Published ahead of print on April 19, 2007, doi:10.1164/rccm.200612-1840OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200612-1840OC
Bronchial Responsiveness in Atopic Adults Increases with Exposure to Cat Allergen1 Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College London, London, United Kingdom; 2 Division of Asthma, Allergy, and Lung Biology, King's College London, London, United Kingdom; 3 Institute of Epidemiology, GSF–National Research Center for Environment and Health, Neuherberg, Germany; 4 Centre for Research in Environmental Epidemiology, Institut Municipal d'Investigació Médica, Barcelona, Spain; 5 Department of Experimental Sciences and Health, Universitat Pompeu Fabra, Barcelona, Spain; 6 Respiratory Medicine and Allergology, and 7 Occupational and Environmental Medicine, University of Uppsala, Uppsala, Sweden; 8 Unit of Occupational Medicine, Department of Medicine and Public Health, University of Verona, Verona, Italy; 9 Department of Thoracic Medicine, Haukeland Hospital, Bergen, Norway; 10 Unit of Epidemiology and Medical Statistics, Department of Medicine and Public Health, University of Verona, Verona, Italy; and 11 Environmental Epidemiology Division, Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, The Netherlands Correspondence and requests for reprints should be addressed to Professor S. Chinn, D.Sc., Respiratory Epidemiology and Public Health Group, National Heart and Lung Institute, Imperial College London, Emmanuel Kaye Building, Manresa Road, London SW3 6LR, UK. E-mail: s.chinn{at}imperial.ac.uk
Rationale: The association of asthma with sensitization and allergen exposure is known to be complex. There have been few studies of bronchial responsiveness in relation to both risk factors in adults. Objectives: To determine the relation of bronchial responsiveness to allergen exposure and IgE sensitization in a community study taking into account the major determinants of bronchial responsiveness in adulthood. Methods: Cross-sectional data were drawn from 1,884 participants in 20 centers in the European Community Respiratory Health Survey follow-up, which included measurement of house dust mite and cat allergen in mattress dust samples, and IgE sensitization to four allergens. Bronchial responsiveness to methacholine was expressed as a continuous variable, and analyzed by multiple regression. Measurements and Main Results: The trend toward greater bronchial responsiveness with increasing exposure to cat allergen was greater in those sensitized to any of the four allergens than those not sensitized (p = 0.001); there was no significant interaction between cat sensitization and Fel d 1 exposure. No trend was found with house dust mite allergen exposure. The difference in bronchial responsiveness between those exposed to the highest levels compared with the lowest was approximately –2.02 doubling doses of PD20 (95% confidence interval, –3.06 to –0.97), and nearly as great in those exposed to more moderate levels. Conclusions: Cat allergen exposure at moderate levels may be harmful to all atopic adults. The clinical implication is that it is insufficient to test patients with asthma for cat sensitization; all atopic individuals may benefit from reduced cat exposure.
