Dengue hemorrhagic fever and shock syndromes*

Suchitra Ranjit, MBBS, MD; Niranjan Kissoon, MBBS, FAAP, FCCM, FACPE
Objectives: To provide a comprehensive review of dengue, with
an emphasis on clinical syndromes, classification, diagnosis, and
management, and to outline relevant aspects of epidemiology,
immunopathogenesis, and prevention strategies. Dengue, a leading cause of childhood mortality in Asia and South America, is the
most rapidly spreading and important arboviral disease in the
world and has a geographic distribution of >100 countries.
Data Source: Boolean searches were carried out by using
PubMed from 1975 to March 2009 and the Cochrane Database of
Systematic Reviews from 1993 to March 2009 to identify potentially
relevant articles by key search terms such as: dengue; dengue
fever; dengue hemorrhagic fever; dengue shock syndrome;
severe dengue and immunopathogenesis, pathogenesis, classification, complications, and management. In addition, authoritative seminal and up-to-date reviews by experts were used.
Study Selection: Original research and up-to-date reviews and
authoritative reviews consensus statements relevant to diagnosis
and therapy were selected.
Data Extraction and Synthesis: We considered the most relevant articles that would be important and of interest to the critical

engue viral infections affect

all age groups and produce a
spectrum of clinical illness
that ranges from asymptomatic to a mild or nonspecific viral syndrome to a severe and occasionally fatal
disease characterized by shock and hemorrhage (1, 2). Dengue fever (DF) is an
old disease; the first record of a clinically
compatible disease was documented in a
Chinese medical encyclopedia in 992 (3).
This illness has reemerged in the last 3 4
decades with an expanded geographic distribution of both the viruses and the mosquito vectors (1, 2, 4 6); in 1998, dengue
was recognized as the most important
tropical infectious disease after malaria

*See also p. 116.

From the Pediatric Intensive Care Unit (SR), Apollo
Childrens Hospital, Chennai, India; Department of Pediatrics (NK), BC Childrens Hospital, Vancouver, BC,
Canada.
The authors have not disclosed any potential conflicts of interest.
For information regarding this article, E-mail:
nkissoon@cw.bc.ca
Copyright 2011 by the Society of Critical Care
Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0b013e3181e911a7

90

care practitioner as well as authoritative consensus statements

from the World Health Organization and the Centers for Disease
Control and Prevention. Dengue viral infections are caused by one
of four single-stranded ribonucleic acid viruses of the family
Flaviviridae and are transmitted by their mosquito vector, Aedes
aegypti. The clinical syndromes caused by dengue viral infections
occur along a continuum; most cases are asymptomatic and few
present with severe forms characterized by shock. Management
is predominantly supportive and includes methods to judiciously
resolve shock and control bleeding while at the same time preventing fluid overload.
Conclusions: Dengue is no longer confined to the tropics and
is a global disease. Treatment is supportive. Outcomes can be
optimized by early recognition and cautious titrated fluid replacement, especially in resource-limited environments. (Pediatr Crit
Care Med 2011; 12:90 100)
KEY WORDS: dengue hemorrhagic fever; dengue shock syndrome; shock; immunopathogenesis; diagnosis; management;
children; critical illness

(1, 2, 4 6). The disease is encountered

virtually throughout the tropics, and the
2005 World Health Assembly resolution
included dengue as an example of a disease that may constitute a public health
emergency of international concern with
implications for health security due to
rapid epidemic spread beyond national
borders (2).
In this article we review the epidemiology, immunopathogenesis, clinical syndromes, diagnosis, management, and
prevention of dengue.

Method
Boolean searches were carried out by
using PubMed from 1975 to March 2009
and the Cochrane Database of Systematic
Reviews from 1993 to December 2009 to
identify potentially relevant articles by
key search terms such as: dengue; dengue fever; dengue hemorrhagic fever;
dengue shock syndrome; dengue and
immunopathogenesis, pathogenesis,
classification, complications, management, and prevention. We also
searched the extensive bibliography lists
of the relevant articles. Case reports were

considered only if pertinent. Only English-language articles were included.

We considered the most relevant articles that would be important and of interest to the critical care practitioner. In
particular, we attempted to find metaanalyses or well-designed randomized,
controlled trials to support a recommendation for intervention and treatment.
When none was available, we cited an
authoritative consensus statement or a
clinical guideline such as those from major medical organizations or international health agencies and bodies such as
the World Health Organization (WHO)
and the Centers for Disease Control and
Prevention.

Epidemiology
In the past 50 yrs, the prevalence of
DF has increased 30-fold, and significant
outbreaks have occurred in five of six
WHO regions. It is now endemic in 112
countries; Southeast Asia and the western Pacific have the most serious afflictions (4, 5, 7). Case fatality rates vary
from 1% to 5% (8) but can be 1% with
appropriate treatment (2). The reasons
for the global resurgence of epidemics of
Pediatr Crit Care Med 2011 Vol. 12, No. 1

dengue are complex and include largescale population migration, increased air
travel, unprecedented global population
growth, and uncontrolled urbanization,
all of which facilitate transmission and
increase densities of Aedes (Ae.) aegypti
borne disease (5, 6, 9). Dengue has also
been transmitted via blood transfusion
and organ transplantation (10).
Dengue Viruses. There are four closely
related but serologically distinct dengue
viruses (DVs), members of the Flavivirus
genus of the Flaviviridae, called DEN-1,
DEN-2, DEN-3, and DEN-4. Lifetime immunity follows infection by one serotype,
but immunity to the other serotypes is
short-lived (11, 12).
Mosquito Vectors. Mosquitoes that belong to the genus Aedes play a pivotal role
in the transmission of dengue. The principal vector is Ae. aegypti, but Ae. albopictus and Ae. polynesiensis may act as
vectors depending on the geographic location (6, 12).
Viral Replication and Transmission
Cycle of DV. Both epidemic and endemic
transmission of DV are maintained
through a human-mosquito-human cycle
in which humans are the amplifying host.
DV is introduced into the skin by the bite
of an infected female Aedes mosquito.
Viremia in susceptible humans begins between 3 and 6 days after subcutaneous
injection, lasts for another 3 6 days, and
ends as the fever resolves (6, 13, 14).
Dengue can essentially be excluded as the
cause of symptoms in a traveler who develops an illness 14 days after returning
from a dengue-endemic country (15).

Immunopathogenesis of DV
Infections
The immunopathogenesis of severe
DV infections is complex and remains incompletely understood; however, severe
dengue is differentiated from its milder
forms by the presence of increased vascular permeability (1, 2, 9, 12). A few salient
features may explain the dramatic clinical
manifestations.

T-Cell Activation and Apoptosis. Intense T-cell activation and massive apoptosis may lead to the sudden onset of
vascular permeability and hemorrhage
that characterizes severe forms of dengue
disease (12). In some patients with secondary dengue infections, however, the
T-cell response may cause suboptimal
killing of the DV-infected monocytes and
serve to augment the severity of the second infection due to higher viral loads
(12, 16).
Neutralizing Antibodies and AntibodyDependent Enhancement. The severity of
secondary infection with a different DV
serotype depends on the balance between
neutralizing vs. enhancing heterotypic
antibodies after the first infection. This
phenomenon has been called antibodydependent enhancement and is one of
the best known hypotheses in the immunopathogenesis of severe dengue (9,
1719).

