Epidemiological study of the genetics and environment of asthma, bronchial hyperresponsiveness, and atopy: phenotype issues.

The Epidemiological Study of the Genetics and Environment of Asthma (EGEA) combined a case-control study and a family study. The total sample of 1,854 consisted of 348 patients with asthma selected through chest clinics and 416 control subjects and nuclear families ascertained through the cases. The protocol included standardized questionnaires, bronchial responsiveness, allergen skin-prick tests according to international protocols, total serum immunoglobulin E (IgE) level measurements, and blood eosinophilia. Criteria used to select subjects with asthma and determine asthma status of relatives for affected sibling pair linkage analysis are described. Based on figures from the 348 asthma cases of the EGEA study, issues relative to the definition of severe asthma and intermediate phenotypes such as bronchial responsiveness and allergic markers are discussed. Given the phenotypic heterogeneity involved, relevant phenotypes that may lead to the detection of genetic factors will depend on the hypothesis tested. Standardization of primary data and subphenotypes is a prerequisite for pooling data, which will be needed in the future to better understand the genetics and environmental factors of asthma.

Ventilation system, indoor air quality, and health outcomes in Parisian modern office workers.

A cross-sectional study was carried out to determine the effect on health of exposure to different types of ventilation, taking indoor environmental measurements (IEMs) of major contaminants and aeroallergens into account. Three buildings ventilated with heating, ventilating, and air conditioning (HVAC), fan coil units (FCUs), and natural ventilation were selected. One thousand one hundred forty-four workers answered health questionnaires. After adjusting for potential confounders, HVAC and FCU systems were related to a slightly higher risk of nonspecific symptoms (compared with natural ventilation), short-term throat irritation, work-related nasal discharge, nasal blockage on awakening, migraine, and usual coughing induced by cold air. Studying the potential effects of environmental contaminants and aeroallergens on health outcomes, taking the floor and type of ventilation into account, did not explain the observed excess of nonspecific symptoms.

Validity of subjective assessment of changes in respiratory health status: a 30 year epidemiological study of workers in Paris.

The validity of scales used for subjective assessment of health, particularly transitional indices, is under discussion. The aim of the present study was to assess the concurrent and predictive validity of a simple estimate of long-term subjective assessment of respiratory health changes. A longitudinal study of 915 workers was conducted over 30 yrs, with both retrospective self-assessment of respiratory health changes and objective measurements of spirometric values 12 yrs apart. An assessment of the reason for death during the subsequent 20 yrs was performed. Subjective assessment of respiratory deterioration over 12 yrs was significantly related to both cross-sectional lung function values and longitudinal lung function changes (forced expiratory volume in one second (FEV1) decline), an association which remained after adjustment for FEV1 level. It was also related to the same risk factors as decline in FEV1 (smoking, occupational exposure). Self-evaluation of respiratory deterioration was significantly predictive of death from all causes, with the highest (but nonsignificant) rate ratio for respiratory causes. Asthmatics exhibited greater long-term variability (objective and subjective) than nonasthmatics. Independent of dyspnoea, self-assessment of respiratory health deterioration was significantly related to FEV1. Subjective assessment of long-term changes in respiratory health provides valid information.

Bronchial hyperresponsiveness as a predictor of wheezing in a follow-up study of healthy men.

We assessed the relationship between bronchial hyperresponsiveness (BHR) and the onset of wheezing 5 years later, by epidemiological analysis of 194 working men without asthma or wheezing at the first examination. In 1985/ 1986 and 1990/1991, subjects answered a British Medical Research Council questionnaire and performed lung function measurements and methacholine challenge tests (total dose 6 mg). BHR was measured in three ways: (1) FEV1 fall > or = 20% (PD20+); (2) the two-point response slope expressed as percentage decline of FEV1/dose, and (3) a four-parameter model: FEV1 at dose (d)/ prechallenge FEV1 = ONE-k(d-delta)+a, where 'k' is the slope of the relative variation of FEV1 with the dose, 'delta' the threshold dose, and 'alpha' a shape factor. In the 13 new wheezers, the mean values of the two-point slope and of k were significantly increased, and the proportion of reactors was almost threefold (the latter was not statistically significant). Among nonsmokers, delta was significantly lower in new wheezers than in the others, whereas the slope and k had similar mean values. Among smokers, new wheezers had increased mean values for the slope and k, and an increased proportion of reactors, whereas delta was not decreased. Thus, BHR was a significant predictor of wheezing, independent of the method of analysis. Moreover, the model distinguished between two components of bronchial response: wheezing was predicted by sensitivity (delta) in nonsmokers, and by reactivity (k) in smokers.

