CONTENTS
Dengue Fever
EDITORIAL BOARD
Co-Editors: Delane Shingadia and Irja Lutsar
Board Members
David Burgner (Melbourne, Australia) Nicol Ritz (Basel, Switzerland) Tobias Tenenbaum (Mannhein, Germany)
Luisa Galli (Rome, Italy) Ira Shah (Mumbai, India) Marc Terbruegge (Southampton, UK)
Christiana Nascimento-Carvalho Matthew Snape (Oxford, UK) Marceline van Furth (Amsterdam,
(Bahia, Brazil) George Syrogiannopoulos The Netherlands)
Ville Peltola (Turku, Finland) (Larissa, Greece) Anne Vergison (Brussels, Belgium)
1020 | www.pidj.com The Pediatric Infectious Disease Journal • Volume 32, Number 9, September 2013
The Pediatric Infectious Disease Journal • Volume 32, Number 9, September 2013 ESPID Reports and Reviews
shock syndrome.1 Although this definition will be missed, appropriate treatment will arthralgia (“break-bone fever”), nausea,
at first was helpful from an educational per- become initiated in a more timely fashion vomiting (more common in children3) and
spective, it did not fully meet clinical needs and overall prognosis of severe dengue will general fatigue. A confluent maculopapular
with respect to initial risk stratification in improve.6 rash (more common in children3) appears
individual patients.6 A major caveat was that during the end of the febrile stage. Typically,
bleeding was defined as the cardinal symp- the face is spared. Other characteristic skin
tom. However, capillary leakage has proven CLINICAL PRESENTATION findings are hyperesthesia and hemorrhagic
to be the more important clinical challenge in The vast majority of patients with lesions, ranging from petechiae and purpura
severe dengue infection—especially in chil- dengue infection is either asymptomatic to bruising around venipuncture sites. Pete-
dren—because it may cause life-threatening or shows only mild symptoms.7 If dengue chiae indicate capillary fragility and may be
shock without bleeding.6 For this reason, the infections become symptomatic, 3 stages provoked with the so-called tourniquet test
World Health Organization revised its case can be distinguished: First, a febrile stage; (syn. Rumpel-Leede test). Laboratory inves-
definitions in 2009 and now distinguishes second, a critical stage during deferves- tigations generally show thrombocytopenia,
among: (1) dengue fever, (2) dengue fever cence; and third, a recovery stage. The ini- leukopenia and a potentially moderate eleva-
with warning signs and (3) severe dengue tial febrile stage begins with rapid-onset, tion of liver aminotransferase levels. These
fever (Fig. 1).1 It is anticipated that by using high-grade fever, which is accompanied by changes are more profound in adults than in
these revised definitions, fewer severe cases retro-orbital headache, severe myalgia and children.3
Fever
Shock
Bleeding IgG
IgM
NS1 antigen
Mosquito
bite
Viremia
-4 -2 0 2 4 6 8 10 12
days
FIGURE 1. A, Revised dengue fever case classification, 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.
