Update on

Management of
Pediatric
Dengue
Yulia Iriani

Disease Burden
2.5 billion people 2/5 of the world's
popula@on are at risk.
50 million dengue infec@ons occur
worldwide
annually.
500 000 require hospitaliza@on each
year.
90% are children < 5 years 2.5% die.

Endemic in >100 countries

Disease burden
Indonesia:
Major public health
problem.
Leading cause of
hospitaliza@on and
death among
children.
Hyperendemicity with all
4 serotypes circula@ng in
urban areas.
Spreading to rural areas.

Causes of DHF Death

Delayed diagnosis:
OPD prolonged shock
IPD uid overload by hypotonic
solu@ons (5% D/ N/2 at M rate)

Not proper IV uid management

Prolonged shock grade

IV
Without proper treatment
> 4 hours
o Hepa@c failure prognosis 50%
survival o +
Renal failure
prognosis 10% survival o + 3
organ failure prognosis Miracle

> 10 hours Death !!!

Goals of dengue
management
Recognize dengue infec@on at an
early stage;
Detect the early onset of plasma
leakage in
these pa@ents; and
Appropriately manage dehydra@on
and
hypovolemia.
Reduce mortality and morbidity

Virus, Vector and

Transmission

Ethiological agent

Aedes aegyp*

Dengue transmission

Disease
Pathogenesis

Current Hypothesis
DENV tropism

Cells of the immune system

Organ pathology
Endothelial cells

Virus virulence
An@body-Dependent Enhancement

Complement system ac@va@on

Autoimmunity
Host gene@c factors
Cross-Reac@ve T-Cell response

Virus virulence
Certain DENV strain responsible for
more
severe disease
Primary infec@on with DENV-1
followed by
infec@on with DENV-2 or DENV-3
Dierent serotype may vary in their
abillity to
infect dierent cell type

Proposed model of heterologous immunity in secondary dengue virus infec@ons and its implica@ons for the
pathogenesis of dengue hemorrhagic fever. Primary DENV-2 infec@on and sequen@al DENV-1 and DENV-2 infec@ons
are compared for illustra@on purposes. The naive T cell repertoire (pale colors) likely contains some cells with
higher avidity for DENV-1 than DENV-2 (red; DENV-1 > DENV-2) and other cells with higher avidity for DENV-2 than
DENV-1 (blue; DENV-2 > DENV-1). During primary infec@on, T cell popula@ons with higher avidity for the infec@ng
serotype are preferen@ally expanded and enter the memory pool (shown as darker colors). When DENV-2 infec@on
follows DENV-1 infec@on, the memory T cell popula@ons with higher avidity for the earlier infec@on expand more
rapidly than do naive T cell popula@ons. Because these DENV-1specic memory T cells have lower avidity for
DENV-2, viral clearance mechanisms are subop@mal, whereas proinammatory responses contribute to disease.

Secondary Infec@on or
Immune
Enhancement Hypothesis

Model of an.body-dependent enhancement of dengue infec.on

An@body (Ab)-dependent enhancement of infec@on occurs when preexis@ng an@bodies present
in the body from
a primary (rst) dengue virus (DENV) infec@on bind to an infec@ng DENV par@cle during a
subsequent infec@on
with a dierent dengue serotype. The an@bodies from the primary infec@on cannot neutralize
the virus. Instead,
the Abvirus complex akaches to receptors called Fc receptors (FcR) on circula@ng
monocytes. The an@bodies

help the virus infect monocytes more eciently. The outcome is an increase in the overall
replica@on of the virus
and a higher risk of severe dengue.
2007 Nature Publishing Group Whitehead, S. S. et al. Prospects for a dengue virus
vaccine. Nature Reviews
Microbiology5, 518528 (2007). doi:10.1038/nrmicro1690 All rights reserved

Transient
autoimmunity
Cross-react with some self-an@gens
An@-NS1 Ab cross-reac@ve with
endothelial cells could trigger
these cells to express NO and
undergo apoptosis (141), enhance
expression IL-6, IL-8, ICAM-1, human
thrombocyte cause
thrombocytopenia

