Cristian Dogaru

A simple asthma prediction tool for preschool children with wheeze or cough

BACKGROUND Many preschool children have wheeze or cough, but only some have asthma later. Existing prediction tools are difficult to apply in clinical practice or exhibit methodological weaknesses. OBJECTIVE We sought to develop a simple and robust tool for predicting asthma at school age in preschool children with wheeze or cough. METHODS From a population-based cohort in Leicestershire, United Kingdom, we included 1- to 3-year-old subjects seeing a doctor for wheeze or cough and assessed the prevalence of asthma 5 years later. We considered only noninvasive predictors that are easy to assess in primary care: demographic and perinatal data, eczema, upper and lower respiratory tract symptoms, and family history of atopy. We developed a model using logistic regression, avoided overfitting with the least absolute shrinkage and selection operator penalty, and then simplified it to a practical tool. We performed internal validation and assessed its predictive performance using the scaled Brier score and the area under the receiver operating characteristic curve. RESULTS Of 1226 symptomatic children with follow-up information, 345 (28%) had asthma 5 years later. The tool consists of 10 predictors yielding a total score between 0 and 15: sex, age, wheeze without colds, wheeze frequency, activity disturbance, shortness of breath, exercise-related and aeroallergen-related wheeze/cough, eczema, and parental history of asthma/bronchitis. The scaled Brier scores for the internally validated model and tool were 0.20 and 0.16, and the areas under the receiver operating characteristic curves were 0.76 and 0.74, respectively. CONCLUSION This tool represents a simple, low-cost, and noninvasive method to predict the risk of later asthma in symptomatic preschool children, which is ready to be tested in other populations.

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.

Etiology of Ethnic Differences in Childhood Spirometry

OBJECTIVES: Age- and height-adjusted spirometric lung function of South Asian children is lower than those of white children. It is unclear whether this is purely genetic, or partly explained by the environment. In this study, we assessed whether cultural factors, socioeconomic status, intrauterine growth, environmental exposures, or a family and personal history of wheeze contribute to explaining the ethnic differences in spirometric lung function. METHODS: We studied children aged 9 to 14 years from a population-based cohort, including 1088 white children and 275 UK-born South Asians. Log-transformed spirometric data were analyzed using multiple linear regressions, adjusting for anthropometric factors. Five different additional models adjusted for (1) cultural factors, (2) indicators of socioeconomic status, (3) perinatal data reflecting intrauterine growth, (4) environmental exposures, and (5) personal and family history of wheeze. RESULTS: Height- and gender-adjusted forced vital capacity (FVC) and forced expired volume in 1 second (FEV1) were lower in South Asian than white children (relative difference –11% and –9% respectively, P < .001), but PEF and FEF50 were similar (P ≥ .5). FEV1/FVC was higher in South Asians (1.8%, P < .001). These differences remained largely unchanged in all 5 alternative models. CONCLUSIONS: Our study confirmed important differences in lung volumes between South Asian and white children. These were not attenuated after adjustment for cultural and socioeconomic factors and intrauterine growth, neither were they explained by differences in environmental exposures nor a personal or family history of wheeze. This suggests that differences in lung function may be mainly genetic in origin. The implication is that ethnicity-specific predicted values remain important specifically for South Asian children.

Use of a Systematic Observational Measure to Assess and Compare Walkability for Older Adults in Vancouver, British Columbia and Portland, Oregon Neighbourhoods

This study assessed neighbourhood walkability for older adults in eight neighbourhoods of Vancouver, British Columbia and Portland Oregon, utilizing the newly developed environmental audit tool ‘SWEAT-R’. The discrete variable based data are complemented with qualitative observation data. Findings indicate that the audit tool has a 95% or higher inter-rater reliability for more than 80% of the items. Neighbourhood environmental data suggest that neighbourhoods in Vancouver region have more urban design features supportive of walking behaviour. Sidewalk and street life environmental features were relatively similar across all four Portland neighbourhoods, however, there were notable differences in sidewalk characteristics among the four Vancouver neighbourhoods. The audit tool is useful in documenting walkable features in urban and suburban neighbourhoods with particular relevance to older adults’ needs.

Copy Number Variation of the Beta-Defensin Genes in Europeans: No Supporting Evidence for Association with Lung Function, Chronic Obstructive Pulmonary Disease or Asthma

Lung function measures are heritable, predict mortality and are relevant in diagnosis of chronic obstructive pulmonary disease (COPD). COPD and asthma are diseases of the airways with major public health impacts and each have a heritable component. Genome-wide association studies of SNPs have revealed novel genetic associations with both diseases but only account for a small proportion of the heritability. Complex copy number variation may account for some of the missing heritability. A well-characterised genomic region of complex copy number variation contains beta-defensin genes (DEFB103, DEFB104 and DEFB4), which have a role in the innate immune response. Previous studies have implicated these and related genes as being associated with asthma or COPD. We hypothesised that copy number variation of these genes may play a role in lung function in the general population and in COPD and asthma risk. We undertook copy number typing of this locus in 1149 adult and 689 children using a paralogue ratio test and investigated association with COPD, asthma and lung function. Replication of findings was assessed in a larger independent sample of COPD cases and smoking controls. We found evidence for an association of beta-defensin copy number with COPD in the adult cohort (OR = 1.4, 95%CI:1.02–1.92, P = 0.039) but this finding, and findings from a previous study, were not replicated in a larger follow-up sample(OR = 0.89, 95%CI:0.72–1.07, P = 0.217). No robust evidence of association with asthma in children was observed. We found no evidence for association between beta-defensin copy number and lung function in the general populations. Our findings suggest that previous reports of association of beta-defensin copy number with COPD should be viewed with caution. Suboptimal measurement of copy number can lead to spurious associations. Further beta-defensin copy number measurement in larger sample sizes of COPD cases and children with asthma are needed.

