Diagnosis and Management of Dengue in Children
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Available online at www.sciencedirect.com
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journal homepage: www.elsevier.com/locate/pid
Review Article
Diagnosis and management of dengue in children:
Recommendations and IAP ID chapter plan of
action
Jaydeep Choudhury a,b, Digant D. Shastri c,d,*
a
Associate Professor, Department of Pediatrics, Institute of Child Health, Kolkata, West Bengal, India
Secretary, IAP Infectious Diseases Chapter, India
c
Consultant Pediatrician, Surat, Gujarat, India
d
Immediate Past Chairperson, IAP Infectious Diseases Chapter, India
b
article info
abstract
Article history:
The epidemiology of dengue fever in the Indian subcontinent has been very complex. It is
Received 23 July 2014
no longer restricted to urban centres, with outbreaks now occurring in rural India also. The
Accepted 28 July 2014
mosquito vectors, Aedes aegypti and Aedes albopictus prefers to breed in artificial water. They
Available online 15 August 2014
are day biters and are most active just after sunrise and just before sunset. As per the new
guidelines dengue is now classified into three categories, dengue, dengue with warning
Keywords:
signs and severe dengue whereas the clinical course of the disease is divided in three
Dengue
phases e febrile, critical, and recovery. The diagnostic tests are NS1 antigen, which can be
NS1 antigen
done by ELISA or rapid test, and serological tests by detection of viral antibodies IgG and
Dengue ELISA
IgM. Depending on the severity, treatment may be as outpatient, inpatient or emergency
Dengue rapid test
treatment. Shock and hemorrhage are the two most dreaded complications which require
Dengue shock
monitoring and intensive care management.
Copyright © 2014, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights
reserved.
Dengue is endemic in Asia, Southeast Asia, several southern
and central Pacific countries and the Americas. There have
been several dengue outbreaks in India.1 Over 2.5 billion people
(more than 40% of the world's population) are now at risk from
dengue. WHO currently estimates that 50e100 million dengue
infections may be occurring worldwide each year. An estimated 500,000 people with severe dengue require hospitalization annually, a large proportion of who are children and
about 2.5% of those affected die.2 Modeling suggests that global
warming will increase the amount of land with a climate
suitable for dengue fever transmission, potentially placing a
higher proportion of the global population at risk.3 It has been
estimated that there were 96 million apparent dengue infections globally in 2010 with an additional 294 (217e392)
million unapparent infections too. India alone contributed 34%
[33 (24e44) million infections] of the global total.4 These estimates of total infection burden (apparent and unapparent) are
more than three times higher than the WHO predicted. The
* Corresponding author. CEO & Chief Consultant Pediatrician, Killol Children Hospital 303 & 304, Takshashila Apartment, Majura Gate,
Surat 395002, India.
E-mail address: [email protected] (D.D. Shastri).
http://dx.doi.org/10.1016/j.pid.2014.07.009
2212-8328/Copyright © 2014, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
global burden of dengue is formidable and represents a
growing challenge to public health officials and policymakers.
The epidemiology of dengue fever in the Indian subcontinent has been very complex and has substantially
changed over almost past six decades in terms of prevalent
strains, affected geographical locations and severity of disease. In India, Indonesia and Myanmar, focal outbreaks
away from the urban areas have reported case-fatality rates
of 3e5%. Cyclic epidemics are increasing in frequency and
in-country
geographic
expansion
is
occurring
in
Bangladesh, India and Maldives. These are the countries in
the deciduous dry and wet climatic zone with multiple virus
serotypes circulating.
Dengue is no longer restricted to urban centres, with outbreaks now occurring in rural India. Nearly every state in
India, including isolated islands such as Andaman and Nicobar, now reports cases. Although dengue has been predominantly a disease of children, it now affects all age groups
worldwide. It has been reported in India that approximately
20% of cases had occurred in infants less than 1 year of age.5
Male and female patients are affected equally.
1.
The virus
Dengue virus (DV) is a single stranded RNA virus belonging to
the Flaviridae family. It has been classified into four serotypes,
DENV-1, DENV-2, DENV-3, and DENV-4, which are genetically
and antigenically different. Infection with one serotype produces lifelong immunity only to that particular serotype.6 The
virus is sensitive to heat and is susceptible to many common
disinfectants including ethanol, sodium hypochlorite and
glutaraldehyde. It is, however, stable in dried blood and exudates for several days at room temperature. Once infected, the
mosquito vector carries the virus for life (one to four months).
In a study conducted in India during an outbreak, phylogenetic analysis revealed that the Indian Dengue-4 isolates
belonged to the genotype I. This study clearly indicated the
sudden dominance of DENV-4 in an Indian Dengue outbreak.7
Orissa state in Eastern India reported the first dengue
outbreak in 2010, followed by extensive outbreaks in 2011,
affecting large number of people. Phylogenetic analyses
revealed the circulation of Indian lineage of DENV-2 (genotype-IV) and DENV-3 (genotype-III) in vectors and patients
serum in Orissa from 2010 to 2011, DENV-2 being the prevailing serotype.8 Co-circulation of several serotypes of
dengue viruses has resulted in concurrent infection in some
patients with multiple serotypes of DV.8 Concurrent infection
with Chikungunya has also been reported in India.9
2.
The vector
Dengue is transmitted by the mosquitoes Aedes aegypti and
Aedes albopictus, which are ubiquitous. The primary mosquito
vector prefers to breed in artificial water holding containers,
although natural containers may also act as breeding sites.
They are day biters and are most active just after sunrise and
just before sunset. A viremic human is the source of infection
for an adult mosquito, which can transmit the virus further
55
within the mosquito population after 8e10 days. In humans,
the intrinsic incubation period is 3e14 days, commonly 4e7
days. A patient with dengue is infectious for mosquitoes from
just before to just after the febrile period. Infection with one
dengue serotype confers lifelong immunity to that serotype
but may result in an increased risk of complications if subsequently infected with another serotype.
3.
Pathogenesis
Several theories seek to explain the pathogenesis including
the ‘immune enhancement hypothesis’ and the ‘selection
pressure hypothesis’. The immune enhancement hypothesis
proposes that patients with a second infection with a heterologous dengue serotype have a higher risk of developing severe dengue.9 The existing heterologous dengue antibody
recognizes the invading virus and establishes an antigeneantibody complex, which binds to the Fc receptor on the
cell membrane of leukocytes. The virus freely replicates
through antibody dependent enhancement. Anti-dengue
virus antibodies cross-react with platelets, clotting factors
and endothelial cells in humans.10 Anti-NS1 antibodies induce
apoptosis in endothelial cells and increase vascular permeability, leading to hypovolemia and shock. The selection
pressure hypothesis claims that dengue virus varies and
mutates as a result of selection pressure as it replicates in
humans and/or mosquitoes.
4.
Dengue classification
4.1.
Old classification
Ranging from asymptomatic infection, to mild undifferentiated fever, to fatal shock; dengue illnesses exhibits an extensive array of clinical presentations. Until recent times WHO
identified two types of dengue illnesses, dengue fever (DF) a
mild self-limiting febrile illness and dengue hemorrhagic
fever (DHF) a potentially fatal condition pathognomonized by
leaky vasculopathy.
