Category: Publications

Moulton SL, Mulligan J, Srikiatkhachorn A, Kalayanarooj S, Grudic GZ, Green S, Gibbons RV, Muniz GW, Hinojosa-Laborde C, Rothman AL, Thomas SJ, Convertino VA

J Med Case Rep 2016 Aug;10(1):233

PMID: 27553703

Abstract

BACKGROUND: Early recognition and treatment of circulatory volume loss is essential in the clinical management of dengue viral infection. We hypothesized that a novel computational algorithm, originally developed for noninvasive monitoring of blood loss in combat casualties, could: (1) indicate the central volume status of children with dengue during the early stages of “shock”; and (2) track fluid resuscitation status.

METHODS: Continuous noninvasive photoplethysmographic waveforms were collected over a 5-month period from three children of Thai ethnicity with clinical suspicion of dengue. Waveform data were processed by the algorithm to calculate each child’s Compensatory Reserve Index, where 1 represents supine normovolemia and 0 represents the circulatory volume at which hemodynamic decompensation occurs. Values between 1 and 0 indicate the proportion of reserve remaining before hemodynamic decompensation.

RESULTS: This case report describes a 7-year-old Thai boy, another 7-year-old Thai boy, and a 9-year-old Thai boy who exhibited signs and symptoms of dengue shock syndrome; all the children had secondary dengue virus infections, documented by serology and reverse transcriptase polymerase chain reaction. The three boys experienced substantial plasma leakage demonstrated by pleural effusion index >25, ascites, and >20 % hemoconcentration. They received fluid administered intravenously; one received a blood transfusion. All three boys showed a significantly low initial Compensatory Reserve Index (≥0.20), indicating a clinical diagnosis of “near shock”. Following 5 days with fluid resuscitation treatment, their Compensatory Reserve Index increased towards “normovolemia” (that is, Compensatory Reserve Index >0.75).

CONCLUSIONS: The results from these cases demonstrate a new variation in the diagnostic capability to manage patients with dengue shock syndrome. The findings shed new light on a method that can avoid possible adverse effects of shock by noninvasive measurement of a patient’s compensatory reserve rather than standard vital signs or invasive diagnostic methods.

Woda M, Friberg H, Currier JR, Srikiatkhachorn A, Macareo LR, Green S, Jarman RG, Rothman AL, Mathew A

J. Infect. Dis. 2016 Oct;214(7):1001-9

PMID: 27443614

Abstract

BACKGROUND: The development of reagents to identify and characterize antigen-specific B cells has been challenging.

METHODS: We recently developed Alexa Fluor-labeled dengue viruses (AF DENVs) to characterize antigen-specific B cells in the peripheral blood of DENV-immune individuals.

RESULTS: In this study, we used AF DENV serotype 1 (AF DENV-1) together with AF DENV-2 on peripheral blood mononuclear cells (PBMCs) from children in Thailand with acute primary or secondary DENV-1 infections to analyze the phenotypes of antigen-specific B cells that reflected their exposure or clinical diagnosis. DENV serotype-specific and cross-reactive B cells were identified in PBMCs from all subjects. Frequencies of AF DENV(+) class-switched memory B cells (IgD(-)CD27(+) CD19(+) cells) reached up to 8% during acute infection and early convalescence. AF DENV-labeled B cells expressed high levels of CD27 and CD38 during acute infection, characteristic of plasmablasts, and transitioned into memory B cells (CD38(-)CD27(+)) at the early convalescent time point. There was higher activation of memory B cells early during acute secondary infection, suggesting reactivation from a previous DENV infection.

CONCLUSIONS: AF DENVs reveal changes in the phenotype of DENV serotype-specific and cross-reactive B cells during and after natural DENV infection and could be useful in analysis of the response to DENV vaccination.

