Early Life Wheeze Research Articles

Intra-breath changes in respiratory mechanics are sensitive to history of respiratory illness in preschool children: the SEPAGES cohort

BackgroundIntra-breath oscillometry has been proposed as a sensitive means of detecting airway obstruction in young children. We aimed to assess the impact of early life wheezing and lower respiratory tract illness on lung function, using both standard and intra-breath oscillometry in 3 year old children.MethodsHistory of doctor-diagnosed asthma, wheezing, bronchiolitis and bronchitis and hospitalisation for respiratory problems were assessed by questionnaires in 384 population-based children. Association of respiratory history with standard and intra-breath oscillometry parameters, including resistance at 7 Hz (R7), frequency-dependence of resistance (R7 − 19), reactance at 7 Hz (X7), area of the reactance curve (AX), end-inspiratory and end-expiratory R (ReI, ReE) and X (XeI, XeE), and volume-dependence of resistance (ΔR = ReE-ReI) was estimated by linear regression adjusted on confounders.ResultsAmong the 320 children who accepted the oscillometry test, 281 (88%) performed 3 technically acceptable and reproducible standard oscillometry measurements and 251 children also performed one intra-breath oscillometry measurement. Asthma was associated with higher ReI, ReE, ΔR and R7 and wheezing was associated with higher ΔR. Bronchiolitis was associated with higher R7 and AX and lower XeI and bronchitis with higher ReI. No statistically significant association was observed for hospitalisation.ConclusionsOur findings confirm the good success rate of oscillometry in 3-year-old children and indicate an association between a history of early-life wheezing and lower respiratory tract illness and lower lung function as assessed by both standard and intra-breath oscillometry. Our study supports the relevance of using intra-breath oscillometry parameters as sensitive outcome measures in preschool children in epidemiological cohorts.

Early Life Wheezing and Childhood Cognition in the Environmental Influences on Child Health Outcomes (ECHO) Program

Early Life Wheezing and Childhood Cognition in the Environmental Influences on Child Health Outcomes (ECHO) Program

Association of Wheezing Requiring Hospitalization Before 2 Years of Age With Autoimmune Diseases During Childhood: A 15-Year Follow-up Study From Birth.

Wheezing in early life is most frequently caused by viral lower respiratory tract illnesses, constituting a significant disease burden in children. This study aimed to investigate the association of wheezing in early life with autoimmune diseases throughout childhood. A population-matched retrospective cohort study was conducted in Korea between 2002 and 2017. The cohort comprised 34,959 children admitted with viral wheezing before 2 years of age and an equal number of the matched unexposed children born in 2002 and 2003. Exposed infants were defined as those hospitalized for bronchiolitis or bronchial asthma before the age of 2. Unexposed controls were matched by sex and birth year at a 1:1 ratio, using incidence density sampling. A Cox proportional hazard model controlled for multiple risk factors was employed. The median age at hospitalization for wheeze was 9 months (interquartile range, 5-15 months), and 63% of the exposed infants were male. Over the mean 15-year follow-up period, the incidence rate of autoimmune diseases was 74.0 and 62.2 per 10,000 person-years in the exposed and matched unexposed cohorts, respectively. The adjusted hazard ratio for any autoimmune disease in the exposed cohort was 1.15 (95% confidence interval, 1.09-1.23) in comparison with the unexposed cohort. The exposed cohort revealed an augmented risk for specific autoimmune diseases, including juvenile idiopathic arthritis, Kawasaki disease, Henoch-Schönlein purpura, psoriasis, idiopathic thrombocytopenic purpura, and immunoglobulin A nephropathy. Risks were heightened for children with multiple wheezing episodes or a persistent wheezing episode after the age of 2 years. This research identifies associations between early-life wheeze and the development of autoimmune diseases in childhood. Understanding these relationships can aid in recognizing the underlying pathophysiology of early-life wheeze and childhood autoimmune diseases, contributing to management strategies for these conditions.

Association of Early Childhood Wheeze and Asthma Diagnosis Documentation by Race, Ethnicity, and Language in Children.