Factors that Influence Disease

Severity
Most DV infections produce, in decreasing order of frequency, an asymptomatic infection, mild nonspecific symptoms, or classic dengue (1, 9). The more
severe manifestations of shock and hemorrhage occur in 5% of DV infections
(9, 11). Complex, interlinked mechanisms determine whether mild or severe
disease occurs (9).
Primary vs. Secondary Infection. The
greatest risk factor for the development
of severe dengue is secondary infection
with a different dengue serotype from the
original infecting virus (9, 11, 12). Severe
illness during secondary dengue infections was associated with higher peak
plasma virus titers (20).
Age. Dengue hemorrhagic fever (DHF)
is primarily a disease of infants and children (1, 9), although adults may also be
afflicted with severe disease (21). Infants
can develop features of severe disease
even during a primary DV infection when
their transplacentally acquired maternal

Figure 1. The traditional 1997 World Health Organization classification of dengue (1).

Pediatr Crit Care Med 2011 Vol. 12, No. 1

antibody levels decline below the neutralization threshold (12, 22, 23).
Nutritional Status. Unlike other infectious diseases, severe forms of dengue are
more common in well-nourished children,
and grade 2 or 3 protein-calorie malnutrition protects against severe dengue vasculopathy. This negative association may be
related to suppression of cellular immunity
in malnutrition (11, 24).

Classification and Clinical

Course of Dengue
The widely used 1997 WHO classification grouped patients with symptomatic
dengue infections into three categories: undifferentiated fever; DF; and DHF (1) (Fig. 1).
However, with dengue being encountered in newer geographical areas, considerable overlap between the groups has
been reported, and it is likely that the
various categories exist as a continuum
rather than separate entities (2, 9, 25
27). Similarly, the classification inherently assumed that DF was a mild disease
and that only cases of DHF were severe;
thus, patients even with severe and lifethreatening manifestations of dengue
could not be included as having DHF
unless all criteria were present. This had
adverse effects at various levels, including
during triage, disposition, and treatment
decisions, the urgency of which was dictated by the severity classification of dengue (25). Furthermore, the term DHF
puts undue emphasis on hemorrhage;
however, the hallmark of severe dengue
(and the manifestation that should be addressed early) is not hemorrhage but increased vascular permeability, which
leads to shock (12). Authors of a WHO/
Tropical Disease Researchsupported,
prospective, clinical, multicenter study
across dengue-endemic regions proposed
a revised and simplified dengue case classification in a move to help clinicians
identify rapidly and treat adequately the
most severe, life-threatening forms of the
disease (2, 28).
The new system divides dengue cases
into just two major categories of severity: a)
dengue (with or without warning signals);
and b) severe dengue (2, 28) (Fig. 2).
Clinical Manifestations and Phases.
Dengue is a systemic and dynamic disease
with a wide spectrum of clinical presentations that range from mild to severe;
however, the clinical evolution and outcome may be highly unpredictable.
The course of illness is characterized
by three well-demarcated phases: febrile;
91

Figure 2. New simplified classification of dengue viral infections, World Health Organization 2009.
CNS, central nervous system.

Figure 3. Phases of dengue in relation to symptoms and laboratory changes. AST, aspartate transaminase; ALT, alanine aminotransferase; CNS, central nervous system; IgM, immunoglobulin M; IgG,
immunoglobulin G. Adapted with permission from World Health Organization: Dengue Hemorrhagic
Fever: Diagnosis, Treatment, Prevention and Control. Third Edition. Geneva, WHO/TDR, 2009.

critical; and recovery (2). Although most

patients recover after a self-limiting, nonsevere, clinical course, a small proportion
progress to have severe disease, which is
characterized by plasma leakage with or
without hemorrhage (2).
Clinical Phases of Dengue. After the
incubation period, the illness begins
abruptly and is followed by the three
phases (Fig. 3).
Phase 1: The febrile phase. Typically, a
patient develops a high-grade fever that
92

lasts 27 days and is acutely unwell with

headache, diffuse erythema, generalized
myalgia, and arthralgia; anorexia, nausea,
and vomiting are also common. Younger
children may develop febrile seizures. It
may be difficult to distinguish dengue
clinically from other viral fevers, although demonstration of microvascular
fragility by a positive tourniquet-test result increases the likelihood that it is
dengue (2). Frequent meticulous monitoring for warning signs and other clini-

cal parameters (Fig. 2) is crucial for recognizing progression to the critical

phase. Although a tender hepatomegaly
and mild hemorrhagic manifestations
(petechiae and mucous membrane bleeding from nasal or oral cavity) may be seen
often, significant bleeding episodes from
the gastrointestinal tract or menorrhagia
are uncommon occurrences in the febrile
phase. The earliest laboratory abnormality is a progressive leukopenia, which is
another clue to the presence of probable
dengue.
Phase 2: The critical phase. The critical phase begins around the period of
defervescence, when several important
occurrences mark their presence in quick
succession. Leukopenia progresses further, and a rapid decrease in platelet
count usually occurs. This precedes the
most specific and life-threatening manifestation of this phase: an increase in
capillary permeability that leads to
plasma leakage and an equivalent rise in
hematocrit (Hct).
Plasma leakage begins during the febrile phase, but at a time when the viral
load and body temperature are declining,
and develops rapidly over a period of
hours. The period of plasma leakage is
short-lived, typically lasting 24 48 hrs.
However, the extent of plasma loss is
highly variable and is the key that determines the clinical severity in the critical
phase (i.e., whether the patient recovers
uneventfully, develops dengue with warning signs, or, in a small proportion with
extensive plasma leak, progresses to have
severe dengue).
Some patients with a nonsevere form
of dengue do not develop plasma leak and
steadily improve after defervescence.
Prolonged uncorrected shock, metabolic acidosis, and thrombocytopenia
may worsen disseminated intravascular
coagulation, which may, in turn, lead to
massive hemorrhage, thus setting off a
progressive downward spiral of worse
shock and hemorrhage (1, 11, 12, 29);
these patients are at high risk of death.
Apart from shock and hemorrhage,
other important consequences of increased capillary permeability are
hemoconcentration, hypoalbuminemia,
and serous fluid collections, usually pleural effusions and ascites, the extent of
which depends both on the magnitude of
plasma leak and the volume of fluids consumed or prescribed (1, 2).
Early confirmation of plasma leakage
in the critical phase may be provided by
serial laboratory studies with complete
Pediatr Crit Care Med 2011 Vol. 12, No. 1

blood counts demonstrating the triad of

progressively increasing Hct, leukopenia,
and thrombocytopenia, ultrasound findings of a thickened gall bladder wall, and
ascitic and pleural fluid and chest radiograph showing pleural effusions (1, 2).
These findings are useful for triage and
therapy because they may be present
much earlier than signs of plasma loss
are clinically manifest and also indicate
progress to the critical phase in patients
who do not defervesce despite the onset
of plasma leakage (2, 11, 12). Evaluating
hemoconcentration in patients with preexisting anemia may be difficult, because
the preillness Hct level may be unavailable at the time of admission. Using the
population baseline may be useful (2),
such as a cutoff Hct value (36%) in Indian
children due to the high prevalence of
iron-deficiency anemia (30).
Phase 3: The recovery phase. After the
critical 24 48 hrs of plasma leakage,
the final recovery phase is heralded by the
gradual resorption of the leaked plasma
back into the intravascular compartment
over the next 48 72 hrs. The patient may
exhibit dramatic improvement with an
overall sense of well-being, improved appetite, a stable hemodynamic status, and
a brisk diuresis. Pruritis and an asymptomatic bradycardia may be marked (1,
2). The blood picture reflects the recovery
phase with a lower Hct level on account
of the reabsorbed fluid and a white cell
increment that may precede platelet recovery.
Recognition of this phase is important
so that intravenous (IV) fluids may be
promptly ceased. This simple intervention may prevent fluid overload (FO),
which, along with severe hemorrhage, is
an important, preventable cause of death
by dengue (Fig. 3).
Features of Severe Dengue. Severe
dengue occurs in a small proportion of
patients and is defined by one or more of
the following: 1) shock due to plasma
leakage, which is usually associated with
fluid accumulation and consequent respiratory symptoms; 2) severe bleeding; and
3) severe organ impairment (liver, neurologic symptoms, renal or myocardial
dysfunction) (Fig. 2) (2, 28).
1) Shock in severe dengue. The hypovolemic shock in dengue may initially be
compensated with a normal systolic
blood pressure (BP), elevated diastolic
BP, narrow pulse pressure, and features
of hypoperfusion, such as cold mottled
skin, although in some patients, significant tachycardia may be absent (31). DifPediatr Crit Care Med 2011 Vol. 12, No. 1

