands. Respiratory health was assessed yearly by questionnaires until the age of 8years; these data were used to identify five wheezing phenotypes. Associations between FeNO and wheezing phenotypes were investigated using weighted linear regression. Data on wheezing phenotypes and FeNO at 4 and 8years were available in 588 and 973 children respectively. Compared with the phenotype of never and transient wheeze, FeNO at 4years was higher in intermediate onset and persistent wheeze. FeNO at 8years of age differed significantly between all phenotypes, with highest FeNO values for persistent, intermediate onset, and late onset wheeze. Rise in FeNO from 4 to 8years in intermediate and late onset wheezers was significantly higher compared to FeNO rise in never and transient wheezers. Stratified analyses showed that the increase in FeNO in persistent, intermediate, and late onset wheeze was only present in children with allergic sensitization at 8years. The FeNO measured at 8years was associated with specific wheezing phenotypes, only among atopic children.

First- and Second-Trimester Fetal Size and Asthma Outcomes at Age 10 Years

Greater early fetal size is associated with reduced asthma risk and improved lung function in early childhood. To test the hypothesis that associations between early fetal size, asthma symptoms, and lung function persist into later childhood. In a longitudinal study, first- and second-trimester fetal measurements were recorded. At 10 years of age a respiratory questionnaire was completed. Spirometry, bronchial challenge, and skin-prick testing were undertaken in a subset. Fetal measurements were available in the first trimester for 853 individuals and the second trimester for 1,453. Questionnaires were returned for 927 children and 449 underwent detailed phenotyping. For each millimeter increase in first trimester size, asthma risk reduced by 6% (95% confidence interval[CI], 1–11) and FEV1 was higher by an average of 6 ml (95% CI, 1–11).First-trimester size was reduced in those with asthma at both 5 and 10 years compared with early or late onset wheeze (P , 0.02). Compared with persistent high growth in first and second trimesters,persistent low growth was associated with increased asthma risk(odds ratio, 2.8; 95% CI, 1.2–6.9) and a mean reduction in FEV1 of 103 ml (95% CI, 13–194), whereas increasing fetal size was associated with increased eczema risk (odds ratio, 2.5; 95% CI, 1.2–5.3). Reduced fetal size from the first trimester is associated with increased risk for asthma and obstructed lung function in childhood. Relative change in size after the first trimester is associated with eczema.

High salivary secretory IgA antibody levels are associated with less late‐onset wheezing in IgE‐sensitized infants

Low levels of secretory IgA (SIgA) and transient IgA deficiency have been associated with an increased risk for allergy, but data are conflicting. The aim was to assess the relationship between salivary SIgA antibody levels at 1 yr and wheezing at age four in a birth cohort, in particular the possible protective role of salivary SIgA in sensitized children. Saliva samples were obtained from all children (n=67) with a positive skin prick test (SPT) at 1 yr and 212 children with a negative SPT. In all, 200 of these children responded to questionnaires at 4 yrs and 183 were skin prick tested at that age. The levels of salivary SIgA and salivary IgA antibodies to the most common food allergen egg and inhalant allergen cat were analyzed by ELISA. Serum was analyzed for IgE antibodies to egg and cat. Development of late-onset wheezing was associated with low SIgA levels in children with positive SPT to at least one allergen both at 1 and 4 yrs of age (p=0.04), as well as in children with circulating IgE antibodies to egg or cat at 1 yr (p=0.02). None of nine persistently sensitized children with SIgA levels in the upper quartile developed wheezing, when compared to 10/20 children with lower levels (p=0.01). Older siblings, more than three infections during infancy, at least one smoking parent, and male gender, were all associated with SIgA in the upper quartile. In conclusion, high levels of SIgA antibodies in sensitized infants were associated with significantly less late-onset wheezing, supporting a protective role against development of asthmatic symptoms. Recurrent infections and other factors supporting an increased microbial pressure during infancy were associated with high levels of salivary SIgA.

