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Asthma Study 2
Sensitisation to airborne moulds and severity of asthma: cross sectional study from European Community respiratory health survey
Mahmoud Zureik, Catherine Neukirch, BÈnÈdicte Leynaert,
Renata Liard, Jean Bousquet,
Françoise Neukirch, on behalf of the European Community Respiratory
Health Survey
Abstract
National Institute of |
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 2044 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.
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 asthmalike
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 (pellitoryofthewall),
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
7080%, severe < 70% predicted), the number of asthma attacks in
the past 12 months (2, 36, > 6), the number of admissions to hospital
for breathing problems in the past 12 months (0, 12, > 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.We used the SASPC statistical package (SAS Institute, Cary, NC) for statistical analysis. We assessed the associations between severity of asthma (mild, moderate, severe) and categorical variables using X2 test and tested for trend with MantelHaenszel 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
Fig 1 Study design and patients involved at each stage for 30 centres included in present analysis |
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.
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 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 1 Characteristics of study population. Figures are numbers (percentage) of participants unless stated otherwise 
|
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.
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 2 Proportions (%) of participants
with asthma with sensitisation to allergens tested in six regions
of European Community respiratory health survey (ECRHS) |
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)  |
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)  |
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.
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 |
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.21We 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
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 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
hyperresponsiveness 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
| What is already known on this topic |
Sensitisation to moulds is a known risk factor
for life threatening exacerbations 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 |
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 10fold 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 moulds-for 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, BergenopZoom, Geleen); New Zealand: J Crane, S Lewis, (Wellington, Christchurch, Hawkes Bay); Norway: A Gulsvik, E Omenaas (Bergen); Portugal: J A Marques, J Alves (Oporto); Spain: J M AntÛ, J Sunyer, F Burgos, J CastellsanguÈ, J Roca, J B Soriano, A TobÌas (Barcelona), N Muniozguren, J Ramos Gonz·les, A Capelastegui (Galdakao), J Castillo, J Rodriguez Portal (Seville), J MartinezMoratalla, E Almar (Albacete), J Maldonado PÈrez, A Pereira, J S·nchez (Huelva), J Quiros, I Huerta, F Pavo, (Oviedo); Sweden: G Boman, C Janson, E Bjˆrnsson (Uppsala), L Rosenhall, E Norrman, B Lundb‰ck (Umea), N Lindholm, P Plaschke (Gothenburg,); Switzerland: U AckermannLiebrich, N K¸nzli, A Perruchoud (Basle); United Kingdom: M Burr, J Layzell (Caerphilly), R Hall (Ipswich), B Harrison (Norwich), J Stark (Cambridge); United States: S Buist, W Vollmer, M Osborne (Portland).
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.
Funding: Australia: Allen & Hanbury, Australia; Belgium:
Belgian Science Policy Office, National Fund for Scientific Research;
France: MinistËre de la SantÈ, Glaxo France, Institut Pneumologique
d'Aquitaine, Contrat de Plan EtatRÈgion LanguedocRoussillon,
CNMATS, CNMRT (90MR/10, 91AF/ 6), Ministre dÈlÈguÈ
de la santÈ, RNSP, MinistËre de l'Environnement (No 96115EN96D4);
Germany: GSF, Bundesminister f¸r Forschung und Technologie, Bonn;
Greece: Greek Secretary General of Research and Technology, Fisons, Astra,
BoehringerIngelheim; India: Bombay Hospital Trust; Italy: Ministero
dell'Univesit‡ 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 FarmacÍutica Lda, Sandoz Portugesa; Spain: Ministero Sanidad
y Consumo FIS (grants 91/0016060/OOE05E, 92/0319, 93/0393), Hospital
General de Albacete, Hospital General Juan RamÛn JimÈnenz,
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, GlaxoWellcome,
BoehringerIngelheim; Switzerland: Swiss National Science Foundation
Grant 402628099; 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 RR0552128.
Competing interests: None declared.
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(Accepted 4 April 2002)
Science commentary: Skin prick testing
Skin prick testing is conventionally used to investigate immediate type
hypersensitivity to allergens in patients with rhinoconjunctivitis, contact
urticaria, asthma, atopic eczema, and suspected food allergy. It is also
a means of detecting allergen specific IgE and has the advantage of being
relatively inexpensive, providing immediate results compared with measurement
of serum allergen specific IgE by radioallergosorbent testing (RAST).
The technique used for skin prick testing involves puncturing the skin
with a calibrated lancet (1 mm) held vertically, or a hypodermic needle
or blood lancet at an angle of 45°, and introducing a drop of diluted
allergen. All patients undergoing skin prick testing should also have
a positive histamine control and negative diluent (saline) control test
included. An itchy weal should develop at the histamine puncture site
within 10 minutes. Test solutions are standardised to give a mean weal
diameter of 6 mm. The maximum or mean diameter of the weals to various
allergens should be read at 15 minutes. A weal of 3 mm or more in diameter
is generally considered to represent a positive response (indicating sensitisation
to the allergen). The negative control is important because it excludes
the presence of dermographism, which if present makes the tests difficult
to interpret.
The relevance of skin prick testing should be interpreted in the context
of the patient's history. Positive results can occur in people without
symptoms and, similarly, false negative results may occur. "Blanket"
allergy testing (whether by skin prick testing or serological methods)
can give false positive results and, particularly in the case of foods
can lead to unnecessary dietary restrictions. Standardised solutions to
a wide range of allergens are available commercially. For more labile
allergens (such as those found in fruit and vegetables) fresh produce
should be used. Skin prick tests to aeroallergens are generally considered
safe, but intramuscular adrenaline should be available and full resuscitation
facilities are needed when test are carried out with other allergens such
as foods and natural rubber latex.