Papers

Sensitisation to airborne moulds and severity of asthma: cross sectional study from European Community respiratory health survey

Mahmoud Zureik, epidemiological researcher ^a, Catherine Neukirch, senior physician in allergology ^a, Bénédicte Leynaert, epidemiological researcher ^a, Renata Liard, epidemiologist ^a, Jean Bousquet, professor ^b, Françoise Neukirch, senior epidemiological researcher ^a,  on behalf of the European Community Respiratory Health Survey.

^a National Institute of Health and Medical Research (INSERM), Unit 408 Epidémiologie, Faculté de Médecine Xavier Bichat, BP 416, 75870 Paris CEDEX 18, France, ^b National Institute of Health and Medical Research (INSERM), Unit U454 Hôpital Arnaud de Villeneuve, 34295 Montpellier Cedex 05, France

Correspondence to: Mahmoud Zureik zureik{at}vjf.inserm.fr

	Abstract

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Objective: To assess whether the severity of asthma is associated with sensitisation to airborne moulds rather than to other seasonal or perennial allergens.
Design: Multicentre epidemiological survey in 30 centres.
Setting: European Community respiratory health survey.
Participants: 1132 adults aged 20-44 years with current asthma and with skin prick test results.
Main outcome measure: Severity of asthma according to score based on forced expiratory volume in one second, number of asthma attacks, hospital admissions for breathing problems, and use of corticosteroids in past 12 months.
Results: The frequency of sensitisation to moulds (Alternaria alternata or Cladosporium herbarum, or both) increased significantly with increasing asthma severity (odds ratio 2.34 (95% confidence interval 1.56 to 3.52) for either for severe v mild asthma). This association existed in all of the study areas (gathered into regions), although there were differences in the frequency of sensitisation. There was no association between asthma severity and sensitisation to pollens or cats. Sensitisation to Dermatophagoides pteronyssinus was also positively associated with severity. In multivariable logistic regressions including sensitisation to moulds, pollens, D pteronyssinus, and cats simultaneously, the odds ratios for sensitisation to moulds were 1.48 (0.97 to 2.26) for moderate v mild asthma and 2.16 (1.37 to 3.35) for severe v mild asthma (P<0.001 for trend).
Conclusions: Sensitisation to moulds is a powerful risk factor for severe asthma in adults. This should be taken into account in primary prevention, management, and patients' education.

What is already known on this topic Sensitisation to moulds is a known risk factor for life threatening exacerbations of asthma It is unknown whether such sensitisation is generally associated with severity of asthma What this study adds The prevalence of sensitisation to moulds (Alternaria alternata or Cladosporium herbarum, or both) increased with increasing severity of asthma In this multicentre epidemiological survey, similar patterns of results were observed in various areas of the world

	Introduction

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The severity of asthma varies widely between patients. Mild cases are characterised by normal lung function and patients are asymptomatic most of the time, whereas severe cases are characterised by permanently impaired lung function and frequent exacerbations. Little is known about the factors associated with severity, but the identification of such factors is necessary for management and prevention.

Sensitisation to airborne allergens might be involved in the underlying mechanisms of severity. The associations between exposure, sensitisation, and asthma have suggested that house dust mite, ^{1 2} animal dander, ^{3 4} cockroaches,⁵ pollens,⁶ and mould spores⁷ have a causal role in development. However, the associations between sensitisation to different allergens and the severity of asthma have been poorly explored.

Sensitisation to moulds has been suggested as a risk factor for life threatening asthma.^8-10 However, the hypothesis that such sensitisation is generally associated with the severity of asthma remains to be investigated.

We used data from 1132 people with asthma from the entire dataset of the European Community respiratory health survey to assess whether the severity of asthma is associated with sensitisation to airborne moulds rather than to other seasonal or perennial allergens.

	Methods

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The methods of the survey have been fully described elsewhere. ^{11 12} Briefly, participating centres randomly selected samples of 20 to 44 year olds, who completed a short postal questionnaire about asthma and asthma-like symptoms (stage 1). At stage 2 a random subsample of responders were invited to complete a more detailed questionnaire and undergo skin prick and blood tests, assessment of lung function by spirometry, and airway challenge with methacholine.