Although most children recover patients with dengue usually present within vaccine based on a recombinant virus con-
directly after the initial stage, a small propor- the first 2 days of disease at healthcare facili- structed from yellow fever virus was able to
tion will develop systemic capillary leakage ties. At this stage, diagnosis only can be show an efficacy of 30% in preventing viro-
during defervescence (days 4–7), which is established by direct viral detection assays. logically confirmed dengue infections in a
the most critical stage of the disease. Cap- However, once hemorrhagic fever or dengue trial conducted in over 3000 Thai school chil-
illary leakage can rapidly lead to severe shock syndrome has developed, diagnosis dren aged 4–11 years.9 Nevertheless, despite
shock. Accordingly, the decline of fever is can only be established by serology because the overall efficacy of this vaccine, protection
the critical time point for both diagnoses of the viremic phase is over. was not satisfactory for serotype 2 strains
the disease and for starting appropriate fluid The differential diagnosis includes (<10% efficacy).9
management. Delayed diagnosis of severe any undifferentiated febrile syndrome, espe- Due to the absence of both specific
dengue is associated with high mortality (up cially malaria, typhoid fever, leptospirosis, treatment options and a vaccine, prophylaxis
to 40%).1 Therefore, the following warning meliodosis, rickettsial diseases, as well as by avoidance of mosquito bites by Aedes
signs for deterioration are of utmost clinical acute viral infections with human immuno- mosquitos remains the cornerstone of den-
importance (Fig. 1A): (1) severe abdominal deficiency, Epstein-Barr, chikungunya and gue prevention. This is especially true for
pain or tenderness, (2) persistent vomit- West Nile virus. In addition, other viral hem- children who have had a first dengue infec-
ing, (3) mucosal bleeding and (4) behavio- orrhagic fevers and measles need to be con- tion and are returning to dengue-endemic
ral changes such as lethargy or restlessness. sidered. areas. Classical but still up-to-date measures
Additional signs of capillary leakage include include the wearing of protective, insecti-
pleural effusions, gallbladder wall thickening cide-impregnated clothing and the usage of
THERAPY AND PREVENTION
and ascites. Thus, repeated abdominal ultra- mosquito repellents, for example, N,N-die-
sound examinations are important for moni- Currently, effective antiviral treatment
for dengue infection is not available. For thyl-metatoluamide. In contrast to malaria,
toring the risk for developing severe disease insecticide-treated bed nets are of very lim-
in all dengue patients. Laboratory changes example, balapiravir, a polymerase inhibitor,
has not shown beneficial effects compared to ited value because Aedes mosquitos bite dur-
of note include hemoconcentration (defined ing the day.1
as increase in hematocrit of ≥20%), progres- placebo.8 Therefore, disease management is
sive thrombocytopenia and hypoproteinemia. primarily supportive and centers on appro-
Increased vascular permeability during the priate fluid management. Patients with mild CONCLUSIONS
critical stage of dengue infection is usually symptoms and sufficient oral fluid intake are Due to the lack of an effective dengue
short, which limits shock duration to 48–72 treated symptomatically with bed rest and vaccine as well as to the absence of targeted
hours. The last stage may manifest with a acetaminophen/paracetamol. Due to their treatment options, the knowledge and skills
secondary maculopapular rash, which may platelet-inhibiting effects, nonsteroidal anti- to recognize and diagnose the disease before
be accompanied by severe itching, but even- inflammatory drugs and acetylsalicylic acid it reaches its critical phase are of utmost
tually heals with desquamation. The duration should be avoided. Daily clinical evaluation importance for clinicians treating dengue
of the recovery period is variable. and laboratory monitoring of complete blood patients.
Although dengue infections dur- count is necessary in order to detect thrombo-
ing pregnancy may cause premature birth cytopenia or—most importantly—capillary REFERENCES
or abortion, vertical infection of the fetus leakage. An increase in hematocrit levels of 1. World Health Organization. Dengue: Guidelines
is rare. Malformations are not known to be more than 20% is a sign of significant plasma for Diagnosis, Treatment, Prevention and
associated with dengue infections during loss and an indication for transferal of the Control - New Edition. Geneva: World Health
patient to the intensive care unit.7 During Organization; 2009.
pregnancy.
the critical phase of defervescence, careful 2. Bhatt S, Gething PW, Brady OJ, et al. The global
monitoring of warning signs is important so distribution and burden of dengue. Nature.
2013;496:504–507.
DIAGNOSIS that intravenous fluid therapy can be started
3. de Souza LJ, Bastos Pessanha L, Carvalho
Dengue infection can be diagnosed as soon as necessary. In the event of dengue Mansur L, et al. Comparison of clinical and labo-
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methods (Fig. 1B). Viral components can be loid solutions should be reserved for patients 4. Zompi S, Harris E. Animal models of dengue
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of the illness.1 Serologic diagnosis is possible to avoid iatrogenic fluid overload. This is Glob Health. 2012;106:94–101.
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duction is often absent, whereas IgG titers severe bleeding.1 omized, double-blind placebo controlled trial of
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