CANCER EPIDEMIOLOGY, BIOMARKERS & PREVENTION | RESEARCH ARTICLE Risk of Leukemia after Dengue Virus Infection: A Population-Based Cohort Study Yu-Wen Chien 1,2 , Chia-Chun Wang 3 , Yu-Ping Wang 1 , Cho-Yin Lee 4,5 , and Guey Chuen Perng 6,7,8 ABSTRACT ◥ Background: Infections account for about 15% of human cancers globally. Although abnormal hematologic profiles and bone mar- row suppression are common in patients with dengue, whether dengue is associated with a higher risk of leukemia has not been investigated. Methods: We conducted a nationwide population-based cohort study by analyzing the National Health Insurance Research Databases in Taiwan. Laboratory-confirmed dengue patients between 2002 and 2011 were identified; five matched non-dengue controls were randomly selected for each patient. Follow-up ended on December 31, 2015. Multivariate Cox proportional hazard regression models were used to evaluate the effect of dengue virus infection on the risk of leukemia. Cancers other than leukemia were used as falsification endpoints to evaluate the validity of this study. Results: We identified 12,573 patients with dengue and 62,865 non-dengue controls. Patients with dengue had a higher risk of leukemia [adjusted HR, 2.03; 95% confidence interval (CI), 1.16– 3.53]. Stratified analyses by different follow-up periods showed that dengue virus infection was significantly associated with a higher risk of leukemia only between 3 and 6 years after infection (adjusted HR, 3.22; 95% CI, 1.25–8.32). There was no significant association between dengue and the risk of other cancers. Conclusions: This study provides the first epidemiologic evidence for the association between dengue virus infection and leukemia. Impact: Considering the rapidly increasing global incidence of dengue and the burden of leukemia, further studies are required to verify this association and to unravel the potential mechanisms of pathogenesis. Introduction According to recent statistics, there are approximately 17.2 million new cancer cases and 8.9 million cancer-related deaths worldwide per year (1). Among them, infections account for about 15% of human cancer cases (2). Several pathogens have been recognized by the International Agency for Research on Cancer as Group 1 carcinogens, which mean that there is sufficient evidence of carcinogenicity in humans or there is both strong evidence in exposed humans that the agent exhibits key characteristics of carcinogens and sufficient evi- dence of carcinogenicity in experimental animals (3). Hepatocellular carcinoma caused by hepatitis virus B or hepatitis virus C, cervical cancer caused by human papillomavirus, nasopharyngeal carcinoma caused by Epstein–Barr virus, and Kaposi sarcoma caused by human herpesvirus-8 are all well-known infection-attributable cancers (2). For hematologic malignancies, examples of such causal relationships include those between human T-cell leukemia virus type I and adult T-cell leukemia, Epstein–Barr virus and Burkitt lymphoma and Hodgkin lymphoma, human immunodeficiency virus and Hodgkin lymphoma and non-Hodgkin lymphoma, hepatitis C virus and non- Hodgkin lymphoma, and Helicobacter pylori and gastric mucosa- associated lymphoid tissue lymphoma (2). Dengue fever is an important mosquito-borne infectious disease (4). Over the past decades, the incidence of dengue has dramatically increased worldwide with significant geographical expansion to new countries and regions, which probably results from rapid urbanization, increasing frequency of travel, and global climate change (5). An estimated 390 million people are infected by dengue virus every year, of which 25% are symptomatic (5, 6). Abnormal hematologic profiles, such as leukopenia, thrombocyto- penia, and atypical lymphocytes, are hallmark laboratory findings in patients with dengue (5). Bone marrow suppression is also commonly observed in patients with dengue in the early stage of infection (7–9). Moreover, dengue virus can be recovered from bone marrows of both fatal and survival human subjects (10). In-line with these clinical observations, cumulative laboratory evidence suggests that hemato- poietic progenitor cells in bone marrow, in both in vitro and ex vivo systems, as well as in vivo nonhuman primates, are highly infectable by dengue virus (11–15). Furthermore, case reports of acute myeloid leukemia precipitated by dengue virus infection (16) and dengue virus infection–mimicking plasma cell leukemia (17) have been documen- ted. These clues guided us to hypothesize that dengue virus infection might be associated with leukemia. Here we investigated whether the risk of leukemia was increased after dengue virus infection by analyzing nationwide population databases in Taiwan. In dengue hyperendemic countries, most of the 1 Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 2 Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, College of Medicine, Nation- al Cheng Kung University, Tainan, Taiwan. 3 Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. 4 Department of Biomedical Engineering, National Yang-Ming University, Taipei, Taiwan. 5 Department of Radiation Oncology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan City, Taiwan. 6 Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 7 Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. 8 Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan. Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/). Corresponding Authors: Guey Chuen Perng, Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 70101, Taiwan. Phone: 886-6235-3535, ext. 5626; Fax: 886-6236-9233; E-mail: gperng@mail.ncku.edu.tw; and Cho-Yin Lee, Department of Biomedical Engineering, National Yang-Ming University, No. 155, Section 2, Linong Street, Beitou District, Taipei City 112, Taiwan. Phone: 8862- 2826-7000, ext. 5368; Fax: 8862-2821-0847; E-mail: choyin.lee@ym.edu.tw Cancer Epidemiol Biomarkers Prev 2020;29:558–64 doi: 10.1158/1055-9965.EPI-19-1214 Ó2020 American Association for Cancer Research. AACRJournals.org | 558 Downloaded from http://aacrjournals.org/cebp/article-pdf/29/3/558/2339917/558.pdf by guest on 24 September 2022