Summary: Much remains to be learned about the pathogenesis of the different manifestations of dengue virus (DENV) infections in humans. They may range from subclinical infection to dengue fever, dengue hemorrhagic fever (DHF), and eventually dengue shock syndrome (DSS). As both cell tropism and tissue tropism of DENV are considered major determinants in the pathogenesis of dengue, there is a critical need for adequate tropism assays, animal models, and human autopsy data. More than 50 years of research on dengue has resulted in a host of literature, which strongly suggests that the pathogenesis of DHF and DSS involves viral virulence factors and detrimental host responses, collectively resulting in abnormal hemostasis and increased vascular permeability. Differential targeting of specific vascular beds is likely to trigger the localized vascular hyperpermeability underlying DSS. A personalized approach to the study of pathogenesis will elucidate the basis of individual risk for development of DHF and DSS as well as identify the genetic and environmental bases for differences in risk for development of severe disease.

Dengue Virus Pathogenesis: an Integrated View

Dengue viral infections are one of the most important mosquito borne diseases in the world. They may be asymptomatic or may give rise to undifferentiated fever, dengue fever, dengue haemorrhagic fever (DHF), or dengue shock syndrome. Annually, 100 million cases of dengue fever and half a million cases of DHF occur worldwide. Ninety percent of DHF subjects are children less than 15 years of age. At present, dengue is endemic in 112 countries in the world. No vaccine is available for preventing this disease. Early recognition and prompt initiation of appropriate treatment are vital if disease related morbidity and mortality are to be limited. This review outlines aspects of the epidemiology of dengue infections, the dengue virus and its mosquito vector, clinical features and pathogenesis of dengue infections, and the management and control of these infections.

https://pmj.bmj.com/content/postgradmedj/80/948/588.full.pdf

Dengue viral infections

Dengue is the most important arthropod-borne viral disease of public health significance. Compared with nine reporting countries in the 1950s, today the geographic distribution includes more than 100 countries worldwide. Many of these had not reported dengue for 20 or more years and several have no known history of the disease. The World Health Organization estimates that more than 2.5 billion people are at risk of dengue infection. First recognised in the 1950s, it has become a leading cause of child mortality in several Asian and South American countries.This paper reviews the changing epidemiology of the disease, focusing on host and societal factors and drawing on national and regional journals as well as international publications. It does not include vaccine and vector issues. We have selected areas where the literature raises challenges to prevailing views and those that are key for improved service delivery in poor countries.Shifts in modal age, rural spread, and social and biological determinants of race- and sex-related susceptibility have major implications for health services. Behavioural risk factors, individual determinants of outcome and leading indicators of severe illness are poorly understood, compromising effectiveness of control programmes. Early detection and case management practices were noted as a critical factor for survival. Inadequacy of sound statistical methods compromised conclusions on case fatality or disease-specific mortality rates, especially since the data were often based on hospitalised patients who actively sought care in tertiary centres.Well-targeted operational research, such as population-based epidemiological studies with clear operational objectives, is urgently needed to make progress in control and prevention.

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Dengue fever: new paradigms for a changing epidemiology.

Dengue hemorrhagic fever (DHF), the most severe form of illness following infection with a dengue virus, is characterized by plasma leakage, thrombocytopenia, and hepatic inflammation. The interrelationships among virus burden, immune activation, and development of DHF were examined in 54 children with secondary dengue-3 virus infections participating in a prospective, hospital-based study. DHF was associated with higher mean plasma viremia early in illness and earlier peak plasma interferon-γ levels. Maximum plasma viremia levels correlated with the degree of plasma leakage and thrombocytopenia. Maximum plasma levels of interleukin (IL)-10 and soluble tumor necrosis factor receptor-II correlated with the degree of thrombocytopenia, independently of viremia levels. Hepatic transaminase elevation correlated with plasma soluble IL-2 receptor levels and not with viremia levels. Quantitative differences in virus burden and host immune responses, and the timing of type 1 cytokine responses, have differing influences on the severity of disease manifestations during secondary dengue-3 virus infections.

Differing Influences of Virus Burden and Immune Activation on Disease Severity in Secondary Dengue-3 Virus Infections

Dengue virus (DENV) is a pathogen with a high impact on human health. It replicates in a wide range of cells involved in the immune response. To efficiently infect humans, DENV must evade or inhibit fundamental elements of the innate immune system, namely the type I interferon response. DENV circumvents the host immune response by expressing proteins that antagonize the cellular innate immunity. We have recently documented the inhibition of type I IFN production by the proteolytic activity of DENV NS2B3 protease complex in human monocyte derived dendritic cells (MDDCs). In the present report we identify the human adaptor molecule STING as a target of the NS2B3 protease complex. We characterize the mechanism of inhibition of type I IFN production in primary human MDDCs by this viral factor. Using different human and mouse primary cells lacking STING, we show enhanced DENV replication. Conversely, mutated versions of STING that cannot be cleaved by the DENV NS2B3 protease induced higher levels of type I IFN after infection with DENV. Additionally, we show that DENV NS2B3 is not able to degrade the mouse version of STING, a phenomenon that severely restricts the replication of DENV in mouse cells, suggesting that STING plays a key role in the inhibition of DENV infection and spread in mice.

