dengue fever in children

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1020 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 32, Number 9, September 2013

The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approvedindependently by the Editorial Board of ESPID.

The ESPID Reports and Reviews of Pediatric Infectious Diseases series topics, authors and contents are chosen and approvedindependently by the Editorial Board of ESPID.

ESPID R EPORTS AND R EVIEWS

Dengue fever is the most frequentlyoccurring mosquito-borne viral diseaseworldwide.1 Using cartographic approaches,researchers now estimate the number of den-gue cases worldwide to have been as high as390 million in 2010.2 The first autochthonouscases reported in France, Croatia and Portu-gal (island of Madeira) demonstrate that thedisease is no longer simply a tropical disease.1 The wide clinical spectrum, which can rangefrom an asymptomatic or mild febrile illness

to a life-threatening hemorrhagic fever syn-drome, constitutes a particular challenge forclinicians, particularly in nonendemic areas.This review summarizes current knowledgeof dengue fever epidemiology, pathogenesis,diagnostics, prophylaxis and therapy in chil-dren. Dengue in children differs significantlyfrom adult disease.3

EPIDEMIOLOGY

Over the last 50 years, the incidenceof dengue has increased 30-fold, with the

highest rates occurring among infants.1 Moreover, infants are at increased risk ofdengue shock. The limited ability of thehemodynamic system in young children tocompensate for capillary leakage is believedto contribute to this phenomenon. Yet, thecase-fatality rate is generally lower amonginfants than among adults.1 Dengue virusinfections are endemic in most parts of thetropics and subtropics.1 Overall, the geo-graphical expansion of the virus has been

limited by the temperature sensitivity of itsmain vector, Aedes aegypti. However, thesecond most important vector, Aedes albop-ictus, has a higher temperature tolerance.This latter vector is most likely responsi- ble for viral transmission in autochthonousdengue cases in Europe.1 Globalization andanticipated climate changes can be expectedto contribute to an increasing number ofautochthonous cases in nontropical countriesin upcoming years.

PATHOGENESIS

Dengue is caused by a flavivirus.Four different serotypes (DEN1–DEN4) areknown. Lack of suitable animal models mim-icking the human disease spectrum hampersunderstanding of dengue pathogenesis.4 Viraltransmission takes place via a blood meal by infected mosquitoes. Although infectionsof nonhuman primates do occur, viremichumans are the most important reservoir fordengue viruses. After vector-borne transmis-sion, the virus initially infects macrophagesand dendritic cells. Then, it replicates inregional lymph nodes. Infection with thevirus is followed by an incubation period of

4 to 10 days, during which the virus becomesdisseminated via blood and lymphatic ves-sels, thereby causing systemic disease. Thiskinetics is clinically important: dengue infec-tion is highly unlikely if a traveler has left anendemic area more than 3 weeks before theonset of fever.

The pathogenetic mechanismsunderlying the variable disease phenotypeare only partially understood. Primaryinfection is considered to result in lifelong

protective serotype-specific immunity,whereas serotype cross-reactive protectionremains incomplete and is limited to thefew months after infection. Moreover, theformation of cross-reactive, non-neutral-izing antibodies in the event of a second-ary infection with a different serotype maytrigger a detrimental systemic inflamma-tory response via the antibody-dependentenhancement. This phenomenon likelycontributes to severe secondary cases andis more common in children.5 Althoughthis mechanism may be considered a viralescape targeting the adaptive immune sys-

tem, the dengue virus may additionallysubvert innate immunity by interferingwith type I interferon release. Moreover,host genetic determinants such as HLAalleles and variants in cytokine genes mayhave an impact on disease severity.5

CASE DEFINITIONS

According to a formerly accepteddefinition outlined by World Health Organi-zation, 3 categories of dengue infectionswere distinguishable: (1) dengue fever, (2)dengue hemorrhagic fever and (3) dengue

Copyright © 2013 by Lippincott Williams & WilkinsISSN: 0891-3668/13/3209-1020DOI: 10.1097/INF.0b013e31829fd0e9

Dengue Fever in Children

Where Are We Now?

Roland Elling, MD,*† Philipp Henneke, MD,*† Christoph Hatz, MD, DTM&H,‡ and Markus Hufnagel, MD, DTM&H*

From the *Center of Pediatrics and Adolescent Medi-cine; †Centre of Chronic Immunodeficiency,University Medical Center Freiburg, Freiburg,Germany; and ‡Swiss Tropical and Public HealthInstitute, Basel, Switzerland.

The authors have no funding or conflicts of interestto disclose.

