subject: Dengue fever pathology and pathogenesis [print this page] Dengue fever pathology and pathogenesis Dengue fever pathology and pathogenesis
Dengue is an arthropod-borne (arbovirus) flavivirus infectioncharacterized by an acute febrile illness with severebone pain, rash and lymphadenopathy. The vectors areAedes mosquitoes. The dengue virus is a 50 nm RNAcontainingflavivirus. Four serotypes are recognized, andthese can be differentiated in a range of standard serologicaltests. The serotypes are closely related antigenically,but cross-protection between serotypes is lacking. Thedengue shock syndrome and haemorrhagic fever occur inpatients, particularly children, experiencing a second infectionwith a different Dengue serotype.
Distribution and incidence Over the last three decades epidemics of dengue haveoccurred in all continents in the tropics, Africa, Asia, theAmericas and the Pacific, such that it is nowthe commonest mosquito-borne infection, and 50% of theworld's population live in endemic areas. With the spreadof dengue there has been a corresponding spread in theincidence of dengue haemorrhagic fever (DHF) whichuntil the 1970s was confined to southeast Asia. The reasonsfor this spread are incompletely understood, but includethe increase in travel worldwide distributing the serotypesto new areas, decline in mosquito control so that Aedesaegypti has proliferated, and the rise of densely populatedperiurban slums with no sanitary facilities except thosethat encourage the proliferation of A. aegypti.
Transmission and epidemiology The most common vector is Aedes aegypti, a day-bitingmosquito that breeds in small collections of water in tincans, car tyres etc. peridomestically, but other species havemore limited roles in transmission. Eight to 11 days afteringesting dengue virus in a human blood meal the mosquitois infective; it remains infective for the rest of its life.Peak biting times are the 2-hour periods after dawn andbefore dusk.Both sexes and all age groups are susceptible to dengueprovided they have not been infected before with thatserotype. Dengue haemorrhagic fever has been predominantlya disease of children, but with spread to new areassecond infections, and hence DHF, are occurring in olderage groups.
Pathology and pathogenesis After inoculation the virus replicates in local lymph nodecells. Viraemia follows and reticuloendothelial cells in skinand other tissues become infected. Local inflammatorychanges occur around small vessels in the skin. Denguehaemorrhagic fever occurs in children who have previouslybeen exposed to infection with a different serotype of thevirus, or who have acquired antibody passively from theirmother. Immune enhancement causes more cells tobecome more heavily infected through immune complexbinding to Fc receptors. Cytotoxic T-cell memory isactivated, causing enhanced clearance of virus but alsoresulting in excess cytokine release, with tissue-damagingconsequences: increased vascular permeability, causinghypovolaemia and coagulation defects owing to the releaseof cytokines with procoagulant properties.Clinical featuresThe incubation period is about 7 days prior to the onset ofhigh fever, headache, eye pains, backache and chills. Limbpain is often severe in dengue and this gives rise to itscommon name, 'breakbone fever'. A blanching erythematousmacular rash may appear on the third or fourth dayof the illness.
Lymphadenopathy may be present.Encephalopathy, cardiomyopathy and liver damage alsooccur. Leukopenia is usual in the peripheral blood.In dengue haemorrhagic fever the patient is more ill, andblood pressure falls as a result of transudation of fluid fromthe vascular compartment. This fluid can accumulate in theabdominal cavity or in the pleural spaces. Monitoringblood pressure, haematocrit and platelet count in additionto urine output and conscious level give warning of itsonset. There may be spontaneous bleeding into the skinand at other sites. The loss of circulating blood volumecauses shock, with low blood pressure, rapid pulse, restlessnessand abdominal pain (the dengue shock syndrome),which can have a mortality of 50% if untreated.
Diagnosis Virus can be isolated from blood using Aedes or mammaliancell lines. Virus can also be identified in blood usingthe polymerase chain reaction, and IgM antibody or arising antibody titre in paired sera obtained 10-14 daysapart are serological indicators of the diagnosis, althoughthe serological response may not be so clear-cut in areaswhere populations are exposed to other flaviviruses.
Management Patients with uncomplicated dengue require supportivemeasures, such as attention to nutrition and hydration andrelief of pain. Paracetamol, not aspirin, should be used forpain relief and as an antipyretic. Intensive management ofsevere dengue haemorrhagic fever can reduce the mortalityfrom 10% to 1% without highly sophisticated facilities.Intravascular volume is restored with Ringer's lactate,giving a volume equal to daily requirements plus 5% ofbody weight, and monitoring pulse, blood pressure andrespiration to avoid overload. Plasma protein fraction anddextran 40 may also be given to replace colloid losses.Haematocrit should be monitored to assess progress.The need for fluid replacement may last only 1-2 days. Nospecific antiviral treatment is beneficial.ControlLive attenuated vaccines are under development. It isimportant that they contain all four serotypes of the virusto avoid the risk of dengue haemorrhagic fever. Vectorcontrol comprises the removal of mosquito breeding sites,which are often collections of water in tins, tyres, tubs andwater storage vessels around homes, and larviciding.
