Reconstruction of 60 Years of Chikungunya Epidemiology in the Philippines Demonstrates Episodic and Focal Transmission

Proper understanding of the long-term epidemiology of chikungunya has been hampered by poor surveillance. Outbreak years are unpredictable and cases often misdiagnosed. Here we analyzed age-specific data from 2 serological studies (from 1973 and 2012) in Cebu, Philippines, to reconstruct both the annual probability of infection and population-level immunity over a 60-year period (1952-2012). We also explored whether seroconversions during 2012-2013 were spatially clustered. Our models identified 4 discrete outbreaks separated by an average delay of 17 years. On average, 23% (95% confidence interval [CI], 16%-37%) of the susceptible population was infected per outbreak, with \u3e 50% of the entire population remaining susceptible at any point. Participants who seroconverted during 2012-2013 were clustered at distances of \u3c 230 m, suggesting focal transmission. Large-scale outbreaks of chikungunya did not result in sustained multiyear transmission. Nevertheless, we estimate that \u3e 350,000 infections were missed by surveillance systems. Serological studies could supplement surveillance to provide important insights on pathogen circulation

Complete Genome Sequences of Zika Virus Strains Isolated from the Blood of Patients in Thailand in 2014 and the Philippines in 2012

Here, we present the complete genome sequences of two Zika virus (ZIKV) strains, Zika virus/Homo sapiens-tc/THA/2014/SV0127-14 and Zika virus/H. sapiens-tc/PHL/2012/CPC-0740, isolated from the blood of patients collected in Thailand, 2014, and the Philippines, 2012, respectively. Sequencing and phylogenetic analysis showed that both strains belong to the Asian lineage

Longitudinal Analysis of Dengue Virus–Specific Memory T Cell Responses and Their Association With Clinical Outcome in Subsequent DENV Infection

Memory T cells resulting from primary dengue virus (DENV) infection are hypothesized to influence the clinical outcome of subsequent DENV infection. However, the few studies involving prospectively collected blood samples have found weak and inconsistent associations with outcome and variable temporal trends in DENV-specific memory T cell responses between subjects. This study used both ex-vivo and cultured ELISPOT assays to further evaluate the associations between DENV serotype-cross-reactive memory T cells and severity of secondary infection. Using ex-vivo ELISPOT assays, frequencies of memory T cells secreting IFN-γ in response to DENV structural and non-structural peptide pools were low in PBMC from multiple time points prior to symptomatic secondary DENV infection and showed a variable response to infection. There were no differences in responses between subjects who were not hospitalized (NH, n=6) and those who were hospitalized with dengue hemorrhagic fever (hDHF, n=4). In contrast, responses in cultured ELISPOT assays were more reliably detectable prior to secondary infection and showed more consistent increases after infection. Responses in cultured ELISPOT assays were higher in individuals with hDHF (n=8) compared to NH (n=9) individuals before the secondary infection, with no difference between these groups after infection. These data demonstrate an association of pre-existing DENV-specific memory responses with the severity of illness in subsequent DENV infection, and suggest that frequencies of DENV-reactive T cells measured after short-term culture may be of particular importance for assessing the risk for more severe dengue disease

Protection from arthritis and myositis in a mouse model of acute chikungunya virus disease by bindarit, an inhibitor of monocyte chemotactic protein-1 synthesis

Chikungunya virus (CHIKV) is associated with outbreaks of infectious rheumatic disease in humans. Using a mouse model of CHIKV arthritis and myositis, we show that tumor necrosis factor-α, interferon-γ, and monocyte chemotactic protein 1 (MCP-1) were dramatically induced in tissues from infected mice. The same factors were detected in the serum of patients with CHIKV-induced polyarthralgia and polyarthritis, with MCP-1 levels being particularly elevated. Bindarit (MCP inhibitor) treatment ameliorated CHIKV disease in mice. Histological analysis of muscle and joint tissues showed a reduction in inflammatory infiltrate in infectedmice treated with bindarit. These results suggest that bindarit may be useful in treating CHIKV-induced arthritides in humans.Facultad de Ciencias Exacta

Protection from arthritis and myositis in a mouse model of acute chikungunya virus disease by bindarit, an inhibitor of monocyte chemotactic protein-1 synthesis