ficulties in successful treatment of severe

dengue stem from the dynamicity of dengue, which makes it a challenge to detect
and manage, especially for the uninitiated physician even experienced clinicians may be caught unaware. It is this
dynamicity that may account for delays in
recognition of the severity of circulatory
compromise, which can be subtle: systolic BP may be maintained until late,
and patients even in advanced shock often remain alert (1, 2).
As shock progresses, the diastolic BPs
and then the systolic BPs become unrecordable, and if they are not promptly
reversed, the patient may progress to
have multiorgan failure and a complicated course.
2) Bleeding and hemorrhagic manifestations in severe dengue. Common sites
are from the gastrointestinal tract manifesting as hematemesis or melena (2, 32,
33). However, even with severe dengue,
in which marked thrombocytopenia and
coagulation abnormalities are frequent
(34, 35), major life-threatening bleeds are
rare: the most important risk factor for
significant hemorrhage is prolonged
shock, especially when complicated by
acidosis and hypoxia (2, 29, 36). Other
risk factors for bleeding are the presence
of hepatic and/or renal dysfunction (2);
drug (e.g., nonsteroidal anti-inflammatory drug) exposure; and procedures such
as nasogastric tube insertion, arterial
puncture, or intramuscular injections.
3) Severe organ impairment. Severe
organ impairment is the third criteria for
severe dengue (37) and includes acute
liver failure, encephalopathy/encephalitis, renal failure, and myocardial dysfunction. These may also contribute to mortality and may occur even in the absence
of severe plasma leakage or shock (2).
Liver failure may be caused by a direct
viral effect with hepatitis or focal necrosis
of the liver and is associated with a high
mortality rate (37, 38). Elevated transaminase levels have been documented to occur as part of dengue (1) and also after
resuscitation from shock (ischemic hepatitis) (38).
Neurologic complications. Patients
with severe dengue may present with a
wide variety of neurologic manifestations
including encephalopathy, seizures, and
acute pure motor weakness (11, 32, 38,
39). The DV has been isolated from the
cerebrospinal fluid of some patients having features of encephalitis (40). In the
critical phase, cerebral hypoperfusion
may result in altered mental status, con-

vulsions, and extensor posturing; these

neurologic signs can improve when the
perfusion normalizes. Other causes of
central nervous system symptoms in the
patient with severe dengue are coexisting
central nervous system infections (bacterial, viral, or malarial), dengue encephalopathy/encephalitis, electrolyte disorders, intracranial hemorrhage, and
fulminant hepatic failure (38). During recovery, cerebral edema from FO may lead
to obtundation and seizures. The precise
cause may be difficult to separate and
requires a consideration of the phase of
dengue and thorough clinical examination in conjunction with laboratory and
radiologic investigations to rule out systemic causes, electrolyte derangements,
and specific organ insults.
Cardiac dysfunction. Plasma leakage
and/or hemorrhage causing hypovolemia
and a compensatory elevated systemic
vascular resistance are the predominant
mechanisms of shock in severe dengue
(2, 31). Although primary myocardial insult in dengue is infrequent, there have
been a few reports of relative bradycardia
contributing to low cardiac output (31)
and acute ST-segment and T-wave
changes on electrocardiogram, together
with low ejection fractions and global hypokinesia on radionuclide ventriculography (41, 42). No myocardial necrosis was
detected in any of the patients, which
suggests that myocardial dysfunction
might either be attributable to humoral
factors or coronary hypoperfusion (43).
Both systolic and diastolic dysfunction
have been reported to cause refractory
shock (38, 44).
Other complications include hemolytic uremic syndrome (1, 32) and coinfections in endemic areas (malaria, leptospirosis, enteric fever) (1, 38). Although
severe abdominal pain presenting as a
surgical emergency had been previously
classified as an uncommon manifestation
(32), severe intense abdominal pain is
now recognized as one of the most important warning signs heralding significant plasma leakage and imminent
shock. Dengue has also been described as
an important cause of hemophagocytic
lymphohistiocytosis (45) and pediatric
multiorgan failure (46, 47).

Diagnosis
Although the diagnosis of acute DV
infection is mainly clinical (1), pediatric
caregivers frequently find making an
early diagnosis challenging, because the
93

initial symptoms are often nonspecific,

many common tropical infections can result in a presentation with fever and
thrombocytopenia with or without shock,
viremia may be below detectable levels,
and serological tests confirm dengue only
late in the course of illness (2, 48). Performing a tourniquet test at each visit
may help differentiate dengue from other
viral infections. Taking note of the temporal sequence of symptoms is as important as recording their presence, because
with dengue, it is at the time of defervescence that the disease manifests its severity, unlike other viral illnesses for which
a clinical improvement is to be expected
with a decline in body temperature (2).
Ramos et al (49) have attempted to identify the clinical features that predict a
laboratory-positive dengue infection and
concluded that the presence of highgrade fever, rash, petechiae, or mucosal
bleeds in the absence of cough and other
respiratory symptoms has a very high
positive predictive value of confirmed
dengue infection.
Differential Diagnosis. In addition to
bacterial septic shock, the differential diagnoses that must be considered in the
appropriate epidemiologic settings include malaria, leptospirosis, typhoid fever, and meningococcal septic shock (1,
2, 11). Confusion may also arise when a
patient with suspected dengue presents
with central nervous system symptoms.
Although central nervous system symptoms may result from the dengue viral
infection or complications detailed previously, coinfections are not uncommon,
and if the clinical or laboratory features
are atypical for dengue, or coexisting infections cannot be ruled out, appropriate
empirical antimicrobials (antibiotics, antiviral agents, or antimalarial agents)
should be initiated after drawing samples
for laboratory confirmation and appropriate cultures.
The choice of antimicrobials depends
on the patients symptoms and signs,
prevalent infections in the community,
and their resistance patterns. Early empirical antibiotics for suspected septic
shock or central nervous system infections are important, because delays in
initiation of appropriate antibiotics have
been shown to worsen outcomes (50).
Cranial imaging may be necessary in the
presence of a neurologic presentation.
Performing a lumbar puncture may be
hazardous in a bleeding, thrombocytopenic patient in whom the hemodynamics
is precarious (51). A lumbar puncture to
94

determine any concurrent central nervous system infection may be more safely
performed when the patient is stable.
Empirical antimicrobials may be deescalated once the clinical picture emerges
with greater clarity and culture results
are available.
Laboratory Confirmation of Dengue.
There are three main methods for diagnosing DV infections (1, 9, 12, 48): serological tests; virological diagnosis; and
molecular methods including the polymerase chain reaction. The choice of test
depends on whether the patient is in the
initial stage, in which fever and viremia
are present (virological and molecular diagnosis most appropriate), or the postpyrexial period, which lasts a few weeks
(serological tests appropriate) (12).
Viral Isolation and Identification by
Using Mosquito Cell Lines. Serum inoculation either into mosquito cell lines or
directly into mosquitoes is the most common method for virus isolation (9).
Molecular Diagnosis. The sensitivity,
specificity, and rapid detection of minute
quantities of dengue viral material in the
patients serum makes reverse-transcriptase polymerase chain reaction useful for the detection of dengue infection
early in the disease (within 48 hrs) when
antibodies are not detected (52). A recently available test that can diagnose
dengue within the first few days of fever is
the nonstructural protein-1 monoclonal
antibody in an enzyme-linked immunosorbent assay format that can detect
dengue nonstructural protein-1 antigen
in blood (12, 53).
Serologic Testing. Confirmation of
acute DV infection is most frequently accomplished by using serology (1, 2). Serologic tests for the diagnosis of acute DV
infection include the hemagglutination
inhibition assay and immunoglobulin G
(IgG) or IgM enzyme immunoassays (52).
The IgM antibody-capture enzyme-linked
immunosorbent assay is the test most
widely used, because it is relatively inexpensive, sensitive, and quick and simple
to perform; however, it suffers from low
sensitivity compared with the hemagglutination-inhibition assay (11, 32).
The development of several rapid diagnostic kits, which use immunochromatographic or immunoblot technologies, has enabled rapid bedside
serological testing; however, the diagnostic accuracy may be low in terms of
sensitivity and specificity (9, 54).
Laboratory Studies to Monitor Disease Progression and Complications. The

