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
oHepa@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
Day of illness
emp
Time of fever defervescence (Saat suhu reda)
Absence of fever, clinical improvement, return of
appetite
Time of fever defervescence DHF
Hari sakit
emp
Clinical worsening, malaise, agitated, cold and calmy
extremities, fast breathing, reduced OUP, no appetite
Critical phase Fever phase Recovery phase
Time of fever defervescence
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 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
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
When Patients Develop DSS: 3 to 6 days after onset of symptoms
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)
Four Criteria for DHF Fever Hemorrhagic manifestations Excessive capillary permeability 100,000/mm3 platelets
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
DHF Gr I and II Management of Cri*cal Phase
Monitoring during Cri@cal Phase
General condi@on, appe@te, vomi@ng, bleeding and other signs and symptoms Monitoring
As frequently as indicated Peripheral perfusion
every 24 hours in non-shock pa@ents 12 hours in shock pa@ents Vital signs
every 4-6 hours in stable cases, more frequent in unstable pa@ents or suspected bleeding
Serial hematocrit
every 8 to 12 hours in uncomplicated cases hourly in profound/prolonged shock or uid overload
Urine output
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
Rate of Infusion in DSS Management of Cri*cal Phase
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.
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