According to results of a large population-based study, patients with a history of dengue viral infection are at increased risk of developing leukemia compared with individuals without a history of dengue fever. The findings from this study were reported in Cancer Epidemiology, Biomarkers, & Prevention.
Dengue fever is an infectious disease caused by the dengue virus that is transmitted by the bite of infected mosquitos. The disease, which is endemic in tropical and subtropical regions of the world, has traditionally been viewed as an acute febrile illness associated with sudden onset of high fever, as well as bone pain, headache, among other symptoms.
Although life-threatening complications, such as severe bleeding and shock, have been reported in a minority of patients with dengue fever, long-term effects have not generally been considered as part of the clinical spectrum for most patients with this disease.
Rationales for investigating whether a potential relationship exists between dengue viral infection and the development of leukemia included observations of abnormal hematologic profiles and bone marrow suppression in patients with the disease. Furthermore, dengue virus has been recovered from the bone marrow of infected patients, and there is evidence that hematopoietic progenitor cells are particularly susceptible to dengue viral infection. In addition, cases of patients developing acute myeloid leukemia — as well as the manifestation of plasma leukemia-like symptoms — following dengue viral infection have been reported.
In this study, dengue cases were identified using the large National Health Insurance Research Databases (NHIRD), which covers more than 99% of the total population of Taiwan, as well as the Notifiable Disease Dataset of Confirmed Cases, since all suspected cases of dengue fever must be reported in Taiwan. Importantly, the low incidence of dengue infection in Taiwan provided the opportunity to compare a cohort of patients with a history dengue viral infection with a large control group of individuals without a history of dengue fever.
For each of the 12,573 cases of eligible individuals without a diagnosis of cancer at baseline and with a confirmed diagnosis of dengue viral infection for which the first appearance of symptoms (ie, index date) occurred between 2002 and 2011, 5 control individuals without dengue infection or a diagnosis of cancer (62,865 individuals) were matched according to age, area of residence, and year of the index date.
At a median follow-up of 8.2 years, the overall incidence rate of leukemia was 17.20% and 7.85% in cases and controls, respectively. Following adjustment for multiple patient-related factors such as age, sex, area of residence, income, and comorbidities, the hazard rate (HR) for development of any type of leukemia was 2.03 (95% CI, 1.16-3.53; P =.013) for those with a history of dengue fever compared with those without a history of this disease.
This elevated leukemia risk in patients with a history of dengue fever was not observed in the first 3 years following development of symptoms. For example, the adjusted HR was only 1.69 (95% CI, 0.44-6.48; P =.446) when cases and controls were followed for less than 3 years following the index date. In contrast, for the periods covered by 3 or more years and 3 to 6 years beyond the index date, the respective HRs were 2.13 (95% CI, 1.15-3.93; P =.016 ) and 3.22 (95% CI, 1.25-8.32; P =.016). However, 6 or more years beyond the index date, no significant association was observed between dengue viral infection and development of leukemia.
Of note, no associations were observed between infection with the dengue virus and development of lymphoma or nonhematologic cancers.
As a major strength of this study, the study authors mentioned their ability to minimize selection bias through the use of highly inclusive national databases. However, they also identified study limitations, including the potential for misclassifying cases as controls due to the high level of asymptomatic dengue viral infection, and the low number of overall cases of dengue fever which precluded specific assessments of leukemia subtype risk. In addition, assessment of leukemia risk in younger individuals was not possible given the low number of patients younger than 18 years whom were included in the analysis.
In their concluding remarks, the study authors said that this study “provides the first epidemiologic evidence of the association between dengue virus and the risk of leukemia.” Nevertheless, they also emphasized that “the results need to be validated in other countries where population-based health information databases are available,” and that “further epidemiologic and experimental studies are required to verify this association and to unravel the potential mechanisms of pathogenesis.”
Chien Y-W, Wang C-C, Wang Y-P, et al. Risk of leukemia after dengue virus infection: A population-based cohort study [published online February 12, 2020]. Cancer Epidemiol Biomarkers Prev. doi: 10.1158/1055-9965.EPI-19-1214