Table 1. Laboratory findings in the critical phase

of dengue
Hematologic investigations
Elevated hematocrit level
Low platelet counts (100,000 cells/mm3)
Progressive leukopenia with atypical
lymphocytes
Abnormal coagulation profile
Biochemical investigations
Hypoalbuminemia
Electrolyte disturbances (hyponatremia)
Metabolic acidosis
Elevated liver enzyme levels
Imaging features
Thickened gall bladder wall
Pleural effusions, right more frequent than
left
Ascites

earliest evidence of plasma leak in the

critical phase of dengue as alluded to
earlier may be obtained by serial blood
counts that demonstrate an increasing
Hct level, progressive leukopenia and
thrombocytopenia, and ultrasound findings of a thickened gall bladder wall, as
well as ascitic and pleural fluid (Table 1)
(2, 12, 55). If formal laboratory services
are unavailable, a microcentrifuge can be
used to estimate capillary Hct at the bedside. Other tests may be dictated by the
clinical status and include measurements
of glucose, electrolytes, blood gases, and
lactate and tests of renal, liver, and coagulation function.

Management of Patients With

Dengue
For such a complex, dynamic, and unpredictable disease, successful outcomes
with mortality rates of 1% can be
achieved in the vast majority of patients
with surprisingly simple and inexpensive
interventions, provided they are early, appropriate, and continuously targeted to
keep pace with the disease evolution. This
underscores the vital importance of empowering the front-line healthcare personnel (doctors and nurses) at primary
and secondary health centers, clinics, and
hospitals to facilitate early recognition
and carefully monitor IV rehydration.
Priorities during initial patient contact are to establish whether a patient has
dengue, determine the phase of disease
(febrile, critical, or recovery), and recognize warning signs and/or the presence of
severe dengue, if present. In addition to a
physical examination, a complete blood
count in the febrile phase serves several useful functions if the patient
Pediatr Crit Care Med 2011 Vol. 12, No. 1

progresses to the critical phase: knowledge of the patients baseline Hct level
can provide early information indicating
onset of plasma leak, can quantitate the
extent of plasma loss, is a good guide to
fluid replacement, and, in conjunction
with other signs, can indicate occult
blood loss (2).
Most patients with DF and DHF can be
managed without hospitalization provided they are alert, there are no warning
signs or evidence of abnormal bleeding,
their oral intake and urine output are
satisfactory, and the caregiver is educated
regarding fever control and avoiding nonsteroidal anti-inflammatory agents and is
familiar with the course of illness. A dengue information/home care card that emphasizes danger/warning signs is important (2). These patients need daily clinical
and/or laboratory assessment by trained
doctors or nurses until the danger period
has passed. For a more detailed guide to
outpatient assessment and monitoring,
the reader may refer to the 2009 WHO/
Tropical Disease Research document on
Dengue (2).
If dengue is suspected or confirmed,
disease notification to public health authorities is important so that preventive
measures may be set into motion.
Indications for hospitalization and IV
fluids include warning signs (Fig. 2) of
significant plasma leak, of which severe,
intense abdominal pain is considered the
most important; other warning signs are
persistent vomiting, restlessness or lethargy, clinical fluid accumulation, mucosal or other significant bleeds, lethargy or
restlessness, and a rise in Hct level, along
with a rapid decrease in platelet count (2,
28). Infants and patients with comorbid
conditions such as diabetes, renal failure,
or obesity may also require admission.
Indications for intensive care unit admission include children with severe dengue manifesting with shock, respiratory
distress, abnormal bleeding, or organ failure, e.g., neurologic complications or
liver and/or renal dysfunction (1, 2, 38).
The three major priorities of management of hospitalized patients with dengue in the critical phase are replacement
of plasma losses, early recognition and
treatment of hemorrhage, and prevention
of FO.
Replacement of Plasma Losses
Goals of Fluid Management in Dengue.
IV rehydration is the single most important intervention that can correct shock
and save lives in both severe and nonsevere forms of dengue, provided it is
Pediatr Crit Care Med 2011 Vol. 12, No. 1

timely and appropriate. Yet, the seemingly simple task of getting the prescribed fluid just right is often challenging, demands the highest level of
clinical judgment, and is ultimately the
key that differentiates a good vs. bad outcome in sick children with dengue. In
resource-limited, tropical areas of the
world in which dengue outbreaks are
most common, intensive care facilities
for monitoring and treatment of shock
and respiratory failure may be unavailable (56). The goals of treatment of dengue shock are necessarily two-pronged
and include both early recognition and
reversal of shock and simultaneously
avoiding FO and the consequent need for
ventilation by using simple monitoring
tools (5759). These goals may be facilitated by aiming to restore a minimally
acceptable circulating volume that is adequate to establish perfusion to vital organs and avoid hemorrhage and multiorgan failure (2, 5759). In addition, serial
monitoring and correction of coexisting
hypoglycemia, hypocalcemia, and electrolyte abnormalities are important.
Titrating fluid therapy in dengue.
Fluid therapy in a patient with dengue
shock has two parts: initial, rapid fluid
boluses to reverse shock followed by titrated fluid volumes to match ongoing
losses (2). However, for a patient who has
warning signs of plasma leakage but is
not yet in shock, the initial fluid boluses
may not be necessary (Table 2).
The best methods for titrating fluid
therapy and detecting early signs of hem-

Table 2. Volume-replacement flowchart for patients with dengue with warning signs
Assess airway and breathing and obtain
baseline Hct level
Commence fluid resuscitation with normal
saline/Ringers lactate at 57 mL/kg over 12
hrs
If hemodynamics and Hct level are stable,
plan a gradually reducing IVF regimen
Titrate fluids on the basis of vital signs,
clinical examination, urine output (aim for
0.51 mL/kg/hr), and serial Hct level
IVFs, 57 mL/kg/hr for 12 hrs, then:
Reduce IVFs to 35 mL/kg/hr for 24 hrs;
Reduce IVFs to 23 mL/kg/hr for 24 hrs
Continue serial close clinical monitoring and
every 68 hourly Hct level
Oral rehydration solutions may suffice when
vomiting subsides and hemodynamics
stabilize
A monitored fluid regimen may be required
for 2448 hrs until danger period subsides
Hct, hematocrit; IVF, intravenous fluid.

