Allergy and Brain Tumors: Something to Sneeze At!

Abstract & Commentary

By William B. Ershler, MD

Synopsis: There have been reports over the past decade of an interesting inverse association between allergy and glioma. In the current report pooling data from four large cohorts, investigators examined (prediagnostic) immunoglobulin E levels in 169 individuals who were to develop glioma and compared these with levels in 520 matched controls. Mildly elevated prediagnosis plasma IgE levels were associated with reduced risk, although this was not apparent for those with higher levels. The data strengthen a causal association of allergy and reduced glioma risk, but the mechanism remains speculative at present.

Sources: Calboli FC, et al. Prediagnostic plasma IgE levels and risk of adult glioma in four prospective cohort studies. J Natl Cancer Inst 2011;103:1588-1595. Davis FG, Al-Alem U. Allergies and adult gliomas: Cohort results strengthen evidence for a causal association. (Editorial). J Natl Cancer Inst 2011;103:1562-1563.

Several observational studies have demonstrated a reciprocal relationship between allergy history and glioma, and two separate meta-analyses revealed a significant risk reduction of almost 40% for people with a history of allergies compared to that for those with no allergy history.1,2 It has been speculated that immunoglobulin E (IgE) plays a critical role in regulating inflammatory responses within the central nervous system3 and this may account for the association of lower risk for glioma in atopic patients. Indeed, an inverse association between serum IgE and risk of glioma was reported recently in a large case-control study,4 but reverse causality and treatment effects remain potential explanations for those findings.

To address this, Calboli and colleagues combined data from four prospective cohort studies and used a nested case-control design to examine more deeply the association between allergy and glioma. Patients were included who had confirmed glioma and prediagnosis blood available for analysis. Also included were three matched control subjects per case subject, and the final numbers for analyses were 169 case subjects and 520 control subjects. Total IgE, food allergen-specific IgE, and respiratory allergen-specific IgE levels were measured. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression analysis. Stratified analyses were conducted by age and birth cohorts.

For those with mildly elevated total IgE levels (25-100 kU/L), there was a statistically significant inverse association with glioma (OR, 0.63: 95% CI, 0.42 to 0.93), compared with clinically normal IgE levels (< 25 kU/L). This inverse association was not present for those with very high levels of IgE (> 100 kU/L) (OR, 0.98; 95% CI, 0.61 to 1.56). The association between glioma and total IgE was consistent for both men and women. Non-statistically significant inverse associations were noted for elevated IgE levels among individuals born before 1930 (OR, 0.67; 95% CI, 0.34 to 1.34), and when restricting analyses to highly fatal (deceased within 2 years of diagnosis), glioma case subjects (OR, 0.64; 95% CI, 0.34 to 1.19) compared to individuals with clinically normal IgE levels. No associations were observed for either food allergen-specific or respiratory allergen-specific IgE levels.

Commentary

The findings from this report support the curious inverse association between allergy and glioma, yet the biological explanation remains to be established. Individuals with borderline elevations in IgE had a modestly lower risk for glioma, but individuals with clearly elevated levels (i.e., >100 kU/L) did not experience reduced risk. A very similar conclusion was also reported in another recent analysis of a separate large prospective cohort.5 In fact, the evidence from the number of observational studies and now two large prospective cohort studies are sufficiently compelling to warrant more in-depth investigation aimed at defining the mechanism(s) involved. Although it is tempting to speculate that heightened levels of IgE are somehow associated with enhanced immune surveillance within the CNS, the role of immunoglobulins in this or any class in tumor surveillance has yet to be established. Also, there seems to be a bell-shaped curve, with a failure to achieve risk reduction at the highest levels of IgE.

Like many epidemiological studies, the findings of greatest interest, especially those that are unexpected, serve to engender hypotheses requiring translation back to the laboratory for explanation. It would seem for glioma, for which treatment and survival remain by all accounts unsatisfactory, investigations that relate to disease occurrence may lead to remarkable advances in both prevention and treatment.

References

1. Linos E, et al. Atopy and risk of brain tumors: A meta-analysis. J Natl Cancer Inst 2007;99:1544-1550.

2. Chen C, et al. Allergy and risk of glioma: A meta-analysis. Eur J Neurol 2011;18:387-395.

3. Harling-Berg CJ, et al. Role of the cervical lymphatics in the Th2-type hierarchy of CNS immune regulation. J Neuroimmunol 1999;101:111-127.

4. Wiemels JL, et al. IgE, allergy, and risk of glioma: Update from the San Francisco Bay Area Adult Glioma Study in the temozolomide era. Int J Cancer 2009;125:680-687.

5. Schlehofer B, et al. Primary brain tumours and specific serum immunoglobulin E: A case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort. Allergy 2011;66:1434-1441.