Jordi Sunyer

The European Community Respiratory Health Survey: what are the main results so far?

The European Community Respiratory Health Survey (ECRHS) was the first study to assess the geographical variation in asthma and allergy in adults using the same instruments and definitions. The database of the ECRHS includes information from approximately 140,000 individuals from 22 countries. The aim of this review is to summarize the results of the ECRHS to date. The ECRHS has shown that there are large geographical differences in the prevalence of asthma, atopy and bronchial responsiveness, with high prevalence rates in English speaking countries and low prevalence rates in the Mediterranean region and Eastern Europe. Analyses of risk factors have highlighted the importance of occupational exposure for asthma in adulthood. The association between sensitization to individual allergens and bronchial responsiveness was strongest for indoor allergens (mite and cat). Analysis of treatment practices has confirmed that the treatment of asthma varies widely between countries and that asthma is often undertreated. In conclusion, the European Community Respiratory Health Survey has shown that the prevalence of asthma varies widely. The fact that the geographical pattern is consistent with the distribution of atopy and bronchial responsiveness supports the conclusion that the geographical variations in the prevalence of asthma are true and most likely due to environmental factors.

Total serum IgE is associated with asthma independently of specific IgE levels. The Spanish Group of the European Study of Asthma

In this study we aimed to assess whether the association between asthma (defined by symptoms and bronchial responsiveness) and total immunoglobulin E (IgE) levels was independent of specific IgE levels to common aeroallergens. A general population-based sample, supplemented with symptomatic individuals, comprising 1,916 young adults, aged 20-44 years, from five areas of Spain, performed a face-to-face respiratory questionnaire, and spirometry, and had total and specific serum IgE levels to mites, pets and moulds recorded. In 1,626 of the subjects, a dose-response methacholine challenge test was completed. Subjects reporting current attacks of asthma showed an association with total IgE (odds ratio (OR) for IgE > 100 kU.L-1 = 4.73, 95% confidence intervals (95% CI) = 2.01-11.12, adjusted for specific IgE, sex, age, smoking, forced expiratory volume in one second (FEV1), and area), which did not vary by bronchial responsiveness. The association between total IgE and asthma also occurred among those with negative specific IgE antibodies (OR 18.0; 95% CI 13.9-120). Individuals with current wheezing and bronchial responsiveness without attacks of asthma also showed an adjusted association with total IgE (OR 4.96; 95% CI 2.32-10.6), which remained for persons without specific IgE (OR 5.86; 95% CI 2.18-1.7). These findings reinforce previous evidence that asthma is associated with increased levels of total IgE, even in subjects negative for specific IgE to common aeroallergens.

Identification and partial characterization of the soybean-dust allergens involved in the Barcelona asthma epidemic

Asthma epidemics in Barcelona, Spain, have been attributed to dust generated by the unloading of soybeans in the harbor. Sera of four different groups of 10 subjects in each group were studied: (1) patients attending an emergency room in Barcelona for an asthma attack on epidemic days, group A, (2) patients attending an emergency room for an attack on nonepidemic days, group B, (3) patients with asthma from other cities, group C, and (4) patients without asthma from Barcelona matched by age and sex with group A, group D. All subjects in group A had IgE to allergens in extracts of various soybean samples. In contrast, only one of the 10 subjects in each of groups B and C and none of those subjects in group D had IgE to uncleaned bean and hull extracts. Radioimmunoassay demonstrated that in sera from patients with asthma during an asthma outbreak reacted primarily to soybean hull and dust extracts. Sodium dodecyl sulfate-polyacrylamide and gel electrophoresis thin-layer isoelectrofocusing demonstrated protein bands of 97.4 to less than 14.4 kd and isoelectric point between 6 and 3.5. By Western blot and thin layer isoelectrofocusing/blotted radioimmunoisoelectrofocusing, IgE of patients with asthma during an asthma outbreak reacted weakly to two protein bands of molecular weight ranging from 42 to 21 kd, strongly to glycoprotein bands with molecular weight less than 14.4 kd, and isoelectric point less than 6, which appeared to be the major allergens.