Key Words: asthma • bronchial responsiveness • sensitization • cat • mite
The associations of the prevalence and incidence of asthma with allergen sensitization and exposure are complex (1). Asthma is strongly related to sensitization to indoor allergens (1, 2). Sensitization does not develop in the absence of exposure (2), but may be influenced by its timing and intensity, and differ between allergens (3, 4). However, there is a lack of direct evidence between exposure and asthma incidence (5), and it has been suggested that allergy "has been overinterpreted as a risk factor for asthma" (6). Prospective studies in children have suggested that early exposure to cat allergen increases the risk of sensitization (7–9), whereas a cross-sectional study of 12- to 13-year-old children reported that high exposure to cat allergen was associated with reduced prevalence of sensitization to cat (10). One cross-sectional study in adults reported decreased prevalence of sensitization to cat in those currently highly exposed (11), whereas no association was found in young adults in the European Community Respiratory Health Survey (ECRHS) (12). In contrast, studies have found the risk of sensitization to house dust mite to increase with exposure in children (7, 8, 13–15), and with current exposure in adults in one study (16). However, there was no association in the ECRHS (12). It is generally assumed that current exposure is required to produce symptoms in sensitized individuals, so that secondary prevention measures aim to reduce exposure (17–19). There have been relatively few population studies of the relation of asthma prevalence or incidence to both sensitization and current exposure, and even fewer that have tested their interaction. Bronchial responsiveness (BHR) to a nonspecific provocation agent, such as methacholine, is the objective measure of choice in epidemiological studies on asthma, complementing the more subjective information provided by symptom data. Patients with asthma have greater BHR when exposed to the allergen to which they are sensitized (20–22), and BHR may be increased in atopic patients with asthma when exposed to allergens to which they are not sensitized (23). However, it is not known if these findings hold in a general population study. The ECRHS was a multicenter study in which the prevalence of cat ownership varied widely between centers at the first survey (ECRHS I) (24). House dust mite and cat allergen exposures were measured in dust samples collected in a subsample of homes in the follow-up study (ECRHS II) (25). The cross-sectional relations of BHR to sensitization in ECRHS I (26) and other risk factors (27) have been published, and the association of change in BHR with smoking has also been reported (28). We analyzed BHR in relation to cat and house dust mite exposure and IgE sensitization to cat, house dust mite, timothy grass, and Cladosporium, together with previously determined risk factors for BHR (27). Some of the results of this study have been previously published in the form of an abstract (29).
Subjects The ECRHS II took place from 1998 to 2002 (25) (see the online supplement). Only cross-sectional data from participants selected in the random sample are included in this article. Data are taken from ECRHS II except where otherwise specified. The majority of centers, 20 in total, performed methacholine challenge and took part in an indoor protocol.
Allergen Concentrations
Total and Specific IgE
Questionnaire Data
Body Mass Index and Lung Function Testing
Bronchial Challenge
Statistical Analysis In the main analysis, BHR slope was analyzed by multiple linear regression adjusted for age, sex, height, and center, in relation to the following: each specific IgE; titers of IgE sensitization; Der 1 and Fel d 1 exposure; log-transformed total IgE; body mass index (BMI); smoking; serious respiratory infection in childhood; hospitalization for lung disease before the age of 2 years; cat ownership in childhood; family history of allergic disease; and season of testing. In addition, BHR was adjusted for FEV1 expressed as a difference from internally derived predicted values for age, height and sex, and FEV1/FVC (26, 27). Interactions considered are specified in the online supplement. Secondary analyses were performed to estimate the relation of BHR to Fel d 1 and Der 1 exposure separately for sensitized and nonsensitized individuals, and for cat owners and non–cat owners in relation to cat allergen exposure. The effect of current cat ownership, in addition to or as a substitute for Fel d 1 exposure, as well as Der p 1 and Der f 1 as separate exposures, was considered.
Participants In the random sample, 3,119 homes were visited, providing dust samples that resulted in 2,890 measurements of Der 1 and 2,817 measurements of Fel d 1. A total of 2,084 random sample participants in the indoor protocol in 20 centers had data for BHR slope. Men were more likely to be current (31.1%) or ex-smokers (32.6%) than women (27.3 and 25.0%, respectively). Ages ranged from 27 to 56 years. Mean FEV1 was 4.09 L in men and 3.03 L in women, FEV1/FVC values were 80.0 and 81.1%, respectively. More men than women were sensitized to house dust mite, 18.5% compared with 13.4% (p < 0.001), and to timothy grass, 16.7 and 14.0%, respectively (p = 0.058), but there was little difference in sensitization to cat (9.0 and 8.3%, p = 0.506) or Cladosporium (1.3 and 0.8%, p = 0.200). More men than women (31.6% compared with 24.6%, p < 0.001) were sensitized to any of the four allergens.
Exposure to House Dust Mite and Cat Allergen
Exposure to Cats Exposure to childhood cats and current cat ownership are shown in Table E1 of the online supplement. Women were more likely than men to own a cat currently and to allow it in the bedroom.
