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SUBJECT SEMINAR

MANAGEMENT OF
DENGUE FEVER

 PRESENTER : Dr.Mohan.T.Shenoy

 CHAIRPERSON: Dr.Nisarga
REFERENCES
 NELSON Textbook of Pediatrics 18th edition
 MEHERBAN SINGH Pediatric Emergencies 4th edition
 IAP Textbook of Pediatrics 4th edition
 Textbook of Pediatric & Neonatal emergencies by SACHDEV
 Textbook of pediatric infectious diseases By Ralph D. Feigin
 Davidson's principles & practice of medicine
 PARK’s Textbook of Preventive and Social medicine 20th edition
 http://www.who.int/ctd/docs/dengue.pdf
 http://www.cdc.gov/
 Jornal de Pediatria - Vol. 83, No.2(Suppl), 2007 -Dengue and
dengue hemorrhagic fever – Singhi S et al.
 Emerged among children in Southeast Asia during the 1950s.

 Has since become a major public health problem worldwide

 Significant cause of pediatric morbidity and mortality.

 The affected children need very careful monitoring.

 The fluid therapy is challenging and needs modification frequently.

 Its severe forms (hemorrhagic fever and shock syndrome) may lead
to multisystem involvement and death.

 Early diagnosis, close monitoring for deterioration & response to


treatment are necessary in all cases.
Risk factors for developing DHF / DSS

• Children are more prone to develop DHF / DSS than adults.

• DHF / DSS is associated more with well nourished than


with under nourished children.

• Primary infection in infants born to dengue immune


mothers.

• Presence of underlying chronic illnesses (eg: heart disease,


anaemia, chronic liver disease)
Warning Signs for Dengue
Shock
Alarm Signals:
• Severe abdominal pain
• Prolonged vomiting
Four Criteria for DHF • Abrupt change from fever
• Fever to hypothermia
• Hemorrhagic manifestations • Change in level of
• Excessive capillary consciousness (irritability
permeability or somnolence)
•  100,000/mm3 platelets

Initial Warning
Signals When Patients Develop
• Disappearance of fever DSS:
• Drop in platelets • 3 to 6 days after onset of
• Increase in hematocrit symptoms
Special attention :High-risk dengue patients
 Infants under 1 year of age

 Overweight/obese patients

 Massive bleeding

 Change of consciousness, esp. restlessness,irritability or


coma

 Presence of underlying diseases e.g. thalassemia, G-6-PD


deficiency, heart disease
Admission in Dengue Fever
 Abdominal pain – may be intense and sustained
 Bleeding tendencies with Positive tourniquet test
 Cold extremities
 Decreased urine output
 Platelet count < 1 Lakh and PCV rise by >20%
 Persistent vomiting
 Altered mental status -Restlessness or somnolence
TREATMENT
DENGUE FEVER
 No specific therapy – only symptomatic

 Rest and Plenty of oral fluids

 Use Paracetamol
 Avoid Aspirin and NSAIDs

 Follow up preferably everyday - from the 3rd day


until afebrile for 24-48 hours
General measures
 Frequent monitoring of vitals.

 Essential nursing care.

 Stop bleeding with proper techniques


 e.g. anterior nasal packing for massive epistaxis.

 Avoid blind invasive procedures


 e.g. no nasogastric tube insertion, no gastric lavage.
Nutritional support
 Soft, balanced, nutritious diet, juice and electrolyte
solution – plain water is not adequate.

 Avoid black- or red-colored food or drinks (may be


mistaken for bleeding
General measures (continued)
 Sedation is needed in some cases to restrain agitated child.

 Chloral hydrate(12.5-50 mg/kg), orally or rectally recommended.


 Avoid Long-acting sedatives.

 NCPAP
 should be preferred if there is Acute respiratory failure
associated with DSS.

 Oxygen via face mask/nasal cannula

 in case of shock/impending shock.


Other supportive,symptomatic treatment
 H2-blockers (ranitidine)
 Recommended in case of gastrointestinal bleeding

 Domperidone
 1 mg/kg/day in three divided doses in case of severe
vomiting for 1-2 days.
 One single dose may be adequate

 Antibiotic
 Not necessary; it may lead to complications
FLUID MANAGEMENT
 In young infants without shock-
 N/2 saline in 5% dextrose

 In patients who already have volume overload, i.e.,


massive pleural effusion
 colloid solutions

 Hydroxyethyl starch at 6% may be preferred in children


with severe shock; the use of dextran is associated with
various adverse reactions
FLUID MANAGEMENT
 WHO guidelines are useful in that they offer an
algorithmic approach to fluid resuscitation in DHF and
DSS.

 However, the usefulness of these guidelines is limited


beyond the immediate resuscitation

 do not address treatment of complicated forms of the disease,


incl. fluid overload and multiple organ failure, which could cause
disability or death.
In case of no response to IV fluids:
 May have myocardial dysfunction and decreased LV
performance, which may be easily detected by
echocardiography.