To determine whether electronic health record (EHR) documentation of certain early childhood risk factors for asthma, such as wheeze differ by race, ethnicity, and language group, and whether these children have different subsequent asthma prevalences. We used EHR data from the Accelerating Data Value Across a National Community Health Center (ADVANCE) Clinical Research Network from children receiving care in US community health centers (n = 71,259 children) across 21 states to examine the presence of ICD-coded documentation of early childhood wheeze and its association with subsequent asthma diagnosis documentation in the EHR by race/ethnicity/language. ICD-coded wheeze was present in 2 to 3% of each race/ethnicity/language group. Among the total sample, 18.5% had asthma diagnosed after age 4. The adjusted prevalence of subsequent asthma diagnosis was greater in children with wheeze than those without. Odds of asthma diagnosis did not differ among children in all race/ethnicity/language groups with early childhood wheeze. Non-Latino Black children without wheeze had higher odds of asthma (OR = 1.19, 95% CI = 1.08-1.32) compared with non-Latino White children without wheeze. In US community health centers which serve medically underserved populations, EHR documentation of early childhood wheeze was uncommon and did not differ significantly among race/ethnicity/language groups. Differences in asthma diagnosis in Latinos may not stem from differences in early-life wheeze documentation. However, our findings suggest that there may be opportunities for improvement in early asthma symptom recognition for non-Latino Black children, especially in those without early childhood wheeze.

Clinical features and later prognosis of replicable early-life wheeze clusters from two birth cohorts 12 years apart.

Clustering techniques can define the heterogeneity of asthma and wheezing. Defining early-life wheezing clusters and associated asthma risk could potentially inform patient management strategies. Clustering models that yield replicable cluster groups will have greater validity and clinical utility. This study sought to identify early-life wheezing clusters that are translatable into clinical practice and assess their stability over time in two whole-population birth cohorts established a decade apart from the same geographical location. Nonparametric K-means cluster analysis was performed separately on two birth cohorts from the Isle of Wight, UK; the Isle of Wight Birth Cohort (IOWBC) and Food Allergy and Intolerance Research Cohort (FAIR), using clinically defining variables in wheezing subjects in the first 3-4 years. Associations of resulting clusters with potential early-life risk factors and 10-year asthma outcomes were further assessed. Five clusters were identified in both cohorts: (1) infantile-onset-transient-non-atopic-wheeze, (2) infantile-onset-persistent-non-atopic-wheeze, (3) infantile-onset-atopic-wheeze, (4) early-childhood-onset-non-atopic-wheeze, and (5) early-childhood-onset-atopic-wheeze. Two atopic wheezing clusters (3 and 5) were associated with greatest early-life wheeze frequency, highest wheeze persistence, and asthma prevalence at 10 years. Cluster 1 was commonest but had lowest early-life wheeze frequency and asthma prevalence at 10 years. Cluster 2, characterized by limited atopy but recurrent infantile respiratory infections and ongoing early-life wheezing, had high 10-year asthma prevalence only in IOWBC. Early-life wheeze comprises several disease clusters (two more severe and three mild-moderate) with differing relationships to later childhood asthma, which can be replicated over time supporting their potential validity and clinical utility.

Early-Life Weight Status and Risk of Childhood Asthma or Recurrent Wheeze in Preterm and Term Offspring.

Excessive weight is associated with the development of childhood asthma. However, trends among preterm and term offspring may differ. To assess whether the association of longitudinal weight for age (WFA) and odds of asthma/recurrent wheeze in early life differs between children born preterm and those born at term. This study used prospectively collected data from the Vitamin D Antenatal Asthma Reduction Trial. Children (n= 804) were followed-up and anthropometric measurements, including WFA, were taken at birth and annually until the age of 6 years. The primary outcome was asthma/recurrent wheeze by age 3 and 6 years. Among the offspring, 71 (8.8%) were premature. In all the children, the odds of asthma/recurrent wheeze increased by 15% (adjusted odds ratio [aOR], 1.15; 95% CI, 1.10-1.20; P < .001) by age 3 years and 9% (aOR, 1.09; 95% CI, 1.07-1.11; P < .001) by age 6 years for each unit increase in WFA z score. Odds were different between term and preterm offspring (Pinteraction < .001). In term offspring, the odds of having asthma/recurrent wheeze by age 3 and 6 years increased by 22% and 15%, respectively (aOR, 1.22, 95% CI, 1.16-1.27, P < .001, and aOR, 1.15, 95% CI, 1.11-1.18, P < .001). In preterm offspring, by age 3 years, odds of asthma/recurrent wheeze decreased by 10% for each unit increase in WFA z score (aOR, 0.90; 95% CI, 0.81-0.99; P= .030) and decreased by 27% by age 6 years (aOR, .73; 95% CI, 0.61-0.86; P < .001). During early life, increasing standardized WFA is associated with higher odds of asthma/recurrent wheeze in term children. In contrast, in preterm children, a higher standardized WFA during catch-up growth may decrease the odds of asthma/recurrent wheeze associated with prematurity.

