Greater parallel heterogeneity of airway narrowing and airway closure in asthma measured by high-resolution CT.

BACKGROUND: Heterogeneous airway narrowing and closure are characteristics of asthma. However, they have never been quantified by direct measurements of parallel sister airways obtained from image data, and the anatomical basis of these processes remains unknown. METHODS: Seven normal and nine asthmatic subjects underwent high-resolution CT, before and after methacholine challenge. Mean lumen areas of the entire airways were measured in 28 and 24 parallel sister airway pairs (a pair of airways arising from the same bifurcation) respectively (range 1.0-8.7 mm diameter). Heterogeneous narrowing was defined as the median difference in percentage narrowing between parallel sister airways. Forced oscillatory respiratory resistance (Rrs) and spirometry were measured before and after methacholine challenge conducted while supine. RESULTS: The airways of asthmatics were smaller at baseline, and following bronchoconstriction there were similar decreases in FEV1, increases in Rrs and mean narrowing of airways for asthmatic and non-asthmatic groups. Non-asthmatics required higher doses of methacholine than asthmatics to achieve the same changes. However, parallel heterogeneity (median (IQR) 33% (27-53%) vs 11% (9-18%), p<0.001) and airway closure (24.1% and 7.7%, p=0.001, χ(2)) were greater in asthmatics versus non-asthmatics. CONCLUSION: We found clear evidence of differences in airway behaviour in the asthmatic group. Asthmatic airways were narrower at baseline and responded to inhaled methacholine by more heterogeneous narrowing of parallel sister airways and greater airway closure.

Small airways function declines after allogeneic haematopoietic stem cell transplantation.

Bronchiolitis obliterans (BO) following allogeneic haematopoietic stem cell transplantation (HSCT) affects peripheral airways. Detection of BO is presently delayed by the low sensitivity of spirometry. We examined the relationship between peripheral airway function and time since HSCT, and compared it with spirometry and clinical indices in 33 clinically stable allogeneic HSCT recipients. The following measurements were performed: lung function, exhaled nitric oxide, forced oscillatory respiratory system resistance and reactance, acinar (S(acin)) and conductive airways ventilation heterogeneity and lung clearance index (LCI) measured by multiple breath nitrogen washout. 22 patients underwent repeat visits from which short-term changes were examined. Median time post HSCT was 12 months. Eight patients were clinically diagnosed as having BO. In multivariate analysis, time since HSCT was predicted by S(acin) and forced expiratory volume in 1 s % predicted. 20 patients had abnormal S(acin) with normal spirometry, whereas none had airflow obstruction with normal S(acin). S(acin) and LCI were the only measures to change significantly between two visits, with both worsening. Change in S(acin) was the only parameter to correlate with change in chronic graft-versus-host disease grade. In conclusion, peripheral airways ventilation heterogeneity worsens with time after HSCT. S(acin) may be more sensitive than spirometry in detecting BO at an early stage, which needs confirmation in a prospective study.

Increased airway closure is a determinant of airway hyperresponsiveness.

In order to investigate whether increased airway closure is a component of airway hyperresponsiveness (AHR), airway closure was compared during induced bronchoconstriction in 62 asthmatic, 41 nonasthmatic nonobese (control) and 20 nonasthmatic obese (obese) subjects. Airway closure and airway narrowing were measured by spirometry as percentage change in forced vital capacity (%DeltaFVC) and change in forced expiratory ratio (DeltaFER), respectively. Multiple regression analyses were used to assess the determinants of AHR, assessed by the dose response slope (DRS). The DRS was significantly increased in asthmatics compared with controls but did not differ between obese and controls. The spirometric predictors of logDRS were baseline FER, DeltaFER, body mass index (BMI) and %DeltaFVC. There was a negative relationship between BMI and logDRS in the regression, suggesting a protective effect. The present findings suggest that the extent of airway closure during induced bronchoconstriction is a determinant of airway hyperresponsiveness, independent of the level of airway narrowing. However, after adjusting for airway closure, obesity appears to protect against airway hyperresponsiveness.

Effect of obesity on breathlessness and airway responsiveness to methacholine in non-asthmatic subjects.