orrhage are repeated, meticulous, clinical

evaluation in conjunction with analysis of
serial Hct trends by experienced caregivers. Sophisticated invasive monitoring is
rarely necessary unless patients arrive
late with established shock. The end
points/targets of fluid administration are
normalization of the systolic BP (if low)
and obtaining a pulse pressure of 30
mm Hg, a urine output of 0.51 mL/
kg/hr with stable vital signs, and a gradual decrease in the elevated baseline Hct
level (1, 2, 5759). Monitoring hourly
urine output serves two important goals:
an output of 0.51.0 mL/kg/hr with stable
vital signs indicates shock reversal and
ensures a minimal acceptable circulating
volume, whereas an output of 1.52
mL/kg/hr may be the earliest indicator of
overhydration/FO with the potential risk
of respiratory insufficiency (59) (Table 3).
Similarly, assessing two Hct values at
4-hr intervals in conjunction with the
circulatory status will provide valuable
clues. A high or increasing Hct level indicates the need for increased volumes of
crystalloids if the patient has unstable
hemodynamics, whereas in a stable patient, an experienced clinician may elect
to monitor the patient closely without
increasing fluid rates. Likewise, a low or
normal Hct level in conjunction with
shock may be an important indicator of
occult hemorrhage and the need for urgent blood transfusion, whereas in a stable patient in the recovering phase,
prompt cessation of IV fluids is the most
important action indicated (2).
The critical phase of plasma loss may
continue for 24 48 hrs, necessitating
constant, careful titration of fluid administration tailored to the clinical status,
Hct level, and urine output for this period
(2, 56 58). A detailed flowchart recording
hourly vital signs, fluid balance, circulatory status, and Hct level is essential.
Table 2 and Figures 4 and 5 suggest an
approach for treating dengue with warning signs and dengue with compensated
shock and hypotensive shock, respectively. Figure 6 outlines the approach to
late presenters with established shock,
and Table 3 provides suggestions for controlled fluid resuscitation in dengue
shock syndrome (DSS) while at the same
time attempting to prevent/minimize FO.
Differences between DSS and septic
shock. Compared to children with septic
shock, who often require rapid, largevolume fluid resuscitation (60), there are
major differences both in the rates and
volumes of fluid resuscitation for dengue
95

Table 3. Guidelines for reversing dengue shock while minimizing fluid overload
1. Severe dengue with compensated shock: Stabilize airway and breathing, obtain baseline Hct
level, initiate fluid resuscitation with NS/RL at 510 mL/kg over 1 hr, and insert urine catheter
early.
2. Severe dengue with hypotension: Stabilize airway and breathing, obtain baseline Hct level,
initiate fluid resuscitation with 12 boluses of 20 mL/kg NS/RL or synthetic colloid over 1520
mins until pulse is palpable, slow down fluid rates when hemodynamics improve, and repeat
second bolus of 10 mL/kg colloid if shock persists and Hct level is still high.
3. Synthetic colloids may limit the severity of fluid overload in severe shock.
4. End points/goals for rapid fluid boluses: Improvement in systolic BP, widening of pulse
pressure, extremity perfusion and the appearance of urine, and normalization of elevated Hct
level.
5. If baseline Hct level is low or normal in presence of shock, hemorrhage likely to have
worsened shock, transfuse fresh WB or fresh PRBCs early.
6. After rapid fluid boluses, continue isotonic fluid titration to match ongoing plasma leakage for
2448 hrs; after shock correction, if patient not vomiting and is alert, oral rehydration fluids
may suffice to match ongoing losses.
7. Check Hct level hourly to twice hourly for first 6 hrs, and decrease frequency as patient
improves.
8. Goals for ongoing fluid titration: Stable vital signs, serial Hct measurement showing gradual
normalization (if not bleeding), and low normal hourly urine output are the most objective
goals indicating adequate circulating volume; adjust fluid rate downward when this is achieved.
9. Plasma leakage is intermittent even during the first 24 hrs after the onset of shock; hence,
fluid requirements are dynamic.
10. Targeting a minimally acceptable hourly urine output (0.51 mL/kg/hr) is an effective and
inexpensive monitoring modality that can signal shock correction and minimize fluid overload.
11. A urine output of 1.52 mL/kg/hr should prompt reduction in fluid infusion rates, provided
hyperglycemia has been ruled out.
12. Separate maintenance fluids are not usually required; glucose and potassium may be
administered separately only if low.
13. Hypotonic fluids can cause fluid overload; also, avoid glucose-containing fluids, such as 1/2
GNS (GNS or I/2 GNS): the resultant hyperglycemia can cause osmotic diuresis and delay
correction of hypovolemia.
14. Commence early enteral feeds when vital signs are stable, usually 48 hrs after admission.
15. All invasive procedures (intubation, central lines, and arterial cannulation) must be avoided; if
essential, they must be performed by the most experienced person. Orogastric tubes are
preferred to nasogastric tubes.
16. Significant hemorrhage mandates early fresh WB or fresh PRBC transfusion; minimize/avoid
transfusions of other blood products, such as platelets and fresh-frozen plasma unless bleeding
is uncontrolled despite 23 aliquots of fresh WB or PRBCs.
NS/RL, normal saline/Ringers lactate; Hct, hematocrit; BP, blood pressure; WB, whole blood;
PRBC, packed red blood cell; GNS, 5% glucose in normal saline; 12 GNS, 5% glucose in 12 normal saline.

Figure 4. Volume-replacement flowchart for patients with severe dengue and compensated shock. IV,
intravenous.

96

shock. Wills et al (57) have used much

lower fluid resuscitation rates in 500
patients with DSS, and these restricted
volumes were successful in not only reversing shock but also minimizing complications of FO, including the need for
assisted ventilation. The authors reported
mortality rates in the range of 0.2% with
slow fluid-filling at rates of 25 mL/kg over
the first 2 hrs. Although there is no evidence that colloids are superior to crystalloids for resuscitation, colloids are often used for severe dengue shock (2, 57).
The significant differences in fluid resuscitation volumes for septic vs. dengue
shock may probably relate to the fact that
patients with dengue shock are vasoconstricted with a narrow pulse pressure as
opposed to the predominantly vasodilated
states in septic shock (2, 59).
When can IV hydration be discontinued? Cessation of IV fluids is important
for preventing FO and can be considered
24 48 hrs after defervescence when the
hemodynamics, Hct level, and urine output are stable, despite minimal IV fluids,
especially if the patient is tolerating oral
fluids.
Recognition and Management of
Hemorrhage. Early detection of signs of
hemorrhage, especially when the losses are
internal, is important. Failure to recognize
and treat occult hemorrhage on an emergent basis is one of the most important yet
preventable causes of death (2). Hemorrhage should be considered in the critical
phase of dengue when the Hct level is normal or lower than expected for the degree
of shock or the hemodynamics fails to normalize despite the initial 40 60 mL/kg of
crystalloids/colloids (2).
Clinical features of significant hemorrhage may be subtle and include increase
in tachycardia, abdominal distension
and/or tenderness, stress-induced leukocytosis (instead of the characteristic leukopenia), agitation/lethargy, acidosis, and
evidence of worsening organ function (2).
Frank hypotension with dengue usually
indicates significant hemorrhage but is a
late manifestation, and blood transfusion
should be initiated emergently before this
occurs. The most important intervention
for a patient with dengue shock and lifethreatening bleeding is restoration of oxygen-carrying capacity with fresh whole
blood (WB) or packed red blood cell
(PRBC) transfusions; this must be done
emergently rather than waiting for the Hct
level to decrease significantly. The 2009
WHO dengue guidelines emphasize that,
in a bleeding patient with dengue, the
Pediatr Crit Care Med 2011 Vol. 12, No. 1

Figure 5. Suggested approach to a patient with severe dengue and hypotension. NS/RL, normal
saline/Ringers lactate.

