Anina M. Pescatore

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.

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

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 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.

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

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.

Increased prevalence of pre-school wheeze is not explained by time trends in body mass index.

To the Editor: Overweight and obesity have been associated with asthma, particularly in adults [1–4]. In children, findings are less consistent [2, 5–7]. Different mechanisms have been proposed to explain this association, including lung mechanics, systemic inflammation and associated comorbidities [1, 2, 8]. In a previous study, we showed that the prevalence of pre-school wheeze doubled in two cohorts in Leicestershire, UK, born 8 years apart [9]. This increase could not be attributed to differences in environmental exposures, socioeconomic status or vaccination status [9, 10]. Because body mass index (BMI) is increasing across the globe [2], we hypothesised that BMI played a role. We therefore sought to determine whether higher BMI in the second cohort could explain the increase in prevalence of pre-school wheezing and asthma. Our data come from the Leicester Respiratory Cohorts, two population-based random samples of children living in Leicestershire [11]. Cohort 1 included children born in 1985–1989; cohort 2 included children born in 1993–1997. At the time the first respiratory questionnaire was administered (1990 and 1998), children were 1–4 years old. An identical study protocol was followed for both cohorts [11]. Parents completed a postal questionnaire that asked for detailed information on respiratory symptoms and environmental exposures. Routine data, including demographic and ethnic information, and data on growth and immunisations, were available from the Leicestershire Health Authority Database. Height and weight had been measured and recorded independently by health visitors. We used the measurements made closest to the date of the questionnaire for analyses. The Leicestershire Health Authority Research Ethics Committee (Leicester, UK) approved the study. We included white pre-school children aged 1–4.99 years, with completed questionnaires and at least one valid …

P87 Is fraction of exhaled nitric oxide (FeNO) in asymptomatic older teenagers related to preschool wheeze and chronic cough

Background Many children with preschool wheeze and chronic cough become asymptomatic in later childhood, only for asthma to be diagnosed in adulthood (1). A previous study found in individuals with apparently outgrown childhood asthma, fraction of exhaled nitric oxide (FeNO) was significantly increased (2). Whether teenagers with a history of preschool wheezing or chronic cough have elevated FeNO, and whether this differs between preschool wheeze phenotypes is unknown. Aims We compared FeNO and induced sputum inflammatory cell counts in asymptomatic teenagers from the Leicestershire Respiratory Cohort, who had persistent ‘multiple trigger’ wheeze (PW), transient viral wheeze (TW), persistent cough (PC), or no respiratory symptoms (controls) during the preschool years. Methods Thirty-six subjects (mean age: 16 years) participated: 7 with PW; 12 with TW; 7 with PC; and 10 controls. FeNO was measured using a portable electrochemical analyser (NIOX MINO® Asthma Inflammation Monitor, Aerocrine AB, Sweden). Sputum was induced with nebulised hypertonic saline and processed according to previously published protocol (3) with an adaptation for smaller samples. Results There was no statistically significant difference in mean logFeNO between groups (p = 0.563) (Figure 1). Median% sputum eosinophils for PW and TW groups were significantly higher than in controls. Sputum total cell counts were significantly greater in PW and PC groups than in controls. Abstract P 87 Figure 1. Fraction of nitric oxide in exhaled breath of persistent wheeze, transient wheeze, persistent cough, and control groups. Conclusions We did not find evidence that FeNO in asymptomatic adolescents is related to history of preschool wheeze and chronic cough. However, we found evidence that eosinophilic airway inflammation is increased in asymptomatic adolescents with preschool PW and TW. The relationship between FeNO and evidence of elevated inflammatory cell counts in sputum remains enigmatic. These findings have implications for the understanding of the natural history of preschool wheeze and chronic cough. References Roorda RJ. Prognostic factors for the outcome of childhood asthma in adolescence. Thorax 1996;51(S1):S7-S12. van Den Toorn LM, et al. Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness. Am J Respir Crit Care Med 2000 Sep;162(3 Pt 1):953–957. Pin I, et al. Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax 1992;47:25–9.

S16 Outcomes of multiple trigger wheeze and exclusive viral wheeze in early childhood: A comparison across two population cohorts

Introduction Early childhood wheeze has been classified according to triggers; exclusive viral wheeze (EVW) and multiple trigger wheeze (MTW). It has been proposed that these phenotypes differ in their aetiology, severity and prognosis. Objectives To examine the prevalence and symptom severity of EVW and MTW in 2–6 year olds. To evaluate the stability of these phenotypes over time, and their association with later wheeze. Method In two longitudinal birth cohorts comprising 18,362 individuals, data on respiratory symptoms were collected at age 2, 4 and 6 years. Parent-reported triggers were used to classify wheeze as EVW or MTW for each 2-year period. Logistic regression analysis was used to estimate odds ratios for current wheeze and relative risk ratios for wheeze phenotypes versus no wheeze, at follow-up compared with baseline. Results At 2 years 17.6% and 22.6% (cohorts 1 and 2 respectively) had wheeze, of which 55.2% and 56.3% had MTW. At 6 years 69.7% and 75.7% of children with wheeze had MTW. Among children with wheeze at baseline, 58–76% with EVW and 46–67% with MTW were in remission 2 years later (cohort 1) and 14–20% and 4–11% (cohort 2). MTW had greater reported symptom-severity at all time-points compared with EVW. When adjusted for symptom-severity, children with EVW at baseline had relative risk ratios (RRR) of 2.9–7.4 and 4.1–15.5 (cohorts 1 and 2 respectively) for EVW and RRR 1.7–2.9 and 1.6–4.0 for MTW at follow-up. Children with MTW at baseline had RRR of 3.1–6.2 in cohort 1 and 3.6–15.6 in cohort 2 for MTW and 1.1–2.7 and 1.4–7.0 respectively for EVW at follow-up. Conclusions When adjusted for symptom severity, wheezing phenotypes based on reported triggers remained stable between 2–6 years of age. Symptom-severity may be a more important determinant than triggers of future wheeze classification in young children.

Airway eosinophils in older teenagers with outgrown preschool wheeze: a pilot study

Preschool wheezing affects one-third of all children growing up in the UK [1]. It varies in clinical presentation and severity, and there is evidence to suggest the co-existence of different wheeze phenotypes [2], some of which have been associated with adult asthma and chronic obstructive pulmonary disease [3]. Using data from the Leicester Respiratory Cohort studies [4], we have previously applied objective data-driven methods to distinguish three distinct preschool wheeze phenotypes: “atopic” and “non-atopic” persistent wheeze (PW) and transient viral wheeze (TVW) [5]. In children with PW, attacks of wheeze with and without colds were observed both at preschool age (0–5 years) and when followed-up at early school-age (4–8 years). Children with TVW, triggered predominantly by colds, had symptoms at age 0–5 years but not at age 4–8 years. Prognosis 5 years later (aged 8–13 years) was markedly better in children with TVW compared to the two PW phenotypes [6]. Teenagers with outgrown childhood wheeze display low level eosinophilic airway inflammation and lung function deficit http://ow.ly/REaMc

Viral wheezing is virus specific and not just host specific

infections are nonsymptomatic and wheezing may be the only symptom of respiratory viral infection. Prospective postbronchiolitis follow-up studies with virus-specific diagnoses and virus-specific outcomes available have provided evidence that viral wheezing is also a virus-specific phenomenon, not only a host-specific phenomenon. There may be different viruses that trigger wheezing in children with exclusively viral wheezing and in children with allergic wheezing.