SECTION 6 International Medicine: Major Tropical Syndromes:
Systemic Infections
133 
Dengue and Chikungunya
CAMERON P. SIMMONS  |  JAMES WHITEHORN  | 
KATHERINE ANDERS  |  VINH CHAU VAN NGUYEN
KEY CONCEPTS
• Dengue and chikungunya are viral diseases transmitted by
Aedes mosquitoes.
• Over 3 billion people are at risk of dengue.
• Explosive outbreaks of chikungunya occur in the Indian Ocean
region and infection is spreading rapidly across the Caribbean
region.
• The pathogenesis of both viruses is complex and incompletely
understood – it involves an interplay between virus and host
factors.
• Dengue treatment is currently limited to supportive care (fluid
replacement and careful monitoring of fluid balance).
• No vaccines are currently available for either virus.
• Novel approaches to vector control may assist dengue control
efforts (e.g. release of Wolbachia-infected Aedes aegypti).
Epidemiology
DENGUE
Dengue is a vector-borne, systemic viral infection and a globally
important public health problem.1 Dengue is transmitted predomi-
nantly by the mosquito Aedes aegypti, which bites in the daytime, is
Distribution of dengue-affected countries
Areas infected with Aedes aegypti
Areas with Aedes aegypti
and dengue epidemic activity
Figure 133-1  Distribution of dengue-affected countries.
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adapted to human habitats and has a preference for human blood
meals. Mosquitoes become infected after feeding on the blood of a
viremic human. More than 3 billion people living in over 100 countries
throughout the tropics and sub-tropics are at risk of dengue (Figure
133-1). Recent probabilistic mapping studies suggest there are approx-
imately 100 million clinically apparent cases of dengue each year, of
which an estimated 2–5% are severe.2 The global scale of the public
health risk posed by dengue is in part due to the geographic expansion
of A. aegypti into new territories. In endemic areas peak dengue trans-
mission dynamics are influenced by factors such as mosquito density,
human population density, co-circulation of dengue virus (DENV)
serotypes, rainfall and humidity.
CHIKUNGUNYA
Chikungunya virus (CHIKV) is an alphavirus within the Togaviridae
family, transmitted by Aedes mosquitoes.3 CHIKV was first isolated in
Tanzania in 1952. Chikungunya is the Makonde (an African dialect
spoken in parts of Tanzania) for ‘that which bends up’– the description
eludes to the severe joint pain that can be seen in those infected. Typi-
cally major epidemics of the disease occur cyclically with long inter-
epidemic periods.4 CHIKV disease has been reported from Africa, Asia
and Australasia; it has recently re-emerged resulting in millions of
infections in the Indian Ocean and Caribbean regions.5 Imported cases
to Europe have resulted in autochthonous outbreaks in Italy. There is
concern that a recent envelope mutation will result in increased infec-
tivity to Aedes albopictus and a further spread of chikungunya’s geo-
graphic footprint.6
1119
1120 SECTION 6  International Medicine: Major Tropical Syndromes: Systemic Infections
Key events in DHF pathogenesis during
secondary dengue virus infection
4–7 days
Viremia and
NS1
antigenemia
Capillary
leakage
Inflammatory cytokines, lymphocyte activation,
apoptosis, immune complex formation,
coagulopathy, thrombocytopenia
Figure 133-2  Key events in dengue pathogenesis during secondary dengue
virus infection.
Dengue Pathogenesis and Pathology
The dengue viruses (DENV serotypes 1, 2, 3 and 4) are enveloped,
single-stranded RNA viruses of the Flaviviridae family. Infection with
any of the four serotypes of dengue virus can be clinically inapparent
or, following an incubation period of 4–10 days, a systemic illness may
develop that is characterized by fever, rash, headache, muscle and joint
ache. Occasionally, more severe manifestations such as shock and
hemorrhage occur, which are largely due to a transient increase in
vascular permeability. Severe dengue is strongly associated with sec-
ondary, heterotypic infections (two sequential infections caused by
different serotypes) (Figure 133-2).7 Severe dengue also occurs during
primary DENV infection of infants born to DENV-immune mothers.8
Infants born to DENV-immune mothers and previously infected chil-
dren or adults have in common a single immune risk factor – DENV-
reactive IgG antibodies.9 The capacity of subneutralizing concentrations
of DENV-reactive IgG antibodies to enhance DENV infections in after a 4–7 day incubation period. This is often accompanied by head-
Fc receptor-bearing cells, a phenomenon called antibody-dependent
enhancement (ADE), might explain the increased risk of severe dengue
in secondary infections and in infants with primary infections.10 None-
theless, most secondary infections do not result in severe disease, sug-
gesting there are other important factors involved. Young age, female
gender, virus strain and genetic variants of the human major histo-
compatibility complex class I-related sequence B and phospholipase C
epsilon 1 genes are also risk factors for severe dengue.11,12
Prevention
There are currently no licensed vaccines for dengue or chikungunya.
