B Rijcken

Histamine airway hyper-responsiveness and mortality from chronic obstructive pulmonary disease: a cohort study

BACKGROUND Smoking and airway lability, which is expressed by histamine airway hyper-responsiveness, are known risk factors for development of respiratory symptoms. Smoking is also associated with increased mortality risks. We studied whether airway hyper-responsiveness is associated with increased mortality, and whether this risk was independent of smoking and reduced lung function. METHODS We followed up 2008 inhabitants of the communities of Vlagtwedde, Vlaardingen, and Meppel (Netherlands), who had histamine challenge test data, from 1964-72 for 30 years. Follow-up was 99% successful (29 patients lost to follow-up) with 1453 participants alive and 526 deaths (246 died from cardiovascular disease, 54 from lung cancer, and 21 from chronic obstructive pulmonary disease [COPD]). FINDINGS Mortality from COPD increased with more severe hyper-responsiveness; relative risks of 3.83 (95% CI 0.97-15.1), 4.40 (1.16-16.7), 4.78 (1.27-18.0), 6.69 (1.71-26.1), and 15.8 (3.72-67.1) were associated with histamine thresholds of 32 g/L, 16 g/L, 8 g/L, 4 g/L, and 1 g/L, respectively, compared with no hyper-responsiveness. These risks were adjusted for sex, age, smoking, lung function, body-mass index, positive skin tests, eosinophilia, asthma, and city of residence. INTERPRETATION Increased histamine airway hyper-responsiveness predicts mortality from COPD. Although this trend was more pronounced in smokers, an increasing proportion of COPD deaths with increasing hyper-responsiveness was also present among individuals who had never smoked.

Effects of ambient air pollution on upper and lower respiratory symptoms and peak expiratory flow in children

BACKGROUND Previous epidemiological studies have shown acute effects of increased amounts of ambient air pollution on the prevalence of respiratory symptoms in children with respiratory disorders. We investigated whether children with bronchial hyperresponsiveness (BHR) and relatively high serum concentrations of total IgE (>60 kU/L, the median value) are susceptible to air pollution. METHODS We collected data from children during three winters (1992-95) in rural and urban areas of the Netherlands. Lower respiratory symptoms (wheeze, attacks of wheezing, shortness of breath), upper respiratory symptoms (sore throat, runny or blocked nose), and peak expiratory flow were recorded daily for 3 months. The acute effects of airborne particulate matter with a diameter of less than 10 microm, black smoke, sulphur dioxide, and nitrogen dioxide were estimated by logistic regression. FINDINGS 459 (73%) of 632 children had complete data. Of these, 26% had BHR and relatively high (above median) serum total IgE, 36% had no BHR and total IgE of 60 kU/L or less, 15% had BHR and total IgE of 60 kU/L or less, and 23% had a total IgE of more than 60 kU/L but no BHR. In children with BHR and relatively high serum total IgE the prevalence of lower respiratory symptoms increased significantly by between 32% and 139% for each 100 microm/m3 increase in particulate matter, and between 16% and 131% for each 40 microm/m3 increase in black smoke, SO2, or NO2. Decrease in peak expiratory flow of more than 10% in that group was more common with increased airborne particulate matter and black smoke. There were no consistent positive or negative associations between increased air pollution and prevalence of respiratory symptoms or decrease in peak expiratory flow in the other three groups of children. INTERPRETATION Children with BHR and relatively high concentrations of serum total IgE are susceptible to air pollution. Although our odds ratios were rather low (range 1.16-2.39) the overall effect of air pollution on public health is likely to be substantial since these odds ratios refer to large numbers of people.

