Arbovirus coinfection and co-transmission: A neglected public health concern?

Abstract

Epidemiological synergy between outbreaks of viruses transmitted by Aedes aegypti mosquitoes, such as chikungunya, dengue, and Zika viruses, has resulted in coinfection of humans with multiple viruses. Despite the potential impact on public health, we know only little about the occurrence and consequences of such coinfections. Here, we review the impact of coinfection on clinical disease in humans, discuss the possibility for co-transmission from mosquito to human, and describe a role for modeling transmission dynamics at various levels of co-transmission. Solving the mystery of virus coinfections will reveal whether they should be viewed as a serious concern for public health.

Fig 1. Overlapping outbreaks of chikungunya, dengue, and Zika viruses.

During 2016–2017, 36 countries reported local cases of chikungunya, dengue, and Zika viruses; more, such as Cuba, Haiti, and Suriname, likely had transmission of all three viruses, but they were not reported. The inserts are examples of synergistic outbreak dynamics, shown as reported cases per month. All data were obtained from the Pan-American Health Organization and are available at https://github.com/grubaughlab/paper_2019_co-infection.

Fig 2. Mosquito and human coinfections occur as a result of simultaneous or sequential infection.

Coinfection may either be the result of simultaneous transmission of multiple viruses between mosquitoes and humans (central panel) or sequential transmission during multiple mosquito bites. Four scenarios may explain the consequences of virus coinfection inside mosquito vectors and human hosts: enhancement, inhibition, competition, or neutral.

Fig 3. Effects of coinfection on clinical disease in humans and virus transmission by mosquitoes.

(A) Clinical outcomes were obtained from studies providing sufficient information for both single infected and coinfected patients [,,,,,,,,,,,,–69]. “Dengue-like illness” summarizes all cases of febrile illness with a range of additional symptoms including arthralgia, myalgia, rash, headache, gastrointestinal symptoms, thrombocytopenia, and conjunctivitis. Hemorrhagic fever includes all patients with clear signs of hemorrhage ranging from mild to severe, and dengue shock syndrome includes patients with hypotension, ascites, and pleural effusion. (B) Data on mosquito transmission were compiled from studies that made a direct comparison between mosquitoes exposed to a single or multiple viruses [–84,87]. Transmission of coexposed mosquitoes was calculated relative to single exposed mosquitoes, with relative transmission being defined as transmission rate of virus X in mosquitoes coexposed to virus X and Y divided by transmission rate of virus X in single exposed mosquitoes. Transmission is expressed as the percentage of mosquitoes with virus in their saliva out of the total number of exposed mosquitoes. Relative transmission of 1 indicates that no difference was observed between transmission rates of single exposed or coexposed mosquitoes. Vertical black bars indicate the median. Data used to calculate relative co-transmission are available at https://github.com/grubaughlab/paper_2019_co-infection. CHIKV, chikungunya virus; DENV, dengue virus; ZIKV, Zika virus.

Fig 4. Model-predicted prevalence over time of two sequentially invading arboviruses.

The transmission parameters of the viruses are identical, and virus Y invades one month after virus X in a population of 1,000,000. The top row shows the overall prevalence of both viruses and coinfection, and the bottom row shows coinfections only, delineated by the cause of the coinfection. The columns represent different scenarios of transmission from coinfected mosquitoes: no co-transmission on the left, 50% co-transmission in the middle, and 100% co-transmission on the right.