Ventilation heterogeneity in children with severe asthma.

Small airway disease, characterised by ventilation heterogeneity (VH), is present in a subgroup of patients with asthma. Ventilation heterogeneity can be measured using multiple breath washout testing. Few studies have been reported in children. We studied the relationship between VH, asthma severity, and spirometry in a cross-sectional observational cohort study involving children with stable mild-moderate and severe asthma by GINA classification and a group of healthy controls. Thirty-seven participants aged 5-16 years completed multiple breath nitrogen washout (MBNW) testing (seven controls, seven mild-moderate asthma, 23 severe asthma). The lung clearance index (LCI) was normal in control and mild-moderate asthmatics. LCI was abnormal in 5/23 (21%) of severe asthmatics. The LCI negatively correlated with FEV1 z-score.Conclusion: VH is present in asthmatic children and appears to be more common in severe asthma. The LCI was significantly higher in the cohort of children with severe asthma, despite no difference in FEV1 between the groups. This supports previous evidence that LCI is a more sensitive marker of airway disease than FEV1. MBNW shows potential as a useful tool to assess children with severe asthma and may help inform clinical decisions. What is Known: • Increased ventilation heterogeneity is present in some children with asthma • Spirometry is not sensitive enough to detect small airway involvement in asthma What is New • Lung clearance index is abnormal in a significant subgroup of children with severe asthma but rarely in children with mild-moderate asthma • Our data suggests that LCI monitoring should be considered in children with severe asthma.

Lung function and asthma control in school-age children managed in UK primary care: a cohort study.

BACKGROUND: Spirometry and fraction of exhaled nitric oxide (FeNO) are commonly used in specialist centres to monitor children with asthma. The National Institute for Health and Care Excellence recommends spirometry for asthma monitoring from 5 years in all healthcare settings. There is little spirometry and FeNO data in children managed for asthma in UK primary care to support their use. OBJECTIVES: To study the prevalence of abnormal spirometry and FeNO in children with asthma managed in primary care and to explore their relationship with asthma control and unplanned healthcare attendances (UHA). METHODS: Prospective observational cohort study in children aged 5-16 years with suspected or doctor-diagnosed asthma attending an asthma review in UK general practice. Spirometry, FeNO, asthma control test (ACT) scores and number of UHAs were studied. RESULTS: Of 612 children from 10 general practices, 23.5% had abnormal spirometry, 36.0% had raised FeNO ≥35 parts per billion and 41.8% reported poor control. Fifty-four per cent of children reporting good asthma control had abnormal spirometry and/or raised FeNO. At follow-up, the mean number of UHAs fell from 0.31/child in the 6 months preceding review to 0.20/child over the 6 months following review (p=0.0004). Median ACT scores improved from 20 to 22 (p=0.032), and children's ACT from 21 to 23 (p<0.0001). CONCLUSIONS: Abnormal lung function and FeNO are common in children attending for asthma review in primary care and relate poorly to symptom scores. A symptoms-based approach to asthma monitoring without objective testing is likely to miss children at high risk of future severe asthma attacks.

Longitudinal Associations Between Respiratory Infections and Asthma in Young Children.

We examined temporal dependencies between repeated assessments of respiratory tract infections (RTIs) and asthma in children in the Leicester Respiratory Cohort, Leicestershire, United Kingdom. Information associated with asthma (i.e., doctor diagnosis, health care visits, wheeze frequency) and RTIs (i.e., cold duration and frequency, cough with colds, ear infections) in the previous 12 months was assessed repeatedly at ages 1, 4, and 6 years for children born between April 1996 and April 1997. We determined associations between contemporaneous and lagged measures of asthma and RTIs, using structural equation modelling. In 1,995 children, asthma was positively associated with contemporaneous infections. Asthma at age 6 years was positively associated with asthma at age 4 years (regression coefficient = 0.87; 95% confidence interval (CI): 0.76, 0.97), but not with asthma at age 1 year (regression coefficient = -0.01; 95% CI: -0.14, 0.11). We found no evidence for direct protective effect of infections at age 1 year on asthma either at age 4 (regression coefficient = -0.20; 95% CI: -0.51, 0.10) or 6 (regression coefficient = 0.24; 95% CI: -0.04, 0.52) years. Adjusting for potential confounders did not qualitatively change those relationships. Based on our findings, we suggest that asthma at age 6 years is directly influenced by asthma history and only indirectly, if at all, by earlier infection episodes. We found little support for a protective effect of preschool infections on asthma at early school age.

Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children.

BACKGROUND: Children born preterm or with a small size for gestational age are at increased risk for childhood asthma. OBJECTIVE: We sought to assess the hypothesis that these associations are explained by reduced airway patency. METHODS: We used individual participant data of 24,938 children from 24 birth cohorts to examine and meta-analyze the associations of gestational age, size for gestational age, and infant weight gain with childhood lung function and asthma (age range, 3.9-19.1 years). Second, we explored whether these lung function outcomes mediated the associations of early growth characteristics with childhood asthma. RESULTS: Children born with a younger gestational age had a lower FEV1, FEV1/forced vital capacity (FVC) ratio, and forced expiratory volume after exhaling 75% of vital capacity (FEF75), whereas those born with a smaller size for gestational age at birth had a lower FEV1 but higher FEV1/FVC ratio (P < .05). Greater infant weight gain was associated with higher FEV1 but lower FEV1/FVC ratio and FEF75 in childhood (P < .05). All associations were present across the full range and independent of other early-life growth characteristics. Preterm birth, low birth weight, and greater infant weight gain were associated with an increased risk of childhood asthma (pooled odds ratio, 1.34 [95% CI, 1.15-1.57], 1.32 [95% CI, 1.07-1.62], and 1.27 [95% CI, 1.21-1.34], respectively). Mediation analyses suggested that FEV1, FEV1/FVC ratio, and FEF75 might explain 7% (95% CI, 2% to 10%) to 45% (95% CI, 15% to 81%) of the associations between early growth characteristics and asthma. CONCLUSIONS: Younger gestational age, smaller size for gestational age, and greater infant weight gain were across the full ranges associated with childhood lung function. These associations explain the risk of childhood asthma to a substantial extent.

Catch-up alveolarization in ex-preterm children: evidence from (3)He magnetic resonance.

RATIONALE: Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair. OBJECTIVES: To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance. METHODS: We recruited schoolchildren aged 10-14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37-42 wk; n = 61); (2) mild preterm (32-36 wk; n = 21); (3) extreme preterm (<32 wk, not oxygen dependent at 4 wk; n = 19); and (4) extreme preterm with chronic lung disease (<32 wk and oxygen dependent beyond 4 wk; n = 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance. MEASUREMENTS AND MAIN RESULTS: The two extreme preterm groups had a lower FEV1 (P = 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm(2)/second (95% confidence interval, 0.089-0.095) in the term group. Corresponding values were 0.096 (0.091-0.101), 0.090 (0085-0.095), and 0.089 (0.083-0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders. CONCLUSIONS: Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.

Comparison of phenotypes of childhood wheeze and cough in 2 independent cohorts.

BACKGROUND: Among children with wheeze and recurrent cough there is great variation in clinical presentation and time course of the disease. We previously distinguished 5 phenotypes of wheeze and cough in early childhood by applying latent class analysis to longitudinal data from a population-based cohort (original cohort). OBJECTIVE: To validate previously identified phenotypes of childhood cough and wheeze in an independent cohort. METHODS: We included 903 children reporting wheeze or recurrent cough from an independent population-based cohort (validation cohort). As in the original cohort, we used latent class analysis to identify phenotypes on the basis of symptoms of wheeze and cough at 2 time points (preschool and school age) and objective measurements of atopy, lung function, and airway responsiveness (school age). Prognostic outcomes (wheeze, bronchodilator use, cough apart from colds) 5 years later were compared across phenotypes. RESULTS: When using a 5-phenotype model, the analysis distinguished 3 phenotypes of wheeze and 2 of cough as in the original cohort. Two phenotypes were closely similar in both cohorts: Atopic persistent wheeze (persistent multiple trigger wheeze and chronic cough, atopy and reduced lung function, poor prognosis) and transient viral wheeze (early-onset transient wheeze with viral triggers, favorable prognosis). The other phenotypes differed more between cohorts. These differences might be explained by differences in age at measurements. CONCLUSIONS: Applying the same method to 2 different cohorts, we consistently identified 2 phenotypes of wheeze (atopic persistent wheeze, transient viral wheeze), suggesting that these represent distinct disease processes. Differences found in other phenotypes suggest that the age when features are assessed is critical and should be considered carefully when defining phenotypes.

