Hospital-Treated Infections and Increased Risk of Two EBV-Related Malignancies: A Nested Case-Control Study

SIMPLE SUMMARY: Epstein–Barr virus (EBV) is associated with the risk of several human malignancies, including Hodgkin’s lymphoma (HL) and nasopharyngeal carcinoma (NPC). However, as EBV infection is widely spread across human populations, whereas only a small proportion of the infected individuals eventually develop such malignancies, additional component causes are likely needed in the development of EBV-related malignancies. We performed a national register-based study in Sweden to examine the role of infections that required hospital treatment on the subsequent risk of HL and NPC. We found that previous hospital-treated infections were associated with a higher risk of HL and NPC and that a positive association was observed for both bacterial and viral infections, especially for respiratory and skin infections. A dose-response relationship was also noted between the number of infections and the risk of HL. These findings suggest that infectious events might contribute to the carcinogenesis of malignancies potentially related to EBV. ABSTRACT: Background: To assess the association of hospital-treated infections with the subsequent risk of two Epstein-Barr virus (EBV)-related malignancies, namely Hodgkin’s lymphoma (HL) and nasopharyngeal carcinoma (NPC). Methods: We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with HL or NPC during 1994–2016 in Sweden, according to the Swedish Cancer Register. For each case, we randomly selected five controls individually matched to the case on sex and year of birth from the general Swedish population. Hospital-treated infections (i.e., infections requiring either inpatient or outpatient hospital care) were identified from the Swedish Patient Register. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of HL and NPC, in relation to hospital-treated infections, after adjustment for age, sex, calendar period, educational achievement, and region of residence. Results: The study included a total of 890 cases of HL and 306 cases of NPC. A hospital-treated infection three years ago or earlier was associated with a higher risk of HL (OR = 1.49, 95%CI: 1.26–1.75) as well as NPC (OR = 1.36; 95%CI: 1.01–1.83). The positive association was noted for both bacterial and viral infections and primarily for respiratory and skin infections. A monotonous dose-response relationship was found between a number of hospital-treated infections and the risk of HL (p = 0.02) but less compelling for NPC (p = 0.06). Using a 5-year lag time rendered similar results (OR = 1.43, 95%CI: 1.21–1.70 for HL; OR = 1.43, 95%CI: 1.05–1.95 for NPC). Conclusions: These findings suggest that infections requiring hospital treatment might contribute to the carcinogenesis of malignancies potentially related to EBV.