Among the U.S. population aged 6 years and older, total serum IgE was associated with doctor-diagnosed current asthma, but only among persons who were atopic, as defined by a panel of allergen-specific IgE tests. Total IgE, in the absence of specific IgE, is not associated with asthma. This finding validates the use of specific IgE to determine the proportion of asthma associated with atopy in a previous publication.13
Among atopics as defined by the presence of at least one specific IgE, the prevalence of asthma increased with both total and specific IgE. However, the impact of total IgE was non-uniform across the asthma-related atopic group; the impact of total IgE increased as the number of positive specific IgEs increased and as the summed concentrations of specific IgEs increased.
The NHANES 2005–2006 findings clearly demonstrate a significant portion of asthma in the population exists independent from IgE – total or specific. It is not correct however to label this group non-atopic asthma. Certainly the asthma independent of IgE identified in the NHANES would be a part of any definition of non-atopic asthma, but a complete definition of non-atopic asthma must also include those individuals who have coincidently developed sensitivities to allergens but whose sensitivities are not related to their asthma.14
The data collected in the NHANES does not allow identification of such individuals.
The concept of non-atopic asthma, defined as the absence of any positive allergen skin test or specific IgE, is not a new one.4
Studies dichotomizing asthma by presence or absence of atopy found differences in distribution by age, gender and risk factors.15–17
For example indoor NO2
is a risk factor among non-atopic but not among atopic inner city asthmatics,18
while markers of atopy and inflammation have been reported to predict steroid responsiveness among asthmatics.19
Other reports have discounted the existence of non-atopic asthma by demonstrating the association of asthma with total IgE in the absence of demonstrated sensitivity to specific allergens (positive allergen skin tests or presence of allergen-specific IgE). The ability of the panel of allergens or specific IgEs used in these studies to completely identify all atopics brings into question the conclusions. In a sample of 2,657 individuals 6 years and older (average age 44 years), total IgE was found to be related to the prevalence of asthma even in the absence of allergen skin test reactivity using a panel of 5 allergen tests that did not include pets.6
Sunyer et al. evaluated 20 to 44 year olds (N=1,916) in Spain using specific IgEs to 5 allergens.7
Among the participants who had no positive specific IgEs, the odds ratio for asthma was 18 (13.9–120) for those above versus below 100 kU/L total IgE. However, previous work based on the European Community Respiratory Health Survey (ECRHS) which was conducted in the same region of Spain recommended a minimum of 7 allergens to identify atopy. 20
The data presented in the Spanish sub-sample of ECRHS indicates that the panel used in the Sunyer analyses was not optimal to identify atopy. Among 1,219 consecutive patients in a pulmonary clinic, using a 150 U/mL total IgE cutoff the prevalence of asthma was elevated among non-atopics (negative to 14 aeroallergens and an additional panel of 8 food allergens) with elevated total IgE.5
This panel did not contain cockroach or rodents.
The number of allergens or specific IgEs which must be included in a panel to identify all the atopics in a population is not certain. A number of studies have looked at this question and have concluded 90 to 95% of atopics can be identified with a relatively small panel. At age 4, only 4 aeroallergens were need to identity 94% of children with a positive (>= 3 mm wheal) allergen skin test reaction to a panel of 12 allergens – 6 aeroallergens and 6 food allergens.21
In the Avon Longitudinal Study of Parents and Children at 7 years allergen skin testing was performed with 6 core allergens and an additional panel of 7 to 8 allergens. Both the core and additional panels contained food allergens. Sensitization (wheal >= 3 mm) to one grass, D. pteronyssinus
or cat allergen identified more that 95% of individuals who reacted to one or more allergen on the complete panel.22
The ECRHS, which studied 20 to 44 year olds, included a panel of 9 allergen skin tests and using a wheal size of > 0 mm to define a positive found on subsequent analyses that 7 were needed to identify almost all of the sensitized individual across the 13 countries contributing data.20
Similarly in the NHANES 2005–2006 only six allergens were needed to identify approximately 92% of the atopics, however, to identify over 99% of the asthmatics required 11 allergens. The misclassification of individuals with positive specific IgEs to the non-atopic group will result in a spurious relationship between total IgE and asthma in the non-atopic group.
