Lung-function trajectories: relevance and implementation in clinical practice.

Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.

Clinical implications of airway obstruction with normal or low FEV1 in childhood and adolescence.

BACKGROUND: Airway obstruction is defined by spirometry as a low forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio. This impaired ratio may originate from a low FEV1 (classic) or a normal FEV1 in combination with a large FVC (dysanaptic). The clinical implications of dysanaptic obstruction during childhood and adolescence in the general population remain unclear. AIMS: To investigate the association between airway obstruction with a low or normal FEV1 in childhood and adolescence, and asthma, wheezing and bronchial hyperresponsiveness (BHR). METHODS: In the BAMSE (Barn/Child, Allergy, Milieu, Stockholm, Epidemiology; Sweden) and PIAMA (Prevention and Incidence of Asthma and Mite Allergy; the Netherlands) birth cohorts, obstruction (FEV1:FVC ratio less than the lower limit of normal, LLN) at ages 8, 12 (PIAMA only) or 16 years was classified as classic (FEV1

Circulating CC16 and Asthma: A Population-based, Multicohort Study from Early Childhood through Adult Life.

Rationale: Club cell secretory protein (CC16) is an antiinflammatory protein highly expressed in the airways. CC16 deficiency has been associated with lung function deficits, but its role in asthma has not been established conclusively. Objectives: To determine 1) the longitudinal association of circulating CC16 with the presence of active asthma from early childhood through adult life and 2) whether CC16 in early childhood predicts the clinical course of childhood asthma into adult life. Methods: We assessed the association of circulating CC16 and asthma in three population-based birth cohorts: the Tucson Children's Respiratory Study (years 6-36; total participants, 814; total observations, 3,042), the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey (years 8-24; total participants, 2,547; total observations, 3,438), and the UK Manchester Asthma and Allergy Study (years 5-18; total participants, 745; total observations, 1,626). Among 233 children who had asthma at the first survey in any of the cohorts, baseline CC16 was also tested for association with persistence of symptoms. Measurements and Main Results: After adjusting for covariates, CC16 deficits were associated with increased risk for the presence of asthma in all cohorts (meta-analyzed adjusted odds ratio per 1-SD CC16 decrease, 1.20; 95% confidence interval [CI], 1.12-1.28; P < 0.0001). The association was particularly strong for asthma with frequent symptoms (meta-analyzed adjusted relative risk ratio, 1.40; 95% CI, 1.24-1.57; P < 0.0001), was confirmed for both atopic and nonatopic asthma, and was independent of lung function impairment. After adjustment for known predictors of persistent asthma, children with asthma in the lowest CC16 tertile had a nearly fourfold increased risk for having frequent symptoms persisting into adult life compared with children with asthma in the other two CC16 tertiles (meta-analyzed adjusted odds ratio, 3.72; 95% CI, 1.78-7.76; P < 0.0001). Conclusions: Circulating CC16 deficits are associated with the presence of asthma with frequent symptoms from childhood through midadult life and predict the persistence of asthma symptoms into adulthood. These findings support a possible protective role of CC16 in asthma and its potential use for risk stratification.

Plasticity of Individual Lung Function States from Childhood to Adulthood.

Rationale: Recent evidence highlights the importance of optimal lung development during childhood for health throughout life. Objectives: To explore the plasticity of individual lung function states during childhood. Methods: Prebronchodilator FEV1 z-scores determined at age 8, 16, and 24 years in the Swedish population-based birth cohort BAMSE (Swedish abbreviation for Child [Barn], Allergy, Milieu, Stockholm, Epidemiological study) (N = 3,069) were used. An unbiased, data-driven dependent mixture model was applied to explore lung function states and individual state chains. Lung function catch-up was defined as participants moving from low or very low states to normal or high or very high states, and growth failure as moving from normal or high or very high states to low or very low states. At 24 years, we compared respiratory symptoms, small airway function (multiple-breath washout), and circulating inflammatory protein levels, by using proteomics, across states. Models were replicated in the independent Dutch population-based PIAMA (Prevention and Incidence of Asthma and Mite Allergy) cohort. Measurements and Main Results: Five lung function states were identified in BAMSE. Lung function catch-up and growth failure were observed in 74 (14.5%) BAMSE participants with low or very low states and 36 (2.4%) participants with normal or high or very high states, respectively. The occurrence of catch-up and growth failure was replicated in PIAMA. Early-life risk factors were cumulatively associated with the very low state, as well as with catch-up (inverse association) and growth failure. The very low state as well as growth failure were associated with respiratory symptoms, airflow limitation, and small airway dysfunction at adulthood. Proteomics identified IL-6 and CXCL10 (C-X-C motif chemokine 10) as potential biomarkers of impaired lung function development. Conclusions: Individual lung function states during childhood are plastic, including catch-up and growth failure.

