Stalin Vilcarromero

House-to-house human movement drives dengue virus transmission

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 vector-borne pathogens, especially the importance of human movement, will lead to improvements in disease prevention.

Influenza-Like Illness Sentinel Surveillance in Peru

Background Acute respiratory illnesses and influenza-like illnesses (ILI) are a significant source of morbidity and mortality worldwide. Despite the public health importance, little is known about the etiology of these acute respiratory illnesses in many regions of South America. In 2006, the Peruvian Ministry of Health (MoH) and the US Naval Medical Research Center Detachment (NMRCD) initiated a collaboration to characterize the viral agents associated with ILI and to describe the clinical and epidemiological presentation of the affected population. Methodology/Principal Findings Patients with ILI (fever ≥38°C and cough or sore throat) were evaluated in clinics and hospitals in 13 Peruvian cities representative of the four main regions of the country. Nasal and oropharyngeal swabs, as well as epidemiological and demographic data, were collected from each patient. During the two years of this study (June 2006 through May 2008), a total of 6,835 patients, with a median age of 13 years, were recruited from 31 clinics and hospitals; 6,308 were enrolled by regular passive surveillance and 527 were enrolled as part of outbreak investigations. At least one respiratory virus was isolated from the specimens of 2,688 (42.6%) patients, with etiologies varying by age and geographical region. Overall the most common viral agents isolated were influenza A virus (25.1%), influenza B virus (9.7%), parainfluenza viruses 1, 2, and 3, (HPIV-1,-2,-3; 3.2%), herpes simplex virus (HSV; 2.6%), and adenoviruses (1.8%). Genetic analyses of influenza virus isolates demonstrated that three lineages of influenza A H1N1, one lineage of influenza A H3N2, and two lineages of influenza B were circulating in Peru during the course of this study. Conclusions To our knowledge this is the most comprehensive study to date of the etiologic agents associated with ILI in Peru. These results demonstrate that a wide range of respiratory pathogens are circulating in Peru and this fact needs to be considered by clinicians when treating patients reporting with ILI. Furthermore, these data have implications for influenza vaccine design and implementation in South America.

Reduced Risk of Disease During Postsecondary Dengue Virus Infections

BACKGROUND Antibodies induced by infection with any 1 of 4 dengue virus (DENV) serotypes (DENV-1-4) may influence the clinical outcome of subsequent heterologous infections. To quantify potential cross-protective effects, we estimated disease risk as a function of DENV infection, using data from longitudinal studies performed from September 2006 through February 2011 in Iquitos, Peru, during periods of DENV-3 and DENV-4 transmission. METHODS DENV infections before and during the study period were determined by analysis of serial serum samples with virus neutralization tests. Third and fourth infections were classified as postsecondary infections. Dengue fever cases were detected by door-to-door surveillance for acute febrile illness. RESULTS Among susceptible participants, 39% (420/1077) and 53% (1595/2997) seroconverted to DENV-3 and DENV-4, respectively. Disease was detected in 7% of DENV-3 infections and 10% of DENV-4 infections. Disease during postsecondary infections was reduced by 93% for DENV-3 and 64% for DENV-4, compared with primary and secondary infections. Despite lower disease rates, postsecondary infections constituted a significant proportion of apparent infections (14% [for DENV-3 infections], 45% [for DENV-4 infections]). CONCLUSIONS Preexisting heterotypic antibodies markedly reduced but did not eliminate the risk of disease in this study population. These results improve understanding of how preinfection history can be associated with dengue outcomes and DENV transmission dynamics.

