Chymase Level Is a Predictive Biomarker of Dengue Hemorrhagic Fever in Pediatric and Adult Patients

Tissera, Hasitha; Rathore, Abhay P. S.; Leong, Wei Yee; Pike, Brian L.; Warkentien, Tyler; Farouk, Farouk S; Syenina, Ayesa; Ooi, Eng Eong; Gubler, Duane J.; Wilder‐Smith, Annelies; John, Ashley L. St.

doi:10.1093/infdis/jix447

Cited by 53 publications

(71 citation statements)

References 37 publications

(46 reference statements)

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“…To the best of our knowledge, this study analyzed DENV infection data from the largest number of countries, and identified a prognostic gene signature that is robust to biological and technical heterogeneity observed in a real-world patient population. In contrast, it remains to be determined whether other predictive markers of severe dengue, such as chymase level ( Tissera et al., 2017 ) and IgG antibody subtype ( Wang et al., 2017 ) or level ( Katzelnick et al., 2017 ), work in such heterogeneous patient populations.…”

Section: Discussionmentioning

confidence: 99%

A 20-Gene Set Predictive of Progression to Severe Dengue

et al. 2019

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Graphical AbstractHighlights d A multi-cohort analysis framework revealed a 20-gene set to predict severe dengue d The 20 genes effectively predict severe dengue in existing and prospective cohorts d The 20-gene set is generalizable across ages, host genetic factors, and virus strains d The 20-gene set has potential implications for the development of a prognostic assay SUMMARY There is a need to identify biomarkers predictive of severe dengue. Single-cohort transcriptomics has not yielded generalizable results or parsimonious, predictive gene sets. We analyzed blood samples of dengue patients from seven gene expression datasets (446 samples, five countries) using an integrated multi-cohort analysis framework and identified a 20-gene set that predicts progression to severe dengue. We validated the predictive power of this 20-gene set in three retrospective dengue datasets (84 samples, three countries) and a prospective Colombia cohort (34 patients), with an area under the receiver operating characteristic curve of 0.89, 100% sensitivity, and 76% specificity. The 20-gene dengue severity scores declined during the disease course, suggesting an infection-triggered host response. This 20-gene set is strongly associated with the progression to severe dengue and represents a predictive signature, generalizable across ages, host genetic factors, and virus strains, with potential implications for the development of a host response-based dengue prognostic assay.

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Section: Discussionmentioning

confidence: 99%

A 20-Gene Set Predictive of Progression to Severe Dengue

et al. 2019

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“…Mast cells are shown to be permissive to infection by the DENV, which is enhanced in the presence of DENV-specific antibodies Syenina et al, 2015). Many proteases and inflammatory mediators produced by mast cells such as chymases, tryptases, platelet activating factor (PAF) and vascular endothelial growth factor (VEGF) have been implicated in vascular leak and disease pathogenesis (Furuta et al, 2012;Jeewandara et al, 2015;Kamaladasa et al, 2016;Tissera et al, 2017;Inokuchi et al, 2018;Malavige et al, 2018). As mast cells reside in tissues and around blood vessels, it has been difficult to determine their infectivity rates by the DENV and phenotypic changes .…”

Section: Mast Cells In Denguementioning

confidence: 99%

Dysfunctional Innate Immune Responses and Severe Dengue

Malavige

Jeewandara

Ogg

2020

Front. Cell. Infect. Microbiol.

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Although infection with the dengue virus (DENV) causes severe dengue, it causes a mild self-limiting illness in the majority of individuals. There is emerging evidence that an aberrant immune response in the initial stages of infection lead to severe disease. Many inflammatory cytokines, chemokines, and lipid mediators are significantly higher in patients with severe dengue compared to those who develop mild infection, during febrile phase of illness. Monocytes, mast cells, and many other cells of the immune system, when infected with the DENV, especially in the presence of poorly neutralizing antibodies, leads to production of pro-inflammatory cytokines and inhibition of interferon signaling pathways. In addition, production of immunosuppressive cytokines such as IL-10 further leads to inhibition of cellular antiviral responses. This dysregulated and aberrant immune response leads to reduced clearance of the virus, and severe dengue by inducing a vascular leak and excessive inflammation due to high levels of inflammatory cytokines. Individuals with comorbid illnesses could be prone to more severe dengue due to low grade endotoxemia, gut microbial dysbiosis and an altered phenotype of innate immune cells. The immunosuppressive and inflammatory lipid mediators and altered phenotype of monocytes are likely to further act on T cells and B cells leading to an impaired adaptive immune response to the virus. Therefore, in order to identify therapeutic targets for treatment of dengue, it would be important to further characterize these mechanisms in order for early intervention. In this review, we discuss the differences in the innate immune responses in those who progress to develop severe dengue, compared to those with milder disease in order to understand the mechanisms that lead to severe dengue.

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“…Several mast cell-derived mediators, such as tryptase, chymase and VEGF contribute to dengue disease severity [ 82 ]. Serum chymase levels could be a predictive biomarker of DHF in pediatric and adult patients [ 106 ]. DENV-infected mice show activated degranulated tissue mast cells.…”

Section: Introductionmentioning

confidence: 99%

The monocyte-macrophage-mast cell axis in dengue pathogenesis

et al. 2018

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Dengue virus, the causative agent of dengue disease which may have hemorrhagic complications, poses a global health threat. Among the numerous target cells for dengue virus in humans are monocytes, macrophages and mast cells which are important regulators of vascular integrity and which undergo dramatic cellular responses after infection by dengue virus. The strategic locations of these three cell types, inside blood vessels (monocytes) or outside blood vessels (macrophages and mast cells) allow them to respond to dengue virus infection with the production of both intracellular and secretory factors which affect virus replication, vascular permeability and/or leukocyte extravasation. Moreover, the expression of Fc receptors on the surface of monocytes, macrophages and mast cells makes them important target cells for antibody-enhanced dengue virus infection which is a major risk factor for severe dengue disease, involving hemorrhage. Collectively, these features of monocytes, macrophages and mast cells contribute to both beneficial and harmful responses of importance to understanding and controlling dengue infection and disease.

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Chymase Level Is a Predictive Biomarker of Dengue Hemorrhagic Fever in Pediatric and Adult Patients

Abstract: Patients with acute dengue who present with high serum chymase levels are at greater risk of dengue hemorrhagic fever or dengue shock syndrome. The chymase level is a prognostic biomarker of severe dengue for adult and pediatric patients before they develop clinical warning signs.

Cited by 53 publications

References 37 publications

A 20-Gene Set Predictive of Progression to Severe Dengue

A 20-Gene Set Predictive of Progression to Severe Dengue

Dysfunctional Innate Immune Responses and Severe Dengue

The monocyte-macrophage-mast cell axis in dengue pathogenesis

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