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In a surprising study from the Amazon rainforest, Brazilian scientists found that symptomatic COVID-19 infections were twice as likely to occur in people who had prior dengue.

The study, led by Marcelo Urbano Ferreira, MD, PhD, of Brazil’s University of São Paulo Biomedical Sciences Institute (ICB-USP), was conducted in Mâncio Lima, a town in the Amazon region of Brazil, and published May 6 in Clinical Infectious Diseases.

In the study, supported by the São Paulo Research Foundation (FAPESP), Ferreira’s team looked at sequential blood samples from 1285 residents of Mâncio Lima.

An earlier study by Miguel Nicolelis, MD, PhD, and colleagues (published as a preprint) had analyzed data from the first COVID-19 wave in Brazil in 2020. It was an “ecological study” and examined dengue cases in different geographic regions of Brazil. That study concluded that dengue actually seemed to protect people from later developing COVID-19.

Ferreira anticipated finding a similar effect. Instead, he found the opposite effect. Although dengue did not increase the risk of subsequent COVID-19 infection, symptomatic COVID-19 became twice as likely in people with prior dengue. His study was longitudinal, following a single group of patients in Mâncio Lima over time.

Ferreira explained to Medscape Medical News that ecological studies are inherently less accurate, as they look at populations in different places. “All the older cases are diagnosed on clinical grounds…Because most infections are either asymptomatic or symptoms can be easily confused with” other diseases, many cases are missed. So, during the dengue transmission season, “We have some overestimation of the actual number of cases, and outside the transmission season, we have underestimation of the cases.”

On the apparent discrepancy with the earlier Nicolelis study, Ferreira commented, “It’s a wonderful study because it’s something you can do quickly and test a hypothesis [in a] very, very timely [manner], but the problem is if your diagnosis is not very reliable.”

Ferreira had another advantage: knowing from sequential blood samples that his patients were exposed to dengue within the past 5 years. He also could tell serologically when they became infected with the SARS-CoV-2 virus, which causes COVID-19.

Ferreira told Medscape that very few of their patients became seriously ill or required hospitalization. Because their sample size was too small, he could not say if prior dengue made the COVID-19 infection worse.

The type of interaction between two infections like dengue and COVID-19 is called a “syndemic,” which the CDC defines as “synergistically interacting epidemics.” Ferreira hypothesized about some of the factors that might be at play but does not yet have enough data. For example, he speculated about a biologic basis, such as a link to autoimmunity or vasculitis from prior dengue, but “has no real data to either support or reject these things.”

Ferreira added that perhaps there are social factors that put certain people at higher risk of infection; for example, maybe some people are “more exposed to high viral loads.”

In Brazil’s first wave of COVID-19, Ferreira’s team calculated dengue seroconversion as about 10%; many cases of dengue were asymptomatic. Ferreira expects they will “have a very different clinical spectrum during the second wave,” with young people becoming much more ill from the P1 variant of concern.

Scott O’Neill, PhD, founder and director of the World Mosquito Program, told Medscape that, while he found the Brazil results intriguing, at present they are not sufficient to say that there’s a causal relationship between dengue and COVID-19. He expressed concern that the results seem counterintuitive and doubts there’s a biological or mechanistic cause. Instead, O’Neill wonders if “there could be something about social or economic conditions or living conditions” that might account for the correlation. For example, perhaps poverty increases exposure to both dengue and COVID-19.

Furthermore, O’Neill told Medscape, he suspects that with the COVID-19 lockdowns, “You might expect to see more dengue.” This is because “most transmission occurs around the house, and so [with] having more people confined to houses, you might expect to see more dengue.” Such appears to be the case in Singapore.

In an article in The Journal of Infectious Diseases,  Jue Tao Lim and colleagues described increased dengue in Singapore during COVID-19. They noted that most employees in Singapore work in air-conditioned settings. With social distancing enforced to try to reduce COVID-19, people stayed at home. The mosquito that transmits dengue, Aedes aegypti, gathers in wet spots in residential areas and bites during the daytime. The authors hypothesized that the spike in dengue was because of this change in habits, which shifted people’s exposure.

The syndemic in Brazil is complicated, with malaria and multiple arboviral diseases (chikungunya, dengue, Zika) overlapping with COVID-19 in areas of high population density, poverty, and poor sanitation, among other social ills. Such overlapping factors make it harder to distinguish correlations from causations. Prospective longitudinal studies might be needed to provide definitive answers.

Ferreira and O’Neill have disclosed no relevant financial relationships.

Clinical Infectious Diseases. Published online May 6, 2021. Abstract

Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research , the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.

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