According to the disease severity DHF was further divided
in to four categories:
Grade I: Thrombocytopenia, hemoconcentration, positive
tourniquet test and absence of spontaneous bleeding;
Grade II: Thrombocytopenia, hemoconcentration, positive
tourniquet test and presence of spontaneous bleeding;
Grade III: Thrombocytopenia, hemoconcentration, positive
tourniquet test and circulatory insufficiency (feeble pulse,
drop of 20 mm Hg or greater in arterial blood pressure, cold
extremities and apprehension);
Grade IV: Thrombocytopenia, positive tourniquet test,
hemoconcentration, imperceptible pulse and blood
pressure.
4.2.
New classification
Pertaining to the new guidelines dengue is now classified into
three categories1 dengue2 dengue with warning signs and3
56
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
severe dengue whereas the clinical course of the disease is
divided in three phases e febrile, critical, and recovery.
5.
Clinical features
Dengue viruses cause symptomatic infections or asymptomatic sero-conversion. Symptomatic dengue infection is a systemic and dynamic disease. It has a wide clinical spectrum
that includes both severe and non-severe clinical manifestations.11 While most patients with dengue recover following a
self-limiting non-severe clinical course, a small proportion
progress to severe disease. Dengue is a dynamic disease which
may have three stages: febrile, critical and recovery.
The febrile phase can last for 2e7 days. The critical phase
may occur anywhere between 3 and 7 days after the start of
illness. A positive tourniquet test in this phase indicates an
increased probability of dengue.12,13 The recovery phase occurs 2e3 days after the critical phase. Dengue has a wide
spectrum of clinical presentations, often with unpredictable
clinical evolution and outcome. Children are more likely to
develop shock because of their intrinsically more permeable
micro-vasculature, although major bleeding, encephalopathy
and liver involvement are more common in adults. Petechiae,
melena, headache, retro-orbital pain, myalgia, joint pain,
nausea and vomiting have been observed more commonly in
adults in contrast to more frequent occurrence of epistaxis,
oliguria and liver enlargement in children.14,15
Critical phase e During the transition from the febrile to
afebrile phase, patients without an increase in capillary
permeability will improve without going through the critical
phase. Instead of improving with the subsidence of high fever;
patients with increased capillary permeability may manifest
with the warning signs, mostly as a result of plasma leakage.
Patients become worse around the time of defervescence,
when the temperature drops to 37.5e38 C or less and remains
below this level, usually on days 3e8 of illness. Progressive
leukopenia followed by a rapid decrease in platelet count
usually precedes plasma leakage. An increasing hematocrit
above the baseline may be one of the earliest additional signs.
The period of clinically significant plasma leakage usually
lasts 24e48 h. The degree of hemoconcentration above the
baseline hematocrit reflects the severity of plasma leakage. In
addition to the plasma leakage, hemorrhagic manifestations
such as easy bruising and bleeding at venepuncture sites
occur frequently.
Warning signs of dengue e Persistent vomiting and severe
abdominal pain are early indications of plasma leakage.
Increasing liver size and a tender liver is frequently observed.
A rapid and progressive decrease in platelet count to about
100,000 cells/mm3 and a rising hematocrit above the baseline
may be the earliest sign of plasma leakage usually preceded by
leukopenia.
Recovery phase e As the patient survives the 24e48 h
critical phase, a gradual reabsorption of extravascular
compartment fluid takes place in the following 48e72 h.
General wellbeing improves, appetite returns, gastrointestinal
symptoms abate, hemodynamic status stabilizes and diuresis
ensues. Some patients have a confluent erythematous or
petechial rash with small areas of normal skin, described as
“isles of white in the sea of red”. Some may experience
generalized pruritus. Bradycardia and electrocardiographic
changes are common during this stage. The hematocrit stabilizes or may be lower due to the dilution effect of reabsorbed
fluid. Respiratory distress from massive pleural effusion and
ascites, pulmonary edema or congestive heart failure will
occur during the critical and/or recovery phases if excessive
intravenous fluids have been administered.
Severe dengue e A case of severe dengue is defined as a
suspected dengue patient with one or more of the following:
(i) Severe plasma leakage that leads to shock (dengue
shock) and/or fluid accumulation with respiratory
distress;
(ii) Severe bleeding;
(iii) Severe organ impairment.
Severe plasma leakage and dengue shock e Dengue shock
syndrome (DSS) is a form of hypovolemic shock and results
from continued vascular permeability and plasma leakage.
This usually takes place around defervescence, i.e. on days
4e5 of illness (range of days 3e8), and is often preceded by
warning signs. From this point onwards, patients who do not
receive prompt intravenous fluid therapy progress rapidly to a
state of shock. Tachycardia (without fever during defervescence), is an early cardiac response to hypovolemia. During
the initial stage of shock, the compensatory mechanism that
maintains a normal systolic BP produces tachycardia, quiet
tachypnea (tachypnea without increased effort), and peripheral vasoconstriction with reduced skin perfusion (manifested
as cold extremities and delayed capillary refill time of >2 s and
weak volume peripheral pulses). As peripheral vascular
resistance increases, the diastolic pressure rises towards the
systolic pressure and the pulse pressure (the difference between the systolic and diastolic pressures) narrows. The patient is considered to have compensated shock if the systolic
pressure is maintained at the normal or slightly above normal
range but the pulse pressure is 20 mmHg in children (e.g.
100/85 mmHg) or if they have signs of poor capillary perfusion
(cold extremities, delayed capillary refill or tachycardia). By
this stage the breathing becomes more rapid and increases in
depth e a compensation for the metabolic acidosis (Kussmaul's breathing). Finally, there is decompensation, both
systolic and diastolic BP disappear suddenly and dramatically,
and the patient is said to have hypotensive or decompensated
shock. One key clinical sign of this deterioration is a change in
mental state as brain perfusion declines. The patient becomes
restless, confused and extremely lethargic. Seizures may
occur and agitation may alternate with lethargy. On the other
hand, children and young adults have been known to have a
clear mental status even in profound shock. The failure of
infants and children to recognize, focus or make eye contact
with parents may be an early ominous sign of cortical hypoperfusion, as is the failure to respond to painful stimuli such
as venepuncture. Prolonged hypotensive shock and hypoxia
lead to severe metabolic acidosis, multiple organ failure and
an extremely difficult clinical course. Patients with severe
plasma leakage may not have shock if prompt fluid replacement has been carried out. Instead, they manifest with respiratory distress due to massive pleural effusion and ascites,
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
which can also be exacerbated by unguided intravenous fluid
therapy. System wise complications of dengue are shown in
Table 1.
6.
Laboratory diagnosis of dengue
The clinical features of dengue are non specific hence early
confirmatory laboratory diagnosis is essential for timely
intervention as the disease may turn fatal in short time.
Diagnosis may involve virus isolation, detection of viral
nucleic acid, antigens or antibodies. In the early stage of the
disease viral isolation, nucleic acid or antigen detection may
be done. After the acute stage of infection antibody detection
is used for diagnosis. Highly sensitive and specific tests like
virus isolation and nucleic acid identification require expertise and available is only few centres as compared to tests
with lesser sensitivity and specificity i.e. antibody detection
which are cheap and easily available.
6.1.
