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Hindawi Publishing CorporationISRN Infectious DiseasesVolume 2013, Article ID 571646, 6 pageshttp://dx.doi.org/10.5402/2013/571646
Review ArticlePathogenesis of Dengue Haemorrhagic Fever and Its Impact onCaseManagement
Kolitha H. Sellahewa
Department of Medicine, Melaka Manipal Medical College, Jalan Batu Hampar, Bukit Baru, 75150 Melaka, Malaysia
Correspondence should be addressed to Kolitha H. Sellahewa; firstname.lastname@example.org
Received 5 September 2012; Accepted 30 September 2012
Academic Editors: R. Bologna, R. Favory, and K. Sawanyawisuth
Copyright 2013 Kolitha H. Sellahewa. is is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Plasma leakage and intrinsic coagulopathy are the pathological hall marks in dengue haemorrhagic fever (DHF). Viral virulence,infection enhancing antibodies, cytokines and chemical mediators in the setting of intense immune activation are the key playersimplicated in the pathogenesis of DHF; the exact nature of which is yet to be fully understood.e pathophysiological changes theattended clinical features of plasma leakage necessitate recognition of changing physiological parameters for the early recognitionof plasma leakage and appropriate uid therapy. On the other hand, the changes in the haematological indices resulting fromcoagulopathy can tempt the clinician to initiate other modalities of therapy. A clearer understanding of the pathogenesis ofDHF and the appreciation that both of these fundamental pathological changes share common pathogenic mechanisms wouldfacilitate the appropriateness of management decisions and the early recognition of severe disease. us, thrombocytopaenia,reduced brinogen, and prolonged partial thromboplastin time early in the disease course connoted severe disease and attendedplasma leakage rather than clinical bleeding. e detection of plasma cytokine prole by a multiple bead immunoassay could alsocomplement clinical parameters in predicting severe disease early in the disease course. us, MIP- indicates good prognosiswhile IFN- portends severe disease.
Infection by any one of the four serotypes of dengue virus(DENV) remains asymptomatic in the vast majority. Clinicalspectrum among symptomatic infection ranges from undif-ferentiated fever (viral syndrome), dengue fever (DF), anddengue haemorrhagic fever (DHF) to the expanded denguesyndrome with isolated organopathy (unusual manifesta-tions). DF can be without haemorrhage or have unusualhaemorrhage,whileDHF can bewithout shock orwith shock,that is, dengue shock syndrome .
e WHO criteria for the clinical diagnosis of DHFrequires the presence of acute and continuous fever of2 to 7 days, haemorrhagic manifestations associated withthrombocytopenia (100,000 cells/c.mm or less) and haemo-concentration (haematocrit >20% from baseline of patientor population of same age). Haemorrhagic manifestationscould be mucosal and or skin or even a positive tourniquettest which is the commonest. Hepatomegaly occurs at some
stage of DHF and oen precedes plasma leakage and hence avaluable early predictor of plasma leakage .
DHF is most commonly seen in children with secondarydengue infection but has been documented in primaryinfection with DENV-1 and DENV-3, as well as in infants.ese infants had acquired maternal dengue antibody andsubsequently experienced a dengue infection . Greaterbaseline vascular permeability among children could also bea contributor for more severe disease among children thanamong adults . Epidemiological and serological studiesdone both in ailand and Cuba support the importance ofsecondary dengue infections as a risk factor for DHF. Sincethe rst observations by Halstead et al. in 170, DHF hasbeen present in situations where more than one serotypecirculates [4, 5]. e disease burden and a resurgence ofrecurrent epidemics of DHF are attributable to social dynam-ics and a variety of epidemiological factors such as a highvector density, a high virus circulation, and a population atrisk of secondary infection by virtue of previous exposure
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. Besides secondary infection, chronic diseases such asbronchial asthma and diabetes have been suggested as riskfactors for DHF. Also, whites have higher risk of developingDHF than blacks. DENV-2 virus is known to replicate tohigher concentration in the peripheral blood cells of whitescompared with those of blacks .
Abnormal haemostasis and plasma leakage are the mainpathophysiological hall marks in DHF. Even though morethan half a century has elapsed since plasma leakage was rstidentied its precise mechanism remains elusive. e mainfactor implicated in the development of DHF rather thanthe relatively innocuous DF in dengue infection is secondarydengue infection but other factors like viral virulence andhost characteristics are also important. Severe disease isthe result of a complex interaction between the virus andthe immune response evoked by the host with secondaryinfection .
