Troublesome Lung Symptoms Research Articles

Prenatal tobacco exposure and risk of asthma and allergy outcomes in childhood.

Harmful effects of prenatal tobacco exposure and possible interaction with 17q12-21 genetic variants have been shown for some asthma outcomes in childhood, whereas findings related to allergy outcomes are more inconsistent. This study aimed to examine the effect of prenatal tobacco exposure and relation to 17q12-21 genotype on a wide array of asthma and allergy-related outcomes in early childhood. Prenatal tobacco exposure was determined by maternal smoking during the third trimester (yes/no) in 411 children from the phenotyped Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort with clinical follow-up to age 7 years. The rs7216389 single nucleotide polymorphism was used as main representative of the 17q12-21 locus. Asthma end-points included asthma diagnosis, exacerbations, episodes with troublesome lung symptoms and lower respiratory tract infections, spirometry, plethysmography, bronchial responsiveness to methacholine, exercise and cold dry air. Allergy-related endpoints included aeroallergen sensitisation, allergic rhinitis, fractional exhaled nitric oxide, blood eosinophil count and urine eosinophil protein X levels. Statistical analyses were done using Cox regression, linear regression, logistic regression and quasi-Poisson regression. Prenatal tobacco exposure increased the risk of asthma (adjusted hazard ratio (aHR) 2.05, 95% CI 1.13-3.73; p=0.02), exacerbations (aHR 3.76, 95% CI 2.05-6.91; p<0.001), number of LRTIs (adjusted incidence rate ratio 1.87, 95% CI 1.34-2.55; p<0.001), and was associated with decreased spirometry indices (forced expiratory volume in 1 s (FEV1) adjusted mean difference (aMD) -0.07 L, 95% CI -0.13- -0.005 L, p=0.03; maximal mid-expiratory flow aMD -0.19 L·s-1, -0.34- -0.04 L·s-1, p=0.01) and increased bronchial responsiveness to methacholine (provocative dose of methacholine causing a 20% drop in FEV1 adjusted geometric mean ratio 0.55, 95% CI 0.31-0.96; p=0.04). In contrast, there was no association with any allergy-related end-points. The effect on asthma depended on 17q12-21 genotype with an increased risk only among children without risk alleles. Prenatal tobacco exposure was associated with asthma dependent on 17q12-21 genotype and with exacerbations, lung function and bronchial responsiveness, but not with any allergy-related outcomes. This suggests that tobacco exposure in utero leads to adverse lung developmental/structural effects rather than susceptibility to develop allergy and type 2 inflammation.

Vitamin D, high-sensitivity C-reactive protein, and airway hyperresponsiveness in infants with recurrent respiratory symptoms

BackgroundVitamin D insufficiency might be associated with biased T-cell responses resulting in inflammatory conditions such as atopy and asthma. Little is known about the role of vitamin D in low-grade systemic inflammation and airway hyperresponsiveness (AHR) in young children. ObjectiveTo evaluate whether vitamin D insufficiency and increased serum high-sensitivity C-reactive protein (hs-CRP) are linked to AHR in symptomatic infants. MethodsSeventy-nine infants with recurrent or persistent lower respiratory tract symptoms underwent comprehensive lung function testing and a bronchial methacholine challenge test. In addition, skin prick tests were performed and serum 25-hydroxyvitamin D (S-25-OHD), hs-CRP, total immunoglobulin E, and blood eosinophil levels were determined. ResultsS-25-OHD was lowest in infants with blood eosinophilia and AHR (n = 10) compared with those with eosinophilia only (n = 6) or AHR only (n = 50) or those with neither (n = 13; P = .035). Moreover, vitamin D insufficiency (S-25-OHD <50 nmol/L) was most common in infants with blood eosinophilia and AHR (P = .041). Serum hs-CRP was lower in infants with recurrent physician-diagnosed wheezing (P = .048) and in those with blood eosinophilia (P = .015) than in infants without these characteristics and was not associated with S-25-OHD or AHR. S-25-OHD levels were significantly lower (median 54 nmol/L) during the autumn-winter season than in the spring-summer season (median 63 nmol/L; P = .026). ConclusionVitamin D insufficiency could underlie eosinophilia and AHR in infants with troublesome lung symptoms, whereas hs-CRP–mediated low-grade systemic inflammation is rare in early childhood wheezing.