threshold for PRBCs/WB must be higher

than that suggested for septic shock, for
which an Hct level of 30% is the usual
transfusion threshold (2, 60). This is because hemorrhage with dengue is most often preceded by a background of protracted
shock due to plasma leak, which results in
the characteristic elevated Hct level.
Correction of shock with two or more
aliquots of fresh WB/PRBCs usually
breaks the vicious cycle of acidosis, hypoperfusion, and disseminated intravascular coagulation by restoring circulating
volume and improving tissue oxygen delivery (2). This should be administered in
a controlled fashion to prevent FO. Administration of other blood components,
such as platelets, fresh-frozen plasma, or
cryoprecipitate, may contribute to volume overload and are not as important as
fresh WB or PRBCs (2) unless the bleeding is ongoing despite 23 aliquots of
blood transfusion. It is also important to
remember that preventive platelet transfusion is unlikely to decrease the incidence of significant bleeding (61). Other
infrequently reported interventions for
patients with bleeding and refractory
thrombocytopenia are IV anti-D immunoglobulin 250 IU/kg (62), IV immunoglobulin (63), and recombinant activated factor VII (64); all these therapies
are expensive, not proven to be of clinical benefit, and not currently recommended (2).
Although the two most important
causes of persistent or recurrent shock
Pediatr Crit Care Med 2011 Vol. 12, No. 1

are uncorrected hypovolemia due to ongoing plasma leakage and hemorrhage,

other infrequent causes of persistent
shock are myocardial dysfunction and abdominal compartment syndrome (ACS),
the latter may be encountered in late
presenters (38, 44).
Myocardial dysfunction in dengue is
most often a secondary phenomena due
to the detrimental adaptive phenomena
of prolonged uncorrected hypovolemic
shock (e.g., excessively elevated systemic
vascular resistance causing coronary
ischemia) that may be further aggravated
by high doses of inotropes/pressors. Although primary myocardial dysfunction,
including both systolic and diastolic dysfunction, has been described in children
with dengue (31, 41 43), it is an uncommon entity and is much less frequent in
DSS compared to septic shock (58). Caregivers must desist from overzealous prescriptions of inotropes, because these
agents can paradoxically worsen the
shock state, especially if hypovolemia is
still uncorrected. Inotrope/pressor support may occasionally be indicated in late
presenters with dengue shock when features of low cardiac output persist, despite having received 40 60 mL/kg of
fluid and correction of blood loss, i.e.,
patients with fluid/blood transfusion refractory shock in whom myocardial dysfunction is suspected or confirmed by
echocardiography (if resources and expertise are available) (Fig. 6). Inotropes
must be ceased if tachycardia or the

shock state worsens after initiation. Pressors may also be indicated before intubation of a patient with dengue shock, because some patients may have
catastrophic decompensation during this
period.
Indications for Central Venous Pressure Monitoring. Central venous pressure
monitoring has limited utility for DSS
and is seldom indicated except in late
presenters (Fig. 6). The risks of central
venous catheter insertion are usually
greater than the benefits, but if shock
persists despite 40 60 mL/kg fluids and
correction of suspected hemorrhage, an
experienced operator may consider insertion of a central venous catheter. Ultrasound-guided placement, if available, will
minimize complications (2).
FO in Severe Dengue. Apart from
plasma leak and hemorrhage, the third
major management issue in the critical
phase of dengue relates to FO and pulmonary edema (PE). IV rehydration is the
sheet anchor of shock therapy; however, a
significant proportion of the administered fluid will inevitably leak out of the
vascular compartment with worse edema,
fluid collections, and respiratory insufficiency. Overhydration and pathologic
fluid collections can easily occur if more
fluid than that sufficient to maintain a
minimal acceptable circulating volume is
prescribed. Apart from PE, overzealous
fluid administration can also cause tense
large-volume ascites, which may lead to
ACS (1, 38). Strategies for preventing
FO/PE include avoiding prophylactic
blood product transfusions in nonbleeding patients (even if thrombocytopenia
and coagulopathy are significant) (2, 6,
61). Also important is prompt cessation
of IV fluids during the recovery phase,
because resorption of the leaked plasma
occurs during this period and extraneous
IV fluid can easily worsen FO, precipitate
PE, and large pleural and/or ascitic collections (2).
Despite these strategies, some patients
may develop hypoxemic respiratory failure
with respiratory distress and need positivepressure ventilation, including nasal continuous positive airway pressure (64).
Treatment of Established FO: Diuretics and Peritoneal Dialysis. Postresuscitation fluid-removal strategies, such as
diuretic infusions, should not be necessary at all if fluid resuscitation was done
judiciously; however, on occasion, furosemide boluses, continuous infusions,
and even peritoneal dialysis have been
used (44). The decision to administer di97

occur (2, 67); prevention of ACS by early

recognition of shock and judicious fluid
administration remains the best policy.
Complications of aggressive invasive
intensive care unit interventions may
lead to significant morbidity and mortality in sick, bleeding children with dengue, although these have been seldom
reported. Catastrophic bleeding may result from intensive care unit practices,
such as insertion of invasive central and
arterial catheters and intubation. Other
potentially risky invasive care practices
are rapid drainage of large-volume pleural and ascitic fluid collections during the
critical phase of plasma leakage, which
can often result in sudden worsening of
the hemodynamic status and catastrophic
hemorrhage (67). Judicious IV hydration
will minimize large-volume effusions and
may completely obviate the need for the
thoracic and/or abdominal paracentesis
with its attendant complications (2).
Other Interventions for DHF/DSS. No
drugs are useful for treating shock in
dengue. Serum cortisol levels are high in
children with dengue shock (68), which
supports a Cochrane database review in
which the authors stated that there is no
good-quality evidence that corticosteroids are helpful for DSS (69).
Experienced clinicians can minimize
dengue deaths with simple inexpensive
strategies that focus on:
Figure 6. Suggested approach to severe dengue and refractory shock (late presenters). CPAP,
continuous positive airway pressure.

uretics to a patient with dengue and FO

requires considerable judgment, because
diuretics can easily worsen the circulatory status in children who are still in the
critical phase of plasma leakage (2). If the
critical period has passed as demonstrated by a stable Hct level, stable hemodynamics, and a good urine output despite minimal IV fluids, a patient with
features of FO/PE may be cautiously commenced on a diuretic infusion at 0.1 mg/
kg/hr (2). Any hemodynamic deterioration should prompt immediate cessation
of the diuretic infusion.
Peritoneal dialysis has been used for
patients with oliguric renal failure or diuretic-resistant FO and for patients with
ACS (38, 44) but may provoke bleeding
and should rarely be necessary.
Complications and Management Issues in Late Presenters With Established
Shock. Late presenters often have a different and difficult course with refractory
shock; catastrophic, uncontrollable hem98

orrhage and significant fluid collections;

a higher prevalence of multiorgan failure;
and the need for invasive and expensive
intensive care unit monitoring and therapy (Fig. 6) (38). It is this group that may
have myocardial dysfunction and pleural
and ascitic collections, including ACS,
that may worsen both respiratory and circulatory status (38, 44). Myocardial dysfunction in this group is usually attributable to prolonged coronary ischemia,
which may be worsened by catecholamines; invasive hemodynamic
monitoring in conjunction with serial
echocardiography may aid in streamlining therapy (Fig. 6). ACS can set off a
vicious cycle due to a combination of
large-volume ascites and ischemic edematous gut in conjunction with positivepressure ventilation (35, 65).
Controlled drainage of ascites may result in improved hemodynamics (66, 67)
but must be performed with great caution,
because hemorrhagic complications can

early recognition of plasma leakage and

shock by an educated front-line workforce;
early institution of a tightly controlled
IV rehydration regimen with isotonic
fluids;
ongoing titration of fluid therapy based
on serial monitoring of vital signs,
urine output, and Hct level;
early recognition of the occult hemorrhage and replacement with fresh WB/
PRBCs;
measures to prevent FO, including
prompt cessation of IV fluid when the
period of plasma leakage has ceased
and avoiding preventive transfusion
with platelets, fresh-frozen plasma, and
other blood products; and
minimizing iatrogenic interventions
that may cause complications (nasogastric tubes, central venous pressure
insertion, pleural and ascitic fluid
drainage).

