BMJ Sensitisation to airborne moulds and severity of asthma: cross sectional study

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BMJ 2002;325:411 ( 24 August )

Papers

Sensitisation to airborne moulds and severity of asthma: cross sectional

study from European Community respiratory health survey

Mahmoud Zureik, epidemiological researcher a, Neukirch, senior

physician in allergology a, Bénédicte Leynaert, epidemiological researcher

a, Renata Liard, epidemiologist a, 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@...

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

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. In a study of 11 patients with episodes of respiratory

arrest, 10 had positive results on skin prick testing for Alternaria

alternata compared with only 31 of the 99 matched controls with asthma and

no history of respiratory arrest.8 It was recently reported that 20 of 37

(54%) patients admitted to an intensive care unit for asthma had a positive

result on skin testing for one or more fungal allergens (Alternaria tenuis,

Cladosporium cladosporoides, Helminthosporium maydis, or Epicoccum nigrum)

compared with 30% in patients not admitted to intensive care units. The

patients admitted to intensive care units were no more likely than the other

patients to have positive results on skin tests for grasses, cat dander, or

house dust mites.9 Furthermore, a study of the effects of environmental

moulds during the pollen season showed that mean concentrations of mould

spores, but not of tree, grass, or ragweed pollen, were significantly higher

on the days when there were deaths related to asthma than on the days when

no such deaths occurred.10 Thus there is evidence for an association between

sensitisation and exposure to moulds and life threatening exacerbations of

asthma. However, the hypothesis that sensitisation to moulds is generally

associated with the severity of asthma remains to be investigated.

In a preliminary study based on data from population samples of young adults

collected in two French centres we found that sensitisation to Alternaria

was associated with severity of asthma in a population of young adults.

However, few participants had severe asthma (n=21) and there were not enough

positive results on skin prick tests to investigate the effect of other

moulds.11

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

The methods of the survey have been fully described elsewhere. 12 13

Briefly, participating centres randomly selected samples of 20 to 44 year

olds. Participants completed a short postal questionnaire about asthma and

asthma-like symptoms (stage 1). At stage 2 about 20% random subsamples of

responders were invited to attend a local test centre to complete a more

detailed questionnaire administered by an interviewer and undergo skin prick

and blood tests, assessment of lung function by spirometry, and airway

challenge with methacholine. In addition, all participants who were not in

the random subsamples but who reported in the postal questionnaire that they

had been woken up by an attack of shortness of breath, had had at least one

asthma attack in the past 12 months, or were currently taking medicine for

asthma were also invited to participate in the stage 2 (symptomatic sample).

The detailed questionnaire included questions about smoking, occupation,

social status, home environment, medication, and use of services.13

Standardised skin prick tests were carried out with allergen coated lancets

(Phazets, Pharmacia Diagnostics, Uppsala, Sweden). The allergens selected in

all centres were A alternata, Cladosporium herbarum, Phleum pratense

(timothy grass), birch, olive, Parietaria judaica (pellitory-of-the-wall),

common ragweed (Ambrosia artemisifolia), Dermatophagoides pteronyssinus

(house dust mite), and cat. An uncoated lancet was used as the negative

control. Tests were performed on the volar surface of the forearm with a

standard template. Weal size was recorded at 15 minutes as the biggest

diameter and the diameter at 90° to its midpoint, each to the nearest whole

millimetre. The mean weal diameter was calculated as the average of the two

diameters. Results were regarded as positive if the mean weal diameter was

at least 3 mm greater than that for the negative control. Baseline forced

expiratory volume in one second and forced vital capacity were measured by

standardised methods, most often with a Biomedin spirometer (Biomedin,

Padua, Italy).14

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 al15 and based on the forced expiratory

volume in one second (mild >80%, moderate 70-80%, severe <70% predicted),

the number of asthma attacks in the past 12 months (2, 3-6, >6), the number

of admissions to hospital for breathing problems in the past 12 months (0,

1-2, >2), and whether inhaled or oral corticosteroids had been taken in the

past 12 month. Each of the first three variables had three levels of

increasing severity (scored 1, 2, 3) and the fourth variable had two levels

(scored 1 or 2). The overall total score therefore ranged from 4 to 11, with

levels of severity levels being mild (score 4 or 5), moderate (6), or severe

(7).

Analysis

We used the data from stage 2 from the 30 centres that performed skin prick

tests for the nine allergens mentioned above. The population, response rate,

and prevalence of asthma in the centres have been reported previously.16-18

Of the 17 089 participants examined for stage 2 in those 30 centres,

complete data for all skin prick tests were available for 14 098. Of those,

1351 currently had asthma and in 1132 severity could be classified (missing

data: 35 for forced expiratory volume in one second, 181 for the number of

attacks, and 3 for both). The 1132 participants included in the analysis did

not differ according to age, sex, smoking, or result to skin prick test from

the 219 patients who could not be classified. Figure 1 shows details of the

study design and the numbers of participants involved at each stage.