 Consider and correct

 Massive plasma leakage


 Concealed internal bleeding – decrease in Hct
 Hypoglycemia – Blood sugar < 60 mg%
 Hyponatremia, hypocalcemia – electrolytes
 Acidosis – indicates metabolic acidosis in blood gas analysis
Blood and platelet transfusion
Platelet transfusion
 Thrombocytopenia with significant bleeding.
 Platelet count < 10,000/mm3

DOSE
10-20 mL/kg
 Platelets or blood should NOT be transfused based upon
platelet count alone.

 Low platelet count may not be predictive of bleeding.

 Only 0.4% of DHF pts need platelet transfusion.

 Mild reductions in platelet counts are usually not associated


with significant bleeding.

 In children with severe thrombocytopenia in absence of


significant bleeding, platelet infusion does not alter the
outcome.

Platelets return to normal within 7-9 days.


Fresh Whole blood / Packed red cell transfusion

 Significant blood loss > 10% (6-8 mL/kg)


 Concealed internal bleeding
 Hemolysis

DOSE

 Fresh whole blood 10 mL/kg/dose


 Packed red cells 5 mL/kg/dose
Role of Steroids

Ineffective in preventing shock in DHF


 It may cause harm

 Treatment with methyl-prednisolone did NOT show any benefit in a


double blind placebo-controlled trial in DSS
Complications of DF/DSS

 DIC
 Myocardial dysfunction incl. Cardiomyopathy
 Hepatitis
 Reye-like syndrome
 Encephalitis
 ARDS
 Glomerulonephritis
Treatment of complications
Fluid overload
 AVOID

 Early IV fluid therapy- in the febrile phase


 Excessive use of hypotonic solutions
 Non-reduction in the rate of IV fluid after initial resuscitation
 Blood loss replaced with fluids in cases with occult bleeding

 Treatment

 Judicious fluid removal


 colloids with controlled diuresis (furosemide 1 mg/kg infusion over 4
hours) or dialysis
Electrolyte imbalance

 Hyponatremia
 Hypocalcemia – 10% Ca gluconate 1 mL/kg/dose, slow IV push
every 6 hour

Large pleural effusions, ascites

 Careful titration of intravenous fluids.

 Avoid insertion of intercostal drains and tracheal intubation.

 Large pleural effusions during recovery phase after 48 hours


furosemide (0.25-0.5 mg/kg at 6 hours’ interval for 1 to 2 doses).
Disseminated intravascular coagulation

 Frequent Clinical assessment

 Regular Coagulation profile

 PT, aPTT, fibrinogen, platelet and FDP mandatory, as indicated.

Seriously sick patients with bleeding & DIC have benefited from :

 Heparin therapy + Cryoprecipitate (1 unit per 5 kg body weight)

 Followed by Platelets (4 units/m2 or 10-20 mL/kg) within 1 hr and


Fresh frozen plasma (FFP 10-20 mL/kg).
 ARDS & Hypotension with Respiratory failure

 Nasal CPAP

 Refractory shock

 Vasopressin
 Desmopressin 0.3 mcg/kg over 30 min 3-4 days
Prognosis
 DF is a very incapacitating disease; however, its prognosis is favorable.

 Significant morbidity and mortality can result if early recognition and


monitoring of severe forms are not done.

 If left untreated, the mortality of DHF or DSS patients may be as high as


40-50%.

 Early recognition of illness, careful monitoring and adequate and


appropriate fluid therapy have decreased mortality to 1%.

 If shock is identified when pulse pressure starts to drop and intravenous


fluids are administered, the outcome will be excellent.
 Recovery is fast and most patients recover in 24-48 hours without
any sequelae.

 The outcome may not be so good if the patient develops cold


extremities.

 Most deaths from DHF/DSS are caused by

 prolonged shock
 massive bleeding
 fluid overload and
 acute liver failure with encephalopathy.

 Severe refractory shock, DIC, ARDS, liver failure and neurological


manifestations singly or in combination were the commonest causes
of death in a recent series.
Criteria for Discharge of patients
 Visible clinical improvement with return of appetite
 Stable pulse, blood pressure and respiratory rate
 Afebrile for 24 hours (without anti-fever therapy)
 Minimum of 3 days after recovery from shock
 Good urinary output and stable haematocrit levels
 Platelet count > 100,000/mm3
 No respiratory distress /pleural effusion /ascites
 No evidence of external or internal bleeding
 Convalescent confluent petechial rash

Pan American Health Organization: Dengue and Dengue Hemorrhagic Fever: Guidelines for
Prevention and Control. PAHO: Washington, D.C., 1994: 69.
Convalescent confluent petechial rash

BETWEEN 8 –10th day of SICKNESS


Signs of recovery
 Stable pulse/BP/Respiratory rate
 Temperature
 Good urine output
 Stable hematocrit
 No evidence of bleed
 Return of appetite
 Absence of vomiting
Common Misconceptions about
Dengue Hemorrhagic Fever
 Positive tourniquet test = DHF
 Tourniquet test is a nonspecific indicator of capillary
fragility
 Dengue + bleeding = DHF
 Need 4 WHO criteria, capillary permeability
 DHF kills only by hemorrhage
 Patient dies as a result of shock

 Poor management turns dengue into DHF


 Poorly managed dengue can be more severe, but DHF is a distinct
condition, which even well-treated patients may develop
Aedes aegypti Breeding Sites
VECTOR CONTROL

 The control is primarily dependent on eradicating mosquito.