Prognosis
Although mortality from dengue ranges
from 1% to 5% (2, 8, 9, 57), mortality
Pediatr Crit Care Med 2011 Vol. 12, No. 1

from severe dengue shock can be much

higher, up to 26%, especially in instances of
profound shock and hemorrhage and when
treatment is delayed (70).

2.

Prevention and Future

Directions
Public health measures for curtailing
this disease are presently focusing on preventive strategies that include measures
for mosquito control and the development of vaccines (9, 71). However, prevention of dengue remains elusive, because control of the Ae. aegypti mosquito
is costly and often ineffective and, hence,
has not met with much success, similar
to vaccine development (72). However,
results of clinical field tests with live attenuated tetravalent vaccines have indicated encouraging preliminary data in
Thai adults and children (73).

3.

4.

5.

6.
7.

Summary and Conclusion

Infections with DVs result in a spectrum of responses, from a mild, undifferentiated, self-limited febrile illness to severe dengue, which can have a high
mortality rate if detected late or treated
inappropriately. The diagnosis of acute
DV infection is based mainly on clinical
signs and symptoms in endemic countries.
In dengue-epidemic regions, mortality
rates of 1% are achievable when highly
trained caregivers at all levels are tuned
to three aspects of management: a thorough understanding of the unpredictable
and dynamic nature of the disease; early
recognition of warning signs and occult
hemorrhage; and continuously monitoring the patient and titrating interventions to match the rapidly evolving clinical status.

ACKNOWLEDGMENTS
We are grateful for the detailed analysis and insightful comments of Dr. Indumathy Santhanam and Dr. Shanthi
Sangaredddy, assistant professors of
emergency medicine and intensive care
from the Institute of Child Health
(Chennai, India), and Dr. Shrishu Kamath and Dr. Gayathri Subramaniam,
junior consultants from Apollo Childrens Hospital (Chennai).

8.
9.
10.

11.

12.
13.

14.

15.

16.

17.

18.

19.

REFERENCES
1. World Health Organization: Dengue Hemorrhagic Fever: Diagnosis, Treatment, Preven-

Pediatr Crit Care Med 2011 Vol. 12, No. 1

20.

tion and Control. Second Edition. Geneva,

World Health Organization, 1997
Dengue Hemorrhagic Fever: Diagnosis,
Treatment, Prevention and Control. Third
Edition. A joint publication of the World
Health Organization (WHO) and the Special
Programme for Research and Training in
Tropical Diseases (TDR), Geneva, 2009
Gubler DJ: Dengue/dengue hemorrhagic fever: History and current status. Novartis
Found Symp 2006; 277:316
Centers for Disease Control and Prevention:
Dengue. Available at http://www.cdc.gov/
NCIDOD/DVBID/DENGUE. Accessed September 2008
Pinheiro FP, Corber SJ: Global situation of
dengue and dengue hemorrhagic fever and
its emergence in the Americas. World Health
Stat Q 1997; 50:161168
Gubler DJ: Dengue and dengue hemorrhagic
fever. Clin Microbiol Rev 1998; 11:480 496
World Health Organization: Scientific working group on dengue, Geneva, 2006. Available
at http://www.who.int/tdr/svc/publications/tdrresearch-publications/swg-report-dengue. Accessed March 2009
Halstead SB: Is there an inapparent dengue
explosion? Lancet 1999; 353:1100 1101
Guzman MG, Kour G: Dengue: An update.
Lancet Infect Dis 2002; 2:33 42
Teo D, Ng LC, Lam S: Is dengue a threat to
the blood supply? Transfus Med 2009; 19:
66 77
Malavige GN, Fernando S, Fernando DJ:
Dengue viral infections. Postgrad Med J
2004; 80:588 601
Halstead SB: Dengue. Lancet 2007; 370:
1644 1652
Vaughn DW, Green S, Kalayanarooj S, et al:
Dengue in the early febrile phase: Viremia
and antibody responses. J Infect Dis 1997;
176:322330
Rothman AL: Pathogenesis of dengue virus
infection, UpToDate 2008. Available at http://
www.Uptodate.com. Accessed September
2008
Shirtcliffe P, Cameron E, Nicholson KG, et
al: Dont forget dengue! Clinical features of
dengue fever in returning travellers. J R Coll
Physicians Lond 1998; 32:235237
Mongkolsapaya J, Dejnirattisai W, Xu XN, et
al: Original antigenic sin and apoptosis in the
pathogenesis of dengue hemorrhagic fever.
Nat Med 2003; 9:921927
Rothman AL: Dengue: Defining protective
versus pathologic immunity. J Clin Invest
2004; 113:946 951
Guzman MG, Alvarez M, Rodriguez-Roche R,
et al: Neutralizing antibodies after infection
with dengue 1 virus. Emerg Infect Dis 2007;
13:282286
Morens DM: Antibody-dependent enhancement of infection and the pathogenesis of
viral disease. Clin Infect Dis 1994; 19:
500 512
Vaughn DW, Green S, Kalayanarooj S, et al:
Dengue viremia titer, antibody response pat-

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

tern, and virus serotype correlate with disease severity. J Infect Dis 2000; 181:29
Binh PT, Matheus S, Huong VT, et al: Early
clinical and biological features of severe clinical manifestations of dengue in Vietnamese
adults. J Clin Virol 2009; 45:276 280
Nguyen TH, Lei HY, Nguyen TL, et al: Dengue hemorrhagic fever in infants: A study of
clinical and cytokine profiles. J Infect Dis
2004; 189:221232
Kliks SC, Nimmanitya S, Nisalak A, et al:
Evidence that maternal dengue antibodies
are important in the development of dengue
hemorrhagic fever in infants. Am J Trop Med
Hyg 1988; 38:411 419
Thisyakorn U, Nimmannitya S: Nutritional
status of children with dengue hemorrhagic
fever. Clin Infect Dis 1993; 16:295297
Bandyopadhyay S, Lum LC, Kroeger A: Classifying dengue: A review of the difficulties in
using the WHO case classification for dengue
haemorrhagic fever. Trop Med Int Health
2006; 11:1238 1255
Rigau-Perez JG: Severe dengue: The need for
new case definitions. Lancet Infect Dis 2006;
6:297302
Deen JL, Harris E, Wills B, et al: The WHO
dengue classification and case definitions:
Time for a reassessment. Lancet 2006; 368:
170 173
TDR: World Health Organization issues new
dengue guidelines. Available at http://
apps.who.int/tdr/svc/publications/tdrnews/
issue-85/tdr-briefly. Accessed July 1, 2010
Wills BA, Oragui EE, Stephens AC, et al:
Coagulation abnormalities in dengue hemorrhagic fever: Serial investigations in 167
Vietnamese children with dengue shock syndrome. Clin Infect Dis 2002; 35:277285
Gomber S, Ramachandran VG, Satish Kumar
KN, et al: Hematological observations as diagnostic markers in dengue hemorrhagic fever: A reappraisal. Indian Pediatr 2001; 38:
477 481
Khongphatthanayothin A, Suesaowalak M,
Muangmingsook S, et al: Hemodynamic profiles of patients with dengue hemorrhagic
fever during toxic stage: An echocardiographic study. Intensive Care Med 2003; 29:
570 574
Rothman AL: Clinical presentation and diagnosis of dengue virus infections UpToDate
2008. Available at http://www.Uptodate.com.
Accessed September 2008
Kabra SK, Jain Y, Pandey RM, et al: Dengue
hemorrhagic fever in children in the 1996
Delhi epidemic. Trans R Soc Trop Med Hyg
1999; 93:294 298
Srichaikul T, Nimmanitaya S, Artchararit N,
et al: Fibrinogen metabolism and disseminated intravascular coagulation in dengue
hemorrhagic fever. Am J Trop Med Hyg
1977; 26:525532
Mitrakul C, Poshyachinda M, Futrakul P, et
al: Hemostatic and platelet kinetic studies in
dengue hemorrhagic fever. Am J Trop Med
Hyg 1977; 26:975984
Lum LCS, Goh AYT, Chan PWK, et al: Risk