Symptoms of asthma, bronchial responsiveness and atopy in immigrants and emigrants in Europe

Migration studies on asthma may provide information on its environmental causes. The European Community Respiratory Health Survey has potential advantages due to the number of countries involved, standardized collection of information, assessment of directionality of migration, and availability of physiological data on bronchial responsiveness and atopy. Prevalence rates of symptoms associated with asthma were compared for immigrants, emigrants and nonmigrants living in centres mostly in western Europe. Similar analyses were carried out for bronchial responsiveness (provocative concentration causing a 20% fall in forced expiratory volume in one second and slope) and atopy. Medication and use of health services were also explored. Overall, 1,678 (8.6%) of 19,516 participants were immigrants in the 18 countries participating in the study, of whom 581 were emigrants from one of the participating countries. Rates of asthma symptoms were higher in immigrants (odds ratio (OR): 1.21, 95% confidence interval (CI): 1.00-1.51) and emigrants (OR: 1.31, 95% CI: 0.96-1.51) compared to nonmigrants after controlling for area, sex, age and smoking status. However, bronchial responsiveness and atopy were equally distributed between immigrants, emigrants and nonmigrants. Use of health services was observed to be similar in migrants and nonmigrants with asthma. In the European Community Respiratory Health Survey, migrants reported more asthma symptoms, but had similar bronchial responsiveness, atopy, and use of health services when compared with the nonmigrant population.

Specific sensitization to common allergens and pulmonary function in the European Community Respiratory Health Survey

Background The role of atopy in the evolution to chronic obstructive disease remains controversial.

CFTR and asthma in the French EGEA study.