Time-varying, serotype-specific force of infection of dengue virus

Significance Using mathematical models to extend knowledge of pathogen transmission and recommend optimized control efforts is dependent on the accuracy of model parameters. The rate at which susceptible individuals become infected [the force of infection (FoI)] is one of the most important parameters, but due to data constraints it is often incorrectly assumed to be constant over time. Using a bespoke method for a 12-y longitudinal dataset of serotype-specific dengue virus (DENV) infections, we estimated time-varying, serotype-specific FoIs for all four DENV serotypes. The FoI varied markedly in time, which implies that DENV transmission dynamics are complex and are best summarized using time-dependent transmission parameters. Our results provide more accurate measures of virus transmission dynamics and a basis for improving selection of control and disease prevention strategies. Infectious disease models play a key role in public health planning. These models rely on accurate estimates of key transmission parameters such as the force of infection (FoI), which is the per-capita risk of a susceptible person being infected. The FoI captures the fundamental dynamics of transmission and is crucial for gauging control efforts, such as identifying vaccination targets. Dengue virus (DENV) is a mosquito-borne, multiserotype pathogen that currently infects ∼390 million people a year. Existing estimates of the DENV FoI are inaccurate because they rely on the unrealistic assumption that risk is constant over time. Dengue models are thus unreliable for designing vaccine deployment strategies. Here, we present to our knowledge the first time-varying (daily), serotype-specific estimates of DENV FoIs using a spline-based fitting procedure designed to examine a 12-y, longitudinal DENV serological dataset from Iquitos, Peru (11,703 individuals, 38,416 samples, and 22,301 serotype-specific DENV infections from 1999 to 2010). The yearly DENV FoI varied markedly across time and serotypes (0–0.33), as did daily basic reproductive numbers (0.49–4.72). During specific time periods, the FoI fluctuations correlated across serotypes, indicating that different DENV serotypes shared common transmission drivers. The marked variation in transmission intensity that we detected indicates that intervention targets based on one-time estimates of the FoI could underestimate the level of effort needed to prevent disease. Our description of dengue virus transmission dynamics is unprecedented in detail, providing a basis for understanding the persistence of this rapidly emerging pathogen and improving disease prevention programs.

Dengue Virus Serotype 4, Northeastern Peru, 2008

In 2008, dengue virus serotype 4 (DENV-4) emerged in northeastern Peru, causing a large outbreak and displacing DENV-3, which had predominated for the previous 6 years. Phylogenetic analysis of 2008 and 2009 isolates support their inclusion into DENV-4 genotype II, forming a lineage distinct from strains that had previously circulated in the region.

Mayaro virus infection, Amazon Basin region, Peru, 2010-2013

During 2010–2013, we recruited 16 persons with confirmed Mayaro virus infection in the Peruvian Amazon to prospectively follow clinical symptoms and serologic response over a 12-month period. Mayaro virus infection caused long-term arthralgia in more than half, similar to reports of other arthritogenic alphaviruses.

Long-Term and Seasonal Dynamics of Dengue in Iquitos, Peru

Introduction Long-term disease surveillance data provide a basis for studying drivers of pathogen transmission dynamics. Dengue is a mosquito-borne disease caused by four distinct, but related, viruses (DENV-1-4) that potentially affect over half the worlds population. Dengue incidence varies seasonally and on longer time scales, presumably driven by the interaction of climate and host susceptibility. Precise understanding of dengue dynamics is constrained, however, by the relative paucity of laboratory-confirmed longitudinal data. Methods We studied 10 years (2000–2010) of laboratory-confirmed, clinic-based surveillance data collected in Iquitos, Peru. We characterized inter and intra-annual patterns of dengue dynamics on a weekly time scale using wavelet analysis. We explored the relationships of case counts to climatic variables with cross-correlation maps on annual and trimester bases. Findings Transmission was dominated by single serotypes, first DENV-3 (2001–2007) then DENV-4 (2008–2010). After 2003, incidence fluctuated inter-annually with outbreaks usually occurring between October and April. We detected a strong positive autocorrelation in case counts at a lag of ∼70 weeks, indicating a shift in the timing of peak incidence year-to-year. All climatic variables showed modest seasonality and correlated weakly with the number of reported dengue cases across a range of time lags. Cases were reduced after citywide insecticide fumigation if conducted early in the transmission season. Conclusions Dengue case counts peaked seasonally despite limited intra-annual variation in climate conditions. Contrary to expectations for this mosquito-borne disease, no climatic variable considered exhibited a strong relationship with transmission. Vector control operations did, however, appear to have a significant impact on transmission some years. Our results indicate that a complicated interplay of factors underlie DENV transmission in contexts such as Iquitos.

