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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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The fungus Alternaria is known to be allergenic and is one of the most common fungi worldwide. We investigated the extent to which exposure to Alternaria increases the severity of asthma. We undertook a prospective cohort study in Australia of 399 school children who had positive skin tests to one or more aeroallergens. Airway responsiveness to histamine, wheeze, and bronchodilator use in 1 mo was measured five times between 1997 and 1999. Airway hyperresponsiveness was defined as PD20FEV1 = 3.9 µmol histamine. Airborne concentrations of Alternaria spores were measured throughout the study, and mean daily concentrations over 1 mo ranged from 2.2 to 307.7 spores/m3 of ambient air. Using generalized estimating equations, we found that airway responsiveness, wheeze, and bronchodilator use increased significantly in association with increased spore concentrations and that the increase in airway responsiveness was greater in children sensitized to Alternarxia than in other children (p = 0.01). The odds ratio for airway hyperresponsiveness in children sensitized to Alternaria was 1.26 (95% CI, 1.14 to 1.39) after an increase in mean exposure of 100 spore/m3/d over 1 mo. These results suggest that Alternaria allergens contribute to severe asthma in regions where exposure to the fungus is high.
Keywords: Alternaria; airway responsiveness; asthma; fungi; children
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Fungi make up the largest proportion of airborne biologic particles (1, 2). Evidence of sensitivity to Alternaria and Cladosporium is commonly obtained by skin prick tests in clinical practice, but the implications of these allergies for respiratory illness have not been well characterized.
Alternaria is one of the most common fungal genera worldwide (1). Species parasitize a wide range of plants, and they are found in both urban and rural areas and are particularly prevalent in warm climates and regions where there is substantial cropping (4). The reported prevalence of sensitization to Alternaria in population samples of children ranges from less than 1% in Austria (8) to 50% in Arizona, USA (9). The major allergen (Alt a1) has been isolated from both the spores and the mycelia of strains of Alternaria alternata (10, 11). The spores, which range between 2 and 8 µm in diameter (12), are small enough to be inhaled and, under laboratory conditions, provoke respiratory symptoms and airway responsiveness in asthmatics (13).
Persons sensitized to Alternaria allergens are at least three times more likely to have asthma than the general population (14, 15). Respiratory arrest in asthmatics sensitized to Alternaria is more likely to occur during harvesting seasons when airborne concentrations of Alternaria spores are high (5).
The effect of natural exposure to Alternaria spores on airway responsiveness and respiratory symptoms in a general population of allergic children has not been investigated. We undertook a prospective cohort study of allergic school children in two regions of New South Wales, Australia, where the prevalence of sensitization to Alternaria was known to be high (16). Our hypothesis was that symptoms and airway responsiveness would increase in association with an increase in airborne concentrations of Alternaria spores, and that this association would only be found in children sensitized to Alternaria.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A prospective cohort study of 399 school children was conducted in two inland rural towns, Wagga Wagga and Moree, in southeastern Australia. The Human Ethics Committee at the University of Sydney gave approval for the study. Population samples of children in the towns had skin prick tests for allergy to eight allergens, including Alternaria, rye grass pollen, Cladosporium, Dermatophagoides pteronyssinus, and cat dander (17). All children in Moree and a random sample of children in Wagga Wagga with a positive skin prick test to Alternaria were selected for study (n = 179). In addition, a random sample of children from both towns with one or more positive skin prick tests to other allergens but not to Alternaria were selected (n = 220). The mean age was 9.1 yr (SD, 1.0) for children sensitized to Alternaria, and it was 9.1 yr (SD, 1.1) for the other children.
The children were assessed on five occasions in each town between August 1997 and June 1999. At each assessment, parents completed a questionnaire about respiratory symptoms in their child during the previous month (18), and lung function and airway responsiveness were measured in the children. Airway responsiveness was measured by a histamine bronchial provocation test (19). Dose-response ratio (DRR), which was the level of airway responsiveness, was calculated as the percent fall in FEV1 at the last dose divided by the total dose of histamine administered (FEV1/µmol) (20, 21). Subjects with a greater than 20% fall in FEV1 at or before the maximum cumulative dose (3.9 µmol) were classified as having airway hyperresponsiveness (AHR).
