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

GUIDELINES

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)

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)

CRITERIA FOR SEVERE DENGUE

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

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 of
dengue.

Conrmed Dengue Fever

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

Conrmed 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

Monitoring

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

signs and symptoms

Peripheral
perfusion

As frequently as indicated

Vital signs

every 24 hours in non-shock pa@ents

12 hours in shock pa@ents

Serial
hematocrit

every 4-6 hours in stable cases,

more frequent in unstable pa@ents or suspected bleeding

Urine
output

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

B-Bleeding
Haematocrit

C-Calcium
Electrolyte,
Ca++

S-Blood
sugar
BS
(dextros@ck)

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.