Viral isolation
It should be done before 5 days of illness from serum, plasma
or mononuclear cells in peripheral blood. As the virus is
extremely heat sensitive the specimen should reach the central laboratory at temperatures between 4 C to 8 C. Results
are available within 1e2 weeks time. The procedure is
expensive, can identify the serotypes but unable to distinguish between primary and secondary infection and reserved
for research purpose.
erroneous report, expert technicians with proper quality
control is important. Expensive equipment and expertise
limits its availability.
RT-PCR (reverse transcriptase-polymerase chain reaction)
assay is usually done having a turnaround time of 1e2 days
but the test is expensive, unable to distinguish between primary and secondary infection and should be done in first 5
days of onset of symptoms. Accuracy of the test is increased if
the nucleic acid extracted from that region of dengue genome
which is specific to dengue and not conserved among other
flavi or related viruses. This is test has a sensitivity of 80e90%
and specificity of more than 95%. The test may be negative in
acute phase specimen, i.e. within first 5 days of symptom due
to undetectable levels of viruses.
6.3.
Detection of virus antigens
NS1, non structural protein 1 is produced by all flaviviruses.
This glycoprotein antigen can be detected in all patients
with both primary and secondary dengue from first day of
symptom upto nine days and even at times upto 18 days
post onset of symptoms. This test can be done by ELISA or
by other rapid methods like immune chromatography where
results are obtained in minutes. The performance characteristics of the test are still under evaluation by competent
authorities. Elisa test due to its specificity may be useful for
differential diagnostics between flaviviruses but other rapid
tests have the drawback of gross reactivity across the flavivirus group.
6.4.
6.2.
57
Serological tests
Viral nucleic acid detection
Dengue virus RNA is also heat labile hence transport of
specimen to laboratory requires temperature maintenance as
in virus isolation. As contamination of sample will result is
Following dengue infection the immune response is production of IgM and IgG antibodies directed against the virus envelope protein depending upon the immune status of the host.
A person who has not previously been infected with dengue or
Table 1 e Complications of dengue e system wise.
Nervous system
Febrile seizures
Dengue encephalopathy
Hepatic encephalopathy
Intracranial hemorrhage
Acute disseminated encephalomyelitis
syndrome
GuillaineBarre
Delirium and depression
Cardiovascular
Myocardial dysfunction (systolic and diastolic)
Refractory shock
Arrhythmias (supraventricular tachycardia and heart block)
Pericardial effusion
Hepatic
Acalculous cholecystitis
Ischemic hepatitis
Fulminant hepatic failure
Gastrointestinal
Appendicitis
Peritonitis
Compartment syndrome
Respiratory
Massive pleural effusion
Acute respiratory distress syndrome
Pulmonary hemorrhage
Transfusion associated lung injury
Hematological
Disseminated intravascular coagulation
Infection associated hemophagocytosis
Visceral bleeding
Unusual hemorrhage (hematuria, menorrhagia, gastrointestinal
bleeding)
Renal
Acute kidney injury, hemolytic uremic syndrome, rhabdomyolysis
Co-infections
Leptospirosis
Chikungunya
Enteric fever
Malaria
Bacterial meningitis
58
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
Fig. 1 e Algorithm for fluid management of compensated shock in infants and children.18
any other flavivirus develops a primary antibody response
manifested by a slow and low titer. IgM antibody are first to
appear in about 50% patient within days 3e5 after onset of
illness. It gradually increases to 99% by day 10 and then declines slowly to undetectable levels over next 2e3 months. IgG
antibodies are detectable at low titer at the end of first week of
illness increasing slowly thereafter and persists for several
months and at times even for life. In contrast patients who
have suffered from dengue or any other flavivirus infections
in the past or has been immunized with anti flavivirus vaccine
shows a secondary response in which antibody titer rise very
rapidly and reacts broadly with many flavivirus. IgG antibodies are detectable in the acute phase and rise dramatically
in the next two weeks and persists for next 10 months to rest
of life. IgM antibody levels are significantly lower after secondary infection is contract to primary. 80% may have
detectable IgM antibody level by day five of illness which in
99% of patients are detectable by day ten of illness continued
to be detectable for over 90 days.
The IgM and IgG antibodies are detectable by various
methods. The rapid tests yield a result within 30 min are done
by immune chromatographic method whereas the ELISA test
are more time consuming (1e2 days) but has recommendation
of the competent authorities. IgM antibodies to dengue
detected by IgM antibody capture enzyme linked immuno
absorbent assay (MAC-ELISA) are classified as having a recent
probable dengue infection. MAC-ELISA test has good sensitivity and specificity only when done on five or more days after
the onset of illness. Low or undectable levels of dengue IgM
response in some secondary infection reduces the diagnostic
accuracy of IgM ELISA test. More over IgM antibodies to
dengue may remain elevated for 2e3 months after illness and
also cross reactivity with other flavivirus infection like Japanese encephalitis virus are draw backs to be taken into
account.
IgG ELISA also shows cross reactivity within the flavivirus
group. It is used for detection of recent or past dengue infection. Samples with negative IgG in acute phase but positive in
the convalescent phase of the infection are primary dengue. In
contrast, sample with positive IgG in acute phase and a fourfold rise is convalescent phase, with atleast 7 days gap between two samples is a secondary dengue.
59
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
Fig. 2 e Algorithm for fluid management in hypotensive shock in infants and children.18
Table 2 e Steps in management of refractory dengue shock.
Step 1
Stabilize, maintain ABC
High flow oxygen, consider intubation
Give colloids 10e20 ml/kg 2e3 boluses
Correct the correctable causes like hypoglycemia, hypocalcemia and acidosis
Repeat hematocrit
Under ideal circumstances, invasive monitoring (CVP/ABP) to be done
Step 2 e If shock persisted after boluses
Look for hematocrit and CVP and look for co-morbidities
If CVP low and HCT normal to high
If CVP normal/high and HCT normal
Titrate crystalloid/colloid till target CVP/HCT
Consider inotropes/vasopressor according to SBP
Watch for respiratory distress
Dopamine/Adrenaline (if SBP low)
Provide positive pressure ventilation
Dobutamine (SBP normal/high)
Watch for SBP and 2D ECHO
Check for raised intra abdominal pressure
Start Inotropes/Vasopressor if indicated
Controlled ascitic fluid tapping
Step 3- Look for unrecognized morbidities
Occult bleed
Myocardial dysfunction (systolic or diastolic)
Elevated intra abdominal pressure
Co existing bacterial shock/malaria
Positive pressure ventilation contributing to poor cardiac output
Wide spread hypoxic ischemic injury with terminal vasoplegic shock (no treatment effective)
SBP e Systolic Blood Pressure, ABP e Arterial Blood Pressure.
If CVP low and HCT low
Check for occult/overt bleeding
Consider blood transfusion to break
anemia-acidosis-shock cycle
60
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
Fig. 3 e Treatment plan of dengue case management.
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
6.5.
Heamological tests
These tests are suggestive but never diagnostic for dengue.
Thrombocytopenia is usually observed in between day 3 and
day 8 after the onset of illness but it is a constant feature of
dengue haemorrhagic fever. Leucopenia precedes thrombocytopenia and a progressive decrease in WBC count should
alert the care giver.
7.
Treatment
Patients may be categorized into the following groups:
< Group A: Outpatient management with instructions
< Group B: Inpatient management
< Group C: Emergency treatment and urgent referral.
7.1.