Breastfeeding and lung function at school age: does maternal asthma modify the effect?

RATIONALE: The evidence for an effect of breastfeeding on lung function is conflicting, in particular whether the effect is modified by maternal asthma. OBJECTIVES: To explore the association between breastfeeding and school-age lung function. METHODS: In the Leicestershire Cohort Studies we assessed duration of breastfeeding (not breastfed, ≤3 months, 4-6 months, and >6 months), other exposures, and respiratory symptoms by repeated questionnaires. Post-bronchodilator FVC, FEV(1), peak expiratory flow (PEF), forced midexpiratory flow (FEF(50)), and skin prick tests were measured at age 12 years. We performed multivariable linear regression and tested potential causal pathways (N = 1,458). MEASUREMENTS AND MAIN RESULTS: In the entire sample, FEF(50) was higher by 130 and 164 ml in children breastfed for 4 to 6 months and longer than 6 months, respectively, compared with those not breastfed (P = 0.048 and 0.041), with larger effects if the mother had asthma. FVC and FEV(1) were associated with breastfeeding only in children of mothers with asthma (P for interaction, 0.018 and 0.008): FVC was increased by 123 and 164 ml for those breastfed 4 to 6 months or longer than 6 months, respectively (P = 0.177 and 0.040) and FEV(1) was increased by 148 and 167 ml, respectively (P = 0.050 and 0.016). Results were unchanged after adjustment for respiratory infections in infancy and asthma and atopy in the child. CONCLUSIONS: In this cohort, breastfeeding for more than 4 months was associated with increased FEF(50) and, in children of mothers with asthma, with increased FEV(1) and FVC. It seems that the effect is not mediated via avoidance of early infections or atopy but rather through a direct effect on lung growth.

Alveolarization continues during childhood and adolescence: new evidence from helium-3 magnetic resonance.

RATIONALE: The current hypothesis that human pulmonary alveolarization is complete by 3 years is contradicted by new evidence of alveolarization throughout adolescence in mammals. OBJECTIVES: We reexamined the current hypothesis using helium-3 ((3)He) magnetic resonance (MR) to assess alveolar size noninvasively between 7 and 21 years, during which lung volume nearly quadruples. If new alveolarization does not occur, alveolar size should increase to the same extent. METHODS: Lung volumes were measured by spirometry and plethysmography in 109 healthy subjects aged 7-21 years. Using (3)HeMR we determined two independent measures of peripheral airspace dimensions: apparent diffusion coefficient (ADC) of (3)He at FRC (n = 109), and average diffusion distance of helium (X(rms)) by q-space analysis (n = 46). We compared the change in these parameters with lung growth against a model of lung expansion with no new alveolarization. MEASUREMENTS AND MAIN RESULTS: ADC increased by 0.19% for every 1% increment in FRC (95% confidence interval [CI], 0.13-0.25), whereas the expected change in the absence of neoalveolarization is 0.41% (95% CI, 0.31-0.52). Similarly, increase of (X(rms)) with FRC was significantly less than the predicted increase in the absence of neoalveolarization. The number of alveoli is estimated to increase 1.94-fold (95% CI, 1.64-2.30) across the age range studied. CONCLUSIONS: Our observations are best explained by postulating that the lungs grow partly by neoalveolarization throughout childhood and adolescence. This has important implications: developing lungs have the potential to recover from early life insults and respond to emerging alveolar therapies. Conversely, drugs, diseases, or environmental exposures could adversely affect alveolarization throughout childhood.

Differences in respiratory oscillometry measurements using mouthpiece, mouth, and nasal mask in healthy adults.