Burkard volumetric traps placed on the roofs of the local hospital were used to measure concentrations of Alternaria spores and pollen in the ambient air in the towns throughout the study period (22). Spore and pollen concentrations were expressed as number per cubic meter of air per 24 h.
The association between Alternaria exposure and presence and severity of asthma was examined using four respiratory outcomes: DRR, AHR, wheeze, and bronchodilator use. Alternaria and pollen exposures were defined as the mean daily airborne concentrations measured in each town for 30 d preceding the mid-date of each assessment period. Generalized estimating equations (GEE) were used to measure the association between outcomes and exposures (23, 24). All analyses were performed using the statistical program STATA.
Separate models relating Alternaria exposure to the respiratory outcomes were constructed for children sensitized to a specific allergen and children who were sensitized to other aeroallergens. We tested whether the relation between Alternaria exposure and the respiratory outcomes differed significantly between the groups of children. Possible confounders were placed in the models one at a time and removed if they did not have an important effect or substantially increased the standard error. Grass pollen could not be tested as a confounder because of the high correlation between Alternaria spore concentrations and grass pollen concentrations. The effects from exposure to Alternaria on the respiratory outcomes were calculated for an increase in mean daily airborne concentration of 100 spores/m3 over 1 mo.
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RESULTS |
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Exposure to Alternaria, Pollen, House Dust Mites, and Meteorologic Factors
Mean daily airborne concentrations of Alternaria spores in
Moree were higher than those in Wagga Wagga for most of
the year. Concentrations were lowest during winter in both
towns and were highest during summer. Mean daily airborne
Alternaria spore concentrations for the 30 d preceding the
mid-date of each of the five assessment periods ranged from
2.2 spores/m3 (range, 0 to 9) to 300.6 spores/m3 (range, 39 to
1,270.5) in Wagga Wagga, and from 14.3 spores/m3 (range, 0 to
55.5) to 307.7 spores/m3 (range, 3 to 916.5) in Moree. Mean
spore counts over 3 d were strongly correlated with spore
counts over 30 d (r = 0.93, p < 0.001). The spore concentrations were also strongly correlated with grass pollen concentrations (r = 0.94, p < 0.001) and with mean daily temperature
for the previous month (r = 0.78, p < 0.001). There were moderate positive correlations between mean Alternaria spore
concentrations and non-grass pollen (r = 0.39, p < 0.001) and
house dust mite allergen concentrations (r = 0.42). Mean Alternaria spore concentrations were negatively correlated with
mean relative humidity (r = 
0.51, p < 0.001) and weakly
positively correlated with mean rainfall (r = 0.13, p < 0.001).
Allergic Sensitization
Sensitization to Cladosporium, mixed grains, and cat dander were more common and sensitization to house dust mite was less common among the children sensitized to Alternaria than among non-Alternaria sensitized children (Table 1). The association was strongest between being sensitized to Alternaria and being sensitized to Cladosporium (kappa coefficient, 0.49; p < 0.0001). There was no difference between the two towns in the distribution of specific sensitization between Alternaria-sensitized children and non-Alternaria-sensitized children. Greater than 88% of the children who tested positive for allergic sensitization to Alternaria at the beginning of the study also tested positive at the final visit (kappa coefficient, 0.74; p < 0.0001).
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The Association between Airway Responsiveness and Alternaria Spore Concentrations
Children sensitized to Alternaria were more likely to have airway hyperresponsiveness than were other allergic children (Figure 1). The difference between Alternaria-sensitized children and other allergic children in the proportion of children with AHR increased with increasing spore concentrations.
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There was a significant difference between Alternaria-sensitized children and other allergic children in the association between Alternaria spore concentrations and presence of AHR (Table 2). The presence of AHR was significantly associated with spore concentrations in Alternaria-sensitized children, whereas it was not in other allergic children. The effect from an increase of 100 spores/m3air/d over 1 mo is shown in Table 2. None of the potential confounders had a strong effect on the association between airway responsiveness and Alternaria spore concentrations, and unadjusted measures of the associations are reported. The odds for AHR after an increase in mean exposure of 300 spores/m3/d over 1 mo almost doubled for children sensitized to Alternaria compared with other allergic children (odds ratio, 1.99; 95% CI, 1.45 to 2.70).
