Brett G. Toelle

The effects of body weight on airway calibre

Increased wheeze and asthma diagnosis in obesity may be due to reduced lung volume with subsequent airway narrowing. Asthma (wheeze and airway hyperresponsiveness), functional residual capacity (FRC) and airway conductance (Gaw) were measured in 276 randomly selected subjects aged 28–30 yrs. Data were initially adjusted for smoking and asthma before examining relationships between weight and FRC (after adjustment for height), and between body mass index (BMI = weight·height−2) and Gaw (after adjustment for FRC) by multiple linear regression, separately for females and males. For males and females, BMI (±95% confidence interval) was 27.0±4.6 kg·m−2 and 25.6±6.0 kg·m−2 respectively, Gaw was 0.64±0.04 L·s−1·cmH2O−1 and 0.57±0.03 L·s−1·cmH2O−1, and FRC was 85.3±3.4 and 84.0±2.9% of predicted. Weight correlated independently with FRC in males and females. BMI correlated independently and inversely with Gaw in males, but only weakly in females. In conclusion, obesity is associated with reduced lung volume, which is linked with airway narrowing. However, in males, airway narrowing is greater than that due to reduced lung volume alone. The mechanisms causing airway narrowing and sex differences in obesity are unknown.

An exercise challenge protocol for epidemiological studies of asthma in children: comparison with histamine challenge

We investigated whether an exercise challenge protocol is suitable for measuring bronchial responsiveness in epidemiological studies of asthma in children, and determined its comparability with histamine challenge. The exercise challenge was 6 minutes of outdoor, free-range running at 85-90% of maximum heart rate, measured by heart rate monitor. Nose clips were worn. Distance run was measured to estimate oxygen consumption. Water content of the inspired air was < 10 mg H2O.l-1. Histamine challenge was by the rapid method. We used questionnaires to measure respiratory symptoms and skin prick tests to measure atopy. A total of 96 children aged 8-11 years were studied. Bronchial hyperresponsiveness (BHR) to exercise challenge was defined as a fall in forced expiratory volume in one second (FEV1) of 13% of greater. Eleven children had a positive response to exercise challenge and 11 to histamine challenge but 12 responded to one challenge and not to the other. The correlation coefficient between the two tests was 0.65 (p = 0.0001). Exercise challenge thus proved to be a practical epidemiological tool for objective measurements of bronchial responsiveness in children. In this sample, some children responded to one challenge and not to the other which suggests that the two challenges identify different abnormalities of the airways.

Continuing the debate about measuring asthma in population studies

The reasons for measuring atopy and airway hyperresponsiveness (AHR) and the methods of validating measurements of asthma in population studies continue to be debated. The debate has centred around standards against which to validate asthma measurements but the absence of a “gold standard” makes the criterion validation of measurements difficult. Questionnaires will always be useful but cannot be validated against a doctor diagnosis because of self-selection and recall biases. In practice, measurements should be selected on the merits of what they measure rather than being regarded as validated or non-validated alternatives. The measurement of AHR is invaluable because it is reliable, not influenced by variations in symptom perception or diagnostic trends, and is closely related to the underlying mechanisms of asthma. The value of AHR lies in its high specificity (rate of true negatives) and low sensitivity (rate of false positives) against asthma symptoms which gives additional information about symptomatic subjects. Atopy is also a useful test and, in quantifying its association with asthma, we should not place any currency on ecological evidence. Atopy is a strong risk factor for asthma in the presence of regionally specific allergens and ecological analyses that ignore these effects are diversionary rather than productive. For preventing asthma, we need to identify the group at greatest risk of developing it, measure the risk factors with precision, and develop interventions that are effective in changing environmental exposures and homogenous outcomes. This is the only approach that has the potential to lead to significant public health benefits.

