In the U.S. population aged 6–59 years, 56.3% of current asthma cases were attributable to atopy, as measured by a positive skin test response to any of 10 allergens. The PAR was significantly greater among males than females, among persons in the highest education category than in lower education categories, and among persons living in highly populated metropolitan areas than in all other areas.
The PAR estimate for the U.S. population is higher than the PAR reported in several studies. In the meta-analysis by Pearce et al.
, the mean PAR was 38% across studies of children and 37% across studies of adults.7
Among 4-year-old children on the Isle of Wight, Arshad et al.
found that atopy (skin prick test positivity to any of 12 allergens) attributed to 35% of asthma cases.1
In a study of adults in the Pirkanmaa District of Southern Finland, Jaakkola et al.
reported a PAR (defined by total and specific IgE) of 30%.13
Among Australian children aged 8–10 years, Ponsonby et al.
found that atopy (defined as skin test positivity to any of 10 aeroallergens) attributed to 33% of asthma cases, although the percentage was 54% for past hospital attendance for asthma.14
And, in the European Community Respiratory Heath Study, a 36-center study of adults in 16 countries, the mean PAR across centers (atopy was defined as specific serum IgE > 0.35 kU/L to any of 5 allergens) was 30%.15
However, the U.S. estimate fell within the range of center-specific PARs (4% to 61%). Centers with a PAR similar to the U.S. estimate were Huelva, Spain (61%); Groningen, the Netherlands (58%); Antwerp, Belgium (55%); Bordeaux, France (55%); Wellington, New Zealand (52%); and Umea, Sweden (50%). The variation in PARs across the studies could reflect differences in environmental exposures and genetics between the populations as well as differences in study methodologies, such as the assessments of atopy and asthma and subject selection.
In the U.S. population, the PAR differed significantly by sex, education, and urbanization categories. Across categories of those characteristics, the atopy-asthma odds ratios differed significantly. Undoubtedly, there are cofactors associated with these characteristics that strengthen or weaken the effects of atopy on asthma. One possible cofactor—and there are likely to be many—is allergen exposure, which was not measured in NHANES III. Data from the National Survey of Lead and Allergens in Housing have shown that people in the above high school education category have a higher mean level of cat allergen in their homes than people in the lower education categories whereas people living in highly populated metropolitan areas are more likely to have elevated levels of cockroach allergen in their homes than people living in other areas.16, 17
In addition, studies from rural areas in Europe have consistently shown that children growing up on farms are less likely to develop atopy and allergic disease,18
the presumption being that certain microbial exposures in early childhood may be beneficial. However, in NHANES III, the urbanization category “all other areas” consists only partially of rural or farm families, so it is not known whether any differences in the PAR by urbanization can be attributed to a protective effect of rural or farm exposures. Whereas females are more likely than males to have asthma, this study found that males are more likely to have atopic asthma. Why the etiology of asthma would differ between males and females is not known, but the difference suggests that reproductive hormones may play a role. If reproductive hormones suppressed atopic asthma or promoted non-atopic asthma in females, or if testosterone suppressed non-atopic asthma in males, a difference in the asthma-atopy association by sex would occur. Leptin, a hormone associated with obesity, might also play a role in the observed difference. A recent study indicated that serum concentrations of leptin was a stronger risk factor for asthma in females than males, and the same study found that BMI was associated with asthma in females but not males.19
However, the authors of that study did not indicate whether leptin or BMI influenced asthma through atopic or non-atopic pathways. Besides hormones, differences in environmental exposures, such as tobacco smoke, alcohol, diet, and occupations, are potential explanations for the differences in PAR by sex.
Of the ten allergens included in the skin test panel, only cat, Alternaria
, and white oak showed significant, positive associations with asthma after adjustment by the subject characteristics and all other allergens. Cat allergen had the largest fully-adjusted odds ratio, and a positive test to cat allergen accounted for the highest percentage of asthma cases (29.3%). Whereas some studies have shown that exposure to cats may be protective for development of allergic sensitization and disease,20
sensitization to cat appears to be a strong risk factor for asthma. In the European Community Respiratory Heath Survey, sensitization to cat allergen had the highest odds ratio for asthma, although sensitization to house dust mite and Timothy grass accounted for more cases of asthma (PARs were 18.2% for dust mite, 17.1% for Timothy grass, and 14.1% for cat).15
In a study of Swedish adults, Plaschke et al.