Dogaru et al. Respond to “Does Breastfeeding Protect Against ‘Asthma’?”

We thank Michael Kramer for his insightful comments (1) on our systematic review and meta-analysis on breastfeeding and childhood asthma (2). Following a concise summary of our findings, he points out the high heterogeneity of the results and addresses issues that might explain this, namely the phenotypic variability of asthma, lack of objective measurements, variable degrees of measurement bias, and residual confounding. We entirely agree with Professor Kramer that “asthma” is a label applied to a heterogeneous syndrome, consisting of several distinct phenotypes, each with its own pathophysiological mechanisms and risk factors (3, 4). Transient wheeze induced by viral infections in an infant is likely a different entity than chronic, multitrigger asthma in an atopic schoolchild. Not accounting for this phenotypic variability might explain part of the heterogeneity we found, but not all. Arguably, breastfeeding can act as protective mechanism for either phenotype through different mechanisms influencing respiratory infections and/or priming the immune system. We think that a big part of the heterogeneity is due to poor or incomplete operational definitions of asthma by the studies analyzed. The definitions of the outcome varied greatly, from “wheezing in the past 12 months” through “Does your child have asthma?” and to more elaborated constructions such as “3 reported episodes of wheeze during first 2 years of life treated with inhaled steroids or signs of hyperactivity without upper respiratory infection.” These definitions describe different outcomes in terms of phenotype and severity and are sometimes incomplete or have insufficient validity. It is essential that asthma studies define and measure more clearly the particular phenotype(s) they are studying by including more standardized asthma-specific survey questions and, whenever possible, objective measurements such as different tests of lung function, bronchial responsiveness, and airway inflammation. Equally important, studies should report more clearly the age at first diagnosis and the history of the condition; these things were rather fuzzy in the studies we analyzed. For a true assessment of a dose-response relationship, breastfeeding should ideally be recorded as duration in months or—less preferred—by using several categories. Only 4 studies used a continuous variable, whereas a third compared breastfeeding “ever” with “never.” The rest used variables with 3–6 categories, which were incompatible across many studies. This made it difficult to investigate dose-response relationships in a consistent way, so we decided on a pragmatic approach and dichotomized breastfeeding duration into more versus less. It might be possible to attempt a follow-up study on a smaller sample of suitable studies and perform a dose-response meta-analysis. It is imperative that studies of breastfeeding record it as a continuous measure. It does not require additional measurement, and maternal recall is reliable (5, 6). A measurement bias due to nonblinding of the observers is also possible, particularly for studies of parent-reported outcomes. However, in more than half of the studies (55 of 117) breastfeeding was not the main exposure; this makes this type of bias less likely. Finally, residual confounding is likely a major source of heterogeneity. There was great variability in the number and type of confounders considered; 40 of 117 studies did not adjust for confounders. Daycare attendance may indeed be relevant, and only 16 of 117 studies adjusted for it. Infants who attend daycare are more exposed to infections; they are also less likely to be breastfed and thus to benefit from breastfeeding’s protective effect. We recognize that we should have introduced this information in our study quality’s list of “essential confounders.” We concur with Professor Kramer’s conclusions and recommendations; we need studies with better diagnostic

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 3Helium (3He) 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.

Hidden Needs in Suffolk

Suffolk is a county in England with an estimated population, in 2016, of 745’300 inhabitants. It has the reputation of being a prosperous, picturesque, mostly rural county, so beautifully presented in the work of John Constable and Thomas Gainsborough, who claim Suffolk as their birthplace. However, the reality of Suffolk is not so shining. In 2011 a first report commissioned by Suffolk Community Foundations introduced the concept of “hidden need”, whereby overall affluence in a region conceals local deprivation. Five years on we revisited the analysis on Suffolk’s hidden needs – and the results are mixed. More than half of Suffolk’s neighbourhoods have experienced increased levels of relative deprivation in the last five years. Over 83’000 people in Suffolk – of which almost 20’000 are children – live in income deprivation at the most minimal standard provided by welfare benefits; this is about 5’000 more than five years before. The county experiences increased pressure from an ageing population with decreased birth rate and a lower proportion of working-age population compared regionally and nationally. While unemployment rates are lower in Suffolk than the regional and national rates, the income levels are also lower, with fewer people working in managerial and professional jobs. The deprivation goes beyond income and it is, in some places, highly localised and concentrated. Many deprived individuals live in affluent areas which – counter-intuitively at a first glance – tend to be rural and more isolated. An important implication is that their needs are indeed ‘hidden’, and they might find it more difficult to gain access to support and services.