Category: Publications

Yoon IK, Rothman AL, Tannitisupawong D, Srikiatkhachorn A, Jarman RG, Aldstadt J, Nisalak A, Mammen MP, Thammapalo S, Green S, Libraty DH, Gibbons RV, Getis A, Endy T, Jones JW, Koenraadt CJ, Morrison AC, Fansiri T, Pimgate C, Scott TW

J. Infect. Dis. 2012 Aug;206(3):389-98

PMID: 22615312

Abstract

BACKGROUND: The understanding of dengue virus (DENV) transmission dynamics and the clinical spectrum of infection are critical to informing surveillance and control measures. Geographic cluster studies can elucidate these features in greater detail than cohort studies alone.

METHODS: A 4-year longitudinal cohort and geographic cluster study was undertaken in rural Thailand. Cohort children underwent pre-/postseason serology and active school absence-based surveillance to detect inapparent and symptomatic dengue. Cluster investigations were triggered by cohort dengue and non-dengue febrile illnesses (positive and negative clusters, respectively).

RESULTS: The annual cohort incidence of symptomatic dengue ranged from 1.3% to 4.4%. DENV-4 predominated in the first 2 years, DENV-1 in the second 2 years. The inapparent-to-symptomatic infection ratio ranged from 1.1:1 to 2.9:1. Positive clusters had a 16.0% infection rate, negative clusters 1.1%. Of 119 infections in positive clusters, 59.7% were febrile, 20.2% were afebrile with other symptoms, and 20.2% were asymptomatic. Of 16 febrile children detected during cluster investigations who continued to attend school, 9 had detectable viremia.

CONCLUSIONS: Dengue transmission risk was high near viremic children in both high- and low-incidence years. Inapparent infections in the cohort overestimated the rate of asymptomatic infections. Ambulatory children with mild febrile viremic infections could represent an important component of dengue transmission.

Anderson KB, Gibbons RV, Thomas SJ, Rothman AL, Nisalak A, Berkelman RL, Libraty DH, Endy TP

PLoS Negl Trop Dis 2011 Oct;5(10):e1311

PMID: 21991398

Abstract

BACKGROUND: Dengue viruses (DENVs) and Japanese encephalitis virus (JEV) have significant cross-reactivity in serological assays; the clinical implications of this remain undefined. An improved understanding of whether and how JEV immunity modulates the clinical outcome of DENV infection is important as large-scale DENV vaccine trials will commence in areas where JEV is co-endemic and/or JEV immunization is routine.

METHODS AND FINDINGS: The association between preexisting JEV neutralizing antibodies (NAbs) and the clinical severity of DENV infection was evaluated in a prospective school-based cohort in Thailand that captured asymptomatic, non-hospitalized, and hospitalized DENV infections. Covariates considered included age, baseline DENV antibody status, school of attendance, epidemic year, and infecting DENV serotype. 942 children experienced at least one DENV infection between 1998 and 2002, out of 3,687 children who were enrolled for at least one full year. In crude analysis, the presence of JEV NAbs was associated with an increased occurrence of symptomatic versus asymptomatic infection (odds ratio [OR]= 1.55, 95% CI: 1.08-2.23) but not hospitalized illness or dengue hemorrhagic fever (DHF). The association was strongest in children with negative DENV serology (DENV-naive) (OR=2.75, 95% CI: 1.12-6.72), for whom the presence of JEV NAbs was also associated with a symptomatic illness of longer duration (5.4 days for JEV NAb+ versus 2.6 days for JEV NAb-, p=0.048). JEV NAbs were associated with increased DHF in younger children with multitypic DENV NAb profiles (OR=4.05, 95% CI: 1.18 to 13.87). Among those with JEV NAbs, the association with symptomatic illness did not vary by antibody titer.

INTERPRETATION: The prior existence of JEV NAbs was associated with an increased probability of symptomatic as compared to asymptomatic DENV illness. These findings are in contrast to previous studies suggesting an attenuating effect of heterologous flavivirus immunity on DENV disease severity.

Mathew A, West K, Kalayanarooj S, Gibbons RV, Srikiatkhachorn A, Green S, Libraty D, Jaiswal S, Rothman AL

J. Infect. Dis. 2011 Nov;204(10):1514-22

PMID: 21930609

Abstract

Low-avidity serotype-cross-reactive antibodies are hypothesized to play a key role in triggering severe disease in patients with secondary dengue virus (DENV) infection. However, there is little systematic information about the frequency, avidity, and cross-reactivity of DENV-specific B cells in individuals experiencing primary instead of secondary infection. We compared DENV-specific B-cell responses in a cohort of Thai children with primary or secondary DENV infection. B cells specific for DENV precursor membrane protein, envelope (E) protein, and nonstructural protein 1 were detectable in immune peripheral blood mononuclear cells with the highest frequencies of DENV E-specific B cells detected in patients experiencing primary DENV-1 infections. DENV E-specific B cells were highly serotype-specific after primary DENV infections, whereas most E-specific B cells in patients with secondary infection were serotype-cross-reactive and secreted antibodies with higher avidity to heterologous DENV serotypes. Our data suggest that the minor populations of serotype-cross-reactive B cells generated by primary DENV infection are preferentially expanded during secondary DENV infection.

Srikiatkhachorn A, Rothman AL, Gibbons RV, Sittisombut N, Malasit P, Ennis FA, Nimmannitya S, Kalayanarooj S

Clin. Infect. Dis. 2011 Sep;53(6):563-7

PMID: 21832264

Abstract

Dengue has emerged as a major public health problem worldwide. Dengue virus infection causes a wide range of clinical manifestations. Since the 1970s, clinical dengue has been classified according to the World Health Organization guideline as dengue fever and dengue hemorrhagic fever. The classification has been criticized with regard to its usefulness and its applicability. In 2009, the World Health Organization issued a new guideline that classifies clinical dengue as dengue and severe dengue. The 2009 classification differs significantly from the previous classification in both conceptual and practical levels. The impacts of the new classification on clinical practice, dengue research, and public health policy are discussed.

Friberg H, Bashyam H, Toyosaki-Maeda T, Potts JA, Greenough T, Kalayanarooj S, Gibbons RV, Nisalak A, Srikiatkhachorn A, Green S, Stephens HA, Rothman AL, Mathew A

Sci Rep 2011;1:51

PMID: 22355570

Abstract

Serotype-cross-reactive memory T cells responding to secondary dengue virus (DENV) infection are thought to contribute to disease. However, epitope-specific T cell responses have not been thoroughly compared between subjects with primary versus secondary DENV infection. We studied CD8(+) T cells specific for the HLA-A*1101-restricted NS3(133) epitope in a cohort of A11(+) DENV-infected patients throughout acute illness and convalescence. We compared the expansion, serotype-cross-reactivity, and activation of these cells in PBMC from patients experiencing primary or secondary infection and mild or severe disease by flow cytometry. Our results show expansion and activation of DENV-specific CD8(+) T cells during acute infection, which are predominantly serotype-cross-reactive regardless of DENV infection history. These data confirm marked T cell activation and serotype-cross-reactivity during the febrile phase of dengue; however, A11-NS3(133)-specific responses did not correlate with prior antigenic exposure or current disease severity.