Sensitivity of newly defined impulse oscillometry indices in preschool children.

Early origins of chronic obstructive pulmonary disease have been recognized. Impulse oscillometry (IOS) is suitable for assessment of lung function also in preschool children, and some novel indices have been connected to assessment of small airway function. However, limited data exist on the sensitivity of these new indices to detect lung function deficits in young symptomatic children. IOS measurements of 103 healthy preschool children were evaluated to establish reference equations for the difference between respiratory resistance at 5 and 20 Hz (R5-20), the relative difference of R5-20 (R5-20%), and area under the reactance curve (AX). Thereafter, IOS results of children with late-onset troublesome lung symptoms (n = 20), a history of early wheeze (n = 37), or a history of bronchopulmonary dysplasia (BPD, n = 8) were compared to healthy children. None of the patient groups differed from healthy regarding respiratory resistance at 5 Hz (R5), and only children with a history of BPD differed from healthy regarding respiratory reactance at 5 Hz (X5). In contrast, z-scores of R5-20, R5-20%, and AX were significantly higher in all patient groups than in healthy children (P < 0.001), showing improved sensitivity (20-55%) compared to R5 and X5 (5-6%). R5-20, R5-20%, and AX are superior to conventional IOS parameters in distinguishing children with current or past lower respiratory tract symptoms from healthy, and may prove valuable for screening early lung function deficits. Pediatr Pulmonol. 2017;52:598-605. © 2016 Wiley Periodicals, Inc.

Effect of Vitamin D3 Supplementation During Pregnancy on Risk of Persistent Wheeze in the Offspring: A Randomized Clinical Trial.

Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring, but the preventive effect of vitamin D supplementation to pregnant women is unknown. To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring. A double-blind, single-center, randomized clinical trial conducted within the Copenhagen Prospective Studies on Asthma in Childhood 2010 cohort. Enrollment began March 2009 with a goal of 708 participants, but due to delayed ethical approval, only 623 women were recruited at 24 weeks of pregnancy. Follow-up of the children (N = 581) was completed when the youngest child reached age 3 years in March 2014. Vitamin D3 (2400 IU/d; n = 315) or matching placebo tablets (n = 308) from pregnancy week 24 to 1 week postpartum. All women received 400 IU/d of vitamin D3 as part of usual pregnancy care. Age at onset of persistent wheeze in the first 3 years of life. Secondary outcomes included number of episodes of troublesome lung symptoms, asthma, respiratory tract infections, and neonatal airway immunology. Adverse events were assessed. Of the 581 children, persistent wheeze was diagnosed during the first 3 years of life in 47 children (16%) in the vitamin D3 group and 57 children (20%) in the control group. Vitamin D3 supplementation was not associated with the risk of persistent wheeze, but the number of episodes of troublesome lung symptoms was reduced, and the airway immune profile was up-regulated (principal component analysis, P = .04). There was no effect on additional end points. Intrauterine death was observed in 1 fetus (<1%) in the vitamin D3 group vs 3 fetuses (1%) in the control group and congenital malformations in 17 neonates (5%) in the vitamin D3 group vs 23 neonates (8%) in the control group. [table: see text]. The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years. However, interpretation of the study is limited by a wide CI that includes a clinically important protective effect. clinicaltrials.gov Identifier: NCT00856947.