Associations of BHR with Exposure to Allergens
Secondary Analyses of Fel d 1 Exposure In subjects without cats in the home, the association of BHR with cat allergen level was weak (Table 4). The overall trend was largely due to the strong association of BHR with cat allergen levels in those with a cat allowed in the home. However, the trend in this group was not statistically significant (p = 0.072), nor was the interaction of cat ownership and trend in exposure (p = 0.173). The trend in BHR with the exposure group was marginally statistically significant (p = 0.040) in the majority group whose members were not sensitized to cat. The trend was greater in the small group that was IgE-sensitized to cat (n = 157) compared with those not sensitized, but not significantly so (p = 0.089). However, the trend in BHR in those sensitized to any of the four allergens was as large as in those sensitized to cat, and highly significant (p < 0.001), and almost as great as in those sensitized to house dust mite, grass, or Cladosporium, but not to cat. There was a very large estimate of trend in the 44 individuals sensitized only to cat (p = 0.009). No trend was observed in those not sensitized to any of the four allergens.
The association of BHR with Fel d 1 exposure was significantly greater in those sensitized to at least one of the four allergens than in those not sensitized to any allergen (interaction p = 0.001). This interaction is shown in Figure 1 in approximate doubling dose units. In those not sensitized, the difference in BHR between those exposed to the highest and lowest groups of Fel d 1 corresponded to approximately –0.28 doubling doses of PD20 (95% CI, –0.90 to 0.34); in those sensitized, the difference was approximately –2.02 doubling doses (95% CI, –3.06 to –0.97). Those sensitized and exposed to levels in the next highest exposure group (0.65 to 8 µg · g–1) showed nearly as great an increase in BHR as those exposed to more than 8 µg · g–1.
Other Secondary Analyses The relation of BHR to Der 1 exposure was neither significant nor monotonic in those sensitized or not sensitized to any allergen. There was no additional effect of current cat ownership to Fel d 1 level on BHR, nor was cat ownership significantly related to BHR when Fel d 1 level was omitted from the analysis. Neither Der p 1 nor Der f 1 exposure was related to BHR when the two components of Der 1 were analyzed.
In this population-based study, higher levels of cat allergen in mattress dust were associated with increased BHR. We hypothesized a priori that the association of BHR with allergen exposure would be greater in those sensitized to the relevant allergen. We did not find a significantly greater trend in BHR with increasing Fel d 1 in those sensitized to cat than in those not sensitized, but the overall trend in BHR with increasing Fel d 1 led us to examine the relation in those sensitized to any allergen, and to any allergen excluding cat; each group showed a strong relation of increasing BHR with greater exposure. The random sample that provided data for this analysis has the following strengths: subjects were not selected according to atopic or asthmatic status, and the sample was large compared with previous studies of adult BHR in relation to adult cat exposure in the general population (33–35). It was large enough to adjust for all potentially confounding main effects, and for interactions of center with IgE sensitization, which was found necessary in a cross-sectional analysis of ECRHS I data (27). Community studies have to balance the amount of information collected with a feasible and affordable sample size, and no study may be large enough to detect or rule out all interactions of potential interest. Our study has a number of strengths apart from sample size. It was a multicenter study, performed to a common protocol, with a range of prevalence of cat ownership from less than 10% in two centers in Spain to more than 35% in the U.K. centers (31). Der 1 concentrations also differed substantially, from being virtually undetectable in Iceland to almost all homes having detectable levels reported in three centers in Spain (30). Despite the considerable variation, no heterogeneity in the relation of BHR to allergen level across centers was detected. Plaschke and colleagues found increased BHR in sensitized patients with asthma exposed to a cat at home compared with those not exposed (20). With exposure defined as more than 10 µg · g–1 Fel d 1, Langley and colleagues found that the lowest mean PD20 (i.e., the greatest BHR) in patients both sensitized and exposed to cat, but a larger