Large phase III trials of a live-attenuated tetravalent dengue vaccine
(ChimeriVax-DEN) indicated this vaccine was safe and well tolerated
but delivered only partial efficacy (55–65%) against symptomatic
dengue (any severity) during the 25-month period of study observa-
tion. Promisingly ChimeriVax-DEN was more efficacious in prevent-
ing dengue hospitalizations.13,14 More recent results from longer-term
follow-up suggest a sustained benefit in vaccine recipients aged
between 9 and 16 years, but intriguingly showed higher rates of hos-
pitalization in vaccine recipients aged under 9 in the third year after
vaccination.15 There remain many questions about the potential place
of this vaccine in dengue control and the results suggest that partial,
waning immunity could be a problem in the development of an effica-
cious dengue vaccine.
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An alternative approach to dengue and chikungunya prevention is
through the replacement of wild-type A. aegypti with A. aegypti infected
with the intracellular bacterium Wolbachia.16 Wolbachia-infected A.
aegypti are resistant to DENV infection and these modified mosquitoes
can be successfully established in the field.16 Alternative approaches to
mosquito control include the release of genetically modified mosqui-
toes that can suppress target populations – field trials of this approach
IgG are underway.17 It is possible that combining these novel approaches
with a partially efficacious vaccine may be a successful approach to
dengue control.
Reduction of mosquito populations currently remains the best
IgM method of preventing transmission of dengue and chikungunya. Nev-
ertheless, the relentless increase in the geographic footprint of dengue
and the recent explosive outbreaks of chikungunya, indicates most
vector control strategies in endemic areas are inadequate, not sustain-
able and/or poorly targeted. For travelers to tropical countries, the only
practical method of prevention is to avoid bites from mosquitoes by
wearing protective clothing and using appropriate N,N-Diethyl-m-
toluamide (DEET)-based repellents.
Clinical Features
DENGUE
DENV infection causes a range of manifestations from asymptomatic
infection through to fulminant shock and hemorrhage.18 The previ-
ously used classification system categorized dengue infection into
‘dengue fever’ and ‘dengue hemorrhagic fever (DHF)’. DHF was
further subdivided into four severity grades, and grades III and IV were
classified as dengue shock syndrome (DSS). Studies have shown that
this rigid classification system had a low sensitivity for severe disease
and that some cases resulting in shock and death did not meet the
WHO case definitions for DHF/DSS.19 The current WHO guidelines
recognize that dengue is a clinical continuum from uncomplicated to
severe disease.18 This system places more emphasis on the early recog-
nition of warning signs suggestive of severe disease, appreciating
patients may move along the disease continuum during the course of
their illness. These warning signs include abdominal pain, vomiting,
liver enlargement, lethargy and restlessness.18 In the early stages of
illness the differential diagnosis of DENV infection is broad.20 The
differential diagnosis depends on the local epidemiology and includes
malaria, chikungunya, measles, typhoid, influenza, Rickettsial diseases
and bacterial sepsis.
In ‘classic’ dengue there is typically an abrupt onset of fever
ache, myalgia and severe retro-orbital pain.21 Other clinical features
seen are sore throat, diarrhea, vomiting, anorexia, conjunctival and
pharyngeal injection.18 Early in the illness the skin typically appears
flushed, with petechiae appearing in the ‘critical’ phase and a macular
rash developing in convalescence (Figure 133-3 and Figure 133-4).
Severe arthralgia and myalgia can be a feature of the illness and perhaps
explains the use of the descriptive term ‘break-bone fever’.22 The early
febrile phase lasts for 2–7 days. Straddling the time of defervescence is
a 24–72 hour ‘critical’ phase when an increase in capillary permeability
with an associated rise in hematocrit can be observed. The degree of
plasma leakage is variable – some patients will develop a detectable
pleural effusion or ascites (Figure 133-5). When a critical volume of
plasma is lost patients will develop hypovolemic shock, called dengue
shock syndrome (Figure 133-6). Thrombocytopenia is almost univer-
sally seen in DENV infection and minor mucosal bleeding can be a
feature of uncomplicated infection. In addition, in many cases eleva-
tion of the PT and APTT with associated reduced fibrinogen levels
is observed. However, there is not the degree of FDP elevation that
would be consistent with disseminated intravascular coagulation.23
Severe gastrointestinal hemorrhage can occur and this is well described
in patients with a history of peptic ulcer disease.24 Less commonly,
intracerebral and pulmonary hemorrhage can occur.25 Other organs
can be affected in dengue, and it is possible that these ‘atypical’ pre-
sentations are under-appreciated.18 These ‘atypical presentations’
 Chapter 133  Dengue and Chikungunya 1121