Clinical Manifesta@on

GUIDELIN
ES

WHO 1997

WHO/TDR 2009

WHO SEARO

2011

Manifesta@on of Dengue Virus

Infec@on

20

Table.
Expanded dengue syndrome
(Unusual or atypical
manifesta@ons of dengue)

Course of Dengue
Illness

Course of Dengue
Illness
Plasma leakage
24 48 hours,
3rd 7th day of illness (usually: 4th
5th daya)

Time of fever defervesence

Fever diminished
Febrile shock/cri@cal phase

Dengue Fever
Absence of fever, clinical
improvement, return of
appetite
Time of fever defervescence
(Saat suhu reda)

emp

Day of illness

Time of fever defervescence DHF

Clinical worsening, malaise,
agitated, cold and calmy
extremities, fast breathing,
reduced OUP, no appetite

emp

Time of fever defervescence

Fever phase

Critical phase

Recovery phase

Hari sakit

Clinical Course of DHF

Clinical Case
Deni@on

Clinical Case
Deni@on
WHO/TDR 2009

WHO/TDR
2009
Dengue is one disease en@ty with
dierent clinical presenta@ons and
osen with unpredictable clinical
evolu@on and outcome

CRITERIA FOR DENGUE

WARNING SIGNS
Probable
Dengue
live in /travel to dengue
endemic
area.
Fever and 2 of the following
criteria:
Nausea, vomi@ng
Rash
Aches and pains
Tourniquet test posi@ve
Leukopenia
Any warning sign
Laboratory-conrmed
dengue (important when no
sign of plasma leakage)

Warning Signs*
Abdominal pain or
tenderness
Persistent vomi@ng
Clinical uid accumula@on
Mucosal bleed
Lethargy, restlessness
Liver enlargment >2 cm
Laboratory: increase in
HCT concurrent with
rapid decrease in platelet
count
*(requiring strict observa@on
and
medical
interven@on)

Laboratory-conrmed dengue

(important when no sign of plasma leakage)

CRITERIA FOR SEVERE

DENGUE

Severe
plasma
leakageleading
to:
Shock (DSS)
Fluid
accumula@on
with
respiratorydistr
ess

Severe
bleeding
as evaluated
by
clinician

Severe
organ
involvement
Liver: AST or
ALT
>=1000
CNS:
Impaired
consciousness
Heart and
other

organs

Clinical Case
Deni@on
WHO 1997
WHO SEARO 2011

Clinical Case Deni@on

Probable Dengue
Fever
Fever of 2 to 7 days
dura@on, with two or
more of the following:
Headache, retroorbital
pain, myalgia,
arthralgia, rash,
hemorrhagic
manifesta@ons,
leukopenia, and
suppor@ve serology or
occurrence at the same
loca@on and @me as
other conrmed cases

Conrmed Dengue
Fever
of
dengue.

 Conrmed by laboratory
criteria (isola@on of the
dengue virus,
demonstra@on of the

dengue virus
an@gen, serology,
or genomic
sequence).

Clinical Case
Deni@on
Probable Dengue
Fever
Acute febrile illness with >= 2 of the
followingl:
Headache.
Retro-orbital pain.
Myalgia.
Arthralgia/bone pain.
Rash.
Haemorrhagic manifesta@ons.
Leucopenia (wbc 5000
cells/mm3).
Thrombocytopenia (platelet
count <150 000
cells/mm3).
Rising haematocrit (5 10%).
and at least one of following:
Suppor@ve serology on single serum
sample:
@tre 1280 with HI test, comparable
IgG @tre

Conrmed Dengue Fever

with ELISA, or posi@ve IgM.
Occurrence at the same loca@on and
@me as
conrmed cases of dengue fever.

Probable case and at least one of the

following:
Isola@on of dengue virus from serum,
CSF or
autopsy samples.
Fourfold or greater increase in
serum IgG (by HI test) or increase in

IgM an@body specic to dengue virus.

Detec@on of dengue virus or Ag in
@ssue,
serum or CSF by IHC, IFA or ELISA.
Detec@on of dengue virus genomic
sequences
by RT-PCR.