Group A: outpatient management with instructions
(for those who can be sent home)
They should be reviewed daily with a clinical examination and
laboratory assessment. They should be encouraged to take
oral rehydration solution and fruit juice to replace losses from
fever and vomiting and reduce the risk of hospitalization.
Paracetamol is the preferred antipyretic with a minimum
dosing interval of 6 h. Non-steroidal anti-inflammatory drugs
may aggravate gastritis and/or bleeding and are to be avoided.
Caregivers must be informed that the patient should be
brought to hospital immediately if any of the following occur:
no clinical improvement, deterioration around the time of
defervescence, severe abdominal pain, persistent vomiting,
cold and clammy extremities, lethargy or irritability/restlessness, bleeding (e.g., black stools or coffee-ground vomiting) or
failure to pass urine for more than 4e6 h.
7.2.
61
compensated shock in infants and children is shown in Fig. 1.
Patients with hypotensive shock should receive boluses of
intravenous isotonic crystalloid or colloid solution at a rate of
10e20 ml/kg over 15 min. Further fluids are adjusted based on
the response and serial hematocrit measurements. A falling
hematocrit at this stage may indicate hemorrhage and should
be treated with blood transfusion (fresh whole blood or
packed red blood cells). Fluid management of hypotensive
shock in infants and children is shown in Fig. 2. There are
three stages of shock in dengue e compensated shock, hypotensive shock and refractory shock. Steps in management
of refractory dengue shock are shown in Table 2.16
The treatment plan of dengue is shown in Fig. 3.
8.
Severe bleeding
Patients at risk of severe bleeding those having prolonged or
refractory shock, renal or liver failure, severe and persistent
metabolic acidosis, anticoagulant therapy, any trauma,
including intramuscular injection and with underlying hemolytic conditions.17
Severe bleeding can be recognized by decrease in hematocrit after fluid resuscitation with unstable hemodynamic
status, refractory shock that fails to respond to consecutive
fluid resuscitation of 40e60 ml/kg, hypotensive shock with
low/normal hematocrit before fluid resuscitation, persistent
or worsening metabolic acidosis with or without wellmaintained systolic blood pressure.17
The most important intervention for a patient with dengue
shock and life threatening bleeding is restoration of oxygen
carrying capacity. Transfuse fresh whole blood or fresh
packed red blood cells. Platelets, FFP or cryoprecipitate are not
indicated in majority of patients of severe bleeding, as they
may contribute to volume overload. They are indicated only if
bleeding is ongoing despite 2e3 aliquots of blood
transfusion.16
Group B: those who should be admitted to hospital
This group includes those with warning signs, co-morbid
conditions or social situations where adequate home care
cannot be ensured.
Choice of intravenous fluids e Most studies on the role of
different fluids in the treatment of dengue infection found no
difference in terms of recovery from shock or outcome,
although colloids have been reported to provide the most
rapid normalization of the hematocrit and restoration of the
cardiac index, without adverse effects. The current WHO
guidelines recommend the use of either isotonic crystalloid or
colloid fluids for the treatment of hypotensive shock.
7.3.
Group C: those who require emergency treatment
for severe dengue
These patients require urgent intravenous resuscitation with
crystalloids or colloids, aimed at maintaining adequate
perfusion and urine output and improving tachycardia. In
patients with compensated shock, fluids are started at a rate
of 5e10 ml/kg/h and titrated based on clinical response and
serial hematocrit measurements. Fluid management of
9.
Fluid overload
Causes of fluid overload in patients of severe dengue are
excessive and/or too rapid intravenous fluids, incorrect use of
hypotonic solutions, large volumes of fluid in patients with
unrecognized severe bleeding, inappropriate transfusion of
fresh-frozen plasma, platelet concentrates and cryoprecipitate, continuation of intravenous fluids after plasma
leakage has resolved (24e48 h from defervescence) as well as
co-morbid conditions such as congenital or ischemic heart
disease, chronic lung and renal diseases.17 Indications for ICU
management in fluid overloaded patients are severe respiratory distress/hypoxemic respiratory failure, pulmonary
edema, tense ascites and irreversible shock (heart failure,
often in combination with ongoing hypovolemia).17 Fluid
overload is the basic mechanism in various complications of
severe dengue like respiratory distress or failure due to pleural
effusion or pulmonary edema; refractory shock due to
increased myocardial work or myocardial ischemia and
persistent acidosis and intractable bleeding due to abdominal
compartment syndrome. So these patients require additional
62
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
investigations and monitoring like chest X-ray, ECG, echocardiography, cardiac enzymes assay and intra abdominal
pressure measurement.17
Management of fluid overload according to clinical parameters includes oxygen therapy or positive pressure ventilation, decreasing or stopping intravenous fluids and oral or
intravenous furosemide 0.1e0.5 mg/kg/dose or a continuous
infusion of furosemide 0.1 mg/kg/hour.17
Patient in shock state with signs of fluid overload may have
occult hemorrhage. Fresh whole blood transfusion is to be
given as soon as possible. Peritoneal dialysis is rarely indicated in diuretic resistant. Rapid drainage of pleural and ascitic fluid may cause sudden hemodynamic instability and
catastrophic hemorrhage.16
Conflicts of interest
4.
5.
6.
7.
8.
9.
All authors have none to declare.
Dengue protocol project: IAP recommendations
and guidelines on diagnosis and management of
dengue fever in children
Chair person
Convener
Academic Coordinator
Executive Coordinator
Writing committee
Contributors
Dr Ashok Kapse, Dr Digant Shastri
Dr Jaydeep Choudhury
Dr. Abhay K Shah
Dr. Bhavesh Patel
1. Dr. Raju C Shah
2. Dr. Vijay Yewale
3. Dr. Rohit Agrawal
4. Dr. Baldev Prajapati
1. Dr S Balasubramanian
2. Dr Ritabrata Kundu
3. Dr A J Chitkara
4. Dr Nirmal Choraria
10.
11.
12.
13.
14.
15.
references
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www.who.int/entity/mediacentre/factsheets/fs117/en.
Accessed 17.01.12.
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effect of population and climate changes on global
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Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW,
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Kabilan L, Balasubramanian S, Keshava SM, Satyanarayana K.
The 2001 dengue epidemic in Chennai. Indian J Pediatr.
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Beasley DW, Barrett ADT. The infectious agent. In:
Halstead SB, ed. Dengue: Tropical Medicine. vol. 5. London:
Imperial College Press; 2008:29e73.
Neeraja M, Lakshmi V, Dash PK, Parida MM, Rao PV. The
clinical, serological and molecular diagnosis of emerging
dengue infection at a tertiary care institute in southern, India.
J Clin Diagn Res. 2013;7:457e461.
Das B, Das M, Dwibedi B, Kar SK, Hazra RK. Molecular
Investigations of Dengue Virus during Outbreaks in Orissa State,
Eastern India from 2010 to 2011. Bhubaneswar: Regional
Medical Research Center; 2011.
Bharaj P, Chahar HS, Pandey A, Diddi K, Dar L, Guleria R.
Concurrent infections by all four dengue virus serotypes
during an outbreak of dengue in 2006 in Delhi, India. Virol J.
2008;5:1.
Martina BE, Koraka P, Osterhaus AD. Dengue virus
pathogenesis: an integrated view. Clin Microbiol Rev.
2009;22:564e581.