Repeatability of peak nasal inspiratory flow measurements and utility for assessing the severity of rhinitis

Background:  The measurement of peak nasal inspiratory flow (PNIF) provides a simple, cheap, fast and readily available tool for determining the extent of nasal airway patency. However, there are questions regarding its repeatability when used to assess the degree of nasal obstruction in large populations. Therefore, this study aimed to evaluate the repeatability of PNIF measurements and to assess their association with the signs and symptoms of rhinitis.

Mite allergen (Der p 1) concentration in houses and its relation to the presence and severity of asthma in a population of Sydney schoolchildren

House dust mite (HDM) allergen exposure and its relation to HDM allergy and asthma was assessed in a case-control study conducted over three seasons in 74 Sydney schoolchildren, 33 of whom were allergic to HDM and 12 of whom had current asthma. In each season histamine inhalation tests and skin prick tests were performed, symptom questionnaires were administered, and dust samples were collected. The mean concentrations of HDM allergen (in micrograms of Der p 1 per gram of fine dust) were: bed, 38.9 (95% confidence interval [CI], 31.8 to 47.5); bedroom floor, 22.4 (95% CI, 18.3 to 27.5); and lounge room floor, 13.7 (95% CI, 10.7 to 17.6). The mean of the highest allergen concentration in each house was 51.0 (95% CI, 43.2 to 60.1). All but two subjects had at least one site in all seasons with an HDM allergen concentration greater than 10 micrograms/gm, the proposed threshold for asthma symptoms. Subjects with allergy to HDM, symptoms of asthma, or airway hyperresponsiveness did not have higher HDM allergen concentrations in their house. In this study we were unable to test hypotheses concerning proposed thresholds for risk of sensitization and for risk of asthma symptoms because virtually all subjects were exposed to HDM allergen levels above the proposed thresholds.

Risk factors for onset and remission of atopy, wheeze, and airway hyperresponsiveness

Background: Although many children with asthma may have a remission as they grow and other children who did not have asthma may develop asthma in adult life, knowledge about the factors that influence the onset and prognosis of asthma during adolescence and young adulthood is very limited. Methods: A cohort of 8–10 year old children (n=718) living in Belmont, New South Wales, Australia were surveyed six times at 2 yearly intervals from 1982 to 1992, and then again 5 years later in 1997. From this cohort, 498 subjects had between three and seven assessments and were included in the analysis. Atopy, airway hyperresponsiveness (AHR), and wheeze in the last 12 months were measured at each survey. Late onset, remission, and persistence were defined based on characteristics at the initial survey and the changes in characteristics at the follow up surveys. Results: The proportion of subjects with late onset atopy (13.7%) and wheeze (12.4%) was greater than the proportion with remission of atopy (3.2%) and wheeze (5.6%). Having atopy at age 8–12 years (OR 2.8, 95% CI 1.5 to 5.1) and having a parental history of asthma (OR 2.0, 95% CI 1.02 to 4.13) were significant risk factors for the onset of wheeze. Having AHR at age 8–12 years was a significant risk factor for the persistence of wheeze (OR 4.3, 95% CI 1.3 to 15.0). Female sex (OR 1.9, 95% CI 1.01 to 3.60) was a significant risk factor for late onset AHR whereas male sex (OR 1.9, 95% CI 1.1 to 2.8) was a significant risk factor for late onset atopy. Conclusions: The onset of AHR is uncommon during adolescence, but the risk of acquiring atopy and recent wheeze for the first time continues during this period. Atopy, particularly present at the age of 8–10 years, predicts the subsequent onset of wheeze.

Childhood factors that predict asthma in young adulthood.