Longitudinal observations of serum IgE and skin prick test response.

The objective of the study was to assess skin prick test and IgE changes in a working population surveyed 5 yr apart and to determine whether age and smoking habits modify these changes. SPTs were performed on 223 subjects by the same method and common allergens (a mixture of grass pollens and a mixture of 95% house dust and 5% house dust mite). IgE measurements were done in duplicate by the same technique at each survey. A SPT-positive response at the first survey was highly predictive of a positive value at the second survey. The prevalence of positive SPT significantly increased in 5 yr (from 17.5 to 24.7%). A strong correlation was observed between IgE levels 5 yr apart (r = 0.92), and the IgE level appeared very stable. The initial IgE level was significantly greater among the converters than in consistently negative subjects (92.3 versus 30.1 IU/ml). Conversely, the initial IgE level was lower for the reverters than in consistently positive subjects (36.8 versus 97.0 IU/ml). In SPT negatives, non- and exsmokers had a greater decrease in IgE than current smokers (p = 0.06). IgE level appears to be a good predictor of SPT changes for both conversion and reversion. The IgE level appears very stable in midadulthood, which suggests that the adult environment may play a small effect in IgE level.

[Contribution of epidemiology to the study of allergic response in children]. / L'apport de l'épidémiologie dans l'étude de la réponse allergique infantile.

Allergy is the conjunction of hereditary predisposition and risk factors encountered in the environment, phenomenon which can be observed very early in individual life. The aim of this review is to present the contribution of epidemiology in the study of allergic response in childhood, from sensitization to clinical manifestations as eczema, asthma and rhinitis. The first contribution of epidemiology has consisted in estimating the scatter of the allergic response, the presence of circulating antibodies against allergens (IgE and IgG), the evaluation of immediate hypersensitivity (such as the response to skin prick tests) and the prevalence of clinical manifestations. Then, knowledge of allergic response has been improved by the contribution of aetiological epidemiology. Various risk factors have been described according to the different stages during life in which their effects are observable. In prenatal life, potential risk factors are maternal immunity and smoking during pregnancy. Later in perinatal or neonatal life they are perinatal complications, month of birth and maternal smoking. Lastly, in infancy a role can be played by feeding, immunological deficiencies, infections, parental smoking and early exposure to allergens or pollution. Perceiving these risk factors helps to determine strategies to prevent allergy occurrence.

Smoking, CD45R0+ (memory), and CD45RA+ (naive) CD4+ T cells.

The relationship between smoking and percentages and counts of T-cell subsets, in particular CD45R0+ (memory) and CD45RA+ (naive) CD4+ lymphocytes, have been assessed in a sample of 311 middle-aged men working in the Paris area. Percentages of lymphocytes with the phenotypes CD4+, CD8+, CD4+CD45R0+, and CD4+CD45RA+ were determined using double immunofluorescence labeling. All cell counts, including CD4+CD45R0+, and CD4+CD45RA+ lymphocytes increased significantly with tobacco consumption, as did the percentages of lymphocytes with the CD4+CD45R0+ and CD4+ phenotypes. The increase in the percentage of lymphocytes with the CD4+CD45RA+ phenotype, although not significant, was similar to that observed in the percentage of CD4+CD45R0+ lymphocytes. When the proportions of CD4+ cells with the CD45R0+ or the CD45RA+ phenotype were considered, no specific modification of any of these two sub-populations was observed: the effect of smoking on memory and naive Cd4+ lymphocytes seemed to be equivalent.

Relationship of upper airways disorders to FEV1 and bronchial hyperresponsiveness in an epidemiological study.

Associations of upper airways disorders (UAD) with forced expiratory volume in one second (FEV1) and bronchial methacholine response were studied, taking smoking habits into account. We used epidemiological data drawn from a population of 324 men, aged 27-58 yrs. Lower FEV1 level was related to hay fever (p = 0.01), usual (p = 0.01) and chronic (p = 0.02) rhinitis and common cold on the day of examination (p = 0.04). Allowance for the major potential confounding factor, tobacco smoking, showed similar results. Bronchial methacholine response was heightened in men reporting hay fever compared to those without (p = 0.01) but also in men reporting chronic rhinitis (p = 0.06), a group which did not exhibit skin prick test positivity more often than other subjects. Exclusion of asthmatics and taking into account smoking and skin prick test positivity yielded mostly similar results. Our data support the hypothesis of an association between lung impairment, as assessed by lower FEV1 and bronchial hyperresponsiveness to methacholine, and different types of UAD, allergic or not.