99

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

100

factors for hemorrhage in severe dengue infections. J Pediatr 2002; 140:629 631
Nimmannitya S, Thisyakorn U, Hemsrichart
V: Dengue haemorrhagic fever with unusual
manifestations. Southeast Asian J Trop Med
Public Health 1987; 18:398 406
Kamath SR, Ranjit S: Clinical features, complications and atypical manifestations of children with severe forms of dengue hemorrhagic fever in South India. Indian J Pediatr
2006; 73:889 895
Solomon T, Dung NM, Vaughn DW, et al:
Neurological manifestations of dengue infection. Lancet 2000; 355:10531059
Lum LC, Lam SK, Choy YS, et al: Dengue
encephalitis: A true entity? Am J Trop Med
Hyg 1996; 54:256 259
Wali JP, Biswas A, Chandra S, et al: Cardiac
involvement in dengue haemorrhagic fever.
Int J Cardiol 1998; 64:3136
Kabra SK, Juneja R, Madhulika, et al: Myocardial dysfunction in children with dengue
haemorrhagic fever. Natl Med J India 1998;
11:59 61
Khongphatthanayothin A, Lertsapcharoen P,
Supachokchaiwattana P, et al: Myocardial depression in dengue hemorrhagic fever: Prevalence and clinical description. Pediatr Crit
Care Med 2007; 8:524 529
Ranjit S, Kissoon N, Jayakumar I: Aggressive
management of dengue shock syndrome may
decrease mortality rate: A suggested protocol. Pediatr Crit Care Med 2005; 6:412 419
Srichaikul T, Punyagupta S, Kanchanapoom
T: Hemophagocytic syndrome in dengue
hemorrhagic fever with severe multiorgan
complications. J Med Assoc Thai 2008; 91:
104 109
Khilnani P, Sarma D, Zimmerman J, et al:
Epidemiology and peculiarities of pediatric
multiple organ dysfunction syndrome in New
Delhi. India Intensive Care Med 2006; 32:
1856 1862
Khilnani P, Sarma D, Singh R, et al: Demographic profile and outcome analysis of a
tertiary level pediatric intensive care unit.
Indian J Pediatr 2004; 71:587591
De Paula SO, da Fonseca BAL: Dengue: A
review of the laboratory tests a clinician
must know to achieve a correct diagnosis.
Braz J Infect Dis 2004; 8:390 398
Ramos M, Tomashek K, Arguello D, et al:
Early clinical features of dengue infection in
Puerto Rico. Trans R Soc Trop Med Hyg
2009; 103:878 884
Kumar A, Roberts D, Wood KE, et al: Dura-

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

tion of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock.
Crit Care Med 2006; 34:1589 1596
Mellor DH: The place of computed tomography and lumbar puncture in suspected bacterial meningitis. Arch Dis Child 1992; 67:
14171419
De Paula SO, Pires Neto RJ, Correa JA, et al:
The use of reverse transcription-polymerase
chain reaction (RT-PCR) for the rapid detection and identification of dengue virus in an
endemic region: A validation study. Trans R
Soc Trop Med Hyg 2002; 96:266 269
Dussart P, Labeau B, Lagathu G, et al: Evaluation of an enzyme immunoassay for detection of dengue virus NS1 antigen in human
serum. Clin Vaccine Immunol 2006; 13:
11851189
Chakravarti A, Gur R, Berry N, et al: Evaluation of three commercially available kits for
serological diagnosis of dengue haemorrhagic fever. Diagn Microbiol Infect Dis
2000; 36:273274
Colbert JA, Gordon A, Roxelin R, et al: Ultrasound measurement of gallbladder wall
thickening as a diagnostic test and prognostic indicator for severe dengue in pediatric
patients. Pediatr Infect Dis J 2007; 26:
850 852
Singhi S, Khilnani P, Lodha R, et al: Guidelines for treatment of septic shock in resource limited environments. J Pediatr Infect Dis 2009; 4:173192
Wills BA, Nguyen MD, Ha TL, et al: Comparison of three fluid solutions for resuscitation
in dengue shock syndrome. N Engl J Med
2005; 353:877 889
Moxon C, Wills B: Management of severe
dengue in children. Adv Exp Med Biol 2008;
609:131144
Ranjit S, Kissoon N, Gandhi D, et al: Early
differentiation between dengue and septic
shock by comparison of admission hemodynamic, clinical, and laboratory variables: A
pilot study. Pediatr Emerg Care 2007; 23:
368 375
Brierley J, Carcillo JA, Choong K, et al: Clinical practice parameters for hemodynamic
support of pediatric and neonatal septic
shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med
2009; 37:666 688
Lum LC, Abdel-Latif Mel-A, Goh AY, et al:
Preventive transfusion in dengue shock syn-

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

drome: Is it necessary? J Pediatr 2003; 143:

682 684
de Castro RA, de Castro JA, Barez MY, et al:
Thrombocytopenia associated with dengue
hemorrhagic fever responds to intravenous
administration of anti-D (Rh(0)-D) immune
globulin. Am J Trop Med Hyg 2007; 76:
737742
Rajapakse S: Intravenous immunoglobulins
in the treatment of dengue illness. Trans R
Soc Trop Med Hyg 2009; 103:867 870
Chuansumrit A, Wangruangsatid S, Lektrakul Y, et al: Control of bleeding in children
with dengue hemorrhagic fever using recombinant activated factor VII: A randomized,
double-blind, placebo-controlled study.
Blood Coagul Fibrinolysis 2005; 16:549 555
Cam BV, Tuan DT, Fonsmark L, et al: Randomized comparison of oxygen mask treatment vs. nasal continuous positive airway
pressure in dengue shock syndrome with
acute respiratory failure. J Trop Pediatr
2002; 48:335339
Carlotti AP, Carvalho WB: Abdominal compartment syndrome: A review. Pediatr Crit
Care Med 2009; 10:115120
Clinical Practice Guideline on Management
of Dengue in Adults. Second Edition. 2008.
Available at http://www.moh.gov.my. Accessed October 25, 2009
Myo-Khin, Soe-Thein, Thein-Thein-Myint, et
al: Serum cortisol levels in children with
dengue haemorrhagic fever. J Trop Pediatr
1995; 41:295297
Panpanich R, Sornchai P, Kanjanaratanakorn K: Corticosteroids for treating dengue
shock syndrome. Cochrane Database Syst
Rev. 2006; 3:CD003488
Cherian T, Ponnuraj E, Kuruvilla T, et al: An
epidemic of dengue haemorrhagic fever &
dengue shock syndrome in & around Vellore.
Indian J Med Res 1994; 100:5156
Rothman AL: UpToDate May 2008. Prevention and treatment of dengue virus infection
UpToDate 2008. Available at http://www.
Uptodate.com. Accessed September 2008
Monath TP: Dengue and yellow fever: Challenges for the development and use of vaccines. N Engl J Med 2007; 357:22222225
Sabchareon A, Lang J, Chanthavanich P, et
al: Safety and immunogenicity of a three
dose regimen of two tetravalent live-attenuated dengue vaccines in five- to twelve-yearold Thai children. Pediatr Infect Dis J 2004;
23:99 109

Pediatr Crit Care Med 2011 Vol. 12, No. 1