Childhood infection experience and risk of Young Adult Hodgkin Lymphoma.

The risk pattern of adolescent/young adult Hodgkin lymphoma (HL) is consistent with causation by a relatively late infection to a common childhood virus. However a causal virus has not yet been convincingly found. Susceptibility is known to be heritable, and a lower genetically determined interleukin-12 [IL-12] response is a risk factor. A lower IL-12 response can also be produced by diminished gastrointestinal exposure to the environmental microbiome, with resulting persistence of a Th2-skewed cytokine phenotype. We have therefore studied twin pairs discordant for HL to search for early life differences in sources of both viral and non-viral infection. HL-discordant twin pairs volunteered for the International Twin Study in ignorance of specific hypotheses. 70% of the questionnaires sent to individual twins were returned producing 188 informative pairs. The Kappa statistic was used to assess between-twin agreement. Designating the twin with HL as the case and the unaffected twin as the control, odds ratios (ORs) and 95% confidence intervals (CI) were calculated using conditional logistic regression for matched pairs. Tonsillectomy or appendectomy at least 5 years prior to diagnosis were associated respectively with a 2- and 3-fold statistically significant increase in risk. Infection with 3 or more childhood exanthems was associated with a 60% decreased risk (95% confidence intervals 0.2, 0.9). Behaviors likely to produce oral exposure to the environmental microbiome conveyed statistically significant decreases in risk (OR=0.2–0.5). A history of eczema increased risk (OR= 2.8, 95% CI= 1.0, 7.8). Kappa statistics were high (>0.8) for significant findings. Our evidence supports a role for early exposure to various infections in the etiology of adolescent/young adult Hodgkin lymphoma. Table 1. History of infections, immune-related surgeries and other childhood experience at least 5 years prior to diagnosis and risk of adolescent-young adult Hodgkin Lymphoma diagnosed between 13–50 years of age in disease-discordant twin pairs from the International Twin International Twin Registry (n = 188 total pairs). | Exposures | Kappa1 | Ratio of Exposure Discordant Pairs2 | Odds Ratio3 | 95% CI4 | |:-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------:| ------ | ----------------------------------- | ----------- | -------- | | 1. Kappa calculated from the 93 double respondent twin pairs (pairs in whom both twins returned questionnaires) | | 2 Total number of twin pairs in which case-twin was exposed and the unaffected co-twin was unexposed/Total number of twin pairs in which unaffected co-twin was exposed and the case-twin was unexposed | | 3 Odds ratio estimated using conditional logistic regression using SAS Version 8.1 | | 4 Confidence interval estimated using conditional logistic regression | | 3 or more childhood exanthems | - | 6/15 | 0.4 | 0.2, 0.9 | | Infectious mononucleosis | 0.72 | 22/19 | 1.2 | 0.6, 2.1 | | Cold Sores (Herpes Simplex 1) | 0.70 | 18/10 | 1.8 | 0.8, 3.9 | | Tonsillectomy | 0.86 | 25/12 | 2.1 | 1.1, 4.1 | | Appendectomy | 0.84 | 33/11 | 3.0 | 1.5, 5.9 | | Eczema | 0.79 | 14/5 | 2.8 | 1.0, 7.8 | | Sucked pacifier/thumb/fingers more as an infant/young child? | 0.87 | 18/34 | 0.5 | 0.3, 0.9 | | Put more things in mouth as an infant/young child? | 0.86 | 10/30 | 0.3 | 0.2, 0.7 |