Biomarkers of severe dengue disease – a review

John, Daisy Vanitha; Lin, Yee Shin; Perng, Guey Chuen

doi:10.1186/s12929-015-0191-6

Cited by 108 publications

(86 citation statements)

References 78 publications

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“…Indeed, most dengue cases from studies performed in other parts of the world (42) and our Indian cohort had some IFN-γ in the plasma (28). This suggests that, perhaps, these cells and/or other immune cells were making IFN-γ in vivo prior to the arrival of the patient at the clinic, but a vast majority of them may have lost the in vitro IFN-γ production capacity by the time the patient experienced clinical symptoms and presented to the clinic.…”

Section: Discussionmentioning

confidence: 90%

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

Chandele

Sewatanon

Gunisetty

et al. 2016

J Virol

100

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Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR+ CD38+ and HLA-DR− CD38+ effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLA-DR+ CD38+ subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue.IMPORTANCE Dengue is becoming a global public health concern. Although CD8 T cells have been implicated both in protection and in the cytokine-mediated immunopathology of dengue, how the balance is maintained between these opposing functions remains unknown. We comprehensively characterized CD8 T cell subsets in dengue patients from India and Thailand and show that these cells expand massively and express phenotypes indicative of overwhelming antigenic stimulus and tissue homing/cytotoxic-effector functions but that a vast majority of them fail to produce IFN-γ in vitro. Interestingly, the cells were fully capable of producing the cytokine when stimulated in a T cell receptor (TCR)-independent manner but failed to do so in TCR-dependent stimulation. These results, together with transcriptomics, revealed that the vast majority of these CD8 T cells from dengue patients become cytokine unresponsive due to TCR signaling insufficiencies. These observations open novel avenues for understanding the mechanisms that fine-tune the balance between CD8-mediated protective versus pathological effects.

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Section: Discussionmentioning

confidence: 90%

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

Chandele

Sewatanon

Gunisetty

et al. 2016

J Virol

100

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“…Activation of 'T' cells results in release of inflammatory cytokines triggering death of cells through apoptosis which contributes to severe dengue. 16 Neutrophilia was noted in 11% of cases and a normal differential in 24%. However, few studies showed a higher proportion of cases with neutrophilia.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of differential count in dengue

2018

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Background: Dengue can occur as epidemics in India. Early diagnosis reduces mortality. Differential white cell count can aid in diagnosing and prognosticating Dengue in resource limited areas. Aim and objectives of this study were to assess patterns and utility of Differential counts in Dengue.Methods: A total of 132 serologically positive Dengue cases were analysed over the month of November 2016. Hematology data obtained from analysers and Leishman smears were tabulated and analysed.Results: The study showed lymphocytosis as the predominant pattern (65%) followed by neutropenia (30%), neutrophilia (11%), eosinophilia (5%), monocytosis (5%) and basophilia (4%). Atypical lymphocytosis ≥ 15% were noted in 65% of the cases with 83% showing Plasmacytoid lymphocytes, 8% apoptotic lymphocytes and 43% showed other atypical lymphocytes. Also, 52% of lymphocytosis and 33% of neutrophilia cases showed severe thrombocytopenia (≤ 0.5 lakhs per cu mm). Lymphocytosis was noted to be an early event but was established in later stages as seen with serology pattern association, 28% associated with NS1 antigen test (non-structural protein 1) and 42% with antibody pattern. However, neutrophilia with 60% of cases seen in antibody pattern was a late event. Plasmacytoid lymphocytosis was noted uniformly through all serology patterns in contrast with other atypical lymphocytosis which was seen mostly (48%) in antibody pattern. Apoptotic lymphocytosis was also a late event associated mainly with antibody pattern (55%).Conclusions: The Differential white cell count can be a useful supplementary test along with serology in resource limited peripheral areas. It additionally serves to drastically reduce morbidity and mortality.

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“…Interestingly, preexisting antibodies acting on bone marrow progenitor cells could facilitate entry, replication, and spread of DENV by a process known as antibody-dependent enhancement have been reported [13]. Infected phagocytic cells may activate other effector mechanisms to produce vasoactive cytokines that cause endothelial cell damage resulting in transient plasma leakage in DHF [6]. Alternatively, activated phagocytic cells can produce proinflammatory cytokines by the CLEC5A-mediated signaling to induce DHF [14].…”

Section: Introductionmentioning

confidence: 99%

“…Many hypotheses have been implicated, including antibody-mediated enhancement on viral entry and replication in Fc-bearing phagocytic cells [3], individual genetic background [4], viral strain differences [5], a cascade of cytokine storm resulting from viral infection in immune cells [6], and hematological disorders [7,8]. …”

Section: Introductionmentioning

confidence: 99%

Transient Monocytosis Subjugates Low Platelet Count in Adult Dengue Patients

Tsai

Chang

et al. 2017

Biomed Hub

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Background: Dengue is one of the most important vector-borne human viral diseases globally. The kinetic changes of hematological parameters of dengue in adult Taiwanese patients have seldomly been systematically investigated and characterized. Methodology/Principal Findings: Serial laboratory data of 1,015 adult patients who were diagnosed with dengue virus serotype 2 (DENV2) and 3 (DENV3) infections in southern Taiwan were retrospectively examined. Prominent parameters were verified with specimens from a 2015 dengue outbreak. Higher absolute monocyte counts on day 5 in severe patients than mild fever subjects after the onset of fever was seen. The absolute number of monocytes was significantly greater in those with DENV2 than DENV3 infections in spite of subtle differences in laboratory tests. Platelet counts were lowest and activated partial thromboplastin time was highest on day 5 in patients with severe conditions. In addition, sudden downward platelet counts corresponding to a transient surge of monocytes on day 4 onward was observed. Fluorescence-activated cell sorting analysis of peripheral blood mononuclear cells obtained from acute dengue patients and experimental investigations revealed that phagocytic effects of innate immune cells contribute to thrombocytopenia in dengue patients. Conclusion: Innate phagocytic cells play an essential role in low platelet counts in adult patients with dengue virus infections.

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Biomarkers of severe dengue disease – a review

Cited by 108 publications

References 78 publications

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

Dynamics of differential count in dengue

Transient Monocytosis Subjugates Low Platelet Count in Adult Dengue Patients

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