View larger version (39K): [in this window] [in a new window]   Fig 1.   Study design and patients involved at each stage for 30 centres included in present analysis

Standardised skin prick tests were carried out with allergen coated lancets (Phazets, Pharmacia Diagnostics, Uppsala, Sweden). The allergens selected in all centres were Alternaria alternata, Cladosporium herbarum, Phleum pratense (timothy grass), birch, olive, Parietaria judaica (pellitory-of-the-wall), common ragweed (Ambrosia artemisiifolia), Dermatophagoides pteronyssinus (house dust mite), and cat. An uncoated lancet was used as the negative control. Results were regarded as positive if the mean weal diameter was at least 3 mm larger than that for the negative control.

Figure 1 shows details of the study design and the numbers of participants involved at each stage.

Definitions of asthma and severity
Participants were defined as currently having asthma if they answered yes to the question"Have you ever had asthma?"and if they had had at least one asthma attack or had taken inhaled or oral corticosteroids for asthma in the past 12 months. Asthma was classified as mild, moderate, or severe according to a score derived from Ronchetti et al.¹⁵ The overall total score ranged from 4 to 11, with levels of severity levels being mild (score 4 or 5), moderate (6), or severe (7).

	Results

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Of the 1132 people with asthma in this study, 564 (50%) had mild asthma, 333 (29%) had moderate asthma, and 235 (21%) had severe asthma. Severity was not related to age, sex, smoking, passive smoking, or parental history of asthma.

The proportion of people with mild asthma varied according to geographical area, ranging from 63% in southern Europe to 42% in Australia and New Zealand. The proportion with severe asthma was 15% in southern Europe, 17% in central Europe, 17% in northern Europe, 21% in the United Kingdom and Republic of Ireland, 28% in Australia and New Zealand, and 26% in Portland.

Over 73% of participants were sensitised to at least one allergen and 65% were sensitised to two or more. Sensitisation to moulds alone was extremely rare: nine people were sensitised to Alternaria only and two to Cladosporium only. The proportion of people with asthma with sensitisation to the various allergens varied according to the regions (table 1). Sensitisation to moulds was the lowest in southern Europe and the highest in Portland and in the United Kingdom and Republic of Ireland.

Table 2 shows that sensitisation to moulds was significantly associated with severity of asthma. For both Alternaria and Cladosporium the proportion of sensitised people increased with increasing severity (P<0.001 for trend). For Alternaria the odds ratio was 1.64 for moderate versus mild asthma and 2.05 for severe versus mild asthma. These remained unchanged in the multivariable models after we adjusted for possible confounding factors. For Cladosporium the odds ratio was >3 for severe versus mild asthma. When we considered sensitisation to either mould, the odds ratio was 2.34 for severe versus mild asthma (P<0.001). We observed similar patterns for the association between sensitisation to moulds and severity of asthma (severe versus mild asthma) in all regions (fig 2). We found no association between severity of asthma and sensitisation to pollens.

View larger version (16K): [in this window] [in a new window]   Fig 2.   Multivariable adjusted odds ratios (95% confidence interval) for association of severe versus mild asthma with sensitisation to moulds (either Alternaria alternata or Cladosporium herbarum, or both) by region (adjusted within region for age, sex, smoking habits, passive smoking, and parental history of asthma) with combined odds ratio from model with region included as random effect

Severity of asthma was positively associated with sensitisation to D pteronyssinus but not with sensitisation to cats. To assess the independent relations between the various allergens and severity of asthma we carried out simultaneous logistic regressions including sensitisation to moulds, pollens, D pteronyssinus, and cats. For moulds (Alternaria or Cladosporium, or both) the odds ratios were 1.48 (0.97 to 2.26) for moderate versus mild asthma and 2.16 (1.37 to 3.35) for severe versus mild asthma (P<0.001 for trend).

The results were virtually identical when we included the number of allergens the participants were sensitised to in the models.

	Discussion

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Our study of asthma from large population based samples of adults living in different countries showed that the severity of asthma is associated with sensitisation to Alternaria and Cladosporium but not to pollens. As expected the severity of asthma was also associated with sensitisation to D pteronyssinus.

Comparison with other studies
Previous studies have shown that sensitisation or exposure to moulds is associated with death from asthma, life threatening exacerbations,^8-10 visits to emergency departments,¹³ and admissions to hospital for asthma,¹⁴ but this is the first population based study that used criteria other than healthcare attendance alone to show that sensitisation to moulds is a risk factor for severe asthma in adults.