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The relation between severity of airway responsiveness measured by DRR and Alternaria spore concentrations also differed significantly between children sensitized to Alternaria compared with children sensitized to other allergens (p = 0.01). After an increase in mean exposure of 100 spores/m3air/d over 1 mo, DRR increased by a factor of 1.14 (95% CI, 1.09 to 1.19) in Alternaria-sensitized children and 1.06 (95% CI, 1.02 to 1.10) in the other allergic children.
It was not possible to directly test the effect of confounding by grass pollen exposure because of the strong correlation between grass pollen and Alternaria spore concentrations. However, there was no difference between rye-grass-sensitized and other allergic children in the association between Alternaria spore concentrations measured by DRR (p = 0.76) or presence of AHR (p = 0.45). There was also no difference between rye- grass-sensitized and other allergic children in the association between grass pollen concentrations and DRR (p = 0.84) or presence of AHR (p = 0.68). Finally, there was a significant difference between Alternaria-sensitized children and other allergic children in the association between grass pollen concentrations and DRR (p = 0.01), although not for the presence of AHR (p = 0.15).
An increase in mean exposure of 100 Alternaria spores/m3/d over 1 mo was associated with a 1.15-fold increase in DRR (95% CI, 1.09 to 1.22) in children sensitized to Cladosporium, which was significantly higher than the effect measured in other children (p = 0.02). There were negative interactions by house dust mite sensitization with Alternaria spore concentrations and AHR (p = 0.002) and DRR (p = 0.02). Children sensitized to house dust mite were less likely to have increased airway responsiveness as Alternaria spore concentrations increased.
The Association between Wheeze and Alternaria Spore Concentrations
The proportion of children with wheeze tended to increase with increasing spore concentrations, but the effect was not specific for children sensitized to Alternaria (Figure 1 and Table 2). There also was no interaction by sensitization to any other allergens in the association between wheeze and spore concentrations, although the interaction with grass pollen sensitization was nearly significant (p = 0.05). The odds ratio for wheeze on some days or more associated with an increase in mean exposure of 100 spores/m3air over 1 mo for children sensitized to Alternaria combined with children sensitized to other allergens was 1.10 (95% CI, 1.00 to 1.20). None of the potential confounders had a strong effect on the association between wheeze and Alternaria spore concentrations.
The Association between Bronchodilator Use and Alternaria Spore Concentrations
The proportion of children using bronchodilator tended to increase with increasing spore concentrations, but the effect was not specific for Alternaria-sensitized children (Figure 1 and Table 2). There was no interaction by sensitization to Alternaria or any other allergens in the association between bronchodilator use and Alternaria spore concentrations for any frequency categories of bronchodilator use (Table 2). The odds ratio for using bronchodilator four or more times a week associated with an increase in mean exposure of 100 spores/m3air over 1 mo for children sensitized to Alternaria combined with children sensitized to other allergens was 1.06 (95% CI, 0.97 to 1.17).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This is the first study to examine the effects of natural exposure to Alternaria in both symptomatic and nonsymptomatic children using an objective measure of airway abnormality. By conducting a long prospective study, we found that the severity of airway hyperresponsiveness, which is a fundamental component of current symptomatic asthma, increased with airborne Alternaria spore concentrations and that the effect was significantly greater in Alternaria-sensitized children. We also found that wheeze increased in periods of high spore concentrations, although this effect was not specific for children sensitized to Alternaria.
Standard methods were used to measure allergic sensitization, symptoms, medication use, and airway responsiveness. We found the strongest association between Alternaria spore concentrations and airway responsiveness. Airway hyperresponsiveness is a highly specific indicator for asthma and asthma exacerbations, airway inflammation and long-term asthma (25). There may have been errors in parental recall of wheeze and bronchodilator use, which could have masked a specific effect related to Alternaria sensitization.
We used a proxy measure for true personal exposure to Alternaria in that we estimated that airborne concentrations from one fixed point in the towns would be a valid measure of inhaled dose. However, personal exposure to Alternaria is likely to vary significantly from estimates of exposure at a fixed point and between individual subjects (29). There would have also been some error in the measurement of exposure because the allergen rather than the spores per se induce an allergic response. Airborne concentrations of Alternaria allergens have been reported as closely related and as unrelated to airborne Alternaria spore concentrations (30, 31). The most likely effect of the measurement errors is that we have underestimated the strength of the relation between Alternaria spore concentrations and the respiratory outcomes (32, 33).