Address for correspondence: Markus Hufnagel, MD,DTM&H, Center for Pediatrics and AdolescentMedicine, Clinical Division of Pediatric InfectiousDiseases and Rheumatology, University Medi-cal Center Freiburg, Mathildenstr. 1, D-79106Freiburg, Germany. E-mail: [email protected].

CONTENTS

Dengue Fever

EDITORIAL BOARD

Co-Editors: Delane Shingadia and Irja Lutsar Board Members

David Burgner (Melbourne, Australia) Luisa Galli (Rome, Italy)

Christiana Nascimento-Carvalho

(Bahia, Brazil)

Ville Peltola (Turku, Finland)

Nicol Ritz (Basel, Switzerland) Ira Shah (Mumbai, India)

Matthew Snape (Oxford, UK)

George Syrogiannopoulos

(Larissa, Greece)

Tobias Tenenbaum (Mannhein, Germany) Marc Terbruegge (Southampton, UK)

Marceline van Furth (Amsterdam,

The Netherlands)

Anne Vergison (Brussels, Belgium)

mailto:[email protected]:[email protected]:[email protected]:[email protected]


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shock syndrome.1 Although this definitionat first was helpful from an educational per-spective, it did not fully meet clinical needswith respect to initial risk stratification inindividual patients.6 A major caveat was thatbleeding was defined as the cardinal symp-

tom. However, capillary leakage has provento be the more important clinical challenge insevere dengue infection—especially in chil-dren—because it may cause life-threateningshock without bleeding.6 For this reason, theWorld Health Organization revised its casedefinitions in 2009 and now distinguishesamong: (1) dengue fever, (2) dengue feverwith warning signs and (3) severe denguefever (Fig. 1).1 It is anticipated that by usingthese revised definitions, fewer severe cases

will be missed, appropriate treatment will become initiated in a more timely fashionand overall prognosis of severe dengue willimprove.6

CLINICAL PRESENTATION

The vast majority of patients withdengue infection is either asymptomaticor shows only mild symptoms.7 If dengueinfections become symptomatic, 3 stagescan be distinguished: First, a febrile stage;second, a critical stage during deferves-cence; and third, a recovery stage. The ini-tial febrile stage begins with rapid-onset,high-grade fever, which is accompanied byretro-orbital headache, severe myalgia and

arthralgia (“break-bone fever”), nausea,vomiting (more common in children3) andgeneral fatigue. A confluent maculopapularrash (more common in children3) appearsduring the end of the febrile stage. Typically,the face is spared. Other characteristic skin

findings are hyperesthesia and hemorrhagiclesions, ranging from petechiae and purpurato bruising around venipuncture sites. Pete-chiae indicate capillary fragility and may be provoked with the so-called tourniquet test(syn. Rumpel-Leede test). Laboratory inves-tigations generally show thrombocytopenia,leukopenia and a potentially moderate eleva-tion of liver aminotransferase levels. Thesechanges are more profound in adults than inchildren.3

Probable Dengue

Fever

Fever plus two of the

following criteria:

1. Nausea / Vomiting2. Rash

3. Aches and Pains

4. Leukopenia

5. Positive Tourniquet Test

6. Any warning sign

Dengue Fever Dengue Fever

plus

warning signs

1. Abdominal pain / tenderness

2. Persistent vomiting

3. Edema

4. Mucosal bleeding

5. Lethargy or restlessness

6. Liver enlargement >2 cm

7. HCT increase >20%

+ rapid PLT decrease

Severe Dengue Fever

1. Severe plasma leakage

with shock (DSS) or

pulmonary edema

2. Severe bleeding

3. Severe organ

dysfunction (AST / ALT

>1.000 U/l, impaired

consciousness, heartand other organs)

Laboratory-

Confirmed Dengue

Fever

!

0 2 4 6 8 10 12-2-4

Febrile Phase Critical Phase Recovery Phase

Viremia

NS1 antigen

Mosquito

bite

IgG

IgM

Fever

Shock

Bleeding

days

A

B

FIGURE 1. A, Revised dengue fever case classication, adapted from World Health Organization 2009.1 B, Clinical course and labo-ratory diagnosis of dengue fever. AST indicates aspartate transaminase; ALT, alanine transaminase; DSS, dengue shock syndrome;HCT, hematocrit; NS1, nonstructural protein 1; PLT, platelet count.