Airways responsiveness and development and remission of chronic respiratory symptoms in adults

BACKGROUND Many patients with chronic obstructive lung disease show increased airways responsiveness to histamine. We investigated the hypothesis that increased airways responsiveness predicts the development and remission of chronic respiratory symptoms. METHODS We used data from 24-year follow-up (1965-90) of 2684 participants in a cohort study in Vlagtwedde and Vlaardingen, Netherlands. Increased airways responsiveness was defined as a PC10 value (concentration of histamine for which challenge led to a 10% fall in forced expiratory volume in 1 s) of less than 8 mg/mL. Information on respiratory symptoms was collected by means of a standard questionnaire every 3 years. Logistic regression was used to control for age, area of residence, cigarette smoking status, and sex. FINDINGS Participants with increased airways responsiveness (1281 observations) were more likely than those without increased airways responsiveness (5801 observations) to develop the following symptoms during any 3-year follow-up interval: chronic cough (odds ratio 1.9 [95% CI 1.2-2.9]), chronic phlegm (2.0 [1.3-3.0]), dyspnoea (2.3 [1.5-3.5]), asthmatic attacks (3.7 [2.2-6.1]), and persistent wheeze (2.7 [1.7-4.4]). The estimate of the odds ratio for the development of any of the six symptoms was 1.7 (1.2-2.3). Participants with increased airways responsiveness were less likely than those without this characteristic to show remission of these respiratory symptoms. The estimate of the odds ratio for the remission of any of the six symptoms was 0.42 (0.28-0.61). INTERPRETATION These prospective analyses show that increased airways responsiveness is positively associated with the development of chronic respiratory symptoms and negatively associated with the remission of these symptoms in adults.

(A)Symptomatic bronchial hyper-responsiveness and asthma

Bronchial responsiveness constitutes the phenomenon of the occurrence of airways obstruction upon physical, chemical and pharmacological stimuli (l-3). The clinical presentation in asthmatic individuals includes wheeze, cough and/or dyspnoea upon exercise and inhalation of e.g. cold air, fog and perfume. The prevalence of bronchial hyper-responsiveness (BHR) in the population varies from 6 to 35% (4-14) and is strongly associated with the presence of respiratory symptoms. Even though BHR is generally accompanied by respiratory symptoms, population studies have shown that it may also occur in subjects without any respiratory symptom, so-called asymptomatic hyper-responsiveness (69,12,15). There is increasing evidence that an inflammatory process in the airway wall is one of the underlying pathophysiologic mechanisms of BHR in asthma. This inflammatory process may directly or indirectly cause smooth muscle contraction, airway wall oedema, and stimulation of the nervous system, leading to symptoms of cough, wheeze and dyspnoea. It is still unclear whether an inflammatory process is also present in asymptomatic individuals, and if so, whether it has similar cellular components. Furthermore, it is important to assess whether asymptomatic hyper-responsiveness has any prognostic importance as an early sign of disease development.

Distribution of peak expiratory flow variability by age, gender and smoking habits in a random population sample aged 20-70 yrs

Peak expiratory flow (PEF) variability can be considered as an index of bronchial lability. Population studies on PEF variability are few. The purpose of the current paper is to describe the distribution of PEF variability in a random population sample of adults with a wide age range (20-70 yrs), and to assess relationships to age, gender and smoking habits. PEF data were collected in 511 participants of the Dutch part of the European Community Respiratory Health Survey. A training effect was found, absolute PEF values on the first measurement day being significantly lower. Females had greater PEF variability (adjusted for age, height and pack-years) and lower absolute PEFs than males. The mean within-day variation (amplitude % mean) was 3.66% (SD 2.03%), whereas the mean day-to-day variation was relatively small: 0.08% (SD 1.53%). Absolute PEFs were lower and amplitude % mean were significantly higher in older age groups. Smoking was significantly associated with lower mean PEFs and greater amplitude % mean. We observed lower mean values of the amplitude % mean than other investigators, possibly related to lower frequency of PEF recording (twice daily). We conclude that PEF and PEF variability have a normal or log-normal distribution. When studying PEF variability, age, gender and smoking habits should be taken into account.

