CONCISE REVIEWS OF PEDIATRIC INFECTIOUS DISEASES®

Dengue Fever and Dengue Hemorrhagic FeverDavid M. Morens, MD

Key Words: dengue, arboviruses, flaviviruses

(Pediatr Infect Dis J 2009;28: 635–636)

Dengue is an acute influenza-like diseasecaused by any of 4 genetically similar mos-quito-borne arboviruses of the Flavivirusfamily.1 Dengue viruses are thus related toyellow fever virus, West Nile virus, Japaneseencephalitis virus, and several other humanpathogens. Although flaviviruses have his-torically been linked to specific geographiclocales, in recent years many have been ex-tending their geographic ranges. Among themost important examples of this phenome-non, dengue has been re-emerging globally,2

along with a potentially fatal, and poorlyunderstood complication known as denguehemorrhagic fever.

ImportanceThe importance of dengue to pediatric

infectious disease practice has been increa-sing.1–4 As dengue has expanded globallyinto new tropical and subtropical areas, therisk of infection to travelers returning to theUnited States (US) has risen. Moreover, den-gue has for decades caused serious problemsin such US jurisdictions as Puerto Rico, theUS Virgin Islands, American Samoa, and otherCommonwealths/Territories, has caused epi-demics in Hawaii (as recently as 2001–2002)and recurrent cases/small outbreaks in South-ern Texas, and is believed by some to posethe threat of urban outbreaks in the 24 otherStates with vector mosquito prevalences.The once-rare complication known as den-gue hemorrhagic fever (see below) has notonly become more highly incident in personswith dengue infection, but has in recent de-cades “spread” from Southeast Asia to theWestern Hemisphere.

EpidemiologyDengue viruses are sustained in mos-

quito-human-mosquito transmission cycles,the major vectors being the “classical” Afri-can-descended vector Aedes aegypti, andmore recently a less-efficient but more adapt-

able vector Aedes albopictus. These mosqui-toes are peridomestic, breeding in or verynear households, in flower pots, cans, jars,discarded car tires, and in other receptacleswhere fresh water meets a solid surface.Dengue is thus an urban problem.2–5 Al-though dengue epidemics once ravaged theUS eastern seaboard as far north as Philadel-phia, the fact that mosquitoes may not sur-vive year round in northern latitudes, as wellas modern sanitation (refuse collection, screen-ing, air conditioning), now afford a degree of“protection.” Nevertheless, the experience ofSingapore, a modern, wealthy, and air-con-ditioned country with the world’s most ag-gressive dengue control program, proves thatdengue epidemics may be nearly impossibleto prevent.

Clinical PictureHistorically, dengue and dengue hem-

orrhagic fever/dengue shock syndrome havebeen considered childhood diseases, but thisis largely a function of their recognition andstudy in highly endemic and hyperendemicareas where adults are immune. As dengueexpands globally, more adult cases of den-gue hemorrhagic fever are being seen. Theincubation period averages 5 days after thebite of an infected mosquito. With the excep-tion of a variable and transient maculopapu-lar rash that may be faint or unrecognizablein dark-skinned persons, the clinical pictureof uncomplicated dengue is almost indistin-guishable from that of influenza and of anumber of other alphavirus and flavivirusinfections, eg, chikungunya: sudden onset offever, myalgia and prostration, with variablecough, anorexia, altered taste, and other non-specific symptoms/signs (Figure).6–8 The fe-ver course has been classically described as“saddle back,” with a relative lowering offever on about the third day, followed by areturn on days 4 and 5, after which deferves-cence occurs. The so-called pathognomonicsymptom of “retro-orbital pain” (severe move-ment-associated ocular myalgia) is seen in anumber of other arboviral diseases and occa-sionally in influenza. Minor bleeding phe-nomena such as epistaxis, gingival bleeding,petechiae, and thrombocytopenia appear inabout 10% of patients without dengue hem-orrhagic fever, and do not by themselvespredict progression of disease severity.Prolonged convalescence associated with

intractable fatigue (up to 2 months) is notuncommon.

Complications: DengueHemorrhagic Fever and DengueShock Syndrome

Dengue hemorrhagic fever and itsmost severe form, dengue shock syndromeare potentially fatal dengue complications ofobscure pathogenesis caused by any of the 4viral types.1 Despite its name, and eventhough hemorrhagic phenomena are near-universal and may occasionally be serious,almost all deaths are caused by hypotensionrather than by hemorrhage. Since hemor-rhagic signs are commonly seen in both den-gue hemorrhagic fever and in uncomplicateddengue, the term “dengue hemorrhagic fe-ver” is something of a misnomer. The under-lying pathogenesis of dengue hemorrhagicfever includes a rapidly developing capillaryleakage syndrome with hemoconcentration andvenous pooling. If uncorrected by fluid admin-istration, it may quickly lead to hypotensionand shock. The diagnostic criteria for denguehemorrhagic fever/dengue shock syndromeand for staging of severity were developeddecades ago by the World Health Organization(Figure),7,9,10 but have recently become con-troversial in their applicability to adult patientsbecause of newer diagnostic tests.1,7

PathogenesisAlthough dengue hemorrhagic fever/

dengue shock syndrome pathogenesis islargely uncharacterized, it has become clearin recent decades that, as had been observedby Halstead and colleagues in the 1960s,major risk factors seem to be secondary (sec-ond dengue or other flavivirus followed bydengue) infections in older children/adults,as well as primary (first dengue) infections ininfants.1 The prevailing hypothesis to ex-plain this observation is that cross-reacting/nonneutralizing IgG antibody against a pre-viously infecting dengue serotype (in thecase of infants, transplacentally acquired IgGantibody), upregulates infection by drivingIgG-bound virus into FcR-bearing cells(antibody-dependent enhancement, or ADE11).