Airway resistance measurements using oscillometry provide a potential alternative to spirometry in assessing airway obstruction and dynamics due to measurements taken during tidal breathing. Oscillometry typically requires participants to form a tight seal around a mouthpiece that can prove challenging for some people. To address this challenge, we conducted a prospective study to evaluate the effect of different interfaces like mouthpiece, mouth mask, and nasal mask on respiratory impedance results from oscillometry in a cohort of healthy adults. Ten healthy adults [7 females; mean age: 38.9 yr (SD ±15.5)] underwent oscillometry using each of the three interfaces. We measured resistance at 5 Hz (Rrs5), frequency dependence of resistance at 5-20 Hz (Rrs5-20), and reactance area (Ax). Rrs5 was not different when using the mouthpiece compared with the mouth mask [mean 2.98 cmH2O/L/s (SD ±0.68) vs. mean 3.2 cmH2O/L/s (SD ±0.81); P = 0.92; 95% CI -0.82 to +0.38], respectively. Nasal mask Rrs5 measurements were significantly higher than mouthpiece measurements (mean 7.31 cmH2O/L/s; SD ±2.62; P < 0.01; 95%CI -6.91 to -1.75). With Ax5, we found a mean of 4.01 cmH2O/L (SD ±2.04) with the mouth mask compared with a mean of 4.02 cmH2O/L (SD ±1.87; P = 1.0 95% CI -1.86 to +1.87) for the mouthpiece, however, we found a significant difference between the mouthpiece and nasal mask for Ax (mean = 10.71; SD ±7.0 H2O/L; P = 0.04, 95% CI -12.96 to -0.43). Our findings show that oscillometry using a mouth mask may be just as effective as using a mouthpiece in assessing airway dynamics and resistance.NEW & NOTEWORTHY This is the first study to compare the use of different interfaces: mouthpiece, mouth mask, and nasal mask, for oscillometry in an adult population. We report that using a mouth mask in oscillometry may provide a valid alternative to a mouthpiece in cohorts who may struggle to form the required tight seal that is typically required in oscillometry or spirometry.

Lung clearance index: assessment and utility in children with asthma.

There is increasing evidence that ventilation heterogeneity and small airway disease are significant factors in asthma, with evidence suggesting that the small airways are involved from an early stage in childhood asthma. Spirometry is commonly used to monitor lung function in asthmatics; however, it is not sensitive to small airway disease. There has been renewed interest in multibreath washout (MBW) tests, with recognition of the lung clearance index (LCI) as a global index of abnormality in gas mixing of the lungs that therefore also reflects small airway disease. This review summarises the technical and practical aspects of the MBW/LCI in children, and the differences between commercially available equipment. Children with severe asthma are more likely to have an abnormal LCI, whereas most children with mild-to-moderate asthma have an LCI within the normal range, but slightly higher than age-matched healthy controls. Monitoring children with asthma with MBW alongside standard spirometry may provide useful additional information.

Age-related changes in childhood wheezing characteristics: A whole population study.

BACKGROUND: Wheezing illnesses are characterized by phenotypic variability, which changes with age, but few studies report on a wide age range of children. We studied how prevalence, severity, and triggers of wheeze vary throughout childhood. METHODS: We analyzed data from a large population-based cohort of children from Leicestershire, UK, who were followed from infancy through late adolescence using postal questionnaires. We used generalized estimating equations to describe age-related changes in prevalence of any wheeze: episodic viral and multiple trigger wheeze; wheeze triggered by exercise, aeroallergens, food/drinks, laughing/crying; and of severe wheeze (frequent attacks, shortness of breath, sleep disturbance, disturbance of daily activities) from age 1-18 years. We analyzed this in the entire cohort (absolute prevalence) and separately among children with wheeze (relative prevalence). RESULTS: This study included 7670 children. Current wheeze was most common in 1-year-olds (36%) and then decreased in prevalence to reach 17% in children aged 14-17 years. Absolute prevalence of episodic viral wheeze (EVW) decreased with age (from 24% to 7%), while multiple trigger wheeze (MTW) remained relatively constant throughout childhood (8-12%). Among children with wheeze, the proportion with EVW decreased, and the proportion with MTW increased with age. In older children, wheeze triggered by exercise or aeroallergens, and wheeze accompanied by shortness of breath became more frequent, while wheeze triggered by food or laughter, and sleep disturbance decreased in prevalence. CONCLUSION: Knowledge of these age-related changes in wheezing illness is informative for health care planning and the design of future research projects and questionnaires.

Association between breastfeeding and eczema during childhood and adolescence: A cohort study.