Whispers of change in preschool asthma phenotypes: Findings in the French ELFE cohort

RationaleEarly life asthma phenotyping remains an unmet need in pediatric asthma. In France, severe pediatric asthma phenotyping has been done extensively; however, phenotypes in the general population remain underexplored. Based on the course and severity of respiratory/allergic symptoms, we aimed to identify and characterize early life wheeze profiles and asthma phenotypes in the general population. MethodsELFE is a general population based birth cohort; which recruited 18,329 newborns in 2011, from 320 maternity units nationwide. Data was collected using parental responses to modified versions of ISAAC questionnaire on eczema, rhinitis, food allergy, cough, wheezing, dyspnoea and sleep disturbance due to wheezing at 3 time points: post-natal (2 months), infancy (age 1) and pre-school (age 5). We built a supervised trajectory for wheeze profiles and an unsupervised approach was used for asthma phenotypes. Chi squared (χ2) test or fisher's exact test was used as appropriate (p < 0.05). ResultsWheeze profiles and asthma phenotypes were ascertained at age 5. Supervised wheeze trajectory of 9161 children resulted in 4 wheeze profiles: Persistent (0.8%), Transient (12.1%), Incident wheezers at age 5 (13.3%) and Non wheezers (73.9%). While 9517 children in unsupervised clusters displayed 4 distinct asthma phenotypes: Mildly symptomatic (70%), Post-natal bronchiolitis with persistent rhinitis (10.2%), Severe early asthma (16.9%) and Early persistent atopy with late onset severe wheeze (2.9%). ConclusionWe successfully determined early life wheeze profiles and asthma phenotypes in the general population of France.

Asthma in pregnancy - Management, maternal co-morbidities, and long-term health.

Asthma is the most prevalent chronic disease in pregnancy, and as symptoms can change with pregnancy, and exacerbations of asthma are common, regular review of asthma symptoms, the provision of self-management education, and appropriate medication use are the hallmarks of management. Co-morbidities are also prevalent among pregnant women with asthma, with obesity, gestational diabetes, hypertension, rhinitis, depression, and anxiety, more common among women with asthma than women without asthma. Less is known about reflux, obstructive sleep apnoea and vocal cord dysfunction, along with nutritional deficiencies to iron and vitamin D. Maternal asthma impacts the offspring's long-term health, particularly in increasing the risk of early life wheeze and asthma in childhood. While breastfeeding may modify the risk of infant wheeze, less is known about the mechanisms involved. More research is needed to further understand the relationship between asthma in pregnancy and the risk of poor neurodevelopmental outcomes, such as autism.

Farm exposure and rates of early life respiratory illness and wheeze

Early childhood exposure to animal farming environments has been associated with decreased incidence of allergy and asthma. We hypothesize that children raised in Wisconsin farm environments will have a lower incidence of viral wheeze in the first two years of life.

Interrupting the Conversation: Implications for Crosstalk Between Viral and Bacterial Infections in the Asthmatic Airway.

Asthma is a heterogeneous, chronic respiratory disease affecting 300 million people and is thought to be driven by different inflammatory endotypes influenced by a myriad of genetic and environmental factors. The complexity of asthma has rendered it challenging to develop preventative and disease modifying therapies and it remains an unmet clinical need. Whilst many factors have been implicated in asthma pathogenesis and exacerbations, evidence indicates a prominent role for respiratory viruses. However, advances in culture-independent detection methods and extensive microbial profiling of the lung, have also demonstrated a role for respiratory bacteria in asthma. In particular, airway colonization by the Proteobacteria species Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) is associated with increased risk of developing recurrent wheeze and asthma in early life, poor clinical outcomes in established adult asthma and the development of more severe inflammatory phenotypes. Furthermore, emerging evidence indicates that bacterial-viral interactions may influence exacerbation risk and disease severity, highlighting the need to consider the impact chronic airway colonization by respiratory bacteria has on influencing host responses to viral infection. In this review, we first outline the currently understood role of viral and bacterial infections in precipitating asthma exacerbations and discuss the underappreciated potential impact of bacteria-virus crosstalk in modulating host responses. We discuss the mechanisms by which early life infection may predispose to asthma development. Finally, we consider how infection and persistent airway colonization may drive different asthma phenotypes, with a view to identifying pathophysiological mechanisms that may prove tractable to new treatment modalities.