Clinical Case Deni@on

WHO Grading of DHF

Clinical Case Deni@on

Clinical Management of
DHF

Principle of DHF
Management
Primary abnormali@es in DHF
Vasculopathy
Thrombocytopenia
Thrombopathy
Coagulopathy
Severe DIC

Strategy of DHF
Management
Suppor@ve therapy
Drug: as indicated
Plasma leakage volume

replacement

How to choose uid solu@on

25% need

colloid

Clinical course of DHF: unpredictable

monitoring:
Early detec@on and prompt treatment of
circulatory disturbance clinically & PCV
bleeding manifesta@on clinically and lab

Outpa@ent management of
pa@ents
with
dengue
Early
dengue
80% of pa@ents make the rst visit to a
medical
doctor within the rst 2 days of fever
follow-up card
diagnosis of suspected dengue, serial full-
blood-count results (to include, at least,
haematocrit [erythrocyte volume frac@on])

and indicators for admission, at the rst

medical contact.

Oral uid

Steps for OPD screening during dengue

outbreak

Outpa@ent management of
pa@ents
with
dengue
Recommenda.ons for CBC:
All febrile pa@ents at the rst visit to
get the
baseline HCT, WBC and PLT.
with warning signs.
fever >3 days.
circulatory disturbance/shock (+
glucose check). If leucopenia and/or
thrombocytopenia (+),

warning signs (+) immediate medical

consulta@on.

Indica@on for admission

Excessive family concern or cant be
followed up
Very weak, cant eat or drink, not
drinking/
feeding poorly
Spontaneous bleeding
Platelete counts 100.00/mm3 and/or
rising Hct
10 20%
Clinical deteriora@on in defervescence

 Severe abdominal pain/vomi@ng

Signicant dehydra@on requiring iv
uids

Admit immediately
Signs

of shock:

Rapid pulse with no fever

Prolonged capillary rell @me
Cold clammy skin, mokling
Narrowing of pulse pressure 20
mmHg
Hypotension
Oliguria, no urine for 4 6 hours
Change of consciousness

Management of Febrile
Phase
Res@ng, oral uids
Reduc@on of fever
Nutri@onal support
Other suppor@ve and symptoma@c
treatment
AB not necessary; may lead to
complica@on
Steroid ineec@ve; may cause harm

Management of Febrile
Phase
IV uids: in case of doubt, provide
iv uids
Guided by: serial Hct, vital signs, urine
output
Volume: ~ mild to moderate isotonic
dehydra@on (5 8% decit)
Just correct dehydra@on, discon@nue
ASAP

Management of Cri@cal
Phase
Treatment of severe dengue (DHF and
DSS):
prompt assessment
replacement of uid needs
live-saving, modify the severity of
disease and
prevent shock.

Warning Signs for Dengue Shock

Four Criteria for DHF
Fever
Hemorrhagic manifestations
Excessive capillary
permeability
100,000/mm3 platelets
Initial Warning Signals
Disappearance of
fever
Drop in platelets
Increase in hematocrite

Alarm Signals
Severe abdominal pain
Prolonged vomiting
Abrupt change from fever
to hypothermia
Change in level of
consciousness (irritability
or somnolence)
When Patients Develop DSS:
3 to 6 days after onset of
symptoms

Management of Cri*cal
Phase

Management of Cri@cal
Phase
Indica@ons for IV uid:
Pa@ent cannot have adequate oral uid
intake or
is vomi@ng.
HCT con@nues to rise 10%20%
despite oral
rehydra@on.
Impending shock/shock.

Management of Cri@cal Phase

General principles of uid therapy in
DHF
Cri@cal period: Isotonic crystalloid
solu@ons
Used hyper-onco@c colloid solu@ons
(osm. >300
mOsm/l) such as dextran 40 or starch
solu@ons in:
massive plasma leakage,
not responding to the minimum volume of
crystalloid

 Obese: ideal body weight used as a

guide to
calculate the uid volume

Management of Cri@cal
Phase
General principles of uid therapy
in DHF
Volume: maintenance +5%
dehydra@on, to maintain a just
adequate intravascular volume and
circula@on.
Dura@on iv uid
therapy
With shock: should not exceed 24 to 48
hours for
Without shock: may have to be longer but

not more
than 60 to 72
hours.

