An inverse association between history of allergies and risk of glioma, as found in this study, is one of the most consistent associations in the brain tumor literature. Although not all statistically significant associations, a decreased risk of glioma has been observed in those with allergic disease (including allergies, asthma, and/or eczema) in many studies (7
), but not all (20
). A meta-analysis of several of these studies found a pooled relative risk of glioma of 0.61 (95% CI: 0.55–0.67) associated with allergy (14
). The authors concluded that this strong inverse relationship was unlikely to be explained away by bias due to proxy responses or publication bias.
Differences in the definition of allergy may influence comparisons of results between studies. Allergies may be grouped with other atopic diseases (such as asthma and/or eczema) or each atopic disease may be investigated individually. For example, Wigertz et al. (13
) found an odds ratio of 0.70 (95% CI: 0.61–0.80) for glioma associated with a diagnosis of any of the following atopic conditions: asthma, hay fever, eczema, or other type of allergy; however, results were similar and statistically significant for each allergic condition individually (asthma, eczema, hay fever, and food allergy). Similarly, Wiemels et al. (11
) found that pollen, dairy and nut allergies were significantly less common in cases than controls, while most other allergens had odds ratios of less than one. Alternatively, allergies may be defined narrowly; for example, only including those with seasonal allergies. In fact, a cohort study and a case-control study found no association with glioma risk and history of hay fever specifically (20
). In our study, we asked study subjects to report only allergies that had been diagnosed by a doctor or other medical personnel. Studies which also allowed reporting of self-diagnosed allergies would have a higher frequency of allergies than our study, which may also influence their results and overall consistency.
The present study found a significant trend in risk reduction of glioma by number of allergy types (seasonal, medication, pet, food, and/or other), as well as by actual number of allergies for each allergy type, consistent with the results of Wiemels et al. (11
) who also found a significant dose-response with increasing numbers of allergens. Similar to findings of previous studies, the present study also found no statistically significant trend in glioma risk with duration of the allergic condition (9
) or age at first allergy diagnosis (9
). However, one previous study found greater risk reduction in those with a recent diagnosis of asthma and hay fever (12
), while a second study found that reduced risks of glioma were confined to current rather than past atopic conditions of eczema, hay fever, and allergy overall, but not asthma (13
Antihistamine use has been investigated in several studies. Similar to the results of our study, both Schlehofer et al. (9
) and Schoemaker et al. (12
) found an inverse association with glioma risk and antihistamine use, although the later study was specific to those with hay fever. Alternatively, Scheurer et al. (22
) found that antihistamine use among those reporting a history of asthma or allergies was associated with an increased risk of glioma (OR= 2.54; 95% CI: 1.28, 5.03), especially for those who reported ≥10 years of regular antihistamine use. There was no association with glioma risk and antihistamine use among those reporting no history of asthma or allergies (OR=0.82; 95% CI: 0.47, 1.44). Our study did not confirm a specific aspect of the Scheurer study, namely the analysis of overall antihistamine use or use of diphenhydramine hydrochloride-containing products by duration of use or stratified by history of allergy. However, differences in study design and characteristics (such as the way questions were asked) prevent a direct comparison of results. For example, because the Scheurer study included all individuals with medically diagnosed allergies or asthma, individuals diagnosed with asthma but not allergies were included in their estimates. The current study restricts analysis to those with medically diagnosed allergies, which may have resulted in a more homogenous group of subjects and may account for some of the discrepancies between studies.
While there is a paucity of literature on the carcinogenicity of diphenhydramine hydrochloride, a study (23
) by the National Toxicology Program reported equivocal evidence for a marginally increased incidence of gliomas in male (but not female) F344/N rats receiving high (i.e., 625 ppm), but non-toxic, doses of diphenhydramine hydrochloride over a 2-year period compared to controls. The same study found no evidence of carcinogenic activity induced by exposure to diets containing up to 313 ppm diphenhydramine hydrochloride in B6C3F1
). The role of diphenhydramine hydrochloride as a possible neurocarcinogen in humans remains undetermined and warrants further study.
Limitations of the study include the potential for both recall and selection bias. There were no proxy interviews conducted for this study; however, study subjects were allowed to have assistance when completing the survey. The accuracy of recalled details related to their allergy diagnosis or medication usage may be different between cases and controls. Cases with brain tumors may have partial cognitive impairment which may affect their ability to accurately recall details, but cases may also spend more time contemplating potential causes of their illness compared to controls. Despite potential differences in the recall of details, reporting of medically diagnosed allergies (as was done in this study) is likely to be accurate, similar to what was found for asthma (25
). Case subjects who completed the survey were more likely to be younger and were more likely to be recruited by Duke University, but did not differ by gender or race, compared to subjects who did not consent or who consented but did not complete the survey. It is possible that these differences may have resulted in bias. In addition, small numbers of subjects, especially for those with low-grade glioma, may limit the interpretations that can be made from this data, as negative results may be because the study was underpowered, while positive results may be due to chance alone. Although controls were selected from clinics at the respective institutions, the conditions for which the controls were being treated at the time are not known to be associated with allergic conditions. In addition, although we made an attempt to frequency-match, the distributions of control characteristics were significantly different from cases. Results were adjusted for age, race, gender, education, and study site, but there is the potential that other factors not controlled for in the analyses could influence the results. Finally, as the biological mechanism is still unknown, we cannot rule out the possibility that the primary effect is due to environmental or other factors related to allergies that are unmeasured in this study, with the factors measured here being mediators.
In summary, our results confirm the overall association with allergies and the trend of decreased glioma risk with increasing number of allergies. The lack of an association with duration and age at onset of allergies and antihistamine usage was consistent with some but not all previous studies. Separate analysis of the antihistamine, diphenhydramine hydrochloride, did not reveal any increased risk associated with gliomas. A comprehensive study of all aspects of allergies and atopic disease, as well as antihistamine use, in those with and without brain tumors using standardized questions and biological markers will be essential to further delineate the biological mechanism that may be involved in brain tumor development.