Introduction1
Dengue fever (also known as “breakbone fever”) is a major health problem of the tropics and subtropics (particularly the Caribbean and Southeast Asia), requiring an estimated 500,000 hospitalizations a year. As many as 390 million people are infected a year, with 40,000 deaths.
It is a mosquito-borne viral disease caused by 1 of 4 closely related but antigenically distinct serotypes of dengue virus, serotypes DENV-1 through DEN-4 belonging to the family Flaviviridae. They are all enveloped viruses. Infection with one dengue serotype confers lifelong homotypic immunity and a brief period of partial heterotypic immunity (2 years), but each individual can eventually be infected by all 4 serotypes.
The viruses are transmitted by the bite of an infected female Aedes (subgenus Stegomyia) mosquito. Whilst both males and females require nectar for energy, females require a blood meal as a source of appropriate protein for egg development. Aedesaegypti is the predominant highly efficient mosquito vector for dengue infection, but the Asian tiger viral receptors e.g mosquito, Aedesalbopictus, and other Aedes species can also transmit dengue with varying degrees of efficiency.
They bite in the daytime and may transmit the infection from one infected human to another .The viraemia lasts about five days. After an uninfected female mosquito ingests the blood, the virus replicates during an extrinsic incubation period of eight to twelve days. The mosquito remains infected for its lifespan of 21 days on average but may range from 15-65 days.
Clinical Presentation
Infection by any one of the four serotypes of dengue virus (DENV) remains asymptomatic in the vast majority. Clinical spectrum among symptomatic infection ranges from undifferentiated fever (viral syndrome), dengue fever (DF), and dengue haemorrhagic fever (DHF) to the expanded dengue syndrome with isolated organopathy (unusual manifestations). DF can be without haemorrhage or have unusual haemorrhage, while DHF can be without shock or with shock (dengue shock syndrome).
The WHO criteria for the clinical diagnosis of DHF requires the presence of acute and continuous fever of 2 to 7 days, haemorrhagic manifestations associated with thrombocytopenia (100,000 cells/c.mm or less) and haemo concentration (haematocrit>20% from baseline of patient or population of same age). Haemorrhagic manifestations could be mucosal and / or skin or even a positive tourniquet test which is the commonest. Hepatomegaly occurs at some stage of DHF and often precedes plasma leakage and hence a valuable early predictor of plasma leakage2.
Pathogenesis of Fever
After the virus enters from a mosquito bite, four processes are set in motion.
(1) Fusion- (a) fuses with membrane proteins ( C-type lectins called C-SIGN , mannose receptor and CEC5A) on the host cell (dendritic cells e.g. Langerhan cells and
(b) binding to viral receptors e.g. heparin sulphate for which its envelope is essential.
The dendritic cell then moves to the nearest lymph node.
(2) Disassembly- breakdown and release of single RNA strands
(3) Replication – multiplication in the endoplasmic reticulum
(4) Viral assembly – restructuring of virus
(5) Release into bloodstream and viraemia
To infect a cell, the virus binds to the cell membrane which engulfs the virus, enveloping it in a pouch-like structure known as an endosome. To begin the infection process, the virus delivers its hereditary material into the cytosol, the fluid interior of the cell, where it begins reproducing itself. To do so, however, it must first release itself from the endosome. The virus does this by fusing its membrane with the endosomal membrane. When the two membranes come together, they form a pore through which the virus’ genetic material is released3.
The white blood cells attack the virus and respond by producing signaling proteins (cytokines and interferon) which are responsible for production of fever and muscle pains.
Severe viraemia also results in many organs being affected, including the liver and bone marrow. As a result, liver function and haemopoiesis are affected. Liver enzymes like transaminases are raised (transaminitis) and platelet production is reduced.
Pathogenesis of bleeding and hypovolaemic shock
Plasma leakage and intrinsic coagulopathy are the pathological hallmarks in dengue haemorrhagic fever (DHF). Viral virulence, infection enhancing antibodies, cytokines and chemical mediators in the setting of intense immune activation are the key players implicated in the pathogenesis of DHF4.
Plasma leakage is specific to the pleural and peritoneal surfaces. In DHF there is no vasculitis and hence no injury to the vessel walls, and plasma leakage results from cytokine mediated increase in vascular permeability. The ensuing movement of albumin and the resultant reduction of intravascular oncotic pressure facilitate further loss of fluid from the intravascular compartment. The basic Starling principle still holds true in explaining microvascular ultrafiltration based on the balance of the oncotic and hydrostatic pressures. However , the glycocalyx, which is a gelatinous layer lining the vascular endothelium is also implicated in controlling fluid movement by the adherence of albumin molecules in to its matrix, damage of which, leads to loss of albumin into the extravascular compartment..
Because DHF is more likely to develop with secondary dengue infection, it is thought that immune system is responsible. The innate immune mechanisms comprising the complement pathway and NK cells as well as humoral and cell-mediated immune mechanisms launched in response to antigenic stimulation a thought to be involved in the clinical manifestations. Complement activation as well as vascular permeability may be influenced by viral products like NS1. Different immune mechanisms in the form of antibody enhanced viral replication leading to an exaggerated cytokine response impacts vascular permeability 5-7
This results in a fall in circulating blood volume and blood pressure. Impaired perfusion of organs lead to dysfunction and failure.
References
- Medscape
- WHO, Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever, 2011.
- NIH News Release (2010 ) . NIH scientists discover how dengue virus infects cells
- Kolitha H. Sellahew( 2013) . Pathogenesis of Dengue Haemorrhagic Fever and Its Impact on Case Management.Review Article | Open AccessVolume 2013 |Article ID 571646 | 6 pages | https://doi.org/10.5402/2013/571646
- Avirutnan P,.Punyadee N, .Noisakran Set al. (2006) Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. Journal of Infectious Diseases, 193 ( 8) pp. 1078–1088
- Avirutnan P, Fuchs A, HauhartR E et al ( 2010) . Antagonism of the complement component C4 by flavivirus nonstructural protein NS1, The Journal of Experimental Medicine 207 (4) 793–806
- Avirutnan P , Zhang L ,Punyadee N et al.(2007) .Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E,” PLoS Pathogens, 3 ( 11) article e183,
Hla Yee Yee MBBS(Rgn);MSc(Mdy);PhD(Lond); FRCP(Edin)(hon); Cert in Leadership for Physician Educators (Harvard Business School)