Associations of improved air quality with lung function growth from childhood to adulthood: the BAMSE study.

BACKGROUND: The beneficial effect of improving air quality on lung function development remains understudied. We assessed associations of changes in ambient air pollution levels with lung function growth from childhood until young adulthood in a Swedish cohort study. METHODS: In the prospective birth cohort BAMSE (Children, Allergy, Environment, Stockholm, Epidemiology (in Swedish)), spirometry was conducted at the 8-year (2002-2004), 16-year (2011-2013) and 24-year (2016-2019) follow-ups. Participants with spirometry data at 8 years and at least one other measurement in subsequent follow-ups were included (1509 participants with 3837 spirometry measurements). Ambient air pollution levels (particulate matter with diameter ≤2.5 µm (PM2.5), particulate matter with diameter ≤10 µm (PM10), black carbon (BC) and nitrogen oxides (NO x )) at residential addresses were estimated using dispersion modelling. Linear mixed effect models were used to estimate associations between air pollution exposure change and lung function development. RESULTS: Overall, air pollution levels decreased progressively during the study period. For example, the median (interquartile range (IQR)) level of PM2.5 decreased from 8.24 (0.92) µg·m-3 during 2002-2004 to 5.21 (0.67) µg·m-3 during 2016-2019. At the individual level, for each IQR reduction of PM2.5 the lung function growth rate increased by 4.63 (95% CI 1.64-7.61) mL per year (p<0.001) for forced expiratory volume in 1 s and 9.38 (95% CI 4.76-14.00) mL per year (p<0.001) for forced vital capacity. Similar associations were also observed for reductions of BC and NO x . Associations persisted after adjustment for potential confounders and were not modified by asthma, allergic sensitisation, overweight, early-life air pollution exposure or dietary antioxidant intake. CONCLUSIONS: Long-term reduction of air pollution is associated with positive lung function development from childhood to young adulthood.

Fruit, vegetable and dietary antioxidant intake in school age, respiratory health up to young adulthood.

BACKGROUND: Dietary antioxidants may protect the lung against oxidative damage and prevent chronic respiratory disease. We aimed to investigate fruit, vegetable and antioxidant intake (measured as total antioxidant capacity, TAC) at age 8 years in relation to asthma and lung function up to 24 years. METHODS: In this study of 2506 participants from a Swedish birth cohort, diet was assessed using food frequency questionnaires. Information on asthma was collected by questionnaires, and lung function was measured by spirometry at ages 8, 16 and 24 years. Generalized estimating equations and mixed effect models were used to assess overall, age- and sex-specific associations. RESULTS: After adjustment for confounders, a higher fruit intake at age 8 years was associated with a tendency to reduced odds of prevalent asthma (T3 vs. T1, OR 0.78; 95% CI 0.60-1.01, p-trend .083), with reduced odds of incident asthma and increased odds of remittent asthma (≥median, OR 0.76; 95% CI 0.58-0.99 and OR 1.60; 95% CI 1.05-2.42, respectively) up to 24 years. Comparable, but non-significant, odds ratios were observed in analyses of long-term fruit intake (mean intake at ages 8 and 16 years). In contrast, no association was observed with vegetable intake. A higher dietary TAC (T3 vs. T1) at 8 years was associated with reduced odds of prevalent asthma (OR 0.73; 95% CI 0.58-0.93, p-trend .010) and improved lung function development (FEV1 -z +0.11; 95% CI 0.01-0.21, p-trend .036 and FVC-z +0.09; 95% CI -0.01-0.20, p-trend .072) up to 24 years. Associations were more pronounced among males, and regarding asthma, participants sensitized to aeroallergens. CONCLUSIONS: Antioxidant intake in school age may improve asthma and lung function up to young adulthood. Although our results should be interpreted with caution, they emphasize the importance of following current dietary guidelines regarding consumption of antioxidant-rich foods as part of a balanced diet.