Association of maternal anemia with increased wheeze and asthma in children

Increasing interest has focused on maternal nutrition and micronutrient status during pregnancy and respiratory disease development in the offspring. To examine the relationship between maternal anemia in pregnancy with wheeze and asthma in early childhood. The cohort included children of women followed through pregnancy and recontacted when the child was 6 years of age to evaluate respiratory health. Exposure was assessed using maternal anemia diagnosis and hemoglobin (Hgb) < 11 during delivery hospitalization. Study outcomes include wheezing in early childhood; patterns of wheeze from birth to age 6 (early-onset transient wheeze; late-onset wheeze; early-onset persistent wheeze); and diagnosis of childhood asthma. Maternal anemia was reported by 11.9% of mothers and was associated with recurrent infant wheeze in the first year (adjusted odds ratio [ORa] = 2.17, 95% confidence interval [CI] 1.18, 4.00), wheezing before age 3 (Ora = 2.42, 95% CI 1.38, 4.23), and early-onset transient and early-onset persistent wheeze patterns (Ora = 2.81, 95%CI 1.38, 5.72, and Ora = 2.07, 95% CI 1.02, 4.22), respectively. Among children of mothers with asthma, maternal anemia was associated with recurrent wheeze in year 1 (Ora = 4.22, 95% CI 1.65, 10.80) and wheeze before age 3 (Ora = 2.73, 95% CI 1.17, 6.35). Offspring of mothers with asthma also had increased odds of asthma diagnosis (Ora = 2.53, 95% CI 1.04, 6.17) and current asthma (Ora = 3.46, 95% CI 1.45, 8.26). Maternal anemia during pregnancy is associated with infant respiratory health outcomes. If this observation is replicated, maternal anemia may be a target for intervention and future research.

S112 The natural history of wheeze from birth to adult life: a cohort study

<h3>Introduction and objectives</h3> Wheeze is a common symptom at all ages. Its natural history from birth to adulthood was studied in a birth cohort of individuals at high risk of atopic illness. The objective was to ascertain factors associated with wheeze at different ages, distinguishing between wheeze that occurred at successive time points (persistent wheeze) and wheeze newly occurring (incident wheeze). <h3>Methods</h3> 497 infants were selected antenatally as having a first-degree relative with a history of asthma, hay fever or eczema. During their first year and at 7 years the children were examined, symptoms were recorded, skin prick tests performed and serum IgE measured. At 15 and 23 years further questionnaires were completed and (at 23) blood and skin tests performed. <h3>Results</h3> Information was obtained on 483 individuals at 1 year, 453 at seven, 363 at 15 and 304 at 23. The prevalence of wheeze was fairly constant over time (around 30%), remission being balanced by incidence over each interval. Wheeze at 1 year predicted wheeze at ages seven and 15, and at seven it predicted wheeze at 15 and 23, but it was associated with different factors at different times and according to whether it was persistent or incident. In infancy it was related to non-atopic factors such as infection, maternal smoking and breastfeeding (protective). Persistent wheeze to age 15 was related to respiratory infections in infancy and to atopy. Incident wheeze from one to 7 years was strongly associated with atopy, while late-onset wheeze was related to rhino conjunctivitis, smoking and (marginally) body mass. <h3>Conclusions</h3> Advances in the understanding and prevention of wheeze may be assisted by directing attention to maternal smoking, breastfeeding and respiratory infections in infancy, atopy in childhood, rhino conjunctivitis in adolescence, and smoking and perhaps obesity in adult life.

Does airway allergic inflammation pre-exist before late onset wheeze in children?

Epidemiological studies show that some children develop wheezing after 3 yr of age which tends to persist. It is unknown how this starts or whether there is a period of asymptomatic inflammation. The aim of this study is to determine whether lower airway allergic inflammation pre-exists in late onset childhood wheeze (LOCW). Follow-up study of children below 5 yr who had a non-bronchoscopic bronchoalveolar lavage (BAL) performed during elective surgery. The children had acted as normal controls. A modified ISAAC questionnaire was sent out at least 7 yr following the initial BAL, and this was used to ascertain whether any children had subsequently developed wheezing or other atopic disease (eczema, allergic rhinitis). Cellular and cytokine data from the original BAL were compared between those who never wheezed (NW) and those who had developed LOCW. Eighty-one normal non-asthmatic children were recruited with a median age of 3.2. Of the 65 children contactable, 9 (16.7%) had developed wheeze, 11 (18.5%) developed eczema and 14 (22.2%) developed hay fever. In five patients, wheeze symptoms developed mean 3.3-yr (range: 2-5 yr) post-BAL. Serum IgE and blood eosinophils were not different in the LOCW and NW, although the blood white cell count was lower in the LOCW group. The median BAL eosinophil % was significantly increased in the patients with LOCW (1.55%, IQR: 0.33 to 3.92) compared to the children who never wheezed, NW (0.1, IQR: 0.0 to 0.3, p = 0.01). No differences were detected for other cell types. There were no significant differences in BAL cytokine concentrations between children with LOCW and NW children. Before late onset childhood wheezing developed, we found evidence of elevated eosinophils in the airways. These data suggest pre-existent airways inflammation in childhood asthma some years before clinical presentation.