BACKGROUND: Obesity is associated with increased prevalence and incidence of asthma, but the mechanism is unknown. Obesity reduces lung volumes, which can increase airway responsiveness, and increases resistive and elastic work of breathing, which can increase dyspnea. OBJECTIVE: To determine if the intensity of dyspnea due to airway narrowing or if airway responsiveness is increased in obese, non-asthmatic subjects. SUBJECTS: Twenty-three obese (BMI (body mass index) > or =30 kg m(-2)) and 26 non-obese (BMI <30 kg m(-2)) non-asthmatic subjects, aged between 18 and 70 years. METHODS: High-dose methacholine challenge was used to determine the sensitivity and the maximal response to methacholine. Respiratory system resistance (Rrs) and reactance were measured, using the forced oscillation technique, as indicators of resistive and elastic loads during challenge. Perception of dyspnea was measured by the Borg score during challenge. Static lung volumes were measured by body plethysmography. RESULTS: Static lung volumes were reduced in the obese subjects. There were no significant differences in the sensitivity or maximal response to methacholine between obese and non-obese subjects. The magnitude of change in Rrs was similar in both groups, but obese subjects had more negative reactance after challenge (P=0.002) indicating a greater elastic load. The intensity of dyspnea was greater in obese subjects (P=0.03). CONCLUSIONS: Obesity reduces lung volumes, but does not alter the sensitivity or maximal response to methacholine. However, obese subjects have enhanced perception of dyspnea, associated with greater apparent stiffness of the respiratory system, and may therefore be at greater risk of symptoms.

Reliability of a respiratory history questionnaire and effect of mode of administration on classification of asthma in children.

Because there is no consensus definition of asthma for epidemiology, we have examined the reliability of a questionnaire and the effect of its mode of administration on classification of asthma in children. A symptom history questionnaire was parent self-administered and then readministered within three months by a nurse. The questions of diagnosed asthma, cumulative wheeze, and recent wheeze (wheeze in the previous 12 months) were more repeatable than questions of night cough, but 7 percent of children changed diagnosed asthma category, 13 percent changed cumulative wheeze category, and 9 percent changed recent wheeze category at second questionnaire. Because the numbers who changed from symptom positive to negative roughly equalled the changes from negative to positive, prevalence estimates were not affected. Methods of measuring asthma with greater precision are urgently needed. Because of reporting bias, epidemiologic information collected by current questionnaires should be treated with some caution.

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.

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. METHODS: The PNIF, rhinitis symptoms, judged by Meltzer questionnaire and rhinitis signs, as determined by anterior rhinoscopy, were assessed in 283 adults representative of the general population. One training and two test PNIF measurements were recorded during the same session. RESULTS: The PNIF was highly reproducible (ICC = 0.92; 95% limits of agreement: +/-36 l/min). The PNIF was strongly correlated with rhinitis signs, measured by anterior rhinoscopy (rs= -0.38, P < 0.0001) but was not correlated with rhinitis symptoms, measured by questionnaire (rs= -0.11, P = 0.057). Differences in PNIF for subjects categorized as asymptomatic, mild or moderate/severe on the basis of rhinitis signs, were highly significant (P < 0.0001), but less significant on the basis of rhinitis symptoms (P = 0.04). A PNIF cut-off of 115 l/min had moderately high specificity (72%) and sensitivity (65%) and a high negative predictive value (90%) for moderate/severe signs of rhinitis. CONCLUSION: In a large general population-based sample of young adults, PNIF was highly reproducible and closely related to the signs of rhinitis, as determined by clinical examination. The PNIF provides information that is qualitatively different to that provided by symptom scores and may be useful to measure the extent of nasal obstruction.

Asthma and allergy associated with occupational exposure to ispaghula and senna products in a pharmaceutical work force.

A cross-sectional study of 125 pharmaceutical workers engaged in the manufacture of bulk laxatives based on ispaghula husks (psyllium) and senna pods was conducted. Skin prick tests with extracts of these components revealed that 7.6% were allergic to ispaghula and 15.3% were allergic to senna. Four (3.2%) cases of occupational asthma were identified. The overall prevalence of asthma (6.4%) was less than in a comparable nonexposed Australian population (odds ration, 0.44). Symptoms referrable to the upper airways, eyes, and skin were more prevalent (52.0%) than in the reference population (odds ratio, 1.53). Smokers and nonatopic subjects were more likely to complain of these symptoms if they were sensitized to senna and/or ispaghula than if they were not sensitized (relative risks, 1.9 and 2.6, respectively). Sensitization to ispaghula and/or senna was not a risk factor for asthma. An IgE-mediated allergic mechanism is probably responsible for the allergic symptoms in many of these subjects. Smoking seems to be a cofactor in this process.

Comparison of bronchial reactivity to histamine and methacholine in asthmatics.

Eight subjects with asthma underwent bronchial challenge with histamine and methacholine. Dose-response curves were drawn on a scale which made the dosage equivalent in molecular weight. The results were analysed in terms of both the slope of the dose-response curve and the dose required to elicit a 20% fall in FEV1. No significant difference between methacholine and histamine was found in either measurement. Because of the similarity of the responses we conclude that the two agents are similar in action and may be used with equal effectiveness in bronchial challenges.