Air pollution exposure impairs lung function in infants.

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

Early-life risk factors for reversible and irreversible airflow limitation in young adults: findings from the BAMSE birth cohort.

We aimed to determine prevalence and early-life risk factors for reversible and irreversible airflow limitation in young adults from the general population. Among young adults in their 20s, the prevalence was 5.3% for reversible airflow limitation and 2.0% for irreversible airflow limitation. While parental asthma was the only risk factor for development of reversible airflow limitation, the risk factors for development of irreversible airflow limitation were current asthma, childhood respiratory tract infections and asthma, and exposure to air pollution.

Assessment of chronic bronchitis and risk factors in young adults: results from BAMSE.

BACKGROUND: Chronic bronchitis is associated with substantial morbidity among elderly adults, but little is known about its prevalence and risk factors in young adults. Our aim was to assess the prevalence and early-life risk factors for chronic bronchitis in young adults. METHODS: Questionnaire data and clinical measures from the 24-year follow-up of the Swedish BAMSE (Child (Barn), Allergy, Milieu, Stockholm, Epidemiological) cohort were used. We assessed chronic bronchitis (CB) as the combination of cough and mucus production in the morning during winter. Environmental and clinical data from birth and onwards were used for analyses of risk factors. RESULTS: At the 24-year follow-up, 75% (n=3064) participants completed the questionnaire and 2030 performed spirometry. The overall prevalence of CB was 5.5% (n=158) with similar estimates in males and females. 49% of CB cases experienced more than three self-reported respiratory infections in the past year compared to 18% in non-CB subjects (p<0.001), and 37% of cases were current smokers (versus 19% of non-CB cases). Statistically significant lower post-bronchodilator forced expiratory volume in 1 s/forced vital capacity were observed in CB compared to non-CB subjects (mean z-score -0.06 versus 0.13, p=0.027). Daily smoking (adjusted (a)OR 3.85, p<0.001), air pollution exposure (black carbon at ages 1-4 years aOR 1.71 per 1 µg·m-3 increase, p=0.009) and exclusive breastfeeding for ≤4 months (aOR 0.66, p=0.044) were associated with CB. CONCLUSION: Chronic bronchitis in young adults is associated with recurrent respiratory infections. Besides smoking, our results support the role of early-life exposures, such as air pollution and exclusive breastfeeding, for respiratory health later in life.

Low-level exposure to polycyclic aromatic hydrocarbons is associated with reduced lung function among Swedish young adults.

BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAHs) has been linked to adverse pulmonary effects. However, the impact of low-level environmental PAH exposure on lung function in early adulthood remains uncertain. OBJECTIVES: To evaluate the associations between urinary PAH metabolites and lung function parameters in young adults. METHODS: Urinary metabolites of pyrene, phenanthrene, and fluorene were analysed in 1000 young adults from Sweden (age 22-25 years) using LC-MS/MS. Lung function and eosinophilic airway inflammation were measured by spirometry and exhaled nitric oxide fraction (FeNO), respectively. Linear regression analysis was used to evaluate associations between PAH metabolites and the outcomes. RESULTS: Median urinary concentrations of 1-OH-pyrene, ∑OH-phenanthrene, and ∑OH-fluorene were 0.066, 0.36, 0.22 µg/L, respectively. We found inverse associations of ∑OH-phenanthrene and ∑OH-fluorene with FEV1 and FVC, as well as between 1-OH-pyrene and FEV1/FVC ratio (adjusted P < 0.05; all participants). An increase of 1% in ∑OH-fluorene was associated with a decrease of 73 mL in FEV1 and 59 mL in FVC. In addition, ∑OH-phenanthrene concentrations were, in a dose-response manner, inversely associated with FEV1 (B from -109 to -48 compared with the lowest quartile of ∑OH-phenanthrene; p trend 0.004) and FVC (B from -159 to -102 compared with lowest quartile; p-trend <0.001). Similar dose-response associations were also observed between ∑OH-fluorene and FEV1 and FVC, as well as between 1-OH-pyrene and FEV1/FVC (p-trend <0.05). There was no association between PAH exposure and FeNO, nor was there an interaction with smoking, sex, or asthma. CONCLUSION: Low-level PAH exposure was, in a dose-response manner, associated with reduced lung function in young adults. Our findings have public health implications due to i) the widespread occurrence of PAHs in the environment and ii) the clinical relevance of lung function in predicting all-cause and cardiovascular disease mortality.