Halstead SB. Pathogenesis of dengue: challenges to molecular
biology. Science. 1988;239:476e481.
rez JG, Clark GG, Gubler DJ, Reiter P, Sanders EJ,
Rigau-Pe
Vorndam AV. Dengue and dengue haemorrhagic fever. Lancet.
1998;352:971e977.
Kalayanarooj S, Vaughn DW, Nimmannitya S. Early clinical
and laboratory indicators of acute dengue illness. J Infect Dis.
1997;176:313e321.
Cao XT, Ngo TN, Wills B, et al, Dong Nai Paediatric
Hospital Study Group. Evaluation of the World Health
Organization standard tourniquet test in the diagnosis of
dengue infection in Vietnam. Trop Med Int Health.
2002;7:125e132.
Kittigul L, Pitakarnjanakul P, Sujirarat D, et al. The differences
of clinical manifestations and laboratory findings in children
and adults with dengue virus infection. J Clin Virol.
2007;39:76e81.
Suchitra R, Kissoon N. Dengue hemorrhagic fever and shock
syndromes. Pediatr Crit Care Med. 2011;12:90e100.
WHO. Dengue Hemorrhagic Fever: Diagnosis, Treatment,
Prevention and Control. A joint publication of the World Health
Organization (WHO) and the Special Programme for Research
and Training in Tropical Diseases (TDR). 3rd ed. Geneva:
World Health Organization; 2009.
WHO. Handbook for Clinical Management of Dengue, WHO.
Geneva: World Health Organization; 2012.
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.elsevier.com/locate/pid
Review Article
Diagnosis and management of dengue in children:
Recommendations and IAP ID chapter plan of
action
Jaydeep Choudhury a,b, Digant D. Shastri c,d,*
a
Associate Professor, Department of Pediatrics, Institute of Child Health, Kolkata, West Bengal, India
Secretary, IAP Infectious Diseases Chapter, India
c
Consultant Pediatrician, Surat, Gujarat, India
d
Immediate Past Chairperson, IAP Infectious Diseases Chapter, India
b
article info
abstract
Article history:
The epidemiology of dengue fever in the Indian subcontinent has been very complex. It is
Received 23 July 2014
no longer restricted to urban centres, with outbreaks now occurring in rural India also. The
Accepted 28 July 2014
mosquito vectors, Aedes aegypti and Aedes albopictus prefers to breed in artificial water. They
Available online 15 August 2014
are day biters and are most active just after sunrise and just before sunset. As per the new
guidelines dengue is now classified into three categories, dengue, dengue with warning
Keywords:
signs and severe dengue whereas the clinical course of the disease is divided in three
Dengue
phases e febrile, critical, and recovery. The diagnostic tests are NS1 antigen, which can be
NS1 antigen
done by ELISA or rapid test, and serological tests by detection of viral antibodies IgG and
Dengue ELISA
IgM. Depending on the severity, treatment may be as outpatient, inpatient or emergency
Dengue rapid test
treatment. Shock and hemorrhage are the two most dreaded complications which require
Dengue shock
monitoring and intensive care management.
Copyright © 2014, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights
reserved.
Dengue is endemic in Asia, Southeast Asia, several southern
and central Pacific countries and the Americas. There have
been several dengue outbreaks in India.1 Over 2.5 billion people
(more than 40% of the world's population) are now at risk from
dengue. WHO currently estimates that 50e100 million dengue
infections may be occurring worldwide each year. An estimated 500,000 people with severe dengue require hospitalization annually, a large proportion of who are children and
about 2.5% of those affected die.2 Modeling suggests that global
warming will increase the amount of land with a climate
suitable for dengue fever transmission, potentially placing a
higher proportion of the global population at risk.3 It has been
estimated that there were 96 million apparent dengue infections globally in 2010 with an additional 294 (217e392)
million unapparent infections too. India alone contributed 34%
[33 (24e44) million infections] of the global total.4 These estimates of total infection burden (apparent and unapparent) are
more than three times higher than the WHO predicted. The
* Corresponding author. CEO & Chief Consultant Pediatrician, Killol Children Hospital 303 & 304, Takshashila Apartment, Majura Gate,
Surat 395002, India.
E-mail address: [email protected] (D.D. Shastri).
http://dx.doi.org/10.1016/j.pid.2014.07.009
2212-8328/Copyright © 2014, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
global burden of dengue is formidable and represents a
growing challenge to public health officials and policymakers.
The epidemiology of dengue fever in the Indian subcontinent has been very complex and has substantially
changed over almost past six decades in terms of prevalent
strains, affected geographical locations and severity of disease. In India, Indonesia and Myanmar, focal outbreaks
away from the urban areas have reported case-fatality rates
of 3e5%. Cyclic epidemics are increasing in frequency and
in-country
geographic
expansion
is
occurring
in
Bangladesh, India and Maldives. These are the countries in
the deciduous dry and wet climatic zone with multiple virus
serotypes circulating.
Dengue is no longer restricted to urban centres, with outbreaks now occurring in rural India. Nearly every state in
India, including isolated islands such as Andaman and Nicobar, now reports cases. Although dengue has been predominantly a disease of children, it now affects all age groups
worldwide. It has been reported in India that approximately
20% of cases had occurred in infants less than 1 year of age.5
Male and female patients are affected equally.
1.
The virus
Dengue virus (DV) is a single stranded RNA virus belonging to
the Flaviridae family. It has been classified into four serotypes,
DENV-1, DENV-2, DENV-3, and DENV-4, which are genetically
and antigenically different. Infection with one serotype produces lifelong immunity only to that particular serotype.6 The
virus is sensitive to heat and is susceptible to many common
disinfectants including ethanol, sodium hypochlorite and
glutaraldehyde. It is, however, stable in dried blood and exudates for several days at room temperature. Once infected, the
mosquito vector carries the virus for life (one to four months).
In a study conducted in India during an outbreak, phylogenetic analysis revealed that the Indian Dengue-4 isolates
belonged to the genotype I. This study clearly indicated the
sudden dominance of DENV-4 in an Indian Dengue outbreak.7
Orissa state in Eastern India reported the first dengue
outbreak in 2010, followed by extensive outbreaks in 2011,
affecting large number of people. Phylogenetic analyses
revealed the circulation of Indian lineage of DENV-2 (genotype-IV) and DENV-3 (genotype-III) in vectors and patients
serum in Orissa from 2010 to 2011, DENV-2 being the prevailing serotype.8 Co-circulation of several serotypes of
dengue viruses has resulted in concurrent infection in some
patients with multiple serotypes of DV.8 Concurrent infection
with Chikungunya has also been reported in India.9
2.
The vector
Dengue is transmitted by the mosquitoes Aedes aegypti and
Aedes albopictus, which are ubiquitous. The primary mosquito
vector prefers to breed in artificial water holding containers,
although natural containers may also act as breeding sites.
They are day biters and are most active just after sunrise and
just before sunset. A viremic human is the source of infection
for an adult mosquito, which can transmit the virus further
55
within the mosquito population after 8e10 days. In humans,
the intrinsic incubation period is 3e14 days, commonly 4e7
days. A patient with dengue is infectious for mosquitoes from
just before to just after the febrile period. Infection with one
dengue serotype confers lifelong immunity to that serotype
but may result in an increased risk of complications if subsequently infected with another serotype.
3.