Fig 1. Study design and patients involved at each stage for 30 centres

included in present analysis

We used the SAS-PC statistical package (SAS Institute, Cary, NC) for

statistical analysis. We assessed the associations between severity of

asthma (mild, moderate, severe) and categorical variables using 2 test and

tested for trend with Mantel-Haenszel tests. We gathered data from the 30

centres within regions: United Kingdom and Republic of Ireland), northern

Europe (Iceland, Norway, Sweden), central Europe (Belgium, France, the

Netherlands), southern Europe (Italy and Spain), Australia and New Zealand,

and United States (Portland was the only area in the United States). As we

found no heterogeneity between regions in the association between severity

and sensitisation to allergens (P>0.30 for all allergens except D

pteronyssinus, for which P=0.13) we performed logistic regressions to

estimate adjusted odds ratios for the associations between severity and

sensitisation, taking potential confounding factors into account and with

regions included in the model as an additional explanatory variable. We used

nominal logistic regressions to assess odds ratios for moderate versus mild

asthma and for severe versus mild asthma (without a linearity hypothesis).

We used ordinal regression to test for linear trends of the associations

between sensitisation and the three categories of severity.

Results

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

(table 1). Table 1 also shows the features of severity that we used to

classify participants into categories.

Table 1. Characteristics of study population. Figures are numbers

(percentage) of participants unless stated otherwise

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 2). 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. Proportions (%) of participants with asthma with sensitisation

to allergens tested in six regions of European Community respiratory health

survey (ECRHS)

Table 3 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).

Table 3. Associations between sensitisation to moulds and severity of

asthma (% of sensitised participants by severity and odds ratios (95%

confidence interval) for moderate versus mild asthma and severe versus mild

asthma)

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

We found no association between severity of asthma and sensitisation to

pollens. Table 4 shows the results for timothy grass and birch and

sensitisation to at least one of the pollens tested. The latter results were

identical when we excluded P judaica and ragweed, which are not ubiquitous,

from the definition of sensitisation to any pollen.

Table 4. Associations between sensitisation to pollens and severity of

asthma (% of sensitised participants by severity and odds ratios (95%

confidence interval) for moderate versus mild asthma and severe versus mild

asthma)

Severity of asthma was positively associated with sensitisation to D

pteronyssinus but not with sensitisation to cats (table 5). 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 (table 6). For moulds (Alternaria

or Cladosporium, or both) the odds ratios were 1.48 for moderate versus mild

asthma and 2.16 for severe versus mild asthma.

Table 5. Associations between sensitisation to Dermatophagoides

pteronyssinus or to cats and severity of asthma (% of sensitised

participants according to severity and odds ratios (95% confidence interval)

for moderate versus mild asthma and severe versus mild asthma)

Table 6. Associations between severity of asthma and sensitisation to

moulds (Alternaria alternata or Cladosporium herbarum), pollens,

Dermatophagoides pteronyssinus, and cats. Multivariate adjusted* odds ratio

(95% confidence interval) for moderate versus mild asthma and for severe

versus mild asthma

The results were virtually identical when we included the number of

allergens the participants were sensitised to in the models.

Discussion

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,19 and admissions to hospital for asthma,20

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.

The definition of severity of asthma in a population study is a difficult

issue.21 We based our classification on a score that included some features

considered as the most relevant.22 It is necessary to consider the use of

drugs to control asthma in the classification of currently treated patients

because otherwise participants would be classified according to control of

asthma rather than severity.23 The inclusion of the use of corticosteroids

in our definition may have influenced the distribution of severity in

different areas because of variation in prescription from country to

country. 16 17 Such variations do not allow international comparisons for

the prevalence of severe asthma. However, similar patterns of results for

the association between severity and sensitisation to moulds were observed

in the different areas. Because it has been suggested that long term use of

oral corticosteroids may modify results of skin prick tests24 we reanalysed

the data after excluding the 110 patients taking oral corticosteroids. The

multivariate adjusted odds ratios for the association between moulds (either

Alternaria or Cladosporium) and severity were 1.65 (95% confidence interval

1.08 to 2.50) for moderate versus mild asthma and 2.49 (1.55 to 3.99) for

severe versus mild asthma. These results are similar to those presented in

table 3.

We considered hospital admissions in the past 12 months in the

classification of asthma severity, but in only a few participants (2.2%) was

this relevant. Our results do not therefore duplicate those of previous

studies of life threatening asthma.