Chikungunya virus (CHIKV) is associated with outbreaks of infectious rheumatic disease in humans. Using a mouse model of CHIKV arthritis and myositis, we show that tumor necrosis factor-α, interferon-γ, and monocyte chemotactic protein 1 (MCP-1) were dramatically induced in tissues from infected mice. The same factors were detected in the serum of patients with CHIKV-induced polyarthralgia and polyarthritis, with MCP-1 levels being particularly elevated. Bindarit (MCP inhibitor) treatment ameliorated CHIKV disease in mice. Histological analysis of muscle and joint tissues showed a reduction in inflammatory infiltrate in infectedmice treated with bindarit. These results suggest that bindarit may be useful in treating CHIKV-induced arthritides in humans.Facultad de Ciencias Exacta

Protection from arthritis and myositis in a mouse model of acute chikungunya virus disease by bindarit, an inhibitor of monocyte chemotactic protein-1 synthesis

Chikungunya virus (CHIKV) is associated with outbreaks of infectious rheumatic disease in humans. Using a mouse model of CHIKV arthritis and myositis, we show that tumor necrosis factor-α, interferon-γ, and monocyte chemotactic protein 1 (MCP-1) were dramatically induced in tissues from infected mice. The same factors were detected in the serum of patients with CHIKV-induced polyarthralgia and polyarthritis, with MCP-1 levels being particularly elevated. Bindarit (MCP inhibitor) treatment ameliorated CHIKV disease in mice. Histological analysis of muscle and joint tissues showed a reduction in inflammatory infiltrate in infectedmice treated with bindarit. These results suggest that bindarit may be useful in treating CHIKV-induced arthritides in humans.Facultad de Ciencias Exacta

Preliminary evaluation of near infrared spectroscopy as a method to detect plasma leakage in children with dengue hemorrhagic fever

BACKGROUND: Dengue viral infections are prevalent in the tropical and sub-tropical regions of the world, resulting in substantial morbidity and mortality. Clinical manifestations range from a self-limited fever to a potential life-threatening plasma leakage syndrome (dengue hemorrhagic fever). The objective of this study was to assess the utility of near infrared spectroscopy (NIRS) measurements of muscle oxygen saturation (SmO2) as a possible continuous measure to detect plasma leakage in children with dengue. METHODS: Children ages 6 months to 15 years of age admitted with suspected dengue were enrolled from the dengue ward at Queen Sirikit National Institute for Child Health. Children were monitored daily until discharge. NIRS data were collected continuously using a prototype CareGuide Oximeter 1100 with sensors placed on the deltoid or thigh. Daily ultrasound of the chest and a right lateral decubitus chest x-ray the day after defervescence were performed to detect and quantitate plasma leakage in the pleural cavity. RESULTS: NIRS data were obtained from 19 children with laboratory-confirmed dengue. Average minimum SmO2 decreased for all subjects prior to defervescence. Average minimum SmO2 subsequently increased in children with no ultrasound evidence of pleural effusion but remained low in children with pleural effusion following defervescence. Average minimum SmO2 was inversely correlated with pleural space fluid volume. ROC analysis revealed a cut-off value for SmO2 which yielded high specificity and sensitivity. CONCLUSIONS: SmO2 measured using NIRS may be a useful guide for real-time and non-invasive identification of plasma leakage in children with dengue. Further investigation of the utility of NIRS measurements for prediction and management of severe dengue syndromes is warranted

Dengue Viral RNA Levels in Peripheral Blood Mononuclear Cells are Associated with Disease Severity and Preexisting Dengue Immune Status

Background Infection with dengue viruses (DENV) causes a wide range of manifestations from asymptomatic infection to a febrile illness called dengue fever (DF), to dengue hemorrhagic fever (DHF). The in vivo targets of DENV and the relation between the viral burden in these cells and disease severity are not known. Method The levels of positive and negative strand viral RNA in peripheral blood monocytes, T/NK cells, and B cells and in plasma of DF and DHF cases were measured by quantitative RT-PCR. Results Positive strand viral RNA was detected in monocytes, T/NK cells and B cells with the highest amounts found in B cells. Viral RNA levels in CD14+ cells and plasma were significantly higher in DHF compared to DF, and in cases with a secondary infection compared to those undergoing a primary infection. The distribution of viral RNA among cell subpopulations was similar in DF and DHF cases. Small amounts of negative strand RNA were found in a few cases only. The severity of plasma leakage correlated with viral RNA levels in plasma and in CD14+ cells. Conclusions B cells were the principal cells containing DENV RNA in peripheral blood, but overall there was little active DENV RNA replication detectable in peripheral blood mononuclear cells (PBMC). Secondary infection and DHF were associated with higher viral burden in PBMC populations, especially CD14+ monocytes, suggesting that viral infection of these cells may be involved in disease pathogenesis