Early Life Wheeze and Risk Factors for Asthma-A Revisit at Age 7 in the GEWAC-Cohort.

One third of all toddlers are in need of medical care because of acute wheeze and many of these children have persistent asthma at school age. Our aims were to assess risk factors for and the prevalence of asthma at age 7 in a cohort of children suffering from an acute wheezing episode as toddlers. A total of 113 children, included during an acute wheezing episode (cases), and 54 healthy controls were followed prospectively from early pre-school age to 7 years. The protocol included questionnaires, ACT, FeNO, nasopharyngeal virus samples, blood sampling for cell count, vitamin D levels, and IgE to food and airborne allergens. The prevalence of asthma at age 7 was 70.8% among cases and 1.9% among controls (p < 0.001). Acute wheeze caused by rhinovirus (RV) infection at inclusion was more common among cases with asthma at age 7 compared to cases without asthma (p = 0.011) and this association remained significant following adjustment for infection with other viruses (OR 3.8, 95% CI 1.4–10.5). Cases with asthma at age 7 had been admitted to hospital more often (p = 0.024) and spent more days admitted (p = 0.01) during the year following inclusion compared to cases without asthma. RV infection stands out as the main associated factor for wheeze evolving to persistent asthma. Cases who developed asthma also had an increased need of hospital time and care for wheeze during the year after inclusion.

Unconjugated bilirubin is associated with protection from early-life wheeze and childhood asthma

Wheeze and allergic sensitization are the strongest early-life predictors of childhood asthma development; the molecular origins of these early-life phenotypes are poorly understood. We sought to identify metabolites associated with early-life wheeze, allergic sensitization, and childhood asthma. We conducted a nested case-control study using Environmental influences on Child Health Outcomes Program cohorts for discovery and independent replication. Wheeze and allergic sensitization were defined by number of wheeze episodes and positive specific IgE at age 1 year, respectively. Asthma was defined as physician diagnosis of asthma at age 5 or 6 years. We used untargeted metabolomics, controlling for observed and latent confounding factors, to assess associations between the plasma metabolome and early-life wheeze, allergy, and childhood asthma. Eighteen plasma metabolites were associated with first-year wheeze in the discovery cohort (n= 338). Z,Z unconjugated bilirubin (UCB) and its related metabolites exhibited a dose-response relationship with wheeze frequency; UCB levels were 13% (β= 0.87; 95% CI, 0.74-1.02) and 22% (β= 0.78; 95% CI, 0.68-0.91) lower in children with 1 to 3 and 4+ wheeze episodes compared with those who never wheezed, respectively. UCB levels were also associated with childhood asthma (β= 0.82; 95% CI, 0.68-0.98). Similar trends were observed in 2 independent cohorts. UCB was significantly negatively correlated with eicosanoid- and oxidative stress-related metabolites. There were no significant associations between metabolites and allergic sensitization. We identified a novel inverse, dose-dependent association between UCB and recurrent wheeze and childhood asthma. Inflammatory lipid mediators and oxidative stress byproducts inversely correlated with UCB, suggesting that UCB modulates pathways critical to the development of early-life recurrent wheeze and childhood asthma.

Cadherin-related family member 3 gene impacts childhood asthma in Chinese children.

A missense variant (rs6967330) of the gene encoding cadherin-related family member 3 (CDHR3) was associated with recurrent severe exacerbations in pre-schoolers. However, there were limited data on its relationship with pre-school lung function and school-age asthma. This study replicated the association between polymorphic markers at the region of CDHR3 around rs6967330 and wheezing phenotypes in two independent cohorts of Chinese children. Ten tagging SNPs located 10kb around rs6967330 were selected by HaploView 5.0 based on 1000 Genomes database for Southern Han Chinese. Their associations with wheezing and lung function were examined in 1341 Chinese pre-school children, while those for asthma phenotypes were examined in an independent group of 2079 school-age children. Genotypic and haplotypic associations were analyzed by multivariate regression, and generalized multifactor dimensionality reduction was used to examine epistatic interactions for wheezing traits. The mean (SD) age of pre-school cohort was 4.7 (1.0) years. Rs6967330 was associated with current wheeze (odds ratio [OR] 1.63, 95% confidence interval [CI] 1.09-2.43) and its severity (OR 1.64, 95% CI 1.10-2.44) among pre-school children. This SNP was also associated with school-age asthma (OR 1.32, 95% CI 1.04-1.69). The minor allele of rs408223 was associated with lower FEV0.5 (β=-2.411, P=.004) and FEV0.5 /FVC (β=-1.292, P=.015). Lower spirometric indices were also associated with minor allele of rs140154310. GAC haplotype from rs4730125, rs6967330, and rs408223 was associated with pre-school current wheeze and school-age asthma. Epistatic interaction was found between unrelated CDHR3 SNPs for FEV0.5 among pre-schoolers. CDHR3 is a candidate gene for early-life wheezing, school-age asthma, and lung function in Chinese children.