Sequential Waves of Gene Expression in Patients with Clinically Defined Dengue Illnesses Reveal Subtle Disease Phases and Predict Disease Severity

Background Dengue virus (DENV) infection can range in severity from mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). Changes in host gene expression, temporally through the progression of DENV infection, especially during the early days, remains poorly characterized. Early diagnostic markers for DHF are also lacking. Methodology/Principal Findings In this study, we investigated host gene expression in a cohort of DENV-infected subjects clinically diagnosed as DF (n = 51) and DHF (n = 13) from Maracay, Venezuela. Blood specimens were collected daily from these subjects from enrollment to early defervescence and at one convalescent time-point. Using convalescent expression levels as baseline, two distinct groups of genes were identified: the “early” group, which included genes associated with innate immunity, type I interferon, cytokine-mediated signaling, chemotaxis, and complement activity peaked at day 0–1 and declined on day 3–4; the second “late” group, comprised of genes associated with cell cycle, emerged from day 4 and peaked at day 5–6. The up-regulation of innate immune response genes coincided with the down-regulation of genes associated with viral replication during day 0–3. Furthermore, DHF patients had lower expression of genes associated with antigen processing and presentation, MHC class II receptor, NK and T cell activities, compared to that of DF patients. These results suggested that the innate and adaptive immunity during the early days of the disease are vital in suppressing DENV replication and in affecting outcome of disease severity. Gene signatures of DHF were identified as early as day 1. Conclusions/Significance Our study reveals a broad and dynamic picture of host responses in DENV infected subjects. Host response to DENV infection can now be understood as two distinct phases with unique transcriptional markers. The DHF signatures identified during day 1–3 may have applications in developing early molecular diagnostics for DHF.

Incomplete Protection against Dengue Virus Type 2 Re-infection in Peru

Background Nearly half of the world’s population is at risk for dengue, yet no licensed vaccine or anti-viral drug is currently available. Dengue is caused by any of four dengue virus serotypes (DENV-1 through DENV-4), and infection by a DENV serotype is assumed to provide life-long protection against re-infection by that serotype. We investigated the validity of this fundamental assumption during a large dengue epidemic caused by DENV-2 in Iquitos, Peru, in 2010–2011, 15 years after the first outbreak of DENV-2 in the region. Methodology/Principal Findings We estimated the age-dependent prevalence of serotype-specific DENV antibodies from longitudinal cohort studies conducted between 1993 and 2010. During the 2010–2011 epidemic, active dengue cases were identified through active community- and clinic-based febrile surveillance studies, and acute inapparent DENV infections were identified through contact tracing studies. Based on the age-specific prevalence of DENV-2 neutralizing antibodies, the age distribution of DENV-2 cases was markedly older than expected. Homologous protection was estimated at 35.1% (95% confidence interval: 0%–65.2%). At the individual level, pre-existing DENV-2 antibodies were associated with an incomplete reduction in the frequency of symptoms. Among dengue cases, 43% (26/66) exhibited elevated DENV-2 neutralizing antibody titers for years prior to infection, compared with 76% (13/17) of inapparent infections (age-adjusted odds ratio: 4.2; 95% confidence interval: 1.1–17.7). Conclusions/Significance Our data indicate that protection from homologous DENV re-infection may be incomplete in some circumstances, which provides context for the limited vaccine efficacy against DENV-2 in recent trials. Further studies are warranted to confirm this phenomenon and to evaluate the potential role of incomplete homologous protection in DENV transmission dynamics.

Lineage II of Southeast Asian/American DENV-2 Is Associated with a Severe Dengue Outbreak in the Peruvian Amazon

During 2010 and 2011, the Loreto region of Peru experienced a dengue outbreak of unprecedented magnitude and severity for the region. This outbreak coincided with the reappearance of dengue virus-2 (DENV-2) in Loreto after almost 8 years. Whole-genome sequence indicated that DENV-2 from the outbreak belonged to lineage II of the southeast Asian/American genotype and was most closely related to viruses circulating in Brazil during 2007 and 2008, whereas DENV-2 previously circulating in Loreto grouped with lineage I (DENV-2 strains circulating in South America since 1990). One amino acid substitution (NS5 A811V) in the 2010 and 2011 isolates resulted from positive selection. However, the 2010 and 2011 DENV-2 did not replicate to higher titers in monocyte-derived dendritic cells and did not infect or disseminate in a higher proportion of Aedes aegypti than DENV-2 isolates previously circulating in Loreto. These results suggest that factors other than enhanced viral replication played a role in the severity of this outbreak.