Category: Publications

Khuntirat B, Love CS, Buddhari D, Heil GL, Gibbons RV, Rothman AL, Srikiatkhachorn A, Gray GC, Yoon IK

J. Clin. Virol. 2015 Aug;69:78-80

PMID: 26209384

Abstract

BACKGROUND: Influenza A/H5N1 actively circulated in Kamphaeng Phet (KPP), Thailand from 2004 to 2006. A prospective longitudinal cohort study of influenza virus infection in 800 adults conducted during 2008-2010 in KPP suggested that subclinical or mild H5N1 infections had occurred among this adult cohort. However, this study was conducted after the peak of H5N1 activity in KPP. Coincidentally, banked serum samples were available from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses from 2004 to 2007 and lived in the same district of KPP as the adult cohort.

OBJECTIVES: We sought to investigate whether subclinical or mild H5N1 infections had occurred among KPP residents during the peak of H5N1 activity from 2004 to 2006.

STUDY DESIGN: H5N1 microneutralization (MN) assay was performed on banked serum samples from a prospective longitudinal cohort study of primary school children who had undergone active surveillance for febrile illnesses in KPP. Annual blood samples collected from 2004 to 2006 from 251 children were selected based on the criteria that they lived in villages with documented H5N1 infection.

RESULT: No H5N1 neutralizing antibodies were detected in 753 annual blood samples from 251 children.

CONCLUSION: During 2004-2006, very few subclinical or mild H5N1 infections occurred in KPP. Elevated H5N1 MN titers found in the adult cohort in 2008 were likely due to cross-reactivity from other influenza virus subtypes highlighting the complexities in interpreting influenza serological data.

Thomas SJ, Aldstadt J, Jarman RG, Buddhari D, Yoon IK, Richardson JH, Ponlawat A, Iamsirithaworn S, Scott TW, Rothman AL, Gibbons RV, Lambrechts L, Endy TP

Am. J. Trop. Med. Hyg. 2015 Jul;93(1):24-32

PMID: 25986580

Abstract

Dengue is of public health importance in tropical and sub-tropical regions. Dengue virus (DENV) transmission dynamics was studied in Kamphaeng Phet Province, Thailand, using an enhanced spatiotemporal surveillance of 93 hospitalized subjects with confirmed dengue (initiates) and associated cluster individuals (associates) with entomologic sampling. A total of 438 associates were enrolled from 208 houses with household members with a history of fever, located within a 200-m radius of an initiate case. Of 409 associates, 86 (21%) had laboratory-confirmed DENV infection. A total of 63 (1.8%) of the 3,565 mosquitoes collected were dengue polymerase chain reaction positive (PCR+). There was a significant relationship between spatial proximity to the initiate case and likelihood of detecting DENV from associate cases and Aedes mosquitoes. The viral detection rate from human hosts and mosquito vectors in this study was higher than previously observed by the study team in the same geographic area using different methodologies. We propose that the sampling strategy used in this study could support surveillance of DENV transmission and vector interactions.

Bhoomiboonchoo P, Nisalak A, Chansatiporn N, Yoon IK, Kalayanarooj S, Thipayamongkolgul M, Endy T, Rothman AL, Green S, Srikiatkhachorn A, Buddhari D, Mammen MP, Gibbons RV

BMC Public Health 2015;15:250

PMID: 25886528

Abstract

BACKGROUND: The effect of prior dengue virus (DENV) exposure on subsequent heterologous infection can be beneficial or detrimental depending on many factors including timing of infection. We sought to evaluate this effect by examining a large database of DENV infections captured by both active and passive surveillance encompassing a wide clinical spectrum of disease.

METHODS: We evaluated datasets from 17 years of hospital-based passive surveillance and nine years of cohort studies, including clinical and subclinical DENV infections, to assess the outcomes of sequential heterologous infections. Chi square or Fisher’s exact test was used to compare proportions of infection outcomes such as disease severity; ANOVA was used for continuous variables. Multivariate logistic regression was used to assess risk factors for infection outcomes.

RESULTS: Of 38,740 DENV infections, two or more infections were detected in 502 individuals; 14 had three infections. The mean ages at the time of the first and second detected infections were 7.6 ± 3.0 and 11.2 ± 3.0 years. The shortest time between sequential infections was 66 days. A longer time interval between sequential infections was associated with dengue hemorrhagic fever (DHF) in the second detected infection (OR 1.3, 95% CI 1.2-1.4). All possible sequential serotype pairs were observed among 201 subjects with DHF at the second detected infection, except DENV-4 followed by DENV-3. Among DENV infections detected in cohort subjects by active study surveillance and subsequent non-study hospital-based passive surveillance, hospitalization at the first detected infection increased the likelihood of hospitalization at the second detected infection.

CONCLUSIONS: Increasing time between sequential DENV infections was associated with greater severity of the second detected infection, supporting the role of heterotypic immunity in both protection and enhancement. Hospitalization was positively associated between the first and second detected infections, suggesting a possible predisposition in some individuals to more severe dengue disease.

Vejbaesya S, Thongpradit R, Kalayanarooj S, Luangtrakool K, Luangtrakool P, Gibbons RV, Srinak D, Ngammthaworn S, Apisawes K, Yoon IK, Thomas SJ, Jarman RG, Srikiakthachorn A, Green S, Chandanayingyong D, Park S, Friedman J, Rothman AL, Stephens HA

J. Infect. Dis. 2015 Sep;212(6):939-47

PMID: 25740956

Abstract

BACKGROUND: Human leukocyte antigen (HLA) supertypes are groups of functionally related alleles that present structurally similar antigens to the immune system.

OBJECTIVES: To analyze HLA class I supertype associations with clinical outcome in hospitalized Thai children with acute dengue illness.

METHODS: Seven hundred sixty-two patients and population-matched controls recruited predominantly in Bangkok were HLA-A and -B typed. HLA supertype frequencies were compared and tested for significant dengue disease associations using logistic regression analyses. Multivariable models were built by conducting forward stepwise selection procedures.

RESULTS: In the final logistic regression model, the HLA-B44 supertype was protective against dengue hemorrhagic fever (DHF) in secondary infections (odds ratio [OR] = 0.46, 95% confidence interval [CI], .30-.72), while the HLA-A02 supertype (OR = 1.92, 95% CI, 1.30-2.83) and the HLA-A01/03 supertype (OR = 3.01, 95% CI, 1.01-8.92) were associated with susceptibility to secondary dengue fever. The B07 supertype was associated with susceptibility to secondary DHF in the univariate analysis (OR = 1.60, 95% CI, 1.05-2.46), whereas that was not retained in the final model.

CONCLUSIONS: As the HLA-B44 supertype is predicted to target conserved epitopes in dengue, our results suggest that B44 supertype-restricted immune responses to highly conserved regions of the dengue proteome may protect against secondary DHF.

Medin CL, Valois S, Patkar CG, Rothman AL

J. Virol. Methods 2015 Jan;211:55-62

PMID: 25445884

Abstract

Cell culture models are used widely to study the effects of dengue virus (DENV) on host cell function. Current methods of identification of cells infected with an unmodified DENV requires fixation and permeablization of cells to allow DENV-specific antibody staining. This method does not permit imaging of viable cells over time. In this report, a plasmid-based reporter was developed to allow non-destructive identification of DENV-infected cells. The plasmid-based reporter was demonstrated to be broadly applicable to the four DENV serotypes, including low-passaged strains, and was specifically cleaved by the viral protease with minimal interference on viral production. This study reveals the potential for this novel reporter system to advance the studies of virus-host interactions during DENV infection.