Underrecognized Mildly Symptomatic Viremic Dengue Virus Infections in Rural Thai Schools and Villages

Yoon, In-Kyu; Rothman, Alan L.; Tannitisupawong, Darunee; Srikiatkhachorn, Anon; Jarman, Richard G.; Aldstadt, Jared; Nisalak, Ananda; Mammen, Mammen P.; Thammapalo, Suwich; Green, Sharone; Libraty, Daniel H.; Gibbons, Robert V.; Getis, Arthur; Endy, Timothy P.; Jones, James W.; Koenraadt, Constantianus J. M.; Morrison, Amy C.; Fansiri, Thanyalak; Pimgate, Chusak; Scott, Thomas W.

doi:10.1093/infdis/jis357

Cited by 88 publications

(125 citation statements)

References 27 publications

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“…Thus, human-mobility patterns on both individual and collective levels had a powerful impact on how DENV moved through the human population. Our results, in combination with conclusions from other studies describing highly focal patterns of DENV transmission around the home (<50 m) (18,20) indicate that transmission occurs among multiple, fine-scale foci connected by the movements of infected and susceptible people. At these short distances from the home, the relative contribution of mosquitoes versus humans to pathogen dispersal is still uncertain, but clearly both are important.…”

Section: Discussionsupporting

confidence: 85%

“…When a febrile person (≥3 y old) was identified, written informed consent was obtained from adult participants or the parents of participants <18 y of age. Assent was obtained from participating children (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Blood was drawn at the time of case identification (acute sample), followed by a convalescent blood sample 14-21 d later.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, much of what we do know about dengue is derived from passive disease-surveillance data that do not take into account that DENV infections in endemic populations are often asymptomatic or cause only mild disease (17,18). This has led to significant uncertainty in our estimates of key factors determining the controllability of dengue, such as the basic reproductive rate (R 0 ) (13).…”

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confidence: 99%

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House-to-house human movement drives dengue virus transmission

Stoddard

Forshey

Morrison

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

447

425

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Dengue is a mosquito-borne disease of growing global health importance. Prevention efforts focus on mosquito control, with limited success. New insights into the spatiotemporal drivers of dengue dynamics are needed to design improved disease-prevention strategies. Given the restricted range of movement of the primary mosquito vector, Aedes aegypti, local human movements may be an important driver of dengue virus (DENV) amplification and spread. Using contact-site cluster investigations in a case-control design, we demonstrate that, at an individual level, risk for human infection is defined by visits to places where contact with infected mosquitoes is likely, independent of distance from the home. Our data indicate that house-to-house human movements underlie spatial patterns of DENV incidence, causing marked heterogeneity in transmission rates. At a collective level, transmission appears to be shaped by social connections because routine movements among the same places, such as the homes of family and friends, are often similar for the infected individual and their contacts. Thus, routine, house-to-house human movements do play a key role in spread of this vector-borne pathogen at fine spatial scales. This finding has important implications for dengue prevention, challenging the appropriateness of current approaches to vector control. We argue that reexamination of existing paradigms regarding the spatiotemporal dynamics of DENV and other vectorborne pathogens, especially the importance of human movement, will lead to improvements in disease prevention.infectious disease | spatial epidemiology | arthropod-borne virus | emerging infections | disease ecology D engue is a mosquito-borne viral infection prevalent in the tropics and subtropics with an incidence and range that have increased substantially over the last three decades (1-4). The incidence of severe, life-threatening disease (dengue hemorrhagic fever or DHF) is also on the rise (5). Dengue virus (DENV) is caused by any of four closely related, but antigenically distinct and genetically diverse, virus serotypes (DENV-1, -2, -3, and -4), which are transmitted by day-biting, peridomestic Aedes mosquitoes, primarily Aedes aegypti (6). Incompletely understood immunological interactions among serotypes that can enhance disease severity (7-9) have hampered the development of effective, commercially available vaccines. A recent trial of a promising vaccine candidate demonstrated only partial (<33%) protection (10). Effective antiviral therapeutics are also not available. Thus, despite nearly a century of research, the only tools presently available to combat dengue target mosquito populations, mostly with insecticides and larval source reduction. In current practice, these tools are most often only partially effective (11). Although new vector control approaches are under development (12), innovations in dengue-control approaches are constrained by our limited understanding of virus-transmission dynamics and its drivers. In particular, the role of human movemen...