2. Plasma Leakage in DHF
2.1. Pathophysiology. Plasma leakage is specic to the pleuraland peritoneal surfaces. In DHF there is no vasculitis andhence no injury to the vessel walls, and plasma leakage resultsfrom cytokine mediated increase in vascular permeability.e ensuing movement of albumin and the resultant reduc-tion of intravascular oncotic pressure facilitate further loss ofuid from the intravascular compartment. e basic Starlingprinciple still holds true in explaining microvascular ultral-tration based on the balance of the oncotic and hydrostaticpressures. However the glycocalyx, which is a gelatinouslayer lining the vascular endothelium is also implicated incontrolling uid movement by the adherence of albuminmolecules in to its matrix, damage of which, leads to loss ofalbumin into the extravascular compartment .
2.2. Immunopathogenesis. e immune system is implicatedin the pathogenesis ofDHFowing to the increased propensityto develop DHF with secondary dengue infection.e innateimmune mechanisms comprising the complement pathwayand NK cells as well as humoral and cell-mediated immunemechanisms launched in response to antigenic stimulationare involved in the clinical manifestations. Complementactivation as well as vascular permeability may be inuencedby viral products like NS1. Different immune mechanisms inthe form of antibody enhanced viral replication leading to anexaggerated cytokine response impacts vascular permeability.
Infection with one dengue serotype elicits immunity tothat serotype but does not provide long-term cross-protectiveimmunity to the remaining serotypes. Subsequent infectionwith a different serotype results in the binding of the newvirus to cross reactive nonneutralising antibody from theprevious infection facilitating the uptake by mononuclearphagocytes enabling amplied viral replication.e resultingincrease in viral load then drives an immunopathogeniccascade and the resultant exaggerated cytokine response leadsto a transient increase in microvascularpermeability. eprecise way in which microvascular permeability is alteredis not clear but is more likely to be a functional change
rather than structural damage, as dengue shock is rapidlyrecoverable, and no inammation is evident in the leakingsurfaces . Adding to the complexity of the under-lying immunopathogenic mechanisms resulting in changesin vascular permeability is the proposal of an alternativemechanismwhereby the rapidmobilisation of serotype cross-reactivememory T cells trigger the release of biologicalmedi-ators. Some of the other factors implicated in this orchestra-tion include viral virulence, molecularmimicry, and immunecomplex and/or complement mediated dysregulation, andgenetic predisposition, all of which have been shown to corre-late with disease severity. However, as yet no mechanism hasbeen identied that links any of these established immuno-logical derangements with a denitive effect on microvascu-lar structure or function consistent with the observed alter-ation in permeability. In addition, most of the immunologicalabnormalities so far identied do not differ substantially fromthose seen in other infections without an apparent effect onpermeability.
Neutralising antibodies are key factors in the aetiopatho-genesis of the disease. However, the cellular immuneresponse is also important. It has been demonstrated thatmemory dengue T lymphocyte response aer a primaryinfection includes both serotype-specic and serotype-cross-reactive T lymphocytes . NS3 protein seems to be themajor target for CD4+ and CD8+ T cells.
Cytokines that may induce plasma leakage such as inter-feron g, interleukin (IL) 2, and tumour necrosis factor (TNF) are increased in DHF cases [20, 21]. Also, interferon enhances uptake of dengue particles by target cells throughincreasing Fc cell receptors .Other cytokines such as IL-6,IL-8, and IL-10 are also increased. A protein of 2225 kDa hasbeen associated with the pathogenesis of DHF.is cytotoxicfactor able to induce increased capillary permeability in miceis capable of reproducing in mice all the pathological lesionsthat are seen in human beings, and has been detected in seraof DHF patients .
A recent study has demonstrated the plasma cytokineprole in dengue fever from a Brailian population whichwas detected by a multiplex bead immunoassay. MIP-was indicated as a good prognostic marker which is incontrast to IFN- that was associated with severe disease.Both cytokines serve to discriminate mild from severe cases.It has also been shown that during the course of denguedifferent cytokine proles may be present and vary accordingto determined clinical manifestations. e cytokine prolesident