To date, there has been little evidence that sensitisation to moulds is

associated with severity of asthma. A study of 343 children aged 7 to 12

years recruited from a paediatric practice investigated the association

between sensitisation to individual allergens and the frequency of episodes

of wheezing. The proportion of children sensitised to A tenuis increased

with the number of episodes. However, significant associations were also

observed for sensitisation to mites and especially to cats.25 The relation

between skin test reactivity and forced expiratory volume in one second was

examined in children aged 6 to 12 years with asthma or frequent wheezing as

part of the second national health and nutrition survey. Low forced

expiratory volume in one second was associated with reactions to house dust,

Alternaria, dogs, ragweed, oak, and Bermuda grass allergens.26

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.27 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.28 In a preliminary study based on

data from two French centres we found that sensitisation to Alternaria was

associated with severity of asthma.11

As the importance of sensitisation to moulds as a risk factor for severe

asthma may be dependent on area, the European survey was an unique

opportunity to assess the consistency of the association. Data were

collected with thoroughly standardised methods in comparable populations.

Consistency of results across the survey areas has not always been observed

for other issues. For example, the association between symptoms of asthma

and lung function and the use of gas appliances varied considerably between

areas. 29 30 In contrast, the association between severity and sensitisation

to moulds was remarkably consistent, though there were differences in the

distribution of severity and in the frequency of sensitisation to the

various allergens in the various areas, despite the fact the gathering of

centres into regions is necessarily arbitrary.

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.31 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.32 More recently, it has been suggested

that moulds may have had a role in the asthma epidemics in Barcelona that

were attributed to soybean.33

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.

Principal participants

Coordinating centre (London) : P Burney, S Chinn, C Luczynska, D Jarvis, E

Lai.

Project management group: P Burney (project leader), S Chinn, C Luczynska, D

Jarvis, P Vermeire (Antwerp), H Kesteloot (Leuven), J Bousquet

(Montpellier), D Nowak (Hamburg), the late J Prichard (Dublin), R De Marco

(Verona), B Rijcken (Groningen), J M Anto (Barcelona), J Alves (Oporto), G

Boman (Uppsala), N Nielsen (Copenhagen), P Paoletti (Pisa).

Participating centres: Austria: W Popp (Vienna); Australia: M Abramson, J

Kutin (Melbourne); Belgium: P Vermeire, F van Bastelaer (Antwerp South,

Antwerp Central); France: J Bousquet, J Knani (Montpellier), F Neukirch, R

Liard (Paris), I Pin, C Pison (Grenoble), A Taytard (Bordeaux); Germany: H

Magnussen, D Nowak (Hamburg), H E Wichmann, J Heinrich (Erfurt); Greece: N

Papageorgiou, P Avarlis, M Gaga, C Marossis (Athens); Iceland: T Gislason, D

Gislason (Reykjavik); Ireland: the late J Prichard, S Allwright, D MacLeod

(Dublin); Italy: M Bugiani, C Bucca, C Romano (Turin), R de Marco Lo Cascio,

C Campello (Verona), A Marinoni, I Cerveri, L Casali (Pavia); the

Netherlands: B Rijcken, A Kremer, (Groningen, Bergen-op-Zoom, Geleen); New

Zealand: J Crane, S , (Wellington, Christchurch, Hawkes Bay); Norway: A

Gulsvik, E Omenaas (Bergen); Portugal: J A Marques, J Alves (Oporto); Spain:

J M Antó, J Sunyer, F Burgos, J Castellsangué, J Roca, J B Soriano, A Tobías

(Barcelona), N Muniozguren, J Ramos Gonzáles, A Capelastegui (Galdakao), J

Castillo, J Portal (Seville), J ez-Moratalla, E Almar

(Albacete), J Maldonado Pérez, A Pereira, J Sánchez (Huelva), J Quiros, I

Huerta, F Pavo, (Oviedo); Sweden: G Boman, C Janson, E Björnsson (Uppsala),

L Rosenhall, E Norrman, B Lundbäck (Umea), N Lindholm, P Plaschke

(Gothenburg,); Switzerland: U Ackermann-Liebrich, N Künzli, A Perruchoud

(Basle); United Kingdom: M Burr, J Layzell (Caerphilly), R Hall (Ipswich), B

on (Norwich), J Stark (Cambridge); United States: S Buist, W Vollmer,

M Osborne (Portland).

Acknowledgments

Contributions: All authors conceived and initiated this study within the

framework of the European Community respiratory health survey. MZ designed

and performed the analysis, wrote the first draft of the paper, and is

guarantor. CN helped with analysis, interpretation, and writing the paper.

BL conducted part of the statistical analysis and helped in interpretation.

RL gave substantial help to writing the paper. JB participated in study

design and interpretation. FN was principal investigator and participated in

study design, analysis, and interpretation. MZ and CN participated in the

data collection for the Paris centre.

Footnotes

Funding: Australia: & 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 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.

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(Accepted 4 April 2002)

© BMJ 2002