Chronic respiratory symptoms and airway responsiveness to methacholine are associated with eosinophilia in older men: the Normative Aging Study

Identification of subsets of patients with chronic obstructive lung disease (COLD) in order to determine disease outcomes and, possibly, the effects of treatment is an area of clinical interest. At present, it remains unclear which patients with COLD are most likely to benefit from anti-inflammatory therapy. We investigated this question in a community-dwelling sample of men. In this study, the relationship of chronic respiratory symptoms, airway responsiveness to methacholine, and skin test reactivity to peripheral-blood eosinophil and neutrophil counts was examined among 894 male participants in the Normative Aging Study (mean age 60 yrs; range 41-90 yrs). The symptoms considered were asthma, persistent wheeze, dyspnoea, chronic cough and phlegm. Responsiveness to methacholine was defined as a provocative dose producing a 20% fall in forced expiratory volume in one second (PD20FEV1) of < or = 8.6 mumol, a positive skin test as a wheal diameter of > or = 5 mm after subtraction of the diameter of any wheal reaction to a glycerin control, and eosinophilia as an eosinophil count of > or = 275 cells.mm-3 in peripheral blood. Chronic symptoms (odds ratio (OR) 2.0; 95% confidence interval (CI) 1.4-2.7), airway responsiveness (OR 1.7; CI 1.1-2.7), and the combination of symptoms and airway responsiveness (OR 3.4; CI 2.0-5.6) were positively and significantly related to peripheral-blood eosinophil counts. These relationships remained significant after adjustment for the effects of age and smoking, and after exclusion of asthmatic subjects. Symptoms and airway responsiveness combined were not significantly related to neutrophil counts.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of methacholine dose-response curves by linear and exponential mathematical models: goodness-of-fit and validity of extrapolation

Several models have been proposed to analyse dose-response curves recorded in bronchoprovocation challenge tests. The aims of the present work were: 1) to investigate which model (linear vs exponential) and which minimization method (trials and errors vs Levenberg-Marquardt) gives better results in terms of data interpolation (goodness-of-fit); and 2) to verify the validity of extrapolation by comparing forced expiratory volume in one second (FEV1) observed after 4 mg methacholine with values extrapolated after truncation of the curves at 2 mg. For these purposes, methacholine dose-response curves were obtained in 832 subjects from a random population sample, as part of the European Community Respiratory Health Survey (ECRHS) in Italy. Methacholine was inhaled up to a maximum dose of 6 mg by dosimeter technique. The coefficient of determination (r2) was significantly higher with the exponential model (0.81 +/- 0.22; mean +/- SD) than with the linear model (0.69 +/- 0.27). With both models, extrapolated values were usually lower than observed values. As a consequence, a 20% fall in FEV1 with respect to postsaline FEV1 was observed in only 24% and 21% of the tests, where a 20% fall had been predicted, respectively, according to the linear and exponential model. In conclusion, exponential models are better than linear models with respect to data interpolation of methacholine dose-response curves. However, they are worse with respect to extrapolation to higher doses. With any model, extrapolation of dose-response curves by one doubling-dose should be avoided.

Doses and models in risk assessment analysis for bronchial hyperresponsiveness

The aims of this study are: (1) to evaluate whether the estimates of the association of risk factors with bronchial hyperresponsiveness (BHR) depends on the accumulated dose administered in challenge tests; and (2) to verify whether a model developed for survival studies (Weibull regression) is suited to analyze methacholine dose-response curves. For these purposes, 863 challenge tests, from EC Respiratory Health Survey in Italy, up to a cumulative dose of 6 mg methacholine, were analyzed by Weibull regression and by traditional methods (logistic model and linear model), both before and after truncation of the curves at 2 mg. With all methods the main risk factors for BHR were respiratory symptoms and atopy while age and airway caliber exerted a protective action. Our results confirmed that in epidemiological surveys 2 mg methacholine is enough to fully appreciate the effect of risk factors on BHR and showed that the Weibull model explains the observed variability better than linear and logistic regressions.