Asthma and atopy in overweight children.

BACKGROUND: Obesity may be associated with an increase in asthma and atopy in children. If so, the effect could be due to an effect of obesity on lung volume and thus airway hyperresponsiveness. METHODS: Data from 5993 caucasian children aged 7-12 years from seven epidemiological studies performed in NSW were analysed. Subjects were included if data were available for height, weight, age, skin prick test results to a common panel of aeroallergens, and a measure of airway responsiveness. History of doctor diagnosed asthma, wheeze, cough, and medication use was obtained by questionnaire. Recent asthma was defined as a doctor diagnosis of asthma ever and wheeze in the last 12 months. Body mass index (BMI) percentiles, divided into quintiles per year age, were used as a measure of standardised weight. Dose response ratio (DRR) was used as a measure of airway responsiveness. Airway hyperresponsiveness was defined as a DRR of >/=8.1. Adjusted odds ratios were obtained by logistic regression. RESULTS: After adjusting for atopy, sex, age, smoking and family history, BMI was a significant risk factor for wheeze ever (OR = 1.06, p = 0.007) and cough (OR = 1.08, p = 0.001), but not for recent asthma (OR = 1.02, p = 0.43) or airway hyperresponsiveness (OR = 0.97 p = 0.17). In girls a higher BMI was significantly associated with higher prevalence of atopy (chi(2) trend 7.9, p = 0.005), wheeze ever (chi(2) trend 10.4, p = 0.001), and cough (chi(2) trend 12.3, p<0.001). These were not significant in boys. CONCLUSIONS: Higher BMI is a risk factor for atopy, wheeze ever, and cough in girls only. Higher BMI is not a risk factor for asthma or airway hyperresponsiveness in either boys or girls.

On adjusting measurements of airway responsiveness for lung size and airway caliber.

It has been suggested that during bronchial challenge with a pharmacologic agent, subjects with small lungs receive a proportionally greater dose of agonist than do those with larger lungs. This infers that measurements of airway hyperresponsiveness (AHR) between different age and gender groups may not be comparable. To examine this, we analyzed data from population samples of 1,613 children 7 to 12 yr of age and 1,484 adults 25 to 50 yr of age in whom we measured airway responsiveness by histamine inhalation test. We used FVC as a surrogate measurement for lung size and FEV1/FVC as a surrogate measurement for airway caliber. When AHR was adjusted for FVC, FEV1/FVC, and gender, the differences in prevalence between age groups was reduced. The prevalence of AHR in those between 7 and 9 yr of age decreased from 20.2% (95% CI, 17.7 to 22.7) to 15.7% (95% CI, 13.4 to 18.0), but the prevalence of AHR in those 35 to 44 yr of age remained the same at 7.6% (95% CI, 5.9 to 9.3). We conclude that FVC and FEV1/FVC have a small but significant effect on the measurement of airway responsiveness and that more precise measurements of the prevalence of AHR can be obtained by standardization for these parameters.

Factors associated with bronchial hyperresponsiveness in Australian adults and children.

To accurately assess putative risk factors for bronchial hyperresponsiveness (BHR), we have used multivariate models to analyse data from 4,366 children living in four regions and from 878 adults. A standard protocol was used to measure bronchial responsiveness to histamine. The prevalence of BHR was high at 7-9 yrs (16-18%), decreased significantly at 11-14 yrs (7-8%), and then increased in adults (12-14%). Atopy was the most important risk factor for BHR at all ages. In children, parental asthma, early respiratory illness and being born in Australia also had a significant influence, and eating fish more than once a week had a protective effect. No effect of parental smoking, gender or race was found. In adults, BHR was associated with being female and with smoking history. It appears that many factors have a significant influence on the presence of BHR, with environmental factors, particularly atopy, birthplace and diet, being the most important.

Prevalence and nature of bronchial hyperresponsiveness in subjects with chronic obstructive pulmonary disease.

The prevalence, nature, and severity of bronchial hyperresponsiveness in subjects with chronic obstructive pulmonary disease (COPD) is not known. To determine these factors, a 1 in 4 random sample of adults attending the Busselton population survey was studied. Subjects answered a modified Medical Research Council questionnaire and had spirometric function tested. They were defined as having COPD or asthma from the questionnaire. Bronchial responsiveness to histamine was measured using the rapid method, and results in the subjects with COPD were compared with those in asthmatic subjects with abnormal lung function. Fifty-nine subjects with COPD had a histamine inhalation test, and of these, 27 had bronchial hyperresponsiveness (BHR) (PD20FEV1 less than 3.9 mumol). The position of the dose response curves of the subjects with COPD overlapped considerably with those obtained from the 17 asthmatics. The geometric mean values for PD20FEV1 for these 2 groups were significantly different (p less than 0.001). There was a good correlation between FEV1/FVC and PD20FEV1 values in the subjects with COPD but not in the asthmatic subjects. Pretreatment with 600 micrograms of aerosolized fenoterol significantly improved the PD20FEV1 values in 11 subjects with COPD (1.26 to 6.16 mumol; p less than 0.001). The results suggest that approximately half the subjects with COPD in a general population have BHR but this BHR has different characteristics from that occurring in asthmatic subjects.

Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects.

In order to determine the effect of drugs on bronchial hyperreactivity in subjects with asthma, 12 atopic asthmatic volunteers underwent bronchial challenge with either histamine or methacholine on three separate days. Before the challenges no medication was given on the first day, on the second 400 microgram of aerosol fenoterol and on the third 5 mg of oral fenoterol were administered. The aerosol fenoterol caused the dose response curves to both histamine and methacholine to be shifted to the right in all subjects. The oral dose produced no significant change from the control values. The slope of the dose response curves was not altered by either the oral or the aerosol drug. It is concluded that aerosol but not oral fenoterol in the clinical dosage, causes a change in the sensitivity but not in the reactivity of the airway of patients with atopic asthma.

Inhaled corticosteroids reduce the severity of bronchial hyperresponsiveness in asthma but oral theophylline does not.

In a double-blind crossover study, we compared the relative effects of inhaled beclomethasone dipropionate (BDP) 800 micrograms per day and oral theophylline on the severity of bronchial hyperresponsiveness (BHR) to histamine. Daily doses of theophylline were sufficient to keep serum levels between 55 and 110 mumol/L. The subjects were 26 patients with severe asthma whose symptoms were inadequately controlled by regular treatment with inhaled salbutamol. The severity of BHR improved within 3 wk in the group treated with BDP, whereas no change occurred in the group treated with theophylline. There were no significant changes in FEV1 in either group during the study. When BDP was changed to theophylline there was a deterioration in BHR. Aerosol steroids, rather than theophylline, are the treatment of choice when reduction in the severity of BHR is the aim of treatment in patients with severe asthma.

Longitudinal changes in atopy during a 4-year period: relation to bronchial hyperresponsiveness and respiratory symptoms in a population sample of Australian schoolchildren.

A total of 380 schoolchildren living in Belmont, New South Wales, a coastal town where the predominant aeroallergens are house dust mites, were studied on three occasions at 2-year intervals. At each study, atopy was measured by skin prick tests to 13 allergens, bronchial responsiveness was measured by histamine inhalation test, and respiratory illness history was assessed by a self-administered questionnaire to parents. The age of the group was 8 to 10 years at enrollment. We found that skin wheals less than 4 mm were not associated with respiratory or allergic illness, and therefore, we defined atopy as the presence of a skin wheal of greater than or equal to 4 mm. In the sample, 24% of the children were atopic at 8 to 10 years (early-onset atopy), and an additional 15% became atopic during the study (late-onset atopy). Both early- and late-onset atopy had a close association with hay fever. Late-onset atopy was strongly associated with inconsistent reporting of symptoms. Early-onset atopy was an important risk factor for bronchial hyperresponsiveness (BHR), diagnosed asthma, and continuing symptoms of wheeze, and was a particularly important risk factor for BHR with current wheeze in late childhood years. We conclude that atopy acquired at an early age is an important predictive factor for respiratory symptoms occurring with BHR and continuing into late childhood.

Effect of therapy on bronchial hyperresponsiveness in the long-term management of asthma.

The aim of this study was to determine if prophylactic therapy leads to a reduction in the severity of bronchial hyperresponsiveness (BHR) in subjects with severe asthma. Measurements of bronchial responsiveness to histamine were made in two groups of subjects for periods up to 2 years. Thirteen subjects in the study group took regular medication and used a home monitor of airway function to determine the medication requirements needed to maintain optimal airway function. A control group of eleven subjects was managed with the same drugs but without daily monitoring and without any attempt to keep daily lung function at optimal levels. Subjects in the study group had a 10- to 100-fold decrease in the severity of BHR, which was independent of the improvement in baseline lung function. All but one subject in the study group became symptom free and six were able to maintain the improvement in BHR and symptoms on reduced medication. There was no change in the severity of BHR or in the baseline lung function in the control group. It is concluded that it is possible to reduce the severity of BHR in subjects with severe asthma by the use of pharmacological agents. This reduction in severity appears to require the long-term use of medications, including aerosol corticosteroids, with daily home monitoring to allow adjustment of the amount of treatment required.