DiagnosisThe most important elements in diag-

nosing dengue are often travel history, a highindex of suspicion, and familiarity with theclinical signs and the epidemiologic picture.In a clinical setting, available diagnostic tests

From the Office of the Director, CAPT, U.S. PublicHealth Service, National Institute of Allergy andInfectious Diseases, National Institutes of Health,Bethesda, MD.

Copyright © 2009 by Lippincott Williams & WilkinsISSN: 0891-3668/09/2807-0635DOI: 10.1097/INF.0b013e3181afcd5b

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such as serologies and PCR may be unreli-able.1 For whatever reason, dengue hemor-rhagic fever/dengue shock syndrome in trav-elers returning to the US has to date (2009)been extremely rare. During epidemics it isimpossible to predict which patients willprogress to dengue hemorrhagic fever/den-gue shock syndrome, but in hyperendemicareas like Thailand, where parents have be-come highly educated about dengue, it isnowadays rare that children are brought tohospitals in the late stages of disease, leadingto a substantial drop in dengue hemorrhagic

fever deaths over recent decades. Hemocon-centration without dehydration is an earlywarning sign of dengue progression (Figure);pericardial and pleural effusions may also bedocumented on X-rays or echograms.6,8,12

TreatmentTreatment strategies and protocols for

dengue hemorrhagic fever/dengue shock syn-drome have been developed by the WorldHealth Organization and are available on-line9,10 (http://www.who.int/csr/disease/dengue/DengueResources.pdf). These rely largely on

anticipation of shock and prompt administra-tion of standard available fluid/electrolyte so-lutions, eg, lactated Ringer’s solution. Severeshock can be treated with dextran 70 or 6%hydroxyethyl starch.1,9,10 Uncomplicated den-gue rarely requires specific treatment. Rest,hydration, nutrition, and antipyretics are themainstays of supportive care in uncomplicatedcases; obviously, aspirin should not be used.No specific drugs or antiserum preparations areavailable.

PreventionDevelopment of dengue vaccines has

been a high priority for decades.7 Several are inphase 1 or 2 clinical trials, but it will probablybe a number of years before any one becomesavailable for routine use. Travelers should beeducated about avoiding Aedes mosquitoes bylearning about their bionomics and by wearingprotective clothing and using insect repellants.In endemic communities, dengue epidemicsrepresent public health crises. Anti-denguepublic health measures rely on public educa-tion via schools, radio/television, and leaflets/posters, and by mosquito control includingadulticiding (chemical spraying), larvaciding,and source reduction (elimination of breedingsites by clean up of debris).

REFERENCES1. Halstead SB. Dengue. Lancet. 2007;370:1644–

1652.

2. Morens DM, et al. Dengue and hemorrhagic fe-ver . . . JAMA. 2008;299:214–216.

3. Gubler DJ. Dengue and dengue hemorrhagic fe-ver . . . In: Gubler DJ, Kuno G (eds). Dengue andDengue Hemorrhagic Fever. Chapter 1. NewYork: CAB International; 1997:1–22.

4. Kyle JL, et al. Global spread and persistence ofdengue. Annu Rev Microbiol. 2008;62:71–92.

5. Gubler DJ. Cities spawn epidemic dengue vi-ruses. Nature Med. 2004;10:129–130.

6. George R, et al. Clinical spectrum . . . In: GublerDJ, Kuno G (eds). Dengue and Dengue Hemor-rhagic Fever. Chapter 5. New York: CAB Inter-national; 1997:89–114.

7. Whitehead SS, et al. Prospects for a dengue virusvaccine. Nature Rev Microbiol. 2007;5:518–528.

8. Potts JA, et al. Clinical and laboratory features. . . Trop Med Int Health. 2008;1:1328–1340.

9. World Health Organization. Dengue Haemor-rhagic Fever . . . Second Edition. Geneve: WorldHealth Organization; 1997.

10. World Health Organization. Prevention and Con-trol of Dengue and Dengue Haemorrhagic Fever:A Comprehensive Guideline. New Delhi: WorldHealth Organization Regional Office for South-East Asia; 1999.

11. Morens DM. Antibody-dependent enhancement ofinfection . . . Clin Infect Dis. 1994;19:500–512.

12. Nimmanitya S. Dengue hemorrhagic fever . . . In:Gubler DJ, Kuno G (eds). Dengue and DengueHemorrhagic Fever. Chapter 7. New York: CABInternational; 1997:133–146.

FIGURE 1. Summary of World Health Organization case definitions of dengue fever(DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). DHFgrade I is established when each of the 4 criteria in “b,” top row, are met. The moresevere stages of DHF are indicated by the signs shown in the lower rows of “b,” andalso in “c.” DHF grades III and IV are also referred to as DSS. A typical time course ofthe events occurring in dengue infection are shown in “d.” Figure courtesy of StephenS. Whitehead, National Institute of Allergy & Infectious Diseases, NIH.7

Concise Reviews The Pediatric Infectious Disease Journal • Volume 28, Number 7, July 2009

© 2009 Lippincott Williams & Wilkins636 | www.pidj.com