Total circulating IgE and FEV1 in adult men. An epidemiologic longitudinal study.

Epidemiologic data relating total circulating immunoglobulin E (IgE), an objective marker of allergy, to cross-sectional and longitudinal FEV1 as well as to methacholine bronchial hyperresponsiveness were obtained from 310 French adult men surveyed five years apart. Skin prick test responses to common aeroallergens, IgE level, and bronchial hyperresponsiveness were assessed at the end of the follow-up. IgE level was not associated with PD20 to methacholine. Cross-sectionally, age and height-adjusted FEV1 score was inversely related to total IgE level (regression coefficient of FEV1 score on Log[IgE] beta = -.20; p = 0.02). Stratified analysis showed that IgE level was associated with FEV1 score only in nonsmokers (beta = -0.52; p less than 0.001), an association that remained after exclusion of asthmatics. Longitudinally, five-year FEV1 decline was related to IgE in nonsmokers (regression coefficient of FEV1 decline on Log[IgE] beta = 19.9; p = 0.03) and exsmokers (beta = 18.9; p = 0.06) but not in current smokers. The relationship persisted, even if with lesser significance, among exsmokers after exclusion of asthmatics (beta = 17.2) and further exclusion of skin prick test-positive men (beta = 18.8). Whether IgE production also reflects factors other than allergy, possibly nonallergic inflammation, needs further investigations.

Relationships of haptoglobin level to FEV1, wheezing, bronchial hyper-responsiveness and allergy.

The relationships of haptoglobin level to respiratory and allergic parameters have been assessed in an epidemiological study conducted in a working population surveyed twice 5 years apart. At the first survey conducted in 892 working men, haptoglobin level was significantly related to FEV1 (r = -0.18; P less than 0.001) and smoking habits. After adjustment for smoking, a history of wheezing was significantly related to lower haptoglobin level. A second survey conducted in 304 men of the original sample 5 years later confirmed that haptoglobin was related to FEV1 (r = -0.21; P less than 0.001) and that wheezing was significantly related to hypohaptoglobinaemia (lower decile; P = 0.04). Men who exhibited bronchial hyper-responsiveness to methacholine had haptoglobin levels 0.35 g/l higher than those who did not (P = 0.01). Haptoglobin level was unrelated to IgE level and skin prick tests. These results support the hypothesis of the role of inflammation in both lower lung function and bronchial hyper-responsiveness. They suggest that some heterogeneity exists within subjects with a history of wheezing.

Relationships of total IgE level, skin prick test response, and smoking habits.

Epidemiologic observations on 331 men showed that increased serum IgE concentration was associated with a wheal response to skin prick testing, but also to an erythema response in the absence of any wheal, and to heavy smoking. The association between IgE and the various skin prick test responses remained after taking into account smoking and asthma.

In utero exposure to parental smoking, cotinine measurements, and cord blood IgE.

The relationship between parental smoking and cord blood IgE has been studied in a survey conducted in 99 unselected newborn infants with a sensitive tests for IgE and cotinine as a biologic marker to validate smoking data. For both cord blood cotinine and maternal urine continine creatinine ratio (CCR), significantly higher levels were observed for smokers compared to nonsmokers. Furthermore, among nonsmokers, passive smokers had significantly higher cotinine levels than true nonsmokers, which demonstrates that cord blood may be used to assess active as well as passive maternal smoking. No association was observed in this study between cord blood IgE and maternal smoking assessed by questionnaire (geometric means of cord blood IgE levels were 0.11 IU/ml for newborn infants of smoking mothers and 0.12 IU/ml for newborn infants of nonsmoking mothers). The same observations were drawn from the analysis of cord blood IgE and cotinine levels, with correlation coefficients of -0.005 for cord blood CCR and 0.003 for maternal CCR. Additional studies are needed to determine whether maternal smoking is causally related to cord blood IgE and by which mechanisms.

Blood eosinophilia and FEV1. Cross-sectional and longitudinal analyses.