Association between respiratory infections in early life and later asthma is independent of virus type

BackgroundLower respiratory tract infections in the first years of life are associated with later asthma, and this observation has led to a focus on the potential causal role of specific respiratory viruses, such as rhinoviruses and respiratory syncytial virus, in asthma development. However, many respiratory viruses and bacteria trigger similar respiratory symptoms and it is possible that the important risk factors for asthma are the underlying susceptibility to infection and the exaggerated reaction to such triggers rather than the particular triggering agent.ObjectiveWe sought to study the association between specific infections in early life and development of asthma later in childhood.MethodsThree hundred thirteen children were followed prospectively in the Copenhagen Prospective Studies of Asthma in Childhood2000 high-risk birth cohort. Nine respiratory virus types (respiratory syncytial virus, rhinoviruses, other picornaviruses, coronaviruses 229E and OC43, parainfluenza viruses 1-3, influenza viruses AH1, AH3, and B, human metapneumovirus, adenoviruses, and bocavirus) and 3 pathogenic airway bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were identified in airway secretions sampled during episodes of troublesome lung symptoms in the first 3 years of life. Asthma was determined by age 7 years.ResultsIn unadjusted analyses, all viruses and pathogenic bacteria identified during episodes of troublesome lung symptoms were associated with increased risk of asthma by age 7 years with similar odds ratios for all viruses and pathogenic bacteria. After adjustment for the frequency of respiratory episodes, the particular triggers were no longer associated with asthma.ConclusionThe number of respiratory episodes in the first years of life, but not the particular viral trigger, was associated with later asthma development. This suggests that future research should focus on the susceptibility and exaggerated response to lower respiratory tract infections in general rather than on the specific triggering agent.

Cord blood 25(OH)-vitamin D deficiency and childhood asthma, allergy and eczema: the COPSAC2000 birth cohort study.

BackgroundEpidemiological studies have suggested an association between maternal vitamin D dietary intake during pregnancy and risk of asthma and allergy in the offspring. However, prospective clinical studies on vitamin D measured in cord blood and development of clinical end-points are sparse.ObjectiveTo investigate the interdependence of cord blood 25-hydroxyvitamin D (25(OH)-Vitamin D) level and investigator-diagnosed asthma- and allergy-related conditions during preschool-age.MethodsCord blood 25(OH)-Vitamin D level was measured in 257 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) at-risk mother-child cohort. Troublesome lung symptoms (TROLS), asthma, respiratory infections, allergic rhinitis, and eczema, at age 0–7 yrs were diagnosed exclusively by the COPSAC pediatricians strictly adhering to predefined algorithms. Objective assessments of lung function and sensitization were performed repeatedly from birth.ResultsAfter adjusting for season of birth, deficient cord blood 25(OH)-Vitamin D level (<50 nmol/L) was associated with a 2.7-fold increased risk of recurrent TROLS (HR = 2.65; 95% CI = 1.02–6.86), but showed no association with respiratory infections or asthma. We saw no association between cord blood 25(OH)-Vitamin D level and lung function, sensitization, rhinitis or eczema. The effects were unaffected from adjusting for multiple lifestyle factors.ConclusionCord blood 25(OH)-Vitamin D deficiency associated with increased risk of recurrent TROLS till age 7 years. Randomized controlled trials of vitamin D supplementation during pregnancy are needed to prove causality.

Assessing direct and indirect airway hyperresponsiveness in children using impulse oscillometry

BackgroundAirway hyperresponsiveness (AHR) is a hallmark of asthma but its assessment is usually restricted to older children who are capable of performing the maneuvers involved in spirometry. In younger children, a feasible option to perform the lung function measurement is impulse oscillometry (IOS), which requires less cooperation. ObjectiveTo evaluate whether assessment of AHR by IOS could differentiate children with various obstructive symptoms from one another. MethodsOne hundred twenty-one children (median age 6.0 years, range 3.7–8.1 years) were examined: 31 with probable asthma characterized by current troublesome lung symptoms, 61 with a history of early wheezing disorder (recurrent wheezing ≤24 months of age), 15 with a history of bronchopulmonary dysplasia, and 14 healthy controls. Indirect AHR was assessed by exercise and mannitol challenge tests, and direct AHR was assessed with methacholine using IOS. AHR to exercise was defined as an increase of at least 40% in respiratory resistance at 5 Hz. In the mannitol and methacholine challenges, the dose causing an increase of 40% in respiratory resistance at 5 Hz was calculated. ResultsAHR to exercise was good at differentiating children with current troublesome lung symptoms from those in the other groups (P < .001). AHR to methacholine separated children with current troublesome lung symptoms, early wheezing disorder, and bronchopulmonary dysplasia from the controls (P < .001), whereas the mannitol test did not distinguish among the study groups (P = .209). ConclusionThe methacholine and exercise challenge tests with IOS identify children with probable asthma characterized by troublesome lung symptoms and therefore may represent a practical aid in the evaluation of AHR in young children.