Figure 133-3  Diffuse macular recovery rash in an adult patient with dengue. The
rash may appear between 3 and 6 days after fever onset. Note the ‘islands’ of
normal skin surrounded by erythematous skin.

Figure 133-5  (a) Anteroposterior chest radiograph showing a large pleural effu-
sion on the right side in an adult patient with dengue shock syndrome. (b) The
same patient at hospital discharge. Such severe radiologic findings occur in
dengue patients with capillary leakage and who have received an excessive
volume of intravenous fluid.

Figure 133-4  Hematoma in a patient with severe dengue. The combination of

increased vascular fragility, platelet dysfunction/thrombocytopenia and coagula-
tion disorders is believed to explain hemorrhagic manifestations in dengue. Frank
hemorrhage, as pictured here, is relatively uncommon given the overall disease
burden.

include encephalitis, myocarditis, hepatitis, pancreatitis, retinitis and

ARDS.26

CHIKUNGUNYA
After infection with CHIKV there is an incubation period of 2–4
days.27 The onset of symptoms is abrupt with high fever, headache,
myalgia and arthralgia. The symptoms resemble those seen with DENV
infection. The skin is commonly involved, with maculopapular rashes
Figure 133-6  A patient with dengue shock syndrome. As shown in this image,
being observed frequently – a bullous rash has been described in chil- patients with severe dengue require fluids (or blood products in cases with severe
dren.28 The striking feature of CHIKV infection is severe arthralgia that bleeding) to maintain hemodynamic stability. Respiratory support can be required
can become chronic.4 Less common features are eye involvement, in cases with severe pleural effusion and respiratory compromise.

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1122 SECTION 6  International Medicine: Major Tropical Syndromes: Systemic Infections

