Author: Bryan P. White
Original Publication: 09/14/2019
Dengue fever is a febrile illness that affects up to 390 million people a year causing an overall high health burden, but relatively low mortality rate (48,000 deaths per year). Recently a vaccine, Dengvaxia (Flasche et al., 2016), has been approved for limited release in various parts of the world, while other types of vaccines are still in development (Bos et al., 2018). Nealon et al. (2019) sought to assess the efficacy of two different study design types (the case-control method vs. the test-negative method) in identifying the success rate of prospective vaccines for Dengue virus as they are deployed around the world. Under the case-control method, for every suspected case of Dengue fever admitted to a hospital, a control case, defined as a person of similar life circumstance and illness but not thought to have Dengue fever is identified. In the test-negative scenario, controls are identified from suspected Dengue fever patients that later test negative for the virus, meaning they had something else other than Dengue fever but all the suspected circumstances that would have made a diagnosis of Dengue seem likely.
Understanding which method produces the most useful results will be critical in ascertaining the success rates of Dengvaxia and other vaccines that are developed, since the use of Dengvaxia has the potential for causing negative effects (potentially fatal hemorrhagic fever) depending on the serotype of infection. In Gordis (2019) the important factors in study design are typically establishing a proper control group, limiting the effects that researchers might have on the study by using blind or double-blind procedures, and determining the correct sample size. In this study (Nealon et al., 2019), establishing proper control and effective sample size are the primary factors evaluated. The authors found that of the 327 subjects recruited for the study, neither method (test-negative or case-control) produced enough control samples to be effective – but for different reasons. Under the test-negative design, only 28 negative controls were found of 155 suspected dengue cases, when a ratio of 1:2 or 1:4 positive to control was desired. Under the case-control method, 172 matched-case controls were found of the 124 verified dengue cases. While case-control studies tend to be vulnerable to biases since controls must be actively sought out, overall they were able to produce a higher control-to-positive ratio, which was desired for this study. That would suggest that overall the case-control method has less limitations than the test-negative method, for this sample population (Malaysia).
Bos, S., Gadea, G., & Despres, P. (2018). Dengue: a growing threat requiring vaccine development for disease prevention. Pathogens and global health, 112(6), 294-305.
Gordis, Leon. Epidemiology E-Book (Gordis, Epidemiology) (p. 155-172). Elsevier Health Sciences. Kindle Edition. Flasche, S., Jit, M., Rodríguez-Barraquer, I., Coudeville, L., Recker, M., Koelle, K., … & Dorigatti, I. (2016). The long-term safety, public health impact, and cost-effectiveness of routine vaccination with a recombinant, live-attenuated dengue vaccine (Dengvaxia): a model comparison study. PLoS medicine, 13(11), e1002181.
Nealon, J., Lim, W. Y., Moureau, A., Lojikip, S. L., Junus, S., Kumar, S., … & Ochiai, R. L. (2019). Feasibility of case-control and test-negative designs to evaluate dengue vaccine effectiveness in Malaysia. Vaccine.
Dengue fever is a mosquito borne disease that infects up to 390 million people per year. Risk of infection by Dengue differs greatly regionally, with strong factors linked to human urbanization, agriculture, and local climate variability. In this assignment, I evaluated 3 research articles to better understand the variation in reported Dengue risk factors. Routine testing for Dengue virus (DENV) includes the detection of viral particles in blood serum using PCR, which means that the person likely experienced a recent DENV infection. In Dhar-Chowdhury et al. (2017), odds ratios (ORs) for testing positive for DENV in Dhaka, Bangladesh were significantly greater for those having visited a garden or park (1.0) vs. having attended a public event (e.g., schools, religious institutions, etc.) (0.32). ORs were also significantly greater for those using mosquito coils (3.21) and sprays or other control methods (4.24) compared to that of bed nets (1.0). In a multivariate analysis, the age group 12-44 was significantly greater to experience DENV infection (OR = 4.13) as well as the 45+ age group (OR =5.90).
In Anders et al. (2011), ORs for DENV infection in Ho Chi Minh City, Vietnam for hospitalized pediatric patients were significantly greater for females (1.19 in females vs. 1.10 in males) and in the age group 6-10 (1.40 in 6-10 compared to 0.95 in 11-15). In Dhar-Chowdhury et al. (2017), ORs for females were also higher (1.10 in females vs. 1.0 in males), but it was not statistically significant (p = 0.38).
In a third study by Brunkard et al. (2004) investigating risk factors for DENV at the Texas-Mexico border, the only statistically significant risk factor found was weekly family income <$100 (OR = 3.22). Increased prevalence of female seropositive for DENV was notably higher but not statistically significant. Since a common factor between these three studies is an effect of sex (female > male OR) but with low statistical power, future studies should be conducted in a way to increase statistical power and sort out this possible risk factor and understand the differential risk.
Anders, K. L., Nguyet, N. M., Chau, N. V. V., Hung, N. T., Thuy, T. T., Farrar, J., … & Simmons, C. P. (2011). Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam. The American journal of tropical medicine and hygiene, 84(1), 127-134.
Brunkard, J. M., López, J. L. R., Ramirez, J., Cifuentes, E., Rothenberg, S. J., Hunsperger, E. A., … & Haddad, B. M. (2007). Dengue fever seroprevalence and risk factors, Texas–Mexico border, 2004. Emerging infectious diseases, 13(10), 1477.
Dhar-Chowdhury, P., Paul, K. K., Haque, C. E., Hossain, S., Lindsay, L. R., Dibernardo, A., … & Drebot, M. A. (2017). Dengue seroprevalence, seroconversion and risk factors in Dhaka, Bangladesh. PLoS neglected tropical diseases, 11(3), e0005475.