It has been suggested that ∆F508 heterozygosity in the CFTR gene and other variants could be risk factors for asthma. Results regarding ∆F508 come from a Danish study conducted in about 9000 subjects from the general population. However, the hypothesis that ∆F508 heterozygosity in the CFTR gene could protect against asthma, was proposed earlier after a study conducted in obligate heterozygotes. Recently, a case control study based on 144 asthmatics recruited in emergency rooms in Barcelona and a first control group of 41 spouses of CF carriers showed an excess of heterozygotes for aminoacid variants in the asthmatics, R75Q, G576A, R668C and L997F being the most frequent. Furthermore, in the asthmatic group only, a positive association of MM or MV in M470V variant in the previous aminoacid variants was observed, whereas the 5T allele in the IVS8-(T)n was never associated with these variants. In a second control group of 184 blood donors, however, the proportion of the four previous aminoacid variants was similar to the distribution in the asthmatics. The potential association of ∆F508 and other CFTR aminoacids and IVS8-(T)n variants to asthma has been studied in the French epidemiological study on the genetics and environment of asthma, bronchial hyper-responsiveness and atopy (EGEA). In that study, cases were recruited in chest clinics in five cities in France with a standardised definition of asthma. They were examined together with populationbased controls and first degree relatives of the cases by a standardised protocol. Association of ∆F508 heterozygosity to positive skin prick test of Aspergillus in a subsample of relatives and controls has been previously reported. In the present analysis, 247 cases and 233 population-based controls (204 without asthma) were compared. They were carefully matched for place of birth (Table 1), taking five regions based on previous knowledge of genetic markers within France. Asthmatics were well characterised and had more severe symptoms than those in the general population, with around one third of asthmatic cases having been hospitalised for asthma, and more than two thirds on inhaled steroids. All subjects were typed blindly to case control status for ∆F508, IVS8-(T)n and M470V in Poitiers. Due to the work load, only the four most common variants previously observed in asthmatics (R75Q, G576A, R668C and L997F), which accounted for 50% of mutations in asthmatics in the Barcelona study, were typed in the EGEA study as previously in the second control group in Barcelona, using the same techniques. The most common mutation in cystic fibrosis, ∆F508 was analysed by acrylamide gel electrophoresis, and the missense variant M470V was analysed by DGGE. The detection of the IVS8-5T, -7T and -9T variants was performed by non-denaturing polyacrylamide gel electrophoresis after PCR amplification. Three missense variants R75Q, G576A, L997F were analyzed by restriction analysis. Variant R668C was analyzed by SSC A. Prevalences in the whole sample of 480 subjects were 2.9%, 3.8%, 4.0%, 4.2% and 0.6% for heterozygosity for ∆F508, R75Q, G576A, R668C and L997F, respectively. Regarding M470V, 18.3%, 47.9% and 33.8% were MM, MV and VV and 5T/occurred in 8.8%. Comparisons between cases and various control groups were performed in order to increase the contrast: cases vs all 233 controls (representing the general population), cases vs the 204 non-asthmatic controls, and cases vs the 174 nonasthmatic controls with both parents without asthma. As conclusions were similar, figures (Table 1) are given for the comparison with the greatest phenotypic contrast only. Controls were older than cases, which also increases the contrast for a disease with a variable age of onset. For ∆F508, the odds ratios were greater than 1, but not statistically significant. No particular pattern was observed considering FEV1, FVC or bronchial responsiveness. Any variant (R75Q, R668C, G576A, L997F), carriers of M allele (M470V), or 5T/-, shows odds ratios lower than 1, which were not statistically significant, except for 5T/-. That unexpected negative association with 5T/needs confirmation in other studies. None of the variants studied was significantly related to the region of birth in France. Analyses taking into account the region of birth led to the same conclusions. Relations between variants suggesting linkage disequilibrium were evidenced. ∆F508, 576A, 668C were significantly (P = 0.001) related to the M allele in M470V, whereas the opposite non-significant trend was observed for 75Q. IVS8-(T)n was also related (P = 0.001) to M470V as 97% of VV vs 39% of MM were 7T7T. The association of M470V with the other variants was similar in cases and controls. The EGEA study differs in its population and its design from previous studies on ∆F508. It is based on a case-control approach with careful matching of cases and controls in respect of geographic origin. A first possible method of assessing the relationship of ∆F508 to asthma consists of comparing the prevalence of asthma in obligate heterozygotes and in non-carriers. In the first study, Schroeder et al first estimated the expected percentage of ∆F508 carriers in relatives of various degrees of relationship to cystic fibrosis patients. They then compared it with the observed number of carriers in those relatives who were asthmatics and concluded that heterozygotes had three times less chance of developing asthma than wild homozygotes. The limitations of this study were the diagnosis of asthma based on nonEuropean Journal of Human Genetics (2001) 9, 67–69

Diagnosis of soybean-induced asthma

BACKGROUND The role of soybean dust as a causal agent of asthma has been clearly established since the Barcelona asthma epidemics in the 1980s. The large number of patients who were first seen with asthma symptoms during those epidemics provided an excellent opportunity to study the possibilities of different diagnostic tests. OBJECTIVE This study was designed to evaluate the usefulness of the skin test and amplified ELISA technique for quantifying specific IgE in the diagnosis of soybean asthma. PATIENTS AND RESULTS Ninety epidemic asthmatic patients and 95 nonepidemic asthmatic patients were studied 2 years after the last epidemic. Results of prick tests and ELISAs for specific IgE with hull and dust extracts showed a significant difference between the two groups of patients (p < 0.001). Sensitivity and specificity of glycerinated prick test with hull extract in epidemic asthmatic patients were 57.7% and 95.3%, respectively, and ELISA values were 56.6% and 93.7%, respectively. Similar results were obtained with dust extracts. CONCLUSION Glycerinated skin prick tests and ELISAs with soybean hull and dust extracts have proved effective in the diagnosis of soybean asthma, even 2 years after the epidemics. Taking into account the sensitivity (90.5%) and specificity (93.7%) of ELISA test results for epidemic asthmatic patients found when the epidemic occurred, data from this study suggest that both tests may be very useful for the diagnosis of soybean dust-induced asthma.

Clinical and functional characteristics of patients two years after being affected by the soybean asthma epidemic in Barcelona.