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Although most children recoverdirectly after the initial stage, a small propor-tion will develop systemic capillary leakageduring defervescence (days 4–7), which isthe most critical stage of the disease. Cap-illary leakage can rapidly lead to severe

shock. Accordingly, the decline of fever isthe critical time point for both diagnoses ofthe disease and for starting appropriate fluidmanagement. Delayed diagnosis of severedengue is associated with high mortality (upto 40%).1 Therefore, the following warningsigns for deterioration are of utmost clinicalimportance (Fig. 1A): (1) severe abdominalpain or tenderness, (2) persistent vomit-ing, (3) mucosal bleeding and (4) behavio-ral changes such as lethargy or restlessness.Additional signs of capillary leakage includepleural effusions, gallbladder wall thickeningand ascites. Thus, repeated abdominal ultra-

sound examinations are important for moni-toring the risk for developing severe diseasein all dengue patients. Laboratory changesof note include hemoconcentration (definedas increase in hematocrit of ≥20%), progres-sive thrombocytopenia and hypoproteinemia.Increased vascular permeability during thecritical stage of dengue infection is usuallyshort, which limits shock duration to 48–72hours. The last stage may manifest with asecondary maculopapular rash, which maybe accompanied by severe itching, but even-tually heals with desquamation. The durationof the recovery period is variable.

Although dengue infections dur-ing pregnancy may cause premature birthor abortion, vertical infection of the fetusis rare. Malformations are not known to beassociated with dengue infections duringpregnancy.

DIAGNOSIS

Dengue infection can be diagnoseddirectly through detection of virus com-ponents or else indirectly via serologicalmethods (Fig. 1B). Viral components can bedetected by reverse-transcriptase polymerase

chain reaction or by immunoassays for thesoluble nonstructural protein 1 antigen. Bothpolymerase chain reaction and nonstructuralprotein 1 antigen assays show comparablesensitivity (80–90%) during the first 3 daysof the illness.1 Serologic diagnosis is possible4 to 5 days after fever onset for anti-DEN-IgM and after 7 to 10 days for anti-DEN-IgGantibodies. In secondary infection, IgM pro-duction is often absent, whereas IgG titersrapidly rise to exceedingly high levels. Anti-DEN-IgG persists for life. Discriminationbetween serotypes is not possible by serology.

The type of diagnostic test used

depends upon the stage of the disease. Due tothe acute onset and severity of the symptoms,

patients with dengue usually present withinthe first 2 days of disease at healthcare facili-ties. At this stage, diagnosis only can beestablished by direct viral detection assays.However, once hemorrhagic fever or dengueshock syndrome has developed, diagnosis

can only be established by serology becausethe viremic phase is over.

The differential diagnosis includesany undifferentiated febrile syndrome, espe-cially malaria, typhoid fever, leptospirosis,meliodosis, rickettsial diseases, as well asacute viral infections with human immuno-deficiency, Epstein-Barr, chikungunya andWest Nile virus. In addition, other viral hem-orrhagic fevers and measles need to be con-sidered.

THERAPY AND PREVENTION

Currently, effective antiviral treatmentfor dengue infection is not available. Forexample, balapiravir, a polymerase inhibitor,has not shown beneficial effects compared to placebo.8 Therefore, disease management is primarily supportive and centers on appropriate fluid management. Patients with mildsymptoms and sufficient oral fluid intake aretreated symptomatically with bed rest andacetaminophen/paracetamol. Due to their platelet-inhibiting effects, nonsteroidal anti-inflammatory drugs and acetylsalicylic acidshould be avoided. Daily clinical evaluationand laboratory monitoring of complete blood

count is necessary in order to detect thrombo-cytopenia or—most importantly—capillaryleakage. An increase in hematocrit levels ofmore than 20% is a sign of significant plasmaloss and an indication for transferal of the patient to the intensive care unit.7 Duringthe critical phase of defervescence, carefulmonitoring of warning signs is important sothat intravenous fluid therapy can be startedas soon as necessary. In the event of dengueshock, rapid resuscitation with crystalloidsolutions is essential for the prognosis. Col-loid solutions should be reserved for patientswith severe and persistent shock. The cur-

rent World Health Organization guidelineson dengue fever offer a precise algorithmwith respect to fluid management in dengue patients.1 After hemodynamic stabilization,infusion rates should be reduced in orderto avoid iatrogenic fluid overload. This isimportant because the duration of dengue-associated shock is typically short. Bloodtransfusions are necessary in the event ofsevere bleeding.1

Currently, a licensed dengue vaccineis not available, but several preparations areunder investigation.7 The provision of cross-reactive protection against all 4 serotypes is

1 of the major challenges in vaccine devel-opment. Recently, an attenuated tetravalent

vaccine based on a recombinant virus con-structed from yellow fever virus was able toshow an efficacy of 30% in preventing viro-logically confirmed dengue infections in atrial conducted in over 3000 Thai school chil-dren aged 4–11 years.9 Nevertheless, despite

the overall efficacy of this vaccine, protectionwas not satisfactory for serotype 2 strains(

dengue fever in children

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