To date, there has been little evidence that sensitisation to moulds is associated with severity of asthma. To our knowledge no population studies apart from the European Community respiratory health survey have investigated the association between severity of asthma and sensitisation to allergens in adults. In a study of the relative importance of sensitisation to individual allergens for bronchial hyper-responsiveness in the United Kingdom within the framework of the European survey, people with positive results to Cladosporium were considerably more responsive than those with positive results to cats or timothy grass.¹⁵ Analysis of Spanish data showed that sensitisation to Alternaria, cats, and timothy grass was associated with a decrease in forced expiratory volume in one second in women.¹⁶

We observed a differential association between moulds and pollens and severity of asthma. Possibly the size of fungal spores allows them to reach the lower airways and also they may be inhaled by means of fragments and other amorphous bioaerosols. Pollens are larger and their effect on asthma requires exceptional situations such as thunderstorms, when pollen is concentrated by changes in air flow, grains are ruptured by osmotic shock, and each grain releases hundreds of starch granules that are small enough to be respired.¹⁷ Other explanations for the different effects of sensitisation to moulds and to pollens are possible. Unlike pollens, moulds are present all through the year with increase in the spore counts during the autumn months. Also, the level of mould exposure is probably greater because the exposure occurs indoors rather than outdoors and people spend most of their time indoors. The severity of asthma was associated with sensitisation to airborne moulds despite the fact that sensitisation to moulds alone was extremely rare. This might suggest a synergistic or additive effect of various sensitisations in determining severity. However, this is unlikely because when the number of positive test results was taken into account in the analysis the results did not change.

Our results of the associations between moulds and severity of asthma may be put together with results from studies on asthma incidence or outbreaks, where the role of moulds can be suspected for effects that were primarily attributed to other allergens. Moulds might be involved in the dramatic increase in incidence in Tucson that was initially attributed in part to a 10-fold increase in atmospheric pollen due to the widespread use of ornamental trees that produce pollen.¹⁸ More recently, it has been suggested that moulds may have had a role in the asthma epidemics in Barcelona that were attributed to soybean.¹⁹

Conclusion
In conclusion, our results show that sensitisation to moulds might be involved in the severity of asthma. Given the increase of asthma and the prevalence of severe asthma in the past decades these results may be relevant for many people. Those people with asthma who are sensitised to airborne moulds should be educated to pay careful attention to symptoms and comply with treatment, particularly during the seasonal increase in mould spore counts. Patients should be encouraged to decrease exposure by avoiding indoor conditions that facilitate the growth of mouldsfor example, by better ventilation and by decreasing dampness.

	Acknowledgments

Details of participating centres can be found with the long version of this paper on bmj.com

Contributions: See bmj.com

	Footnotes

Funding: Australia: Allen & Hanbury, Australia; Belgium: Belgian Science Policy Office, National Fund for Scientific Research; France: Ministère de la Santé, Glaxo France, Institut Pneumologique d'Aquitaine, Contrat de Plan Etat-Région Languedoc-Roussillon, CNMATS, CNMRT (90MR/10, 91AF/6), Ministre délégué de la santé, RNSP, Ministère de l'Environnement (No 96115-EN96D4); Germany: GSF, Bundesminister für Forschung und Technologie, Bonn; Greece: Greek Secretary General of Research and Technology, Fisons, Astra, Boehringer-Ingelheim; India: Bombay Hospital Trust; Italy: Ministero dell'Univesità e della Ricerca Scientifica e Tecnologica, CNR, Regione Veneto Grant RSF No 381/05.93; New Zealand: Asthma Foundation of New Zealand, Lotteries Grant Board, Health Research Council of New Zealand; Norway: Norwegian Research Council project No 101422/310; Portugal: Glaxo Farmacêutica Lda, Sandoz Portugesa; Spain: Ministero Sanidad y Consumo FIS (grants 91/0016060/OOE-05E, 92/0319, 93/0393), Hospital General de Albacete, Hospital General Juan Ramón Jiménenz, Consejeria de Sanidad Principado de Asturias; Sweden: Swedish Medical Research Council, Swedish Heart Lung Foundation, Swedish Association against Asthma and Allergy, Swedish Society of Medicine, Astra, Glaxo-Wellcome, Boehringer-Ingelheim; Switzerland: Swiss National Science Foundation Grant 4026-28099; United Kingdom: National Asthma Campaign, British Lung Foundation, Department of Health, South Thames Regional Health Authority; United States: US Department of Health, Education and Welfare Public Health Service Grant No 2 S07 RR05521-28.

Competing interests: None declared.

The full version of this article appears on bmj.com

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(Accepted 4 April 2002)