Clapham HE, Rodriguez-Barraquer I, Azman AS, Althouse BM, Salje H, Gibbons RV, Rothman AL, Jarman RG, Nisalak A, Thaisomboonsuk B, Kalayanarooj S, Nimmannitya S, Vaughn DW, Green S, Yoon IK, Cummings DA

J. Infect. Dis. 2016 May;213(9):1428-35

PMID: 26704615

Abstract

The immune response to dengue virus (DENV) infection is complex and not fully understood. Using longitudinal data from 181 children with dengue in Thailand who were followed for up to 3 years, we describe neutralizing antibody kinetics following symptomatic DENV infection. We observed that antibody titers varied by serotype, homotypic vs heterotypic responses, and primary versus postprimary infections. The rates of change in antibody titers over time varied between primary and postprimary responses. For primary infections, titers increased from convalescence to 6 months. By comparing homotypic and heterotypic antibody titers, we saw an increase in type specificity from convalescence to 6 months for primary DENV3 infections but not primary DENV1 infections. In postprimary cases, there was a decrease in titers from convalescence up until 6 months after infection. Beginning 1 year after both primary and postprimary infections, there was evidence of increasing antibody titers, with greater increases in children with lower titers, suggesting that antibody titers were boosted due to infection and that higher levels of neutralizing antibody may be more likely to confer a sterilizing immune response. These findings may help to model virus transmission dynamics and provide baseline data to support the development of vaccines and therapeutics.

Nisalak A, Clapham HE, Kalayanarooj S, Klungthong C, Thaisomboonsuk B, Fernandez S, Reiser J, Srikiatkhachorn A, Macareo LR, Lessler JT, Cummings DA, Yoon IK

Am. J. Trop. Med. Hyg. 2016 06;94(6):1342-7

PMID: 27022151

Abstract

Long-term observational studies can provide valuable insights into overall dengue epidemiology. Here, we present analysis of dengue cases at a pediatric hospital in Bangkok, Thailand, during a 40-year period from 1973 to 2012. Data were analyzed from 25,715 hospitalized patients with laboratory-confirmed dengue virus (DENV) infection. Several long-term trends in dengue disease were identified including an increase in mean age of hospitalized cases from an average of 7-8 years, an increase after 1990 in the proportion of post-primary cases for DENV-1 and DENV-3, and a decrease in the proportion of dengue hemorrhagic fever and dengue shock syndrome cases in primary and post-primary cases over time. Exploratory mechanistic analysis of these observed trends considered changes in diagnostic methods, demography, force of infection, and Japanese encephalitis vaccination as possible explanations. Thailand is an important setting for studying DENV transmission as it has a “mature” dengue epidemiology with a strong surveillance system in place since the early 1970s. We characterized changes in dengue epidemiology over four decades, and possible impact of demographic and other changes in the human population. These results may inform other countries where similar changes in transmission and population demographics may now or may soon be occurring.

Townsley E, O’Connor G, Cosgrove C, Woda M, Co M, Thomas SJ, Kalayanarooj S, Yoon IK, Nisalak A, Srikiatkhachorn A, Green S, Stephens HA, Gostick E, Price DA, Carrington M, Alter G, McVicar DW, Rothman AL, Mathew A

Clin. Exp. Immunol. 2016 Mar;183(3):419-30

PMID: 26439909

Abstract

Killer immunoglobulin-like receptors (KIRs) interact with human leucocyte antigen (HLA) class I ligands and play a key role in the regulation and activation of NK cells. The functional importance of KIR-HLA interactions has been demonstrated for a number of chronic viral infections, but to date only a few studies have been performed in the context of acute self-limited viral infections. During our investigation of CD8(+) T cell responses to a conserved HLA-B57-restricted epitope derived from dengue virus (DENV) non-structural protein-1 (NS1), we observed substantial binding of the tetrameric complex to non-T/non-B lymphocytes in peripheral blood mononuclear cells (PBMC) from a long-standing clinical cohort in Thailand. We confirmed binding of the NS1 tetramer to CD56(dim) NK cells, which are known to express KIRs. Using depletion studies and KIR-transfected cell lines, we demonstrated further that the NS1 tetramer bound the inhibitory receptor KIR3DL1. Phenotypical analysis of PBMC from HLA-B57(+) subjects with acute DENV infection revealed marked activation of NS1 tetramer-binding natural killer (NK) cells around the time of defervescence in subjects with severe dengue disease. Collectively, our findings indicate that subsets of NK cells are activated relatively late in the course of acute DENV illness and reveal a possible role for specific KIR-HLA interactions in the modulation of disease outcomes.