BACKGROUND: Breastfeeding is said to protect children from eczema (atopic dermatitis), but the available evidence is conflicting and subject to the influences of parental atopy and reverse causation (when mothers extended duration of breastfeeding because their children had eczema). METHODS: In the prospective, population-based Leicester Respiratory Cohort study, we assessed duration of breastfeeding in children aged 1-4 years. Prevalence of eczema was determined by questionnaire surveys that were repeated until the children were 17 years old. We investigated the association between having been breastfed and current eczema using generalized estimating equations, adjusting for potential confounders, and tested for effect modification by parental atopy. We also assessed the association between having been breastfed and incident eczema at ages 2, 4, and 6 years using multivariable logistic regression. RESULTS: Among the 5,676 children in the study, 2,284 (40%) had never been breastfed, while 1,610 (28%), 705 (12%), and 1,077 (19%) had been breastfed for 0-3, 4-6, and >6 months, respectively. Prevalence of current eczema decreased from 36% in 1-year-olds to 18% in children aged 10-17 years. Breastfeeding was not associated with current eczema. Compared with children who had never been breastfed, the adjusted odds ratios for current eczema at any age were 1.02 (95% confidence interval 0.90-1.15) for children who had been breastfed for 0-3 months, 0.97 (0.82-1.13) for children breastfed for 4-6 months, and 0.98 (0.85-1.14) for children breastfed for >6 months. There was no strong evidence for an effect modification by parental atopy (p-value for interaction term was 0.061) and no association between having been breastfed and incident eczema later in childhood. CONCLUSIONS: This population-based cohort study found no evidence for protection of breastfeeding against childhood eczema at any age, from infancy through adolescence.

Breastfeeding and respiratory tract infections during the first 2 years of life.

Breastfeeding and respiratory tract infections http://ow.ly/Isd9309JS69.

"Attacks" or "Whistling": Impact of Questionnaire Wording on Wheeze Prevalence Estimates.

BACKGROUND: Estimates of prevalence of wheeze depend on questionnaires. However, wording of questions may vary between studies. We investigated effects of alternative wording on estimates of prevalence and severity of wheeze, and associations with risk factors. METHODS: White and South Asian children from a population-based cohort (UK) were randomly assigned to two groups and followed up at one, four and six years (1998, 2001, 2003). Parents were asked either if their child ever had "attacks of wheeze" (attack group, N=535), or "wheezing or whistling in the chest" (whistling group, N=2859). All other study aspects were identical, including questions about other respiratory symptoms. RESULTS: Prevalence of wheeze ever was lower in the attack group than in the whistling group for all surveys (32 vs. 40% in white children aged one year, p<0.001). Prevalence of other respiratory symptoms did not differ between groups. Wheeze tended to be more severe in the attack group. The strength of association with risk factors was comparable in the two groups. CONCLUSIONS: The wording of questions on wheeze can affect estimates of prevalence, but has less impact on measured associations with risk factors. Question wording is a potential source of between-study-heterogeneity in meta-analyses.

Breastfeeding, lung volumes and alveolar size at school-age.

BACKGROUND: Previous studies found larger lung volumes at school-age in formerly breastfed children, with some studies suggesting an effect modification by maternal asthma. We wanted to explore this further in children who had undergone extensive lung function testing. The current study aimed to assess whether breastfeeding was associated with larger lung volumes and, if so, whether all compartments were affected. We also assessed association of breastfeeding with apparent diffusion coefficient (ADC), which measures freedom of gas diffusion in alveolar-acinar compartments and is a surrogate of alveolar dimensions. Additionally, we assessed whether these effects were modified by maternal asthma. METHODS: We analysed data from 111 children and young adults aged 11-21 years, who had participated in detailed lung function testing, including spirometry, plethysmography and measurement of ADC of (3)Helium ((3)He) by MR. Information on breastfeeding came from questionnaires applied in early childhood (age 1-4 years). We determined the association between breastfeeding and these measurements using linear regression, controlling for potential confounders. RESULTS: We did not find significant evidence for an association between duration of breastfeeding and lung volumes or alveolar dimensions in the entire sample. In breastfed children of mothers with asthma, we observed larger lung volumes and larger average alveolar size than in non-breastfed children, but the differences did not reach significance levels. CONCLUSIONS: Confirmation of effects of breastfeeding on lung volumes would have important implications for public health. Further investigations with larger sample sizes are warranted.