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.

Eosinophilia is associated with increased all-cause mortality after a follow-up of 30 years in a general population sample.

We investigated whether allergy is associated with increased all-cause mortality. Two allergy markers, peripheral blood eosinophilia (> or =275 eosinophilic cells per mm3) and positive skin tests (sum score > or =3), were available for 5,383 subjects of a cohort study on asthma and chronic obstructive pulmonary disease in general population samples of Vlagtwedde and Vlaardingen, the Netherlands, in 1965-1972. During 30 years of follow-up, 1,135 subjects died. In a Cox regression analysis, eosinophilia was associated with an increased risk (relative risk = 1.4; 95% confidence interval = 1.2-1.7) of all-cause mortality, independent of gender, age, smoking habits, percentage predicted forced expiratory volume in 1 second (FEV1 % predicted), and positive skin tests at the start of the study. Subjects with positive skin tests had only an increased risk of all-cause mortality in the subgroup of subjects with FEV1 <80% of predicted (relative risk = 1.7; 95% confidence interval = 1.0-2.8). These results remained essentially unchanged after exclusion of subjects with asthma. We conclude that eosinophilia is associated with increased all-cause mortality. An increased number of peripheral blood eosinophils may reflect an increased inflammatory response, resulting in tissue injury. It is possible that the association between a low FEV1% predicted and all-cause mortality is partly mediated by an atopic constitution.

Performance of population specific job exposure matrices (JEMs): European collaborative analyses on occupational risk factors for chronic obstructive pulmonary disease with job exposure matrices (ECOJEM).

OBJECTIVES: To compare the performance of population specific job exposure matrices (JEMs) and self reported occupational exposure with data on exposure and lung function from three European general populations. METHODS: Self reported occupational exposure (yes or no) and present occupation were recorded in the three general population surveys conducted in France, The Netherlands, and Norway. Analysis was performed on subjects, aged 25-64, who provided good forced expiratory volume in 1 second (FEV1) tracings and whose occupations were performed by at least two people, in the French (6217 men and 5571 women), the Dutch (men from urban (854) and rural (780) areas), and the Norwegian (395 men) surveys. Two population specific JEMs, based on the percentage of subjects who reported themselves exposed in each job, were constructed for each survey and each sex. The first matrix classified jobs into three categories of exposure according to the proportion of subjects who reported themselves exposed in each job (P10-50 JEM, low < 10%, moderate 10-49%, high > or = 50%). For the second matrix, a dichotomous variable was constructed to have the same statistical power as the self reported exposure--that is, the exposure prevalence (p) was the same with both exposure assessment methods (Pp JEM). Relations between occupational exposure, as estimated by the two JEMs and self reported exposure, and age, height, city, and smoking adjusted FEV1 score were compared. RESULTS: Significant associations between occupational exposure estimated by the population specific JEM and lung function were found in the French and the rural Dutch surveys, whereas no significant relation was found with self reported exposure. In populations with few subjects in most jobs, exposure cannot be estimated with sufficient precision by a population specific JEM, which may explain the lack of relation in the Norwegian and the Dutch (urban area) surveys. CONCLUSION: The population specific JEM, which was easy to construct and cost little, seemed to perform better than crude self reported exposures, in populations with sufficient numbers of subjects per job.

Risk factors for growth and decline of lung function in asthmatic individuals up to age 42 years. A 30-year follow-up study.

Little is known about factors determining the outcome of childhood asthma. The purpose of this longitudinal study was to assess the factors in childhood that determine the level of FEV(1) in early adulthood in asthmatic individuals, and to examine factors associated with decline in FEV(1) during adulthood. Between 1966 and 1969, 119 allergic asthmatic subjects aged 5 to 14 yr were studied (Visit 1). Of these subjects, 101 (85%) were reinvestigated at ages 22 to 32 yr (Visit 2) and 32 to 42 yr (Visit 3). At the first survey and during follow-up, a standardized questionnaire was used, serum total IgE and peripheral blood eosinophils were measured, and physical examination, skin tests, lung function tests, and histamine challenge (provocative concentration causing a 10% decline in FEV(1); PC(10)) tests were performed according to the same protocol. Multiple linear regression analyses were performed with FEV(1) at Visit 2 and with the change of FEV(1) from Visit 2 to Visit 3 as outcome variables. A low FEV(1)% predicted at Visit 1 and PC(10)

Asthma attacks with eosinophilia predict mortality from chronic obstructive pulmonary disease in a general population sample.