Pathogenesis
Several theories seek to explain the pathogenesis including
the ‘immune enhancement hypothesis’ and the ‘selection
pressure hypothesis’. The immune enhancement hypothesis
proposes that patients with a second infection with a heterologous dengue serotype have a higher risk of developing severe dengue.9 The existing heterologous dengue antibody
recognizes the invading virus and establishes an antigeneantibody complex, which binds to the Fc receptor on the
cell membrane of leukocytes. The virus freely replicates
through antibody dependent enhancement. Anti-dengue
virus antibodies cross-react with platelets, clotting factors
and endothelial cells in humans.10 Anti-NS1 antibodies induce
apoptosis in endothelial cells and increase vascular permeability, leading to hypovolemia and shock. The selection
pressure hypothesis claims that dengue virus varies and
mutates as a result of selection pressure as it replicates in
humans and/or mosquitoes.
4.
Dengue classification
4.1.
Old classification
Ranging from asymptomatic infection, to mild undifferentiated fever, to fatal shock; dengue illnesses exhibits an extensive array of clinical presentations. Until recent times WHO
identified two types of dengue illnesses, dengue fever (DF) a
mild self-limiting febrile illness and dengue hemorrhagic
fever (DHF) a potentially fatal condition pathognomonized by
leaky vasculopathy.
According to the disease severity DHF was further divided
in to four categories:
Grade I: Thrombocytopenia, hemoconcentration, positive
tourniquet test and absence of spontaneous bleeding;
Grade II: Thrombocytopenia, hemoconcentration, positive
tourniquet test and presence of spontaneous bleeding;
Grade III: Thrombocytopenia, hemoconcentration, positive
tourniquet test and circulatory insufficiency (feeble pulse,
drop of 20 mm Hg or greater in arterial blood pressure, cold
extremities and apprehension);
Grade IV: Thrombocytopenia, positive tourniquet test,
hemoconcentration, imperceptible pulse and blood
pressure.
4.2.
New classification
Pertaining to the new guidelines dengue is now classified into
three categories1 dengue2 dengue with warning signs and3
56
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
severe dengue whereas the clinical course of the disease is
divided in three phases e febrile, critical, and recovery.
5.
Clinical features
Dengue viruses cause symptomatic infections or asymptomatic sero-conversion. Symptomatic dengue infection is a systemic and dynamic disease. It has a wide clinical spectrum
that includes both severe and non-severe clinical manifestations.11 While most patients with dengue recover following a
self-limiting non-severe clinical course, a small proportion
progress to severe disease. Dengue is a dynamic disease which
may have three stages: febrile, critical and recovery.
The febrile phase can last for 2e7 days. The critical phase
may occur anywhere between 3 and 7 days after the start of
illness. A positive tourniquet test in this phase indicates an
increased probability of dengue.12,13 The recovery phase occurs 2e3 days after the critical phase. Dengue has a wide
spectrum of clinical presentations, often with unpredictable
clinical evolution and outcome. Children are more likely to
develop shock because of their intrinsically more permeable
micro-vasculature, although major bleeding, encephalopathy
and liver involvement are more common in adults. Petechiae,
melena, headache, retro-orbital pain, myalgia, joint pain,
nausea and vomiting have been observed more commonly in
adults in contrast to more frequent occurrence of epistaxis,
oliguria and liver enlargement in children.14,15
Critical phase e During the transition from the febrile to
afebrile phase, patients without an increase in capillary
permeability will improve without going through the critical
phase. Instead of improving with the subsidence of high fever;
patients with increased capillary permeability may manifest
with the warning signs, mostly as a result of plasma leakage.
Patients become worse around the time of defervescence,
when the temperature drops to 37.5e38 C or less and remains
below this level, usually on days 3e8 of illness. Progressive
leukopenia followed by a rapid decrease in platelet count
usually precedes plasma leakage. An increasing hematocrit
above the baseline may be one of the earliest additional signs.
The period of clinically significant plasma leakage usually
lasts 24e48 h. The degree of hemoconcentration above the
baseline hematocrit reflects the severity of plasma leakage. In
addition to the plasma leakage, hemorrhagic manifestations
such as easy bruising and bleeding at venepuncture sites
occur frequently.
Warning signs of dengue e Persistent vomiting and severe
abdominal pain are early indications of plasma leakage.
Increasing liver size and a tender liver is frequently observed.
A rapid and progressive decrease in platelet count to about
100,000 cells/mm3 and a rising hematocrit above the baseline
may be the earliest sign of plasma leakage usually preceded by
leukopenia.
Recovery phase e As the patient survives the 24e48 h
critical phase, a gradual reabsorption of extravascular
compartment fluid takes place in the following 48e72 h.
General wellbeing improves, appetite returns, gastrointestinal
symptoms abate, hemodynamic status stabilizes and diuresis
ensues. Some patients have a confluent erythematous or
petechial rash with small areas of normal skin, described as
“isles of white in the sea of red”. Some may experience
generalized pruritus. Bradycardia and electrocardiographic
changes are common during this stage. The hematocrit stabilizes or may be lower due to the dilution effect of reabsorbed
fluid. Respiratory distress from massive pleural effusion and
ascites, pulmonary edema or congestive heart failure will
occur during the critical and/or recovery phases if excessive
intravenous fluids have been administered.
Severe dengue e A case of severe dengue is defined as a
suspected dengue patient with one or more of the following:
(i) Severe plasma leakage that leads to shock (dengue
shock) and/or fluid accumulation with respiratory
distress;
(ii) Severe bleeding;
(iii) Severe organ impairment.
Severe plasma leakage and dengue shock e Dengue shock
syndrome (DSS) is a form of hypovolemic shock and results
from continued vascular permeability and plasma leakage.
This usually takes place around defervescence, i.e. on days
4e5 of illness (range of days 3e8), and is often preceded by
warning signs. From this point onwards, patients who do not
receive prompt intravenous fluid therapy progress rapidly to a
state of shock. Tachycardia (without fever during defervescence), is an early cardiac response to hypovolemia. During
the initial stage of shock, the compensatory mechanism that
maintains a normal systolic BP produces tachycardia, quiet
tachypnea (tachypnea without increased effort), and peripheral vasoconstriction with reduced skin perfusion (manifested
as cold extremities and delayed capillary refill time of >2 s and
weak volume peripheral pulses). As peripheral vascular
resistance increases, the diastolic pressure rises towards the
systolic pressure and the pulse pressure (the difference between the systolic and diastolic pressures) narrows. The patient is considered to have compensated shock if the systolic
pressure is maintained at the normal or slightly above normal
range but the pulse pressure is 20 mmHg in children (e.g.
100/85 mmHg) or if they have signs of poor capillary perfusion
(cold extremities, delayed capillary refill or tachycardia). By
this stage the breathing becomes more rapid and increases in
depth e a compensation for the metabolic acidosis (Kussmaul's breathing). Finally, there is decompensation, both
systolic and diastolic BP disappear suddenly and dramatically,
and the patient is said to have hypotensive or decompensated
shock. One key clinical sign of this deterioration is a change in
mental state as brain perfusion declines. The patient becomes
restless, confused and extremely lethargic. Seizures may
occur and agitation may alternate with lethargy. On the other
hand, children and young adults have been known to have a
clear mental status even in profound shock. The failure of
infants and children to recognize, focus or make eye contact
with parents may be an early ominous sign of cortical hypoperfusion, as is the failure to respond to painful stimuli such
as venepuncture. Prolonged hypotensive shock and hypoxia
lead to severe metabolic acidosis, multiple organ failure and
an extremely difficult clinical course. Patients with severe
plasma leakage may not have shock if prompt fluid replacement has been carried out. Instead, they manifest with respiratory distress due to massive pleural effusion and ascites,
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
which can also be exacerbated by unguided intravenous fluid
therapy. System wise complications of dengue are shown in
Table 1.