mean PD20 in those exposed and not sensitized than in those not exposed or sensitized, contributed to the weakly significant interaction between sensitization and exposure (22). In a later report by the same authors, PD20 did not differ significantly between non–cat-sensitized atopic patients with asthma who were exposed or not exposed to cat (23). They concluded that atopic subjects with asthma who are exposed to high levels of house dust mite or cat have evidence of increased BHR. To some extent, our findings support this earlier work. Our results show that individuals sensitized to house dust mite, timothy grass, or Cladosporium, but not cat, and who are exposed to high levels of cat allergen, have raised BHR (Table 4), but we did not see the equivalent result for exposure to house dust mite allergen. Some caution must be expressed over the results, as the subgroup analyses and tests of interaction were not all preplanned. In a follow-up in adulthood of 224 participants in a childhood study in New South Wales, de Meer and coworkers reported nonsignificantly greater BHR at age 28 in those owning a cat at age 18 years or older compared with never cat owners (33). A study in Melbourne followed the main ECRHS protocol, but performed a separate indoor protocol (34, 35), and their data were not included in the current analysis. Their separate cross-sectional analysis suggested that "current asthma," defined as BHR with wheeze, was increased in the highest quartile group of bed Fel d 1 exposure (34). In their longitudinal analysis, a doubling of Fel d 1 exposure at follow-up was associated with a 73% greater odds of incident self-reported doctor-diagnosed asthma, but not with a significant increase in BHR (35). The relation of IgE sensitization to mattress Fel d 1 concentration was not statistically significant in the ECRHS II (12), although sensitization was marginally related to allowing a cat indoors in ECRHS I (24). There is little consensus on the association of IgE sensitization to cat and the keeping of cats in childhood, with some studies reporting a positive association (7–9, 36, 37), and others suggesting that early exposure may be protective (24, 38, 39). Results in relation to exposure in adults are harder to interpret. Custovic and colleagues found decreased sensitization in adults exposed to high levels of Fel d 1 (11), and in those reporting current cat ownership (11, 16). Oryszczyn and coworkers found a positive skin-prick test to cat to be reduced in adults with early exposure to a cat or dog, but unrelated to current pet exposure (40). Adults with symptoms may avoid cat ownership, and selective avoidance may contribute to the inconsistent findings (16, 41). In addition, the definition of "high" exposure varies. A concentration of at least 8 µg · g–1 has been suggested as a threshold for symptoms of asthma (34), and more than 10 µg · g–1 has also been used (22), but most authors have divided their skewed distributions into quantile groups. Studies have varied according to whether carpet (7, 35, 42) or mattress concentration (8, 11, 16, 36), or both (9, 22, 23, 34), were measured. The reported adverse association between cat allergen exposure and BHR was not confined to cat-sensitized subjects. Exposures other than cat allergen, but which are related to cat allergen concentration or cat ownership, may be implicated. One possible confounding exposure is environmental tobacco smoke. Munir and colleagues (43) found a positive correlation between Fel d 1 and small airborne particles, the latter dominated by tobacco smoke in the homes of smokers. No significant relation was found in ECRHS I between BHR and environmental tobacco smoke (44), and adjusting for the number of smokers in the home in ECRHS II did not alter the association (Table 4) between BHR and Fel d 1 in those sensitized but not to cat. Building characteristics are also possible confounders, but adjusting for age of house, reported water damage in the last 12 months, or reported mold or mildew in the last 12 months did not alter the estimate. Several studies—for example, Heinrich and colleagues (45)—have found higher concentrations for endotoxin in cat owners' homes. In addition to its known immune-stimulating properties, in one study endotoxin was marginally significantly associated with asthmatic symptoms (46). Thus, cat allergen exposure or cat ownership may be a proxy for increased exposure to endotoxin that leads to increased BHR, and we cannot rule out this explanation in the current data. No relation of BHR to mattress Der 1 level was detected, nor interaction with any