minor bleeding, myocarditis and hepatitis.29 The shock characteristic
of severe dengue is not seen and severe hemorrhage is very rare. The
laboratory features of CHIKV infection are distinct from those
observed in DENV – lymphopenia and hypocalcemia are common.30
Mild elevations of liver enzymes are observed but severe thrombocy-
topenia is rare.
Diagnosis
DENGUE
Virological confirmation of DENV infection can be obtained by detec-
tion of the virus-expressed NS1 protein in serum samples via enzyme-
linked immunosorbent assays (ELISA) or rapid test. This method has
high specificity but variable sensitivity. Real time reverse transcription
(RT)-PCR can also be used to detect DENV nucleic acid and allow
differentiation between serotypes, but this method is generally only
used in research settings because of cost. Detection of NS1 and DENV
nucleic acid is most sensitive in the febrile phase of illness.
A presumptive diagnosis of dengue can be obtained by detection
of IgM antibodies in the acute phase. There are several commercially
available ELISA and rapid tests for detection of DENV-reactive IgM,
and some of these rapid tests combine IgM and NS1 tests in the same
assay.
CHIKUNGUNYA
Diagnosis of CHIKV is often made on clinical and epidemiological
grounds alone. Molecular assays are useful in the early stages of illness.
RT-PCR assays are available that target the envelope or nonstructural
protein genes.31 Serological diagnosis via ELISA is an option – IgM is
detectable after 2–3 days of illness and can persist for 3 months (in
some cases years).4 Rapid tests are also available but their reliability is
uncertain.3
Management
DENGUE
Supportive care is the mainstay of dengue case management. Uncom-
plicated infections can be managed in the outpatient setting with
access to further clinical reviews to assess for the development of any
complications.18 It is important that patients managed in the outpa-
tient setting are able to tolerate oral fluids, and are encouraged to
maintain a good oral intake.18 Paracetamol is the recommended anti-
pyretic as nonsteroidal anti-inflammatory drugs (NSAIDs) are associ-
ated with an increased risk of hemorrhage and gastritis, and aspirin
has an association with the development of Reye’s syndrome.18
Patients with warning signs suggestive of severe disease should be
admitted. In addition, patients with co-morbidities and those who
cannot practically be managed as outpatients should also be admit-
ted.18 Patients who have warning signs should have a baseline hema-
tocrit measured and then should be started on parenteral isotonic
fluids commencing at 5–7 ml/kg/hour for 1–2 hours – this infusion
rate should be reduced according to the clinical response.18 Parenteral
fluids are generally needed for only 24–48 hours – the ‘critical’ phase.
Continuing parenteral fluids for longer than this carries a significant
risk of fluid overloading the patient.
In severe cases the administration of parenteral fluid is life-
saving.18,32 Patients with shock require more intensive management
with an initial 20 ml/kg fluid bolus. Further fluid administration is
guided by the patient’s clinical response. The use of isotonic fluids in
the resuscitation of children with shock is supported by clinical evi-
dence, and colloid solutions have been suggested for use in more severe
cases.32 In cases of hemorrhage the transfusion of blood products
is often indicated. However cases involving mucosal bleeding without
hemodynamic compromise require careful observation as opposed
to transfusion.18 Platelet transfusions are advocated in some settings
as prophylaxis against hemorrhage. However this practice lacks
an evidence base, has the potential to cause harm and is not
recommended.33
Trials of both immunomodulatory and antiviral agents have been
conducted but no intervention has demonstrated efficacy.34
CHIKUNGUNYA
There is currently no specific antiviral agent for CHIKV – management
is predominantly supportive with analgesia and antipyretics. There is
some evidence that those who have joint symptoms persisting for more
than 2 weeks after the febrile illness may benefit from ribavirin.35
Zika
Zika virus is a flavivirus that was first described in Uganda in 1947 and
until recently was a relatively mild and obscure infection confined to
central Africa. Since 2010, in a manner very analogous to the spread
of Chikungunya infection, it has crossed the world.36 It has appeared
in the Americas – initially in Brazil but then speading northwards to
much of South America, Central America and the Caribbean. Addi-
tionally it has become endemic in South East Asia and Polynesia.
Sporadic cases in returning travelers have been seen elsewhere. The
virus is transmitted by aedes mosquitoes, especially A. aegypti. In most
cases, infection has been asymptomatic or mild with fever, muscle
aches, conjunctivitis and a maculopapular rash. Severe dengue-like
infection has not been described. The most recent outbreaks have
highlighted potential associations with severe neurological conse-
quences. An outbreak in French Polynesia was associated with a paral-
lel increase in Guillain-Barre syndrome. Of greatest concern is the
potential link between infection in pregnant women and subsequent
microcephaly in their infants. This was first noted in Brazil, but has
been reported elsewhere. A cause and effect relationship remains
unproven, but public health authorities in many countries are now
advising additional precautions for women of child-bearing age
including avoidance of pregnancy or travel to affected countries.37
There is no specific treatment for Zika other than supportive care.
Prevention efforts are similar to other arthropod-associated flavivi-
ruses and center on vector avoidance and control.
References available online at expertconsult.com.

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Bhatt S., Gething P.W., Brady O.J., et al.: The global distri-
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Capeding M.R., Tran N.H., Hadinegoro S.R., et al.: Clinical
efficacy and safety of a novel tetravalent dengue vaccine
in healthy children in Asia: a phase 3, randomised,
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384(9951):1358-1365.
Dejnirattisai W., Jumnainsong A., Onsirisakul N., et al.:
Cross-reacting antibodies enhance dengue virus infection
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Khor C.C., Chau T.N., Pang J., et al.: Genome-wide associa-
tion study identifies susceptibility loci for dengue shock
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Moreira L.A., Iturbe-Ormaetxe I., Jeffery J.A., et al.: A Wol-
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dengue, chikungunya, and Plasmodium. Cell 2009;
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Simmons C.P., Farrar J.J., Nguyen v V., et al.: Dengue.
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Villar L., Dayan G.H., Arredondo-Garcia J.L., et al.: Efficacy
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Whitehorn J., Yacoub S., Anders K.L., et al.: Dengue thera-
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Chapter 133  Dengue and Chikungunya 1122.e1
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