We studied the association between allergy defined as eosinophilia (>/= 275 cells/mm(3)) and/or positive skin tests (sum score >/= 3) and mortality from chronic obstructive pulmonary disease (COPD) after adjustment for major risk factors. In addition, we investigated this association in subgroups of respiratory symptoms and lung function. We used data from 7,556 participants of the respiratory surveys in 1964 -1972 in the general populations of Vlagtwedde, Vlaardingen, and Meppel (The Netherlands; mean age +/- SD: 39.3 yr +/- 14 in the 1960s). In 1995, the vital status was available (5,135 alive, 106 lost to follow-up, 121 primary deaths from COPD, and 2,194 other primary causes of which 137 had a secondary death cause from COPD. Positive skin tests were not associated with increased COPD mortality. The association between eosinophilia and COPD mortality was restricted to those who had reported asthma attacks and was present for both COPD as a primary cause (relative risk [RR] = 4.80; 95% confidence interval [CI] 1.9 to 11.9) and combined primary and secondary causes of death (RR = 3. 90; 95% CI 2.05 to 7.40). We conclude that eosinophilia with asthma attacks is a risk factor for COPD mortality in addition to known risk factors also found in our study such as male gender, older age, current smoking, low lung function, underweight, and dyspnea.

Eosinophilia and positive skin tests predict cardiovascular mortality in a general population sample followed for 30 years.

The authors investigated whether two objective allergy markers, peripheral blood eosinophilia and skin tests for common aeroallergens, were associated with cardiovascular death. Of 5,382 subjects in the Vlagtwedde-Vlaardingen Study (the Netherlands) with data on allergy markers in 1965-1972, 507 subjects died from cardiovascular disease during 30 years of follow-up. Subjects with eosinophilia had an increased risk of cardiovascular death (relative risk (RR) = 1.7; 95% confidence interval (CI): 1.4, 2.2), including ischemic heart disease death (RR = 1.6; 95% CI: 1.2, 2.2) and cerebrovascular death (RR = 2.3; 95% CI: 1.4, 3.8), independent of major risk factors. This association was limited to subjects with a percentage of the predicted forced expiratory volume in 1 second (FEV1 % predicted) of <100%. Positive skin tests were associated with a significantly reduced cardiovascular mortality in subjects with normal lung function and weight who did not smoke (RR = 0.15; 95% CI: 0.05, 0.46). Conversely, when subjects with positive skin tests had a body mass index of > or =25 kg/m2, had an FEV1 % predicted of <80%, or smoked, they had an increased risk for cardiovascular mortality. These results were not restricted to asthmatics. Our data suggest a possible link between eosinophilia and positive skin tests and cardiovascular mortality, especially in combination with other risk factors associated with its mortality.

Risk factors from childhood to adulthood for bronchial responsiveness at age 32-42 yr.

UNLABELLED: Bronchial responsiveness (BR) is an important risk factor for the development and outcome of asthma. This study assessed childhood risk factors for both the severity of BR in adulthood and either improvement or worsening of BR over time. Finally, we studied cross-sectional risk factors of BR in adulthood. Between 1966 and 1969, 119 allergic asthmatic children (5-14 yr of age) were studied. Of these, 101 (85%) subjects were reinvestigated at age 22-32 yr (visit 2), and at age 32-42 yr (visit 3). Spirometry, PC10 histamine, skin tests, blood eosinophils, and serum total IgE were measured and a questionnaire was used. Higher FEV1 values in childhood were associated with less severe BR at age 32-42 yr independent of other potential risk factors. Larger increases in FEV1 values both from visit 1 to 2 and from visit 2 to 3, a longer time interval from visit 1 to 3, and having pets in childhood were associated with less severe BR at age 32-42 yr. The same factors were found to be associated with less deterioration of BR from visit 2 to 3. In nonsmokers a higher IgE level at visit 2 was a risk factor for an increase in BR. At age 32-42 yr, a low level of lung function and the presence of asthma symptoms were associated with more severe BR, and older age and having pets were associated with less severe BR. IgE was related to more severe BR only in nonsmokers. CONCLUSIONS: A lower lung function in childhood and less improvement in FEV1 over time were associated with more severe BR in adulthood.

Smoking and airway hyperresponsiveness especially in the presence of blood eosinophilia increase the risk to develop respiratory symptoms: a 25-year follow-up study in the general adult population.