PD53 ‐ Budesonide therapy reduces sCD30‐levels in atopic infants with recurrent respiratory symptoms

Only minority of infants with recurrent or persistent respiratory symptoms will develop asthma. The development of asthma is associated with Th1- and Th2-cell activity imbalance. Increased levels of Th1 activation marker, serum soluble CD26 (sCD26), and Th2 activation marker, serum soluble CD30 (sCD30) have been found in asthmatic adults and school children. Whether these markers are of clinical use in infants with troublesome lung symptoms has not been evaluated before. Altogether 43 children aged 4 to 26 months with persistent cough, recurrent wheeze, or shortness of breath were investigated clinically and randomized to receive either budesonide 400 ug/day or placebo for 6 weeks. There were no differences in baseline data like gender, atopic traits, clinical findings, or whole body plethysmography measurements between these two intervention groups. At baseline, serum sCD26 and sCD30 levels did not differ between the intervention groups. After the 6-week intervention there was a significant decrease in sCD30 levels in atopic (i.e. skin prick test positive and/or having atopic eczema) children treated with budesonide (p=0.028), and in non-atopic children who received placebo (p=0.008), but no changes in sCD30 levels in atopic children treated with placebo (p=0.753), or in non-atopic children treated with budesonide (p=0.695) (Fig.​(Fig.1).1). As regards sCD26, a significant increase was seen between the levels measured before and after the 6-week intervention (p=0.012), but the increase was independent of the type of the intervention. Figure 1 In conclusion, Th1-type immunity is suppressed and Th2-type immunity activated in infants with troublesome lung symptoms. However, only atopic infants may benefit of anti-inflammatory inhalants.

PD08 ‐ Measuring direct and indirect airway hyperresponsiveness in young children with obstructive symptoms

Methods A total of 121 children (3.7-8.1 yr) were studied (31 with troublesome lung symptoms (TLS), 15 with bronchopulmonary dysplasia (BPD), 61 with history of early wheezing disorder and 14 healthy controls) to assess AHR by exercise test, mannitol and methacholine challenges with IOS. If the child used asthma control medication, it was stopped four weeks before the lung function tests. Tests were performed in separate days within two weeks period. AHR to exercise was defined as a ≥ 35% increase in Rrs5. For mannitol and methacholine challenges, the dose causing an increase of 40 % in Rrs5 (PD40Rrs5) was calculated.

Neonatal Airway Colonization Is Associated with Troublesome Lung Symptoms in Infants

Neonatal Airway Colonization Is Associated with Troublesome Lung Symptoms in Infants

Asthma in school‐aged children, it's time to reveal its entities

Asthma in school‐aged children, it's time to reveal its entities

“To wheeze or not to wheeze”: That is not the question

The diagnosis of asthma in young children is difficult and based on clinical assessment of symptoms and results of physical examination. Respiratory wheeze has traditionally been used to define asthma in young children. We sought to compare the qualitative diagnosis of wheeze with a quantitative global assessment of significant troublesome lung symptoms during the first 3 years of life as a predictor of asthma by age 7 years. Children born to asthmatic mothers (n= 411) were followed prospectively to age 7 years. Parents were instructed to visit the research clinic during the first 3 years of life each time the child had significant troublesome lung symptoms for 3 days. At the clinic, a research physician performed a physical examination, including auscultation for wheeze and excluding differential diagnoses. We tested whether wheeze was independently associated with asthma at age 7 years after adjusting for the total number of episodes. Three hundred thirteen children had full follow-up by age 7 years. In a multivariable analysis the total number of acute clinic visits for asthma symptom was significantly associated with later asthma (P< .0001), whereas the presence of wheeze at these visits was not (P= .5). The total number of acute clinic visits for significant troublesome lung symptoms was also significantly associated with later asthma in children who had never presented with any wheeze (P= .03). A quantitative global assessment of significant troublesome lung symptoms in the first 3 years of life is a better predictor of asthma than assessment of wheeze. Doctor-diagnosed wheeze is not a prerequisite for the diagnosis of asthma, and relying on the symptom of wheeze will likely be an important cause of undertreatment.