BACKGROUND--Patients affected during the asthma outbreaks caused by soybean dust inhalation in Barcelona presented with sudden onset of severe asthma followed by the rapid relief of symptoms after treatment. Two years after the epidemics ended, a case-control study was conducted in which the clinical, functional, and immunological characteristics of these asthma patients (a randomised sample of asthmatic patients admitted as emergency cases on epidemic days, n = 213) were compared with those of a control group (a random sample of asthmatic patients admitted as emergency cases for attacks of asthma on non-epidemic days, n = 170). METHODS--The study included the administration of the ATS-DLD78 standardised respiratory questionnaire, the measurement of atopy, and performance of spirometric tests and a methacholine inhalation test. RESULTS--Patients with epidemic asthma reported fewer symptoms of asthma, had attended emergency departments less frequently during the previous year for acute attacks of asthma, were taking fewer inhaled corticosteroids at the time of the study, and attended medical follow up less frequently than did the patients with non-epidemic asthma. However, the cases and controls showed no differences in ventilatory capacity or reactivity to the methacholine bronchoprovocation test. CONCLUSIONS--Two years after the end of the soybean epidemics, people affected by epidemic asthma had a favourable prognosis. This finding contrasts with a higher risk of life threatening asthma and death during the epidemics. This paradox could be the result of a complex interaction between host and conditions of exposure.

Prevalence of Possible Occupational Asthma in Hairdressers Working in Hair Salons for Women

Background: The aim of this study was to determine the prevalence of possible occupational asthma (OA) in hairdressers. Methods: A telephone questionnaire (Q1) was administered to 1,334 individuals from a total of 1,875 hairdressers working in hair salons for women in Barcelona (response rate 71%) to identify those with respiratory symptoms. Multiple correspondence analysis showed 5 specific questions for assessing symptoms of asthma. Individuals who gave a positive response to 1 of these questions (n = 251) were given a second validated questionnaire (Q2) to identify those with suspected OA. OA was defined according to a classification tree based on the response to queries on nasal itching, daily symptoms throughout the week at work, nasal secretions, voice loss, wheezing, and sputum production as reported previously. Moreover, we calculated the prevalence of OA according to the conventional criteria of improvement and/or worsening of symptoms in relation to exposure at work and during off-work time on weekends and during vacations. Results: Asthma was present in 9.5% of hairdressers. From Q2 data, 72 were classified as having possible OA, yielding a prevalence of OA from 5.4 (72/1,334) to 7.8% according to the classification tree previously described. A prevalence from 4.6 (62/1,334) to 6.7% was obtained using conventional criteria. Rhinitis or dermatitis (OR 7.80), as well as exacerbation of symptoms at work and persistence of symptoms on weekends (OR 2.99) were associated with the development of OA. Conclusions: Hairdressing employment can induce asthma. Episodes of rhinitis or dermatitis seem to be risk factors for the development of OA in this population.

Association study of proposed candidate genes/regions in a population of Spanish asthmatics

A number of genes/regions have recently been reported to be linked to asthma or its related phenotypes (i.e. atopy and bronchial hyperresponsiveness), by genetic linkage and allele-sharing methods. We have performed a case–control study comparing the allelic distribution of nine microsatellite markers and two genetic variants in a group of patients attended at emergency room departments because of an acute attack of asthma with respect to an external healthy population of controls. A total of 146 asthmatic subjects and 50 population controls from Barcelona, Spain, were genotyped for nine microsatellite markers from some asthma/atopy candidate genes/regions: the β-subunit of the high-affinity IgE receptor (FcεRI-β) located on chromosome 11; the 5q31–32 candidate region; the T-cell receptor genes, TCR-α on chromosome 14 and TCR-β on chromosome 7. Two genetic variants of the β-subunit of the high-affinity IgE receptor (FcεRI-β) gene were also analyzed. None of the asthmatic or control individuals carried the Ile181Leu variant. There were no significant differences between asthmatic and control subjects neither for the polymorphic markers nor for the other variant of the β-subunit of the high-affinity IgE receptor (FcεRI-β) gene. No association could be observed in this sample of Spanish asthmatics with the genes/regions studied.