6.
Laboratory diagnosis of dengue
The clinical features of dengue are non specific hence early
confirmatory laboratory diagnosis is essential for timely
intervention as the disease may turn fatal in short time.
Diagnosis may involve virus isolation, detection of viral
nucleic acid, antigens or antibodies. In the early stage of the
disease viral isolation, nucleic acid or antigen detection may
be done. After the acute stage of infection antibody detection
is used for diagnosis. Highly sensitive and specific tests like
virus isolation and nucleic acid identification require expertise and available is only few centres as compared to tests
with lesser sensitivity and specificity i.e. antibody detection
which are cheap and easily available.
6.1.
Viral isolation
It should be done before 5 days of illness from serum, plasma
or mononuclear cells in peripheral blood. As the virus is
extremely heat sensitive the specimen should reach the central laboratory at temperatures between 4 C to 8 C. Results
are available within 1e2 weeks time. The procedure is
expensive, can identify the serotypes but unable to distinguish between primary and secondary infection and reserved
for research purpose.
erroneous report, expert technicians with proper quality
control is important. Expensive equipment and expertise
limits its availability.
RT-PCR (reverse transcriptase-polymerase chain reaction)
assay is usually done having a turnaround time of 1e2 days
but the test is expensive, unable to distinguish between primary and secondary infection and should be done in first 5
days of onset of symptoms. Accuracy of the test is increased if
the nucleic acid extracted from that region of dengue genome
which is specific to dengue and not conserved among other
flavi or related viruses. This is test has a sensitivity of 80e90%
and specificity of more than 95%. The test may be negative in
acute phase specimen, i.e. within first 5 days of symptom due
to undetectable levels of viruses.
6.3.
Detection of virus antigens
NS1, non structural protein 1 is produced by all flaviviruses.
This glycoprotein antigen can be detected in all patients
with both primary and secondary dengue from first day of
symptom upto nine days and even at times upto 18 days
post onset of symptoms. This test can be done by ELISA or
by other rapid methods like immune chromatography where
results are obtained in minutes. The performance characteristics of the test are still under evaluation by competent
authorities. Elisa test due to its specificity may be useful for
differential diagnostics between flaviviruses but other rapid
tests have the drawback of gross reactivity across the flavivirus group.
6.4.
6.2.
57
Serological tests
Viral nucleic acid detection
Dengue virus RNA is also heat labile hence transport of
specimen to laboratory requires temperature maintenance as
in virus isolation. As contamination of sample will result is
Following dengue infection the immune response is production of IgM and IgG antibodies directed against the virus envelope protein depending upon the immune status of the host.
A person who has not previously been infected with dengue or
Table 1 e Complications of dengue e system wise.
Nervous system
Febrile seizures
Dengue encephalopathy
Hepatic encephalopathy
Intracranial hemorrhage
Acute disseminated encephalomyelitis
syndrome
GuillaineBarre
Delirium and depression
Cardiovascular
Myocardial dysfunction (systolic and diastolic)
Refractory shock
Arrhythmias (supraventricular tachycardia and heart block)
Pericardial effusion
Hepatic
Acalculous cholecystitis
Ischemic hepatitis
Fulminant hepatic failure
Gastrointestinal
Appendicitis
Peritonitis
Compartment syndrome
Respiratory
Massive pleural effusion
Acute respiratory distress syndrome
Pulmonary hemorrhage
Transfusion associated lung injury
Hematological
Disseminated intravascular coagulation
Infection associated hemophagocytosis
Visceral bleeding
Unusual hemorrhage (hematuria, menorrhagia, gastrointestinal
bleeding)
Renal
Acute kidney injury, hemolytic uremic syndrome, rhabdomyolysis
Co-infections
Leptospirosis
Chikungunya
Enteric fever
Malaria
Bacterial meningitis
58
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
Fig. 1 e Algorithm for fluid management of compensated shock in infants and children.18
any other flavivirus develops a primary antibody response
manifested by a slow and low titer. IgM antibody are first to
appear in about 50% patient within days 3e5 after onset of
illness. It gradually increases to 99% by day 10 and then declines slowly to undetectable levels over next 2e3 months. IgG
antibodies are detectable at low titer at the end of first week of
illness increasing slowly thereafter and persists for several
months and at times even for life. In contrast patients who
have suffered from dengue or any other flavivirus infections
in the past or has been immunized with anti flavivirus vaccine
shows a secondary response in which antibody titer rise very
rapidly and reacts broadly with many flavivirus. IgG antibodies are detectable in the acute phase and rise dramatically
in the next two weeks and persists for next 10 months to rest
of life. IgM antibody levels are significantly lower after secondary infection is contract to primary. 80% may have
detectable IgM antibody level by day five of illness which in
99% of patients are detectable by day ten of illness continued
to be detectable for over 90 days.
The IgM and IgG antibodies are detectable by various
methods. The rapid tests yield a result within 30 min are done
by immune chromatographic method whereas the ELISA test
are more time consuming (1e2 days) but has recommendation
of the competent authorities. IgM antibodies to dengue
detected by IgM antibody capture enzyme linked immuno
absorbent assay (MAC-ELISA) are classified as having a recent
probable dengue infection. MAC-ELISA test has good sensitivity and specificity only when done on five or more days after
the onset of illness. Low or undectable levels of dengue IgM
response in some secondary infection reduces the diagnostic
accuracy of IgM ELISA test. More over IgM antibodies to
dengue may remain elevated for 2e3 months after illness and
also cross reactivity with other flavivirus infection like Japanese encephalitis virus are draw backs to be taken into
account.
IgG ELISA also shows cross reactivity within the flavivirus
group. It is used for detection of recent or past dengue infection. Samples with negative IgG in acute phase but positive in
the convalescent phase of the infection are primary dengue. In
contrast, sample with positive IgG in acute phase and a fourfold rise is convalescent phase, with atleast 7 days gap between two samples is a secondary dengue.
59
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
Fig. 2 e Algorithm for fluid management in hypotensive shock in infants and children.18
Table 2 e Steps in management of refractory dengue shock.
Step 1
Stabilize, maintain ABC
High flow oxygen, consider intubation
Give colloids 10e20 ml/kg 2e3 boluses
Correct the correctable causes like hypoglycemia, hypocalcemia and acidosis
Repeat hematocrit
Under ideal circumstances, invasive monitoring (CVP/ABP) to be done
Step 2 e If shock persisted after boluses
Look for hematocrit and CVP and look for co-morbidities
If CVP low and HCT normal to high
If CVP normal/high and HCT normal
Titrate crystalloid/colloid till target CVP/HCT
Consider inotropes/vasopressor according to SBP
Watch for respiratory distress
Dopamine/Adrenaline (if SBP low)
Provide positive pressure ventilation
Dobutamine (SBP normal/high)
Watch for SBP and 2D ECHO
Check for raised intra abdominal pressure
Start Inotropes/Vasopressor if indicated
Controlled ascitic fluid tapping
Step 3- Look for unrecognized morbidities
Occult bleed
Myocardial dysfunction (systolic or diastolic)
Elevated intra abdominal pressure
Co existing bacterial shock/malaria
Positive pressure ventilation contributing to poor cardiac output
Wide spread hypoxic ischemic injury with terminal vasoplegic shock (no treatment effective)
SBP e Systolic Blood Pressure, ABP e Arterial Blood Pressure.