It is possible that exposure to other allergens whose airborne concentrations were closely correlated with Alternaria could explain some of the observed effects. Grass-pollen concentrations were closely correlated with spore concentrations but we found no evidence of an increase in airway responsiveness or bronchodilator use that was specific to children who were sensitized to rye grass. The association with wheeze frequency may have been related to rye-grass sensitization status as the test of interaction was borderline-significant. There was evidence of a specific relation with airway responsiveness in children sensitized to Cladosporium. We did not measure airborne concentrations of Cladosporium and are therefore unable to determine whether this relation exits because of a close correlation between Alternaria and Cladosporium spore concentrations or because of the strong association between being sensitized to Alternaria and also being sensitized to Cladosporium. We conclude that the observed association between Alternaria spore concentrations and airway responsiveness can be attributed to fungal exposure. However, the apparent association with wheeze frequency may be attributable to other confounding factors, possibly grass pollen exposure.
The association observed between airway responsiveness and Alternaria spore concentrations was based on mean airborne concentrations over 1 mo for 10 mo in different seasons over 2 yr. The effect of changes in allergen exposure on level of airway hyperresponsiveness is known to extend for several weeks, and therefore the averaging period of 4 wk may be appropriate for measuring the effect of Alternaria exposure on this feature of asthma (34, 35). As we expected increased airway responsiveness to be associated with more frequent symptoms and need for bronchodilator, we believed that it was appropriate to measure these outcomes in the same context. However, because of the limited number of measurements of exposure, we are unable to describe the nature of the dose- response relation in detail, and the period of exposure necessary to cause an adverse respiratory outcome may be less than 1 mo. A significant association has been measured between daily airborne Alternaria spore concentrations and daily asthma symptoms using time series analysis in a cohort study of 19 asthmatics living in Southern California (36).
In regions where exposure to Alternaria is high, sensitization to the fungus is more strongly associated with asthma than sensitization to other allergens (9, 15). The airborne concentrations of Alternaria that we measured in Moree and in Wagga Wagga, and have been measured in other hot dry inland regions, are orders of magnitude higher than concentrations measured in cold temperate climates (37). In Arizona, children are more likely to have persistent asthma if they are sensitized to Alternaria than if they are sensitized to house dust mite (9). In coastal New South Wales, where airborne concentrations of Alternaria are lower than they are in Moree and Wagga Wagga, children with asthma are more likely to be sensitized to house dust mite than they are to Alternaria (15, 16, 22, 40).
We also found that the proportion of children sensitized to Alternaria who had airway hyperresponsiveness was approximately twice that of other allergic children, even during periods of "low" airborne concentrations of Alternaria. A study in France has found that sensitization to Alternaria is more strongly associated with reports of severe asthma than with reports of mild asthma (41).
In conclusion, we found that increases in respiratory symptoms and airway responsiveness were associated with increases in airborne concentrations of Alternaria. In addition, the association between spore concentrations and airway responsiveness was significantly stronger in children who were sensitized to Alternaria. This suggests that exposure to Alternaria is an important cause of more severe asthma in regions when exposure to the fungus is high. Further research is needed to more closely define the dose-response relation between Alternaria exposure and asthma and to develop effective environmental and therapeutic interventions.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Ms. Sara Downs, Institute of Respiratory Medicine, P.O. Box M77, Missenden Road Post Office, Camperdown NSW 2050, Australia. Email: shd{at}mail.med.usyd.edu.au
(Received in original form August 7, 2000 and in revised form April 5, 2001).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.orgAcknowledgments: The writers thank the children, parents, and school staff in Wagga Wagga and Moree for their friendly assistance that enabled us to undertake the study. They also thank Robyn Paton, Florence Smith, Margi Jones, Colin Rice, Lewis Macey, Tony Day, Rob Hibbard, Peter Hansen, Janet Li, and Anne Maine for their invaluable help in collecting the data.
Supported by grants from the National Health and Medical Research Council Australia, Glaxo Wellcome, Swiss National Science Foundation, and Novartis Foundation, Switzerland.
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References |
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