Dietary antioxidant intake in school age and lung function development up to adolescence.

Dietary antioxidant intake has been hypothesised to influence lung function. The association between total antioxidant capacity (TAC) of the diet at age 8 years and lung function development up to 16 years in 2307 participants from the Swedish population-based birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiology) was investigated.Information on TAC was obtained from a food frequency questionnaire at 8 years. Lung function was measured by spirometry at 8 and 16 years, impulse oscillometry (IOS) and exhaled nitric oxide fraction (F eNO) at 16 years. Low lung function was defined as forced expiratory volume in 1 s (FEV1) z-score below the 25th percentile. Longitudinal associations between TAC and lung function were analysed by mixed effect models adjusted for potential confounders. Stratification by asthma at 8 years was performed to examine effect modification.The median TAC intake was 10 067 µmol Trolox equivalents (TE)·g-1, with males having a lower mean compared to females (9963 versus 10 819 µmol TE·g-1). In analyses of lung function change between 8 and 16 years, there were no statistically significant associations between TAC in tertiles and spirometry results for the total study population. Among children with asthma at 8 years (prevalence 7%), higher TAC was associated with higher mean FEV1 (0.46 sd, 95% CI 0.11-0.80) and decreased odds of low lung function at 16 years (OR 0.28, 95% CI 0.12-0.65). There were no associations between TAC and forced vital capacity or IOS/F eNO results.High dietary antioxidant intake in school age may be associated with improved lung function development from school age to adolescence among children with asthma.

Changes of DNA methylation are associated with changes in lung function during adolescence.

BACKGROUND: Adolescence is a significant period for the gender-dependent development of lung function. Prior studies have shown that DNA methylation (DNA-M) is associated with lung function and DNA-M at some cytosine-phosphate-guanine dinucleotide sites (CpGs) changes over time. This study examined whether changes of DNA-M at lung-function-related CpGs are associated with changes in lung function during adolescence for each gender, and if so, the biological significance of the detected CpGs. METHODS: Genome-scale DNA-M was measured in peripheral blood samples at ages 10 (n = 330) and 18 years (n = 476) from the Isle of Wight (IOW) birth cohort in United Kingdom, using Illumina Infinium arrays (450 K and EPIC). Spirometry was conducted at both ages. A training and testing method was used to screen 402,714 CpGs for their potential associations with lung function. Linear regressions were applied to assess the association of changes in lung function with changes of DNA-M at those CpGs potentially related to lung function. Adolescence-related and personal and family-related confounders were included in the model. The analyses were stratified by gender. Multiple testing was adjusted by controlling false discovery rate of 0.05. Findings were further examined in two independent birth cohorts, the Avon Longitudinal Study of Children and Parents (ALSPAC) and the Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohort. Pathway analyses were performed on genes to which the identified CpGs were mapped. RESULTS: For females, 42 CpGs showed statistically significant associations with change in FEV1/FVC, but none for change in FEV1 or FVC. No CpGs were identified for males. In replication analyses, 16 and 21 of the 42 CpGs showed the same direction of associations among the females in the ALSPAC and BAMSE cohorts, respectively, with 11 CpGs overlapping across all the three cohorts. Through pathway analyses, significant biological processes were identified that have previously been related to lung function development. CONCLUSIONS: The detected 11 CpGs in all three cohorts have the potential to serve as the candidate epigenetic markers for changes in lung function during adolescence in females.

Adverse pregnancy outcomes and risk of later allergic rhinitis-Nationwide Swedish cohort study.