If CVP low and HCT low
Check for occult/overt bleeding
Consider blood transfusion to break
anemia-acidosis-shock cycle
60
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
Fig. 3 e Treatment plan of dengue case management.
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
6.5.
Heamological tests
These tests are suggestive but never diagnostic for dengue.
Thrombocytopenia is usually observed in between day 3 and
day 8 after the onset of illness but it is a constant feature of
dengue haemorrhagic fever. Leucopenia precedes thrombocytopenia and a progressive decrease in WBC count should
alert the care giver.
7.
Treatment
Patients may be categorized into the following groups:
< Group A: Outpatient management with instructions
< Group B: Inpatient management
< Group C: Emergency treatment and urgent referral.
7.1.
Group A: outpatient management with instructions
(for those who can be sent home)
They should be reviewed daily with a clinical examination and
laboratory assessment. They should be encouraged to take
oral rehydration solution and fruit juice to replace losses from
fever and vomiting and reduce the risk of hospitalization.
Paracetamol is the preferred antipyretic with a minimum
dosing interval of 6 h. Non-steroidal anti-inflammatory drugs
may aggravate gastritis and/or bleeding and are to be avoided.
Caregivers must be informed that the patient should be
brought to hospital immediately if any of the following occur:
no clinical improvement, deterioration around the time of
defervescence, severe abdominal pain, persistent vomiting,
cold and clammy extremities, lethargy or irritability/restlessness, bleeding (e.g., black stools or coffee-ground vomiting) or
failure to pass urine for more than 4e6 h.
7.2.
61
compensated shock in infants and children is shown in Fig. 1.
Patients with hypotensive shock should receive boluses of
intravenous isotonic crystalloid or colloid solution at a rate of
10e20 ml/kg over 15 min. Further fluids are adjusted based on
the response and serial hematocrit measurements. A falling
hematocrit at this stage may indicate hemorrhage and should
be treated with blood transfusion (fresh whole blood or
packed red blood cells). Fluid management of hypotensive
shock in infants and children is shown in Fig. 2. There are
three stages of shock in dengue e compensated shock, hypotensive shock and refractory shock. Steps in management
of refractory dengue shock are shown in Table 2.16
The treatment plan of dengue is shown in Fig. 3.
8.
Severe bleeding
Patients at risk of severe bleeding those having prolonged or
refractory shock, renal or liver failure, severe and persistent
metabolic acidosis, anticoagulant therapy, any trauma,
including intramuscular injection and with underlying hemolytic conditions.17
Severe bleeding can be recognized by decrease in hematocrit after fluid resuscitation with unstable hemodynamic
status, refractory shock that fails to respond to consecutive
fluid resuscitation of 40e60 ml/kg, hypotensive shock with
low/normal hematocrit before fluid resuscitation, persistent
or worsening metabolic acidosis with or without wellmaintained systolic blood pressure.17
The most important intervention for a patient with dengue
shock and life threatening bleeding is restoration of oxygen
carrying capacity. Transfuse fresh whole blood or fresh
packed red blood cells. Platelets, FFP or cryoprecipitate are not
indicated in majority of patients of severe bleeding, as they
may contribute to volume overload. They are indicated only if
bleeding is ongoing despite 2e3 aliquots of blood
transfusion.16
Group B: those who should be admitted to hospital
This group includes those with warning signs, co-morbid
conditions or social situations where adequate home care
cannot be ensured.
Choice of intravenous fluids e Most studies on the role of
different fluids in the treatment of dengue infection found no
difference in terms of recovery from shock or outcome,
although colloids have been reported to provide the most
rapid normalization of the hematocrit and restoration of the
cardiac index, without adverse effects. The current WHO
guidelines recommend the use of either isotonic crystalloid or
colloid fluids for the treatment of hypotensive shock.
7.3.
Group C: those who require emergency treatment
for severe dengue
These patients require urgent intravenous resuscitation with
crystalloids or colloids, aimed at maintaining adequate
perfusion and urine output and improving tachycardia. In
patients with compensated shock, fluids are started at a rate
of 5e10 ml/kg/h and titrated based on clinical response and
serial hematocrit measurements. Fluid management of
9.
Fluid overload
Causes of fluid overload in patients of severe dengue are
excessive and/or too rapid intravenous fluids, incorrect use of
hypotonic solutions, large volumes of fluid in patients with
unrecognized severe bleeding, inappropriate transfusion of
fresh-frozen plasma, platelet concentrates and cryoprecipitate, continuation of intravenous fluids after plasma
leakage has resolved (24e48 h from defervescence) as well as
co-morbid conditions such as congenital or ischemic heart
disease, chronic lung and renal diseases.17 Indications for ICU
management in fluid overloaded patients are severe respiratory distress/hypoxemic respiratory failure, pulmonary
edema, tense ascites and irreversible shock (heart failure,
often in combination with ongoing hypovolemia).17 Fluid
overload is the basic mechanism in various complications of
severe dengue like respiratory distress or failure due to pleural
effusion or pulmonary edema; refractory shock due to
increased myocardial work or myocardial ischemia and
persistent acidosis and intractable bleeding due to abdominal
compartment syndrome. So these patients require additional
62
p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 5 4 e6 2
investigations and monitoring like chest X-ray, ECG, echocardiography, cardiac enzymes assay and intra abdominal
pressure measurement.17
Management of fluid overload according to clinical parameters includes oxygen therapy or positive pressure ventilation, decreasing or stopping intravenous fluids and oral or
intravenous furosemide 0.1e0.5 mg/kg/dose or a continuous
infusion of furosemide 0.1 mg/kg/hour.17
Patient in shock state with signs of fluid overload may have
occult hemorrhage. Fresh whole blood transfusion is to be
given as soon as possible. Peritoneal dialysis is rarely indicated in diuretic resistant. Rapid drainage of pleural and ascitic fluid may cause sudden hemodynamic instability and
catastrophic hemorrhage.16
Conflicts of interest
4.
5.
6.
7.
8.
9.
All authors have none to declare.
Dengue protocol project: IAP recommendations
and guidelines on diagnosis and management of
dengue fever in children
Chair person
Convener
Academic Coordinator
Executive Coordinator
Writing committee
Contributors
Dr Ashok Kapse, Dr Digant Shastri
Dr Jaydeep Choudhury
Dr. Abhay K Shah
Dr. Bhavesh Patel
1. Dr. Raju C Shah
2. Dr. Vijay Yewale
3. Dr. Rohit Agrawal
4. Dr. Baldev Prajapati
1. Dr S Balasubramanian
2. Dr Ritabrata Kundu
3. Dr A J Chitkara
4. Dr Nirmal Choraria
10.
11.
12.
13.
14.
15.
references
16.
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