Association Between Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection in Early Life and Recurrent Wheeze and Asthma in Later Childhood.

Recurrent wheeze and asthma in childhood are commons causes of chronic respiratory morbidity globally. We aimed to explore the association between respiratory syncytial virus (RSV) infection in early life and subsequent respiratory sequelae up to age 12 years. We estimated the strength of association by 3 control groups and 3 follow-up age groups, with data from studies published between January 1995 and May 2018. We also estimated associations by diagnostic criteria, age at infection, and high-risk population. Overall, we included 41 studies. A statistically significant association was observed between early life RSV infection and subsequent childhood recurrent wheeze, in comparison to those who were healthy or those without respiratory symptoms: OR 3.05 (95% confidence interval [CI], 2.50-3.71) for 0 to <36 months follow-up age; OR 2.60 (95% CI, 1.67-4.04) for 36-72 months; and OR 2.14 (95% CI, 1.33-3.45) for 73-144 months. For the subsequent development of asthma, a statistically significant association was observed only in relation to those aged 73-144 months at follow-up: OR 2.95 (95% CI, 1.96-4.46). Further studies using standardized definitions and from diverse settings are needed to elucidate the role of confounders and provide more robust estimates.

Temporal association of the development of oropharyngeal microbiota with early life wheeze in a population-based birth cohort

BackgroundA critical window in infancy has been proposed, during which the microbiota may affect subsequent health. The longitudinal development of the oropharyngeal microbiota is under-studied and may be associated with early-life wheeze. We aimed to investigate the temporal association of the development of the oropharyngeal microbiota with early-life wheeze. MethodsA population-based birth cohort based in London, UK was followed for 24 months. We collected oropharyngeal swabs at six time-points. Microbiota was determined using sequencing of the V3-V5 region of the 16S rRNA-encoding gene. Medical records were reviewed for the outcome of doctor diagnosed wheeze. We used a time-varying model to investigate the temporal association between the development of microbiota and doctor-diagnosed wheeze. Findings159 participants completed the study to 24 months and for 98 there was complete sequencing data at all timepoints and outcome data. Of these, 26 had doctor-diagnosed wheeze. We observed significant increase in the abundance of Neisseria between 9 and 24 months in children who developed wheeze (p = 0∙003), while in those without wheezing there was a significant increment in the abundance of Granulicatella (p = 0∙012) between 9 and 12 months, and of Prevotella (p = 0∙018) after 18 months. InterpretationA temporal association between the respiratory commensal Granulicatella and also Prevotella with wheeze (negative), and between Neisseria and wheeze (positive) was identified in infants prior to one year of age. This adds to evidence for the proposed role of the microbiota in the development of wheeze. FundResearch funding from the Winnicott Foundation, Meningitis Now and Micropathology Ltd.

Epigenome-wide association study of asthma and wheeze characterizes loci within HK1

BackgroundTo identify novel epigenetic markers of adolescent asthma and replicate findings in an independent cohort, then explore whether such markers are detectable at birth, predictive of early-life wheeze, and associated with gene expression in cord blood.MethodsWe performed epigenome-wide screening with recursive random forest feature selection and internal validation in the IOW birth cohort. We then tested whether we could replicate these findings in the independent cohort ALSPAC and followed-up our top finding with children of the IOW cohort.ResultsWe identified 10 CpG sites associated with adolescent asthma at a 5% false discovery rate (IOW, n = 370), five of which exhibited evidence of associations in the replication study (ALSPAC, n = 720). One site, cg16658191, within HK1 displayed particularly strong associations after cellular heterogeneity adjustments in both cohorts (ORIOW = 0.17, 95% CI 0.04–0.57) (ORALSPAC = 0.57, 95% CI 0.38–0.87). Additionally, higher expression of HK1 (OR = 3.81, 95% CI 1.41–11.77) in cord blood was predictive of wheezing in infancy (n = 82).ConclusionWe identified novel associations between asthma and wheeze with methylation at cg16658191 and the expression of HK1, which may serve as markers of, predictors of, and potentially etiologic factors involved in asthma and early life wheeze.