BACKGROUND: Perinatal conditions may be associated with future allergic disease; however, data are conflicting and incomplete for childhood allergic rhinitis (AR). The aim of this study was to examine pregnancy outcome (cesarean delivery, preterm birth, low birthweight) and offspring AR as defined by national registers. METHODS: Nationwide longitudinal cohort study using prospectively recorded register data from 1 059 600 singleton livebirths born in Sweden in 2001-2012. Cox regression adjusted for infant sex and maternal factors (age at delivery, country of birth, parity, smoking, body mass index, and asthma/pulmonary disease) estimated hazard ratios (HRs) for AR during childhood. RESULTS: During the study period 2001-2013, 22 386 (2.11%) children were diagnosed with AR. AR was more common in infants born through cesarean delivery (2.34%) than in those born vaginally (2.10%) (HR = 1.12; 95% confidence interval [95% CI] = 1.08-1.16). This was equivalent to one extra case of AR in 383 children followed up in our study. AR was also associated with moderately preterm birth (≥32-36 weeks of gestation: HR = 1.12, 95% CI = 1.04-1.20), large for gestational age (HR = 1.05, 95% CI = 1.01-1.10), and low (<7) 5-minute Apgar score (HR = 1.15, 95% CI = 1.02-1.30). Similar risk estimates were obtained when we restricted the outcome to ≥2 hospital-based records of AR. No association was observed between very preterm birth, post-term birth, low birthweight, or small for gestational age and AR. CONCLUSION: Our study indicates an association between pregnancy outcomes and childhood AR, although observed effect sizes were generally modest.

Lung function and pulmonary vascular resistance are not associated in 6-year-old children born extremely preterm.

AIM: Children born preterm are at increased risk of reduced lung function. The aim was to test whether lung function was associated with pulmonary vascular resistance. METHODS: Participants were recruited from a population-based cohort born in 2004-2007. Lung function was assessed with spirometry after administration of a beta2-agonist. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1 ) were determined. Estimations of pulmonary vascular resistance, arterial dimensions, right ventricular wall thickness, sphericity, and systolic (TAPSE) and diastolic functions were performed with echocardiography. Adjusted regression analyses were used to study associations. RESULTS: Sixty-six children (33 boys) born at 22-26 weeks of gestational age (birthweights 460-1134 g) were assessed at a mean age of 6.7 years. Despite large variations in lung function with FVC z-scores ranging from -4.6 to +2.8, there were no associations between lung function and pulmonary arterial pressure, right ventricular structure or function. Children with higher FVC z-scores (r = .52, ß = .55 mm, P = .015) and higher FEV1 z-scores (r = .58, ß = .73 mm, P = .001) exhibited larger pulmonary arteries. CONCLUSION: In children born extremely preterm, lung function was not associated with pulmonary vascular resistance. Routine echocardiographic evaluation of extremely preterm children may not be indicated at age 6.5 years.

Pulmonary outcomes in adults with a history of Bronchopulmonary Dysplasia differ from patients with asthma.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a risk factor for respiratory disease in adulthood. Despite the differences in underlying pathology, patients with a history of BPD are often treated as asthmatics. We hypothesized that pulmonary outcomes and health-related quality of life (HRQoL) were different in adults born preterm with and without a history of BPD compared to asthmatics and healthy individuals. METHODS: We evaluated 96 young adults from the LUNAPRE cohort ( clinicaltrials.gov/ct2/show/NCT02923648 ), including 26 individuals born preterm with a history of BPD (BPD), 23 born preterm without BPD (preterm), 23 asthmatics and 24 healthy controls. Extensive lung function testing and HRQoL were assessed. RESULTS: The BPD group had more severe airway obstruction compared to the preterm-, (FEV1- 0.94 vs. 0.28 z-scores; p ≤ 0.001); asthmatic- (0.14 z-scores, p ≤ 0.01) and healthy groups (0.78 z-scores, p ≤ 0.001). Further, they had increased ventilation inhomogeneity compared to the preterm- (LCI 6.97 vs. 6.73, p ≤ 0.05), asthmatic- (6.75, p = 0.05) and healthy groups (6.50 p ≤ 0.001). Both preterm groups had lower DLCO compared to healthy controls (p ≤ 0.001 for both). HRQoL showed less physical but more psychological symptoms in the BPD group compared to asthmatics. CONCLUSIONS: Lung function impairment and HRQoL in adults with a history of BPD differed from that in asthmatics highlighting the need for objective assessment of lung health.

Linking COPD epidemiology with pediatric asthma care: Implications for the patient and the physician.

