Increased Risk of Lymphoid Malignancy in Patients with Herpes Zoster: A Longitudinal Follow-up Study Using a National Cohort Study

Introduction: A causal relationship between viral infection or decreased immunity and certain types of lymphoid malignancy has already been established. We performed a matched-control prospective follow-up study from a nationwide population-based dataset in South Korea to explore the association between herpes zoster exposure and the subsequent risk of lymphoid malignancies.

Methods: Data in the Korean National Health Insurance Service-National Sample Cohort were collected from 2002 to 2013. We extracted the data of herpes zoster participants (n = 64,152) and their matched controls at a ratio of 1:4 (n = 1,061,539) and analyzed the occurrence of lymphoid neoplasms. Herpes zoster was diagnosed as ICD-10 B02, among them, we selected the participants who were treated for it ≥ 2 times or who were treated with antiviral medication ≥ 1 time. Lymphoid neoplasms were included using ICD-10 codes C81, C82, C83, C84, C85, C88, C90, and C91. For accurate participant inclusion, we used claim codes to select participants who were treated for lymphoid neoplasm ≥ 3 times or who were treated with chemotherapy or radiation therapy (n = 1,399). The matches were processed for age, group, sex, income group, region of residence, and past medical histories (hypertension, diabetes, and dyslipidemia). In both the herpes zoster and control groups, participants with a history of hematologic malignancy (lymphoid malignancy and acute leukemia) before the index date were excluded. In the herpes zoster group, 198 participants were excluded. The herpes zoster participants for whom we could not identify enough matching participants were excluded (n = 420). We excluded participants who were under 20 years old (n = 4,039). Finally, 1:4 matching resulted in the inclusion of 59,495 herpes zoster participants and 237,980 control participants. However, they were not matched for ischemic heart disease, cerebral stroke, or a history of depression as such strict matching increases participant drop out the due to lack of control participants. The income groups were initially divided into 41 classes (one health aid class, 20 self-employment health insurance classes, and 20 employment health insurance classes). These groups were recategorized into 11 classes (class 1 [lowest income] - 11 [highest income]). Region of residence was divided into 16 areas according to administrative district in South Korea. The past medical histories of participants were evaluated using ICD-10 codes. For accurate diagnosis, the presence of hypertension (I10 and I15), diabetes (E10-E14), and dyslipidemia (E78) was checked if the participants were treated ≥ 2 times. Ischemic heart disease (I24 and I25) and cerebral stroke (I60-I66) were assessed if the participants were treated ≥ 1 time. Depression was defined using the ICD-10 codes F31 (bipolar affective disorder) through F39 (unspecified mood disorder) diagnosed by a psychiatrist ≥ 2 times.

Results: The rate of lymphoid neoplasm was higher in the herpes zoster group (0.15% [90/59,495]) than in the control group (0.08% [212/237,980], P < 0.001). The general characteristics (age, sex, income group, region of residence, and hypertension, diabetes, and dyslipidemia histories) of the participants were exactly the same due to the matching (P = 1.000). The rates of a history of ischemic heart disease and depression were higher in the herpes zoster group (each P < 0.05). The crude and adjusted HRs for lymphoid neoplasm were 1.70 (95% CI = 1.33 - 2.17) and 1.69 (95% CI = 1.32 - 2.16) in the herpes zoster group, respectively (each P < 0.001). In the subgroup analyses, the crude and adjusted HRs for lymphoid neoplasm were higher in all herpes zoster groups (each P < 0.05). The adjusted HRs were 1.72 (95% CI = 1.18 - 2.50) for those < 60 years old, 1.66 (95% CI = 1.20 - 2.31) for those ≥ 60 years old, 1.76 (95% CI = 1.24 - 2.48) for men, and 1.62 (95% CI = 1.14 - 2.31) for women.

Conclusion: Our study demonstrates that herpes zoster infection increases the risk of subsequent lymphoid malignancies irrespective of age and gender in the Korean population.