Airway hyperresponsiveness (AHR) constitutes a risk for development of respiratory symptoms. We assessed whether blood eosinophilia (>/= 275 eosinophils/microliters), skin test positivity (sum score >/= 3) and cigarette smoking (never, ex-smoker, 1-14 cig/d, 15-24 cig/d, >/= 25 cig/d) at the first of two successive surveys are related to the development of respiratory symptoms (chronic cough or phlegm, bronchitis, persistent wheeze, dyspnea, and asthma) at the second survey, and whether these relations are the same in subjects with (PC10

Wheezing in school children is not always asthma.

Our objective was to study whether children with reported asthma differed from children with wheeze but without asthma, and from children with neither asthma nor wheeze, regarding lung function, bronchial hyper-responsiveness (BHR) using methacholine inhalation, exercise-induced bronchoconstriction (EIB), and skin prick test (SPT) reactivity. School children (n=2188), enrolled in a survey of asthma, were classified into three mutually exclusive groups by parental report of: asthma, wheeze, and no asthma/no wheeze. A random sample of 80 children in each group was tested (n=240). Among asthmatics, 68% (95% confidence interval (CI), 57-79) had a BHR (measured as PD20 forced expiratory volume in 1 s (FEV1) < or = 8.16 micromol using methacholine) compared to 31% (CI 20-42%) and 30% (CI 19-40%) in the wheeze and no asthma/no wheeze groups. The dose-response slope (DRS) confirmed the PD20 data and distinguished equally between groups. EIB (> or =10% fall in FEV1) was more frequent (40%, CI 29-52%) among asthmatics than among children with wheeze (12%, CI 4-19%) and no asthma/no wheeze (7%, CI 1-13%). The prevalence of at least one positive SPT was twice as high in the asthma group (58%, CI 47-69%) than in the wheeze (27%, CI 16-37%) and the no asthma/no wheeze (25%, CI 15-35%) groups. These results indicate that children with asthma differ from children with wheeze and children with no asthma/no wheeze regarding lung function, BHR, EIB, and SPT reactivity. Children with wheeze are more similar to children with no asthma/no wheeze with respect to these parameters.

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.

Higher dosage nicotine patches increase one-year smoking cessation rates: results from the European CEASE trial. Collaborative European Anti-Smoking Evaluation. European Respiratory Society.

The Collaborative European Anti-Smoking Evaluation (CEASE) was a European multicentre, randomized, double-blind placebo controlled smoking cessation study. The objectives were to determine whether higher dosage and longer duration of nicotine patch therapy would increase the success rate. Thirty-six chest clinics enrolled a total of 3,575 smokers. Subjects were allocated to one of five treatment arms: placebo and either standard or higher dose nicotine patches (15 mg and 25 mg daily) each given for 8 or 22 weeks with adjunctive moderately intensive support. The 12 month sustained success rates were: 25 mg patch for 22 weeks (L-25), 15.4%; 25 mg patch for 8 weeks (S-25), 15.9%; 15 mg patch for 22 weeks (L-15), 13.7%; 15 mg patch for 8 weeks (S-15), 11.7%; and placebo (P-0) 9.9% (placebo versus 15 mg, p<0.05; 25 mg versus 15 mg, p<0.03; 25 mg versus placebo, p<0.001, Chi-squared test). There was no significant difference in success rate between the two active treatment durations. Of the first week abstainers (n=1,698), 25.1% achieved success at 12 months as opposed to first week smokers, 2.7% of 1,877 subjects (p< 0.001). In summary, a higher than standard dose of nicotine patch was associated with an increase in the long-term success in smoking cessation but continuation of treatment beyond 8-12 weeks did not increase the success rates.

The relationship of skin test positivity, high serum total IgE levels, and peripheral blood eosinophilia to symptomatic and asymptomatic airway hyperresponsiveness.

The relationships of skin test positivity, high serum total IgE levels (> 100 kU/L), and peripheral blood eosinophilia (>/= 275 cells/microliter) to symptomatic (either chronic cough, chronic phlegm, bronchitis episodes, dyspnea, wheeze, or asthma) and asymptomatic bronchial hyperresponsiveness (BHR) were studied cross-sectionally in 620 adult subjects who participated in the Vlagtwedde-Vlaardingen Study of 1989 and 1990. Eosinophilia (OR = 2.06, 95% CI = 1.28 to 3.31) and skin test positivity (OR = 1.66, 95% CI = 1.02 to 2.71) were both significantly associated with BHR independent of age, sex, smoking, and urban area of residence. High serum total IgE levels were not associated with BHR (OR = 1.29, 95% CI = 0.81 to 2.03). Separate analyses for symptomatic and asymptomatic subjects showed that the higher risk of BHR with skin test positivity applied only to symptomatic subjects (OR = 5.78, 95% CI = 1.63 to 20.51), independent of eosinophilia and high serum total IgE levels. The higher risk of BHR with eosinophilia was not different between symptomatic and asymptomatic subjects, and independent of skin test positivity and high serum total IgE levels. The results of this study show that, in the general adult population, eosinophilia is associated with BHR both in symptomatic and asymptomatic persons, whereas skin test positivity is associated with BHR only in symptomatic subjects.