What are the implications of a lower than expected forced expiratory volume in one second (FEV1) in childhood on respiratory health later in adulthood? Lung function is known to track with age, and there is evidence from recent epidemiologic studies that impaired lung function early in life is associated with later chronic airflow limitation, or even chronic obstructive pulmonary disease, COPD. This risk seems particularly strong in subjects with persistent and severe forms of childhood asthma. Can we translate findings from longitudinal cohort studies to individual risk predictions and preventive guidelines in our pediatric care? In this review, we discuss the clinical implementations of recent epidemiological respiratory studies and the importance of preserved lung health across the life course. Also, we evaluate available clinical tools, primarily lung function measures, and profiles of risk factors, including biomarkers, that may help identifying children at risk of chronic airway disease in adulthood. We conclude that translating population level results to the individual patient in the pediatric care setting is not straight forward, and that there is a need for studies specifically designed to evaluate performance of prediction of risk profiles for long-term sequelae of childhood asthma and lung function impairment.

Impact of IgE sensitization and rhinitis on inflammatory biomarkers and lung function in adolescents with and without asthma.

BACKGROUND: Both allergic and non-allergic rhinitis are associated with worse asthma control. However, it is unclear how IgE sensitization and/or rhinitis are associated with lung function. We therefore evaluated the effect of rhinitis and sensitization on lung function, including the periphery of the airway system, and inflammatory biomarkers in individuals with and without asthma. METHODS: Participants in the BAMSE longitudinal birth cohort study underwent measures of spirometry, impulse oscillometry, and FeNO at age 16 years. Questionnaires were used to obtain data on asthma and rhinitis. Blood samples were analyzed for eosinophils and allergen-specific IgE. RESULTS: Groups based on the combination of asthma, rhinitis, and sensitization were compared to a healthy reference group. Lower FEV1 /FVC levels were seen for groups with asthma only (adjusted mean difference -2.8% units (95% CI -4.7; -1.0), P < 0.01), asthma with sensitization (-2.0 (-3.9; -0.2), P < 0.05), and asthma with sensitization and rhinitis (-2.5 (-3.6; -1.4), P < 0.001). The index of peripheral airway resistance R5-20 was higher in groups with asthma and sensitization (adjusted median difference 94.9 Pa L-1  s-1 (95% CI 60.4; 129.3), P < 0.001), as well as asthma with sensitization and rhinitis (36.9(15.0; 58.8), P < 0.01). These groups also had increased FeNO and blood eosinophil levels. CONCLUSIONS: We found signs of peripheral airway obstruction and increased levels of inflammatory biomarkers in the presence of allergic asthma, irrespective of rhinitis status. Despite having a reduced FEV1 /FVC, peripheral airway engagement was not seen in non-sensitized adolescents with asthma. We suggest that small airway disease is a feature related to the eosinophilic inflammation in allergic asthma in adolescence.

Cesarean delivery, preterm birth, and risk of food allergy: Nationwide Swedish cohort study of more than 1 million children.

BACKGROUND: Little is known about early-life risk factors for food allergy in children. OBJECTIVES: We examined the association between perinatal characteristics and future risk of food allergy in offspring. METHODS: This nationwide Swedish cohort study of 1,086,378 children born in Sweden in 2001-2012 used prospectively recorded data from health care registers. Using Cox regression, we estimated hazard ratios (HRs) with 95% CIs for the association between perinatal characteristics (eg, cesarean delivery and preterm birth) and food allergy as defined by diagnoses in the National Patient Register, adjusting for infant sex and maternal factors (age at delivery, country of birth, parity, smoking, body mass index, and asthma/pulmonary disease). RESULTS: During the 13-year follow-up, 26,732 (2.5%) children were given a diagnosis of food allergy. Food allergy was positively associated with cesarean delivery (HR, 1.21; 95% CI, 1.18-1.25), large for gestational age (HR, 1.15; 95% CI, 1.10-1.19), and low 5-minute Apgar score (HR, 1.22; 95% CI, 1.10-1.36) but negatively associated with very preterm birth (<32 weeks of gestation: HR, 0.74; 95% CI, 0.56-0.98). No association was found between food allergy and moderately preterm birth, low birth weight, or small for gestational age. Risk estimates were similar when the outcome was restricted to 2 records of diagnosed food allergy. In 1,000 children undergoing cesarean delivery, an extra 5 developed food allergy compared with the reference group, suggesting that 17% of food allergy in children born by means of cesarean delivery can be explained by this exposure (attributable fraction). CONCLUSIONS: Cesarean delivery was associated with increased risk of food allergy, whereas very preterm birth decreased risk.