The lack of reported asthma below certain levels total IgE has been used promulgated as evidence of the lack of or rarity of asthma independent of IgE. Sears et al. 8
studied 562 children (11-years of age) and reported the prevalence of diagnosed asthma was positively related to total IgE levels – specific allergens were not evaluated in this study. No asthma was reported in participants with less that 32 IU/ml of total IgE. Burrows et al. 6
studied 2,657 white non-Mexican Americans age 6 years and older living in Tucson AZ and reported that no asthma was reported among individuals with the lowest total IgE levels (<−1.46 Z score). The findings of NHANES 2005–2006 clearly show that asthma unassociated with IgE is a large and important group and deserves further study. The larger sample size (N= 7398) of the NHANES allowed a more complete enumeration of asthma at low levels of total IgE.
For the most part, the variation in total IgE across socio-demographic variables in the NHANES 2005–2006 is consistent with what has been previously reported in the literature. In regards to age, the peak of total IgE in the 16 to 19 year old group is slightly later than the previous literature would suggest where the peak was reported in 6 to 14 years of age,23
before 10 years of age,24
or the 8 to 14 years of age.25
Among adults, the level of total IgE is generally reported to decrease with age 23, 26
but not in all studies.27, 28
Our data show a clear decrease in total IgE among the older population. Additionally, our findings on the relationship of total IgE with other socio-demographic, environmental, and atopic factors is generally consistent with the reported literature. Total IgE has consistently been reported to be higher in men,23, 25–29
those with self-reported atopic disease or positive allergen skin tests 7, 23, 25, 28–31
and smoking has generally been reported to increase total IgE.25, 26, 29, 32
While fewer studies have looked at racial/ethnic differences, whites have consistently had lower total IgE as compared to blacks.24, 30, 31
One study including Latinos reported elevated levels compared to whites.30
Total IgE has been reported to increase with poverty or decreased education.30
The representative nature of the NHANES 2005–2006 makes it an excellent data source to examine the allergic basis of asthma. The individuals were not selected on the basis of disease but to reflect the civilian non-institutionalized U.S. population. The survey is comprehensive; asthma and allergy assessments were but a small part, therefore limiting any possibility that respondents were aware of the research question being evaluated in this paper. The data were collected and processed in a standardized, consistent fashion across all sites. A major limitation is the cross-sectional nature of the study, and the self-report of asthma with no confirmatory measures of bronchoreactivity. A self-report of asthma may undercount the number of patients with asthma in the population, but the patients with asthma identified will have a high probability of truly having asthma.33
A number of other limitation also apply to this data. Only a single measure of total IgE was available in NHANES 2005–2006. While over the lifespan total IgE raises and falls, over the span of several years the values are highly correlated as shown in the report from the German Multicenter Allergy Study (MAS) where a correlation of greater than 0.8 was observed for total IgE was measured at ages 6, 7, and 10 years of age.34
IgE levels in symptomatic individuals can vary with season. No information is available as to the time of the year the individual specimens were collected. However, the NHANES data collection occurred all year around so the impact of seasonal variation in IgE levels should be minimized. Finally while the specific IgE panel in the NHANES 2005–2006 was optimized for the US population, it may not be optimal for a specific region or individual.
The implications of the NHANES 2005–2006 total IgE data are clear. In the absence of specific IgE, asthma prevalence is independent from total IgE. The measurement of total IgE should not be a routine measurement in the evaluation of an individual with asthma. However, in certain clinical situations such as the evaluation of an asthmatic for allergic bronchopulmonary aspergillosis measurement of total IgE is still required. Asthma independent of IgE appears to be a phenotype of asthma which is large in number and therefore requires further study. However, the complete identification of non-atopic asthma will require the ability to determine if the co-existence of allergen sensitization and asthma within an individual are clinically related. At present this is not possible. Identification of clinically meaningful phenotypes is an important step in untangling the conflicting findings on risk factors, treatment response, and prognosis which are found in the asthma literature.