Vitamin D and childhood asthma: causation and contribution to disease activity

To review the literature of the past 18 months (April 2017 through September, 2018) relating to vitamin D and childhood asthma. A combined analysis of two clinical trials of maternal vitamin D supplementation trials showed a significant protective effect of vitamin D supplementation trials in the primary prevention of asthma and recurrent wheeze up to age 3 years. Secondary analyses from these trials have also suggested that initial maternal vitamin D status could affect the response to supplementation during pregnancy, with the biggest protective effect in children born to mothers with initial 25hydroxyvitamin D (25OHD) levels of at least 30 ng/ml. A postnatal, 6-month vitamin D supplementation trial in black, premature babies showed a 34% decreased risk of recurrent wheezing at 1 year among the infants who received supplementation. An individual patient data meta-analysis of published clinical trials concluded that vitamin D supplementation decreased the risk of asthma exacerbations in those with 25OHD levels less than 10 ng/ml. Results of observational analyses on primary prevention of asthma and in prevention of exacerbations remain mixed, with the bulk of the evidence suggesting that there is a protective effect of higher vitamin D levels. Evidence continues to accumulate that vitamin D supplementation helps to prevent the development of asthma and recurrent wheeze in early life, and may also help in the management of asthma. The level(s) of circulating vitamin D that maximizes these effects remains to be identified.

Is there a role for inhaled corticosteroids in early life wheeze?

Is there a role for inhaled corticosteroids in early life wheeze?

The effect of montelukast on early-life wheezing: A randomized, double-blinded placebo-controlled study.

Cysteinyl-leukotrienes are increased in the airways of infants with virus-associated wheezing. We aimed to determine the effects of a cysteinyl-leukotriene-1 receptor antagonist on symptoms during an early-life wheezing illness and to investigate the factors that affect the response to this drug. This placebo-controlled double-blinded randomized controlled trial recruited children aged 3-36months with wheezing illness and randomized to active drug or placebo for 56days. A symptom score diary (SSD) was kept by the children's caregivers. One-hundred patients completed the study, and 62 (30 montelukast and 32 placebo) were analyzed. There were no significant differences in the percent of symptom-free days, symptom scores, and the need for rescue salbutamol between the two groups. However, the percent of symptom-free days within the first week was significantly higher for the montelukast than for the placebo group (13.8±4.1% vs. 5.4±3.4%; P=0.028); wheezing score at 7th day was significantly lower for the montelukast than for the placebo group (0.5±0.1 vs. 1.4±0.2; P=0.002). In addition, the number of inhaled ß2 -agonist rescue episodes per day during the first week was significantly lower for the montelukast compared with the placebo group (12.7±1.8 vs. 19.2±1.6; P=0.013). Conclusions Our results indicate that montelukast may be effective for reducing caregiver-observed wheezing and the need for salbutamol during the first week of treatment for early-life wheezing. The impact for caregivers and the optimal duration of treatment will need to be explored in studies of larger size.

Defining 'healthy' in preschool-aged children for forced oscillation technique reference equations.

Selecting 'healthy' preschool-aged children for reference ranges may not be straightforward. Relaxing inclusion criteria for normative data does not affect spirometry z-scores. We therefore investigated the effect of similarly relaxing inclusion criteria in preschoolers on reference ranges for respiratory impedance (Zrs) using a modified forced oscillation technique (FOT). The International Study of Asthma and Allergies in Childhood questionnaire classified 585 children into a healthy and five mutually exclusive groups. Zrs was measured between 4 and 26 Hz and resistance (R) and compliance (C) obtained by model fitting. Prediction models were determined using mixed effect models and z-scores compared between healthy children and the five groups. Zrs data were obtained for 494 participants (4.30 ± 0.7 years) on 587 occasions. Comparison of the Zrs z-scores between the healthy children and the health groups found significant differences in children with asthma, current wheeze and respiratory symptoms, but not in children born preterm or with early-life wheeze. Adding these two groups to the healthy dataset had no significant effect on the distribution of z-scores and increased the size of the dataset by 22.3%. Our data suggest that preschool-aged children born preterm or with early-life wheeze can be included in FOT reference equations, while those with asthma, current wheeze and respiratory symptoms within 4 weeks of testing should be excluded. This more inclusive approach results in more robust FOT reference ranges.