reported that skin prick test positivity to cats and dogs had the strongest associations with asthma, while associations with dust mites and grass were less pronounced.21
Why did most of the allergen-specific skin tests lose statistical significance with asthma after adjustment by all the allergen-specific tests? One potential explanation is that some allergens were associated with asthma before adjustment not because they were independently associated with asthma but because they often occurred with one or more allergens that were. The mean number of positive skin test responses among persons with at least one positive response was 3.5. Thus, for any given allergen, a positive test to that allergen usually occurred with a positive response to other allergens, perhaps other allergens that were more strongly associated with asthma. For example, on average, people who tested positive to dust mite allergen tested positive to 4.9 allergens (). Unadjusted, the odds ratio for dust mite was 2.5 (); however, as a solitary response () or as a response fully adjusted by all the allergens (), the odds ratio was 1.3.
Because the allergen-specific results represent averages across the U.S. population, some caution must be used in interpreting them when considering an individual. For a given individual, or among individuals within specific regions or subpopulations of the U.S., some of the allergen-specific sensitizations may play a more or less predominant role in asthma.
The most important limitation to the study is that the data is cross-sectional, a limitation common to many of the published papers that have examined the percentage of asthma cases attributable to atopy. The estimation of population attributable risk assumes that the exposure was present before the disease—a criterion for causality. However, because asthma and skin test responses were assessed at the same point in time, the temporal relationship between the two variables cannot be established. If the onset of asthma occurred prior to the onset of allergic sensitization in a significant percentage of asthma cases, then this study has overestimated the contribution of atopy to asthma.
The estimation of PAR also assumes that the relative risk estimate is unconfounded.11
Because adjustment by the 9 subject characteristics had little effect on the atopy-asthma association (unadjusted OR = 3.3 and adjusted OR = 3.5), confounding was likely well controlled in the analyses of atopy. However, for the allergen-specific skin tests, the odds ratios changed dramatically with adjustment by other allergens. Because many allergens were not skin tested, it is possible that the fully-adjusted allergen-specific odds ratios reported in were confounded.
Other important limitations were that the assessment of atopy was limited to the skin testing of only 10 allergens, neither total nor allergen-specific serum IgE was measured, and neither subjects younger than 6 years nor older than 59 years were skin tested in NHANES III. Without a larger panel of allergens or the availability of serum IgE measurements, this study may have underestimated the prevalence of atopy, which would cause the PARs to be underestimated. In an attempt to address this limitation, atopy was redefined in a secondary analysis as either hay fever or a positive skin test response. The inclusion of hay fever into the definition only increased the prevalence of atopy in the total population from 54.2% to 56.0%, which suggests that the 10-allergen skin test panel included allergens to which most hay fever cases would respond. With the PAR peaking in the middle category (), it is possible that there would have been an age effect if all ages had been included. In NHANES 2005–2006, total IgE and specific IgE to 19 allergens was measured on all subjects aged 1 year and older. Those data, when made available, will allow for a more precise estimate of atopy and a broader assessment of age effects.
The results of this study have two implications. First, the population attributable risk conveys a sense of how much disease can be prevented by eliminating the exposure or blocking its effects.22
Therefore, if atopy could be prevented, reversed, or blocked, then a large percentage of current asthma cases could be prevented. Atopy, by definition, is the result of gene-environment interactions; therefore, at least in theory, intervention at either the genetic or environmental level could prevent atopy. However, intervention at the genetic level is not yet possible and intervention at the environmental level by altering allergen and other exposures has had mixed results, perhaps because of our limited understanding of the environmental exposures that influence atopy and how to modify those exposures. Blocking the pathway between atopy and asthma through immunotherapy, medication, or reduction in allergen and other environmental exposures should also lead to a large reduction in asthma cases. Second, this study’s results highlight the need for research into the non-atopic causes of asthma since one-third to one-half of the asthma cases apparently have a non-atopic etiology. Pearce et al.
have suggested that atopic asthma research has been at the expense of non-atopic asthma research;7
however, for the burden of asthma in the population to be significantly reduced, asthma research needs to address the causes of and interventions for both atopic and non-atopic asthma.