sensitization, even after adjustment for the interaction of Fel d 1 with sensitization (not shown). BHR was strongly related to sensitization to house dust mite, and to degree of sensitization, in ECRHS I, with some between-center heterogeneity in the latter association (26), and studies have shown the prevalence of asthma to be related to sensitization to house dust mite. Sensitization to house dust mite has been shown to be related to exposure in several studies (1). Sporik and Platts-Mills gave reasons why a direct relation between exposure and asthma might not be observed (2), including seasonal variation, variation in the dominant allergen between areas, and possible nonlinearity between exposure and sensitization. However, house dust mite is present at all seasons in most environments, with no suggestion that high levels are protective. Sporik and colleagues reported a relation of incidence of asthma and early exposure to house dust mite in one U.K. study (14), and of prevalence of asthma with exposure in atopic children when three case-control studies were combined (47). Allergen exposure modification studies in adults with asthma have been targeted at reduction of mite allergen exposure (17, 18). Our results suggest that this may be less important for adults than reduction of cat allergen exposure, even for individuals not sensitized to cat. At least one study has found wheezing in children to be related to cat allergen but not to mite (48). Despite the relation of BHR to allergen exposure found here, and the relation of exposure to community cat prevalence (31), it was not possible to demonstrate a relation of BHR in non–cat owners to community cat prevalence across the 20 centers (not shown). This is not surprising, because the range of allergen levels in the home is much greater than the range of geometric mean values across the centers (31), and there are many factors associated with BHR besides cat exposure. We considered whether our results could be explained by insensitivity of specific IgE measurement for cat sensitization, but we believe this to be unlikely. First, the cutoff we used for presence of IgE to cat was low (0.35 kUA · L–1). Second, there was almost no trend in those not IgE-sensitized to any of the four allergens. Third, we estimate that a zero trend in those sensitized to one of three allergens but not to cat would require around half of these 354 participants to have false-negative test results for IgE to cat. Fourth, a review of skin-prick test data collected in the first survey for 316 of these 354 subjects showed that only 31 had a positive weal (> 0 mm) for cat. The trend in BHR with Fel d 1 in the 285 subjects negative to both serum IgE at follow-up and skin-prick test about 9 years earlier was –0.17 (95% CI, –0.35 to 0.01; p = 0.058), which, although less than the estimate presented in Table 4 and not quite statistically significant, is compatible with a relation in those not sensitized to cat. An alternative explanation is that there are false negatives in each test. Whichever is true, advice should be against cat ownership in those showing sensitization to any allergen. Gehring and colleagues reported increased breathlessness and cough at night in subjects exposed to Fel d 1 of more than 8 µg · g–1, and who were not IgE-sensitized to any of 13 allergens (46). However, a relatively high cutoff of 0.7 kU · L–1 or greater was used to define sensitization. Our results suggest that avoidance of exposure to cat allergen and cats may be beneficial in terms of BHR for a wider group of individuals than previously anticipated. Over a quarter of adults in the ECRHS were sensitized to at least one of the four allergens, and hence at risk. Cat allergen levels are ubiquitous in cat-owning communities (42), and our results show an effect at levels below that usually regarded as high enough to produce symptoms (34), and associated with a cat in the home (2). The estimated effect on BHR of cat allergen exposure in the highest compared with the lowest exposure group, in those sensitized to at least one of the four allergens, was almost as great as the difference between participants with and without asthma in the U.K. centers in ECRHS I (32). The findings suggest that, within the population, there are people who may benefit from reduced cat exposure even though serum IgE tests suggest that they are not sensitized to cats. This group of individuals can be identified by their IgE sensitization to common allergens. A reduction in cat ownership in countries in which this exposure is high could benefit a large section of the population.