Body mass index in young children and allergic disease: gender differences in a longitudinal study

The increase in allergic diseases has occurred in parallel with the obesity epidemic, suggesting a possible association. We investigated the relationship of body mass index (BMI) up to age 8 years with allergic disease within a birth cohort. Children were followed from birth and were reviewed at age 3, 5 and 8 years (n=731; male 406). Parents completed questionnaires; children were weighed, measured, skin prick tested and examined. Increasing BMI at 3, 5 and 8 years increased the risk of current wheezing at the corresponding age (odds ratio [95% confidence interval] per standardized deviation score: age 3, 1.26 [1.04-1.53], P=0.02; age 5, 1.33 [1.06-1.67], P=0.02; age 8, 1.27 [1.0-1.62], P=0.05). The effect of BMI on wheeze at age 8 years differed between boys and girls, with a significant positive association in girls, but not in boys (P=0.04 for interaction). The effect of BMI at earlier ages on current or subsequent wheezing did not differ significantly between genders. Increasing BMI significantly increased the risk of physician-diagnosed eczema at age 5 (1.23 [1.04-1.47], P=0.02) and 8 (1.23 [1.03-1.45], P=0.02), with a significant interaction between gender and BMI at age 5 (P=0.04). There was no association between BMI and sensitization. Being overweight at age 3 years was significantly associated with late-onset wheeze (3.83 [1.51-9.75], P=0.005), persistent wheeze (4.15 [2.07-8.32], P<0.001) and persistent eczema (1.79 [1.03-3.13], P=0.04) in both boys and girls. Being overweight is associated with an increased risk of allergic disease in childhood. However, the strength of the association varies with the gender, age and atopic phenotype.

Phenotypes of childhood asthma: are they real?

It has been suggested that there are several distinct phenotypes of childhood asthma or childhood wheezing. Here, we review the research relating to these phenotypes, with a focus on the methods used to define and validate them. Childhood wheezing disorders manifest themselves in a range of observable (phenotypic) features such as lung function, bronchial responsiveness, atopy and a highly variable time course (prognosis). The underlying causes are not sufficiently understood to define disease entities based on aetiology. Nevertheless, there is a need for a classification that would (i) facilitate research into aetiology and pathophysiology, (ii) allow targeted treatment and preventive measures and (iii) improve the prediction of long-term outcome. Classical attempts to define phenotypes have been one-dimensional, relying on few or single features such as triggers (exclusive viral wheeze vs. multiple trigger wheeze) or time course (early transient wheeze, persistent and late onset wheeze). These definitions are simple but essentially subjective. Recently, a multi-dimensional approach has been adopted. This approach is based on a wide range of features and relies on multivariate methods such as cluster or latent class analysis. Phenotypes identified in this manner are more complex but arguably more objective. Although phenotypes have an undisputed standing in current research on childhood asthma and wheezing, there is confusion about the meaning of the term 'phenotype' causing much circular debate. If phenotypes are meant to represent 'real' underlying disease entities rather than superficial features, there is a need for validation and harmonization of definitions. The multi-dimensional approach allows validation by replication across different populations and may contribute to a more reliable classification of childhood wheezing disorders and to improved precision of research relying on phenotype recognition, particularly in genetics. Ultimately, the underlying pathophysiology and aetiology will need to be understood to properly characterize the diseases causing recurrent wheeze in children.

Wheezing and Bronchial Hyper-responsiveness in Early Childhood as Predictors of Newly Diagnosed Asthma in Early Adulthood: A Longitudinal Birth-Cohort Study

Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Lancet. 2008;372(9643):1058–1064PURPOSE OF THE STUDY. To estimate the contributions of gender and early life factors to newly diagnosed and persistent asthma in young adults.STUDY POPULATION. The study evaluated 849 enrollees of the Tucson Children's Respiratory Study who had adult data at 22 years of age.METHODS. The cohort was derived from all healthy infants born in Tucson, Arizona, between 1980 and 1984. Shortly after birth, the parents completed a questionnaire on demographic data and were instructed to see a collaborating pediatrician at the first sign of lower respiratory illness. Physician-diagnosed asthma or wheezing was assessed at 2, 3, 6, 8, 11, and 16 years of age. At 6 years of age, allergy skin-prick tests were performed for all participants, and cold air bronchial challenge was performed for participants with a history of lower respiratory illness. At 22 years of age, an in-depth evaluation was performed with questionnaires on asthma symptoms, asthma medication use, and smoking history. Allergy skin-prick tests and spirometry were performed for participants still living in the Tucson area.RESULTS. Subjects with adult data at 22 years of age were more likely to have nonsmoking, nonminority parents with higher levels of education than were those without adult data. Of the 849 participants, 255 (30%) had asthma diagnosed at some time in their lives, 181 (22%) had active asthma, and 224 (26%) reported current smoking. Participants with inactive asthma had pre- and postbronchodilator spirometry results comparable to those of participants who never had asthma. Participants with newly diagnosed asthma had lower forced expiratory volume in 1 second/forced vital capacity ratios, which were not bronchodilator responsive. Factors associated with newly diagnosed asthma, chronic asthma, or shortness of breath with wheezing at 22 years of age included female gender, parental asthma, late-onset (>3 years of age) wheeze, persistent wheeze, Alternaria mold sensitivity at 6 years of age, cold air bronchial hyperresponsiveness, and reduced air flow rates at 6 years of age. Seventy percent of participants with current asthma and 63% with newly diagnosed asthma reported episodes of wheeze before 6 years of age. Male gender was a significant indicator of asthma remission by early adulthood. The combination of Alternaria sensitivity and cold air bronchial hyperresponsiveness at age 6 years and persistent wheeze at age 6 years were strong predictors of chronic asthma at age 22 years.CONCLUSIONS. Children with transient early wheezing were at much less risk for chronic asthma that persisted through childhood or reappeared more intensely in early adult life, compared with children with persistent or late-onset wheezing. Women were twice as likely to have new asthma diagnosed between 16 and 22 years of age.REVIEWER COMMENTS. This comprehensive study confirms previous longitudinal studies of the same age group. The lack of bronchodilator response of the forced expiratory volume in 1 second in newly diagnosed asthma is disconcerting but does not necessarily reflect permanent obstruction. Initial oral corticosteroid treatment has been shown to improve pulmonary function and to unmask bronchodilator responsiveness. Limitations of the study include the use of physician-diagnosed asthma in the absence of the demonstration of bronchodilator reversibility, a significant loss of participants over the course of time, with resulting skewed participant demographic characteristics, and selected assessment of responses to cold air. No risk factor alone identifies all of the possible forms of asthma.

Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study

Incidence of asthma increases during early adulthood. We aimed to estimate the contributions of sex and early life factors to asthma diagnosed in young adults. 1246 healthy newborn babies were enrolled in the Tucson Children's Respiratory Study. Parental characteristics, early-life wheezing phenotypes, airway function, and bronchial hyper-responsiveness to cold dry air and sensitisation to Alternaria alternata were determined before age 6 years. Physician-diagnosed asthma, both chronic and newly diagnosed, and airway function were recorded at age 22 years. Of 1246 babies enrolled, 849 had follow-up data at 22 years. Average incidence of asthma at age 16-22 years was 12.6 per thousand person-years. 49 (27%) of all 181 cases of active asthma at 22 years were newly diagnosed, of which 35 (71%) were women. Asthma remittance by 22 years was higher in men than in women (multinomial odds ratio [M-OR] 2.0, 95% CI 1.2-3.2, p=0.008). Age at diagnosis was linearly associated with the ratio of forced expiratory volume at 1 s to forced vital capacity at age 22 years. Factors independently associated with chronic asthma at 22 years included onset at 6 years (7.4, 3.9-14.0) and persistent wheezing (14.0, 6.8-28.0) in early life, sensitisation to A alternata (3.6, 2.1-6.4), low airway function at age 6 years (2.1, 1.1-3.9), and bronchial hyper-responsiveness at 6 years (4.5, 1.9-10.0). Bronchial hyper-responsiveness (6.9, 2.3-21.0), low airway function at 6 years (2.8, 1.1-6.9), and late-onset (4.6, 1.7-12.0) and persistent wheezing (4.0, 1.2-14.0) predicted newly diagnosed asthma at age 22 years. Asthma with onset in early adulthood has its origins in early childhood.