A previous cross-sectional analysis of 1980 data from a population of working men in the Paris area has shown a significant relationship of blood eosinophilia to a reduced FEV1 among nonsmokers, remaining after excluding men with a history of asthma. In the present report, we reexamine this relationship, after taking into account asthma, bronchial hyperresponsiveness, and positive skin prick tests, using data collected in 1985 in a subsample of 363 men from the initial population. Blood eosinophilia, defined by 5% or more eosinophils or by 250 or more eosinophils per cubic millimeter appeared to be associated with a lower FEV1, primarily in nonsmokers. A difference of approximately 0.40 L was observed in never-smokers with eosinophilia (greater than or equal to 5% of eosinophils) compared with those without. This association persisted after exclusion of subjects with atopy, asthma, and bronchial hyperresponsiveness. Longitudinally, no significant association was observed between 1980 eosinophilia and the annual FEV1 decline between 1980 and 1985, even in nonsmokers. The results of our cross-sectional analyses suggest that asthma or asthma-like disorder does not explain the association between eosinophilia and FEV1. The role of eosinophil in respiratory disorders may go beyond its intervention in allergy. Further longitudinal studies are needed to better understand discrepancies between cross-sectional and longitudinal data and whether eosinophilia is a risk factor for chronic air-flow limitation.

An epidemiological reconsideration of the Geschwind-Galaburda theory of cerebral lateralization.

To contribute to the Geschwind-Galaburda theory of cerebral lateralization, we examined the relationship of left-handedness to allergic disorders and stuttering, using epidemiological data of two French samples, one of which (N = 9591) is representative of the French male population between 17 and 24 years of age. Results showed a higher frequency of stuttering but not of allergic disorders in left-handers. Extreme right-handedness was observed to be significantly associated with a lower frequency of allergic disorders; response bias might explain such a relationship. Findings were confirmed after allowing for potential confounding factors, such as age and education. In both samples, stuttering and allergic disorders were significantly related.

Efficiency of the logistic regression and Cox proportional hazards models in longitudinal studies.

Both logistic regression and Cox proportional hazards models are used widely in longitudinal epidemiologic studies for analysing the relationship between several risk factors and a time-related dichotomous event. The two models yield similar estimates of regression coefficients in studies with short follow-up and low incidence of event occurrence. Further, with just one dichotomous covariate and identical censoring times for all subjects, the asymptotic relative efficiency of the two models is very close to 1 unless the duration of follow-up is extended. We generalize this result to several qualitative or quantitative covariates. This was motivated by the analysis of mortality data from a study where all subjects are followed up during the same fixed period without loss except by death. Logistic and Cox models were applied to these data. Similar results were obtained for the two models in shorter periods of follow-up of five years or less, but not in longer periods of ten years or more, where the survival rate was lower.

The relation between snoring and smoking, body mass index, age, alcohol consumption and respiratory symptoms.

Potential risk factors for snoring were studied in a population of 457 middle-aged men. Eversnoring was reported by 60% of the men and snoring with an age of onset before or equal to 20 years by 13%. Eversnoring was significantly related to older age, higher body mass index and smoking habits. Alcohol consumption, estimated by questionnaire and gamma-glutamyl transpeptidase was unrelated to a history of snoring. Logistic regression showed that snoring was independently associated with age, body mass index and smoking habits. An exposure-effect relationship clearly appeared between tobacco consumption and snoring. After adjustment for smoking habits, none of the upper or lower respiratory symptoms was significantly related to snoring.

Leukocyte count and bronchial hyperresponsiveness.

The relationship of total and differential blood leukocyte counts with bronchial methacholine response was studied in a population-based sample of 324 men. Geometric mean total leukocyte counts were significantly higher in reactors (6567 cells/mm3) than in nonreactors (5732 cells/mm3; p = 0.003). After adjusting for smoking habits, a factor contributing to both an elevation in peripheral leukocyte count and an increased level of airway responsiveness, reactor status remained significantly associated with leukocyte count. This association also persisted after controlling, with a logistic model, for atopy and common cold (marker of infection) and after excluding men with a history of asthma, chronic bronchitis, or low FEV1. Study of the differential leukocyte counts has shown that an increase was present for almost every type of leukocyte, and particularly evident for neutrophils. Whether these findings reflect an association between bronchial hyperresponsiveness and cellular inflammation needs more investigation.