/pdf/denv-inhibits-type-i-ifn-production-in-infected-cells-by-33vnqok4hs.pdf

DENV inhibits type I IFN production in infected cells by cleaving human STING.

Dengue virus causes dengue fever, a mild febrile illness, and at times dengue hemorrhagic fever (DHF), a severe illness the pathogenesis of which is not fully understood. Given the crucial roles played by interleukin-8 (IL-8) as a chemoattractant cytokine and in inflammatory processes, levels of circulating IL-8 in the sera and IL-8 mRNA in the peripheral blood mononuclear cells (PBMC) were measured in 99 patients of a recent dengue epidemic that occurred in India in 1996 and in 21 normal healthy controls. Twenty-six of the patients had dengue fever (DF) and the remaining 73 were diagnosed as having different grades of DHF. All the control normal sera were negative for IL-8, so were their PBMC for IL-8 mRNA. Increased levels of IL-8 in the sera and IL-8 mRNA in their PBMC were observed in patients with severe illness of DHF grades III and IV. Only two out of 26 patients of DF and one out of 10 DHF grade I patient were positive for IL-8 and all three deteriorated to DHF grade IV within 24 hr. All six patients of DHF grade IV who died had higher serum level of IL-8 above 200 pg/ml, the highest being 5,568 pg/ml in one patient; the presence of mRNA for IL-8 was very high in all patients. A striking correlation was observed between increased levels of IL-8 and severe DHF, with greater levels in patients with increased grade of the disease and death. These results suggest that IL-8 may have an important role and may be an indicator of increasing severity of the disease and death.

Elevated levels of IL-8 in dengue hemorrhagic fever

This paper describes the clinical findings in 206 patients with dengue fever (DF) or with dengue hemorrhagic fever (DHF) during the epidemic of 1996 at Lucknow. The age group affected most was 11 to 30 years and 21% of the patients were less than 10 years old. The male:female ratio was 1.9:1. The onset was abrupt in all the patients, severe frontal headache was observed in 97%, myalgia in 90%, skin rash in 40%, vomiting in 29% and arthralgia in knee and hip joints in 9%. Anuria was seen in two patients. Lymphadenopathy was noted in 14%, hepatomegaly in 4%, being associated with mild jaundice in one patient, and splenomegaly in 2% of the patients. Involvement of the heart and lungs was seen in one patient each and no case with encephalitis was recorded. Hemorrhages from various sites were observed in 54% patients and 17 patients had profound shock. The commonest bleeding site was gums. Profound shock was preceded by various warning signs, the commonest being sudden hypotension. Among the patients with profound shock the mortality was 47% while the overall fatality rate was 3.8%. A number of the risk factors existed for a long time in this part of the world, but what precipitated the present epidemic at this time, is not known.

A clinical study of the patients with dengue hemorrhagic fever during the epidemic of 1996 at Lucknow, India

Shift from a th1-type response to th2-type in dengue haemorrhagic fever

A unique cytokine, human cytotoxic factor (hCF), has been shown to occur in the sera of patients with dengue fever (DF) and dengue haemorrhagic fever (DHF). The present study was undertaken to investigate the ability of fresh PBMC of such patients to produce hCF. The PBMC were cultured for 24 h and the culture supernatants (CS) were analysed for the presence of hCF by cytotoxicity assay, competitive ELISA and dot blot tests. In 90% of 246 cases CS were positive for hCF by the three tests. CS were positive for hCF in PBMC collected from days 1-20 of illness but not at later periods. Higher cytotoxic activity was observed in CS of days 1-4 of illness and was highest in cases of DHF grade IV and lowest in cases of DF. Dot blot hybridization of RNA extracted from the PBMC of the patients showed the presence of mRNA for hCF in 94% of cases. A similar number of patients showed the presence of hCF in situ in the PBMC smears by fluorescent antibody technique. hCF was found only in CD4 + T cells. The findings thus present direct evidence of the production of hCF by CD4 T cells of cases of DF/DHF.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2249.1998.00598.x

S. Kapoor

Papers

Elevated levels of IL-8 in dengue hemorrhagic fever

A clinical study of the patients with dengue hemorrhagic fever during the epidemic of 1996 at Lucknow, India

Shift from a th1-type response to th2-type in dengue haemorrhagic fever

Production of cytotoxic factor by peripheral blood mononuclear cells (PBMC) in patients with dengue haemorrhagic fever.

Cd4 positive t-cells produce cytotoxic factor in cases of dengue haemorrhagic fever