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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House-to-house human movement drives dengue virus transmission

Stoddard

Forshey

Morrison

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

447

425

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“…The ratio of symptomatic to asymptomatic dengue infection of 1:1.7 found in this study, reinforces the knowledge of a higher frequency of unapparent infection compared with symptomatic infection detected by active surveillance 20 . During the child follow up, approximately 25% of clinically suspected dengue cases were virologically-confirmed.…”

Section: Discussionsupporting

confidence: 90%

Prospective birth cohort in a hyperendemic dengue area in Northeast Brazil: methods and preliminary results

et al. 2016

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“…Before the development of studies based on geographic cluster sampling around index cases (16,17), inapparent DENV infections could only be detected in very small numbers or retrospectively in cohort studies after the viremic period had ended (18,19). We overcame this obstacle by capturing DENV-infected people across the continuum of disease manifestations while they were viremic using a comprehensive catchment system combining passive, hospital-based surveillance and cluster investigations in and around the households of hospitalized index cases (Materials and Methods).…”

Section: Resultsmentioning

confidence: 99%

Asymptomatic humans transmit dengue virus to mosquitoes

Duong

Lambrechts

Rácz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

401

367

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Three-quarters of the estimated 390 million dengue virus (DENV) infections each year are clinically inapparent. People with inapparent dengue virus infections are generally considered dead-end hosts for transmission because they do not reach sufficiently high viremia levels to infect mosquitoes. Here, we show that, despite their lower average level of viremia, asymptomatic people can be infectious to mosquitoes. Moreover, at a given level of viremia, DENV-infected people with no detectable symptoms or before the onset of symptoms are significantly more infectious to mosquitoes than people with symptomatic infections. Because DENV viremic people without clinical symptoms may be exposed to more mosquitoes through their undisrupted daily routines than sick people and represent the bulk of DENV infections, our data indicate that they have the potential to contribute significantly more to virus transmission to mosquitoes than previously recognized.mosquito experimental infection | Cambodia | Aedes aegypti | human-to-mosquito transmission | dengue W ith 3.97 billion people living in 128 countries currently at risk for infection, dengue viruses (DENV-1 to -4) cause more human morbidity and mortality worldwide than any other arthropod-borne virus (1, 2). Aedes aegypti mosquitoes are the primary vectors of DENV throughout the tropics (3). Dengue prevention relies on the control of Ae. aegypti populations, which is failing in most parts of the world due to lack of resources, lack of political will, and/or ineffective implementation (4).Virus transmission from infected humans to mosquitoes is a critical step in dengue epidemiology, but due to logistical constraints it has been directly examined only in a handful of studies to date (5). In initial experimental infections of human volunteers during the 1920s (6, 7), the onset of clinical symptoms occurred 4-9 d after virus inoculation by mosquito bite (8). DENV-infected humans were infectious to mosquitoes from 2 d before to 2 d after the onset of symptoms, and Ae. aegypti fed on viremic people were able to transmit virus to another person after at least 11 d of extrinsic incubation (8). Results from later studies indicated that, for naturally infected people with clinically apparent dengue, the duration of detectable viremia was on average 4-5 d after the onset of symptoms, but could range from 2 to 12 d (9, 10). Investigators in Vietnam fed Ae. aegypti directly on 208 symptomatic, hospitalized dengue patients and reported that the probability of successful human-to-mosquito DENV transmission was coincident with the kinetics of viremia (11). Dengue patients were infectious up to 5 d after the onset of symptoms, which generally corresponded with "defervescence" (11).All previous studies on human-to-mosquito DENV transmission were limited to people with overt illness and did not consider subclinical infections. An estimated 300 million of the total 390 million DENV infections per year are clinically inapparent or mildly symptomatic, i.e., no illness that disrupted a person's ...

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Underrecognized Mildly Symptomatic Viremic Dengue Virus Infections in Rural Thai Schools and Villages

Cited by 88 publications

References 27 publications

House-to-house human movement drives dengue virus transmission

House-to-house human movement drives dengue virus transmission

Prospective birth cohort in a hyperendemic dengue area in Northeast Brazil: methods and preliminary results

Asymptomatic humans transmit dengue virus to mosquitoes

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