Predicting adult asthma, using childhood characteristics, is important for advising on prognosis and, potentially, for secondary prevention. A novel use of multivariate likelihood ratios (LRs) to quantify prognosis is described here. Of 718 subjects of a community-based cohort, 575 (80%) members were recruited at age 8–10 yrs and were re-assessed 15–17 yrs later. At baseline, information about symptoms, spirometry, histamine challenge and skin-prick tests were collected. At follow-up “asthma symptoms” were defined as wheeze, sleep disturbance from asthma or inhaled steroid use within the previous year. LRs were calculated for significant predictors of this outcome. Shinkage factors were applied to yield multivariate LRs. Childhood characteristics that independently predicted asthma symptoms in adulthood were obstructive spirometry (adjusted (adj)LR 2.9, 95% confidence interval (CI) 1.3–6.5), airway hyperresponsiveness (adjLR 2.6, 95% CI 1.8–3.7), atopy (adjLR 2.0, 95% CI 1.5–2.7), recent wheeze (adjLR 1.9, 95% CI 1.5–2.5) and being female (adjLR 1.29, 95% CI 0.8–2.1). Children with all five characteristics had a cumulative LR of 36.9 for asthma symptoms in adulthood. Most adults who had asthma symptoms did not have manifestations of asthma as children. However, the presence of obstructive spirometry, airway hyperresponsiveness and atopy in childhood identifies individuals with increased likelihood of having asthma in adulthood. Cumulative likelihood ratios are more valuable than odds ratios for quantifying risk in individuals and for identifying people with most to gain from preventive interventions.

Analysis of adherence to peak flow monitoring when recording of data is electronic

Peak flow monitoring is widely recommended in international asthma guidelines. However, suspicions about the accuracy of conventional pen and paper records were confirmed when studies with electronic spirometers showed poor adherence and falsification of data.1 There seems to be a prevailing nihilistic attitude to peak flow monitoring, largely based on the perception that satisfactory adherence cannot be achieved. We aimed to measure long term adherence to electronic peak flow monitoring when participants were aware that data were being stored and used to guide treatment. We obtained data from a 72 week randomised study comparing two starting doses of budesonide in patients aged 18-75 with poorly controlled asthma. The design and outcomes of the study are reported elsewhere.2 The study incorporated two novel features: twice daily monitoring with electronic diary spirometers (MicroMedical DiaryCard; MicroMedical, Rochester, UK) and titration of dose of budesonide (weeks 17-72) by using a clinical algorithm based on peak flow and diary data. …

The association of comorbid anxiety and depression with asthma‐related quality of life and symptom perception in adults

Background and objective:  There are limited data on the association and interaction between anxiety and depression comorbidity and asthma‐related quality of life (AQOL) and symptom perception. This study evaluated these associations in patients subsequent to an emergency department (ED) visit for asthma.

Robust Estimation of Experimentwise P Values Applied to a Genome Scan of Multiple Asthma Traits Identifies a New Region of Significant Linkage on Chromosome 20q13

Over 30 genomic regions show linkage to asthma traits. Six asthma genes have been cloned, but the putative loci in many linked regions have not been identified. To search for asthma susceptibility loci, we performed genomewide univariate linkage analyses of seven asthma traits, using 202 Australian families ascertained through a twin proband. House-dust mite sensitivity (Dpter) exceeded the empirical threshold for significant linkage at 102 cM on chromosome 20q13, near marker D20S173 (empirical pointwise P = .00001 and genomewide P = .005, both uncorrected for multiple-trait testing). Atopy, bronchial hyperresponsiveness (BHR), and forced expiratory volume in 1 s (FEV1) were also linked to this region. In addition, 16 regions were linked to at least one trait at the suggestive level, including 12q24, which has consistently shown linkage to asthma traits in other studies. Some regions were expected to be false-positives arising from multiple-trait testing. To address this, we developed a new approach to estimate genomewide significance that accounts for multiple-trait testing and for correlation between traits and that does not require a Bonferroni correction. With this approach, Dpter remained significantly linked to 20q13 (empirical genomewide P = .042), and airway obstruction remained linked to 12q24 at the suggestive level. Finally, we extended this method to show that the linkage of Dpter, atopy, BHR, FEV1, asthma, and airway obstruction to chromosome 20q13 is unlikely to be due to chance and may result from a quantitative trait locus in this region that affects several of these traits.