Requirement of uid based on ideal body

weight

Rate of IV uid in adults and

children

DHF Gr I and II
uid allowance (oral + IV): maintenance (for
one day)
+ 5% decit (oral and IV uid together),
administered
over 48 hours

Adjusted according to the rate

of plasma loss, guided by :
clinical condi@on,
vital signs,
urine output and
haematocrit levels.

Management of Cri*cal
Phase

Management of Cri*cal
Phase

DHF Gr I and II

Monitoring during Cri@cal

Phase
Monitorin
g

General condi@on, appe@te, vomi@ng, bleeding

and other
signs and symptoms

Peripher
al
perfusion

As frequently as indicated

Vital
signs
Seria
l
hematocr

every 24 hours in non-shock pa@ents

12 hours in shock pa@ents
it

 every
4-6 hours
Urine
output

in stable cases,
more frequent in unstable pa@ents or suspected
bleeding
every 8 to 12 hours in uncomplicated cases
hourly in profound/prolonged shock or uid
overload

Management of Cri*cal
Phase

Dengue Shock
Syndrome
DSS: hypovolemic shock caused by
plasma
leakage
Fluid resuscita@on is dierent from other
types of
shock.

DHF Grade III

>> respond to 10 ml/kg over 1 hour or
bolus
Fluid adjustment ~ clinical condi@on,

vital signs,
urine output and haematocrit levels
Management of Cri*cal
Phase

Management of Cri*cal
Phase

Management of Cri*cal Phase

Rate of Infusion in DSS

Management of Cri*cal

Phase

Prolonged/profound shock:
DHF Grade IV
Fluid resuscita@on more vigorous
10 20 ml/kg of bolus uid as fast as
possible,
ideally within 10 to 15 minutes failed:
2nd bolus failed:
Correc@on ABCS

Inves@ga@on of ABCS

Management of Cri*cal
Phase

Laboratory
Inves@ga@ons
Profound shock
Complica@ons
No clinical
improvement in
spite of
adequate
volume
replacement
ABCS

A-Acidosis
Blood gas
LFT, BUN,
Cr

C-Calcium
Electrolyt
e,
Ca++

B-Bleeding
Haematoc
rit

S-Blood
suga
r
BS
(dextros@c

k)

Management of Cri*cal
Phase

Treatment of
Complica@on
Electrolyte imbalance
Hyponatremia
Hypocalcemia 10% Ca gluconate 1
mL/kg/dose, IV push slowly every 6 hours

Treatment of
Complica@on
Fluid overload:
avoid the common causes of uid
overload, which
are
Early IV uid therapy- in the febrile phase
Excessive use of hypotonic solu@ons
Non-reduc@on in the rate of IV uid aser ini@al
resuscita@on
Blood loss replaced with uids in cases with
occult bleeding
Judicious uid removal using colloids with
controlled diuresis (furosemide 1 mg/kg

infusion over 4 hours) or dialysis

Treatment of
Complica@on
Large pleural eusions, ascites
Careful @tra@on of intravenous uids
Large pleural eusions during the
recovery phase
aser 48 hours - small doses of
furosemide (0.25-0.5 mg/kg at 6
hours interval for 1 to 2 doses).
Avoid inser@on of intercostal drains and
tracheal
intuba@on

Treatment of
Complica@on
Disseminated intravascular
coagula@on
Seriously sick pa@ents + bleeding and
DIC
heparin therapy and cryoprecipitate (1
unit per 5 kg
body weight) followed by platelets (4
units/m2 or
10-20 mL/kg) within 1 hour and fresh
frozen plasma (FFP 10-20 mL/kg).

Frequent clinical assessment and

regular coagula@on prole (PT, aPTT,

brinogen, platelet and FDP) are
mandatory, as indicated

Criteria for discharging

Fever (-), at least 24 hours without
an@pyre@c
Return of appe@te.
Visible clinical improvement.
Sa@sfactory urine output.
A minimum of 23 days have elapsed
aser
recovery from shock.
No respiratory distress from pleural
eusion and

no ascites.
Platelet count >50 000/mm3.