Elevated Eosinophil Protein X in Urine from Healthy Neonates Precedes Development of Atopy in the First 6 Years of Life

Biomarkers predicting development of atopic disease are needed for targeted preventive measures and to study if disease pathology may be active before onset of symptoms. To investigate whether eosinophil protein X, leukotriene-C4/D4/E4, and 11β-prostaglandin (PG) F2α (PGD2 metabolite) assessed in urine from healthy at-risk neonates precede development of atopic disease during the first 6 years of life. We measured eosinophil protein X (n = 369), leukotriene-C4/D4/E4 (n = 367), and 11β-PGF2α (n = 366) in urine from 1-month-old children participating in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. Clinical data on development of allergic sensitization, allergic rhinitis, nasal eosinophilia, blood eosinophilia, eczema, troublesome lung symptoms (significant cough or wheeze or dyspnea), and asthma were collected prospectively until age 6 years. Associations between urinary biomarkers and development of atopic traits were investigated using general estimating equations, logistic regression, and Cox regression. Eosinophil protein X in the urine of the asymptomatic 1-month-old neonates was significantly associated with development of allergic sensitization (odds ratio, 1.49; 95% confidence interval [CI], 1.08–1.89), nasal eosinophilia (odds ratio, 3.2; 95% CI, 1.2–8.8), and eczema (hazard ratio, 1.4; 95% CI, 1.0–2.0), but not with allergic rhinitis, asthma, or blood eosinophilia. Neither leukotriene-C4/D4/E4 nor 11β-PGF2α was associated with any of the atopic phenotypes. Eosinophil protein X in urine from asymptomatic neonates is a biomarker significantly associated with later development of allergic sensitization, nasal eosinophilia, and eczema during the first 6 years of life. These findings suggest activation of eosinophil granulocytes early in life before development of atopy-related symptoms.

The Editors’ Choice

The Editors’ Choice

Endotyping early childhood asthma by quantitative symptom assessment

Asthmatic symptoms in young children reflect a heterogeneous group of diseases. Symptoms remain the primary end-point in both research and clinical management, but there is a need for standardized symptom assessment. We sought to explore endotyping of early childhood asthma by prospective daily diary recordings of globally assessed symptoms during the first 6 years of life. Globally assessed troublesome lung symptoms were recorded in daily diaries during the first 6 years of life in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort born of mothers with asthma. Symptom recordings adjusted for missing values were used to categorize children based on the temporal symptom pattern. We propose an alternative approach of quantitating symptom frequency and longitudinal assessment of age-at-onset to segment children. These different methods were compared by estimating the risk from the well-established genetic risk variants of ORMDL3. Six years of daily diary recordings were available in 307 children (75% of the birth cohort). We confirmed the archetypal temporal categories of transient early, persistent, and late-onset troublesome lung symptoms based on 3-year periods, finding no benefit from a finer temporal categorization of 2- or 1-year periods. Restricting categorization to symptoms during the summer improved specificity at the expense of sensitivity. Our alternative approach quantitating symptom frequency and age-at-onset exhibited a more powerful association with ORMDL3, whereas the study power was lost by restricting to doctor-verified wheeze. We propose a novel method for endotyping of early childhood asthma based on the frequency and age-of-onset of globally assessed troublesome lung symptoms analyzed longitudinally. This method showed the closest association with genetic variants, hence underlying molecular mechanisms and endotypes.