The coordination of ECRHS II was supported by the European Commission, as part of their Quality of Life program. Funding for the individual centers is listed at www.ecrhs.org. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200612-1840OC on April 19, 2007 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Coordinating Center:Project Leader: Peter Burney; Statistician: Susan Chinn; Principal Investigator: Deborah Jarvis; Project Coordinator: Jill Knox; Principal Investigator: Christina Luczynska (deceased); Assistant Statistician: James Potts; Data Manager: Sandra Arinze. Steering Committee for ECRHS II:Professor Josep M. Antó, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra; Professor Peter Burney, King's College London (Project Leader); Dr. Isa Cerveri, University of Pavia; Professor Susan Chinn, King's College London; Professor Roberto de Marco, University of Verona; Dr. Thorarinn Gislason, Iceland University Hospital; Dr. Joachim Heinrich, GSF–Institute of Epidemiology; Associate Professor Christer Janson, Uppsala University; Dr. Deborah Jarvis, King's College London; Miss Jill Knox, King's College London; Dr. Nino Künzli, University of Basel and University of Southern California, Los Angeles; Dr. Bénédicte Leynaert, Institut National de la Santé et de la Recherche Médicale; Dr. Christina Luczynska, King's College London; Dr. Françoise Neukirch, Institut National de la Santé et de la Recherche Médicale; Dr. J. Schouten, University of Groningen; Dr. Jordi Sunyer, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra; Dr. Cecilie Svanes, University of Bergen; Professor Paul Vermeire, University of Antwerp; Dr. Matthias Wjst, GSF–Institute of Epidemiology. List of Principal Investigators and Senior Scientific Team:Belgium: South Antwerp and Antwerp City (P. Vermeire, J. Weyler, M. Van Sprundel, V. Nelen). Estonia: Tartu (R. Jogi, A. Soon). France: Paris (F. Neukirch, B. Leynaert, R. Liard, M. Zureik), Grenoble (I. Pin, J. Ferran-Quentin), Pessac (A. Taytard, C. Raherison). Germany: Erfurt (J. Heinrich, M. Wjst, C. Frye, I. Meyer). Iceland: Reykjavik (T. Gislason, E. Bjornsson, D. Gislason, T. Blondal, K.B. Jorundsdottir). Italy: Turin (M. Bugiani, P. Piccioni, E. Caria, A. Carosso, E. Migliore, G. Castiglioni), Verona (R. de Marco, G. Verlato, E. Zanolin, S. Accordini, A. Poli, V. Lo Cascio, M. Ferrari), Pavia (A. Marinoni, S. Villani, M. Ponzio, F. Frigerio, M. Comelli, M. Grassi, I. Cerveri, A. Corsico). The Netherlands: Groningen and Geleen (J. Schouten, M. Kerkhof). Norway: Bergen (A. Gulsvik, E. Omenaas, C. Svanes, B. Laerum). Spain: Barcelona (J.M. Antó, J. Sunyer, M. Kogevinas, J.P. Zock, X. Basagana, A. Jaen, F. Burgos), Huelva (J. Maldonado, A. Pereira, J.L. Sanchez), Albacete (J. Martinez-Moratalla Rovira, E. Almar), Galdakao (N. Muniozguren, I. Urritia), Oviedo (F. Payo). Sweden: Uppsala (C. Janson, G. Boman, D. Norback, M. Gunnbjornsdottir), Goteborg (K. Toren, L. Lillienberg, A.C. Olin, B. Balder, A. Pfeifer-Nilsson, R. Sundberg), Umea (E. Norrman, M. Soderberg, K. Franklin, B. Lundback, B. Forsberg, L. Nystrom). Switzerland: Basel (N. Künzli, B. Dibbert, M. Hazenkamp, M. Brutsche, U. Ackermann-Liebrich). United Kingdom: Norwich (D. Jarvis, B. Harrison), Ipswich (D. Jarvis, R. Hall, D. Seaton). Centers Taking Part at Their Own Expense:France: Bordeaux (A. Taytard, C. Raherison), Montpellier (J. Bousquet, P. Demoly). Germany: Hamburg (K. Richter). United States: Portland (M. Osborne, S. Buist, W. Vollmer, L. Johnson). Received in original form August 21, 2006; accepted in final form April 16, 2007
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ABSTRACT
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