Peak expiratory flow variability, bronchial responsiveness, and susceptibility to ambient air pollution in adults.

Bronchial hyperresponsiveness (BHR) and peak expiratory flow (PEF) variability are associated expressions of airway lability, yet probably reflect different underlying pathophysiologic mechanisms. We investigated whether both measures can be used interchangeably to identify subjects who are susceptible to ambient air pollution. Data on BHR (>= 20% fall in FEV1), PEF variability (ampl%mean PEF > 5% on any day during an 8-d period with low air pollution levels) and diary data on upper and lower respiratory symptoms, cough, and phlegm were collected in 189 subjects (48-73 yr). The acute effects (lag0) of particulate matter with a diameter less than 10 micrometers (PM10), black smoke, SO2 and NO2 on the prevalence of symptoms were estimated with logistic regression. In subjects with airway lability, both when expressed as PEF variability (69%) and BHR (28%), the prevalence of symptoms increased significantly with increasing levels of air pollution, especially in those with the greater PEF variability (n = 55, 29%). We found no such consistent positive associations in adults without airway lability. PEF variability, and to a smaller extent BHR, can be used to identify adults who are susceptible to air pollution. Though odds ratios were rather low (ranging from 1.13 to 1.41), the impact on public health can be substantial because it applies to large populations.

Breathlessness in elderly individuals is related to low lung function and reversibility of airway obstruction.

The perception of breathlessness is a subject-related factor which is linked to respiratory disease, cardiac disease and overweight. We studied the distribution of breathlessness, its association with respiratory disease, cardiac disease and overweight, as well as its association with lung function, reversibility of airway obstruction ("reversibility") and peak expiratory flow (PEF) variability in an elderly population. Data on breathlessness (rated with Borg scale), lung function, reversibility, PEF variability, respiratory symptoms, cardiac disease and overweight were collected in a random sample of 210 elderly (>55 yrs old) who participated in a physical fitness test. Individuals with a Borg score >0 were taken to have breathlessness. Subjects with a Borg score >0 (n=50, 24%) were three to five times more likely to have a low lung function and large reversibility than subjects with a Borg score of zero, independent of the presence of respiratory symptoms, cardiac disease or overweight, although these three factors were all associated with low lung function and a large reversibility and PEF variability. Reversibility was not associated with PEF variability whatsoever. In elderly individuals, breathlessness is frequently present. Assessment of breathlessness using the Borg-scale seems an important clinical measurement, because it is an important independent predictor of lung function impairment in the elderly.

Occurrence of occupational asthma in aluminum potroom workers in relation to preventive measures.

The purpose of this study was to investigate whether preventive measures such as reduction of exposure and the introduction of the histamine provocation test (HPT) as a selection instrument resulted in a lower incidence of potroom asthma (PA) and a longer time lag between the commencement of employment and the occurrence of PA. Between 1970 and 1990, 179 cases of PA were diagnosed. This period was divided into three periods. During period 1 (1970-1975), no exposure data were available. Period 2 (1976-1981) is characterized by known exposure data obtained by means of fluoride determinations in urine. At the beginning of period 3 (1982-1990) the HPT was incorporated into the preemployment medical examination. We computed the incidence density (ID) in the three periods and analyzed the timelag in relation to the year of employment and confounding factors such as age, atopic history, blood eosinophil counts, lung function, smoking habits at preemployment, and exposure level. After introduction of the preemployment HPT the ID decreased, but cases continued to occur (ID 11.6 in period 2 versus 2.5 in period 3). The time lag was did not differ when subjects with bronchial hyperresponsiveness were screened out. The exposure level and an atopic history were factors associated with the period of employment and, therefore, confounded the results. The results of this study support the role of an atopic history as a risk factor for development of PA at lower exposure levels and suggest that potroom exposure not only incites asthmatic symptoms but also acts as an inducer of respiratory disease.

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.

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.