 Public spraying for mosquitoes is the most important aspect of this
approach.

PERSONAL PROTECTION

 Avoiding endemic areas


 Cover exposed skin
 Mosquito nets, repellents
 Use of DEET-impregnated bed nets
Immunopathogenic
Cascade of DHF/DSS
 Macrophage – monocyte infection
 Previous infection with heterologous
Dengue serotype results in production
of non protective antiviral antibodies
 These Ab bind to the virion’s surface
Fc receptor and focus the Dengue virus
on to the target cells – macro/monocytes
 T cell - cytokines, interferon, TNF alpha
 At present, no specific drug or vaccine is available against the
dengue virus.

 The tetravalent live attenuated DEN vaccine trial has been done in
Thailand.

 Produces 80-90% seroconversion rates to all 4 serotypes after


administration of 2 doses in young children

SUGGESTIONS FROM THE TRIAL

 Vaccine has moderate, but improvable reactogenicity

 High seroconversion rates against four serotypes of DEN virus


GLOBAL STATUS
• Endemic in 112 countries
• 40% of the world’s population
•About 2.5 billion people in tropical and subtropical areas at risk.
•Every year about 50-100 million cases of dengue infection
• Hospitalized cases: 5,00,000/year (90% are children)
• At least 12,000 deaths occur worldwide
• Disease burden: 465,000 DALY
BURDEN OF DISEASE IN S.E.ASIA

 CATEGORY-A
 (INDONESIA,MYANMAR,AND THAILAND)

 CATEGORY-B
 (INDIA,BANGALADESH,MALDIVES,AND SRILANKA)

 CATEGORY-C
 (BHUTAN, NEPAL)

 CATEGORY-D
 (DPR KOREA)
The Dengue Virus
 Single stranded RNA virus
 Positive sense
 40 to 50 nanometers
 Flavivirus
 Four sero-sub types
 Type 1 to 4

 Arthropod borne (zoonotic)


 Man is accidentally infected
 Other vertebrates are reservoirs
Aedes aegypti Mosquito

Day-biting urban thriving mosquito


White bands or scale patterns on its legs and thorax.
Highly domesticated tropical mosquito, lives around human habitation
 Single infective mosquito may cause an outbreak
Transmission Cycle
Extrinsic
Vector Incubation
Humidity: Period:
Rainfall & Temp. 8-10 days

Intrinsic Incubation Period:


3-14 days

Susceptible hosts,
(population)
Viraemia & Fever: 5-7 days Source patients
 During dengue epidemics, attack rates among susceptible
individuals are often 40-50%, but may reach 80-90%.

 An estimated 500,000 cases of DHF require hospitalization


each year, of which a very large proportion are children.

 At least 2.5% of cases die, although case fatality could be


twice as high.

 Without proper treatment, DHF case fatality rates can


exceed 20%.

 With modern intensive supportive therapy, such rates can be


reduced to less than 1%.
DENGUE ILLNESS: DISTRIBUTION
SPECTRUM OF DENGUE INFECTION

Population

24%
Infection
76%

Asymptomatic Clinical Cases 3%


97%
Infection

DF DHF/DSS 0.8%
(non-DHF) 99.2%

survive Death
Rates in dengue model by Shepard et al. Vaccine. 2004, 22:1275-1280.
Clinical Features
 Fever – biphasic/saddle-back type
 Headache with retro-orbital pain
 Muscle and joint pain
 Nausea/vomiting
 Rash
 Hemorrhagic manifestations
 Abdominal pain
 Polyserositis
Undifferentiated Fever

• Many silent dengue infections precede and


accompany DHF epidemics.

• During outbreaks,150-200 silent dengue


infections for each dengue shock syndrome

• Uncommon in pediatric age group

DS Burke, et al. A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg 1988;
38:172-80.
ERYTHEMATOUS FLUSH

Suffused + Swollen face with purplish lips, injected eyes


Reddened malar regions and ear lobules
Dengue fever with unusual hemorrhage

 Do not satisfy criteria for DHF/DSS

 Seen in significant numbers in epidemics

 Varying degree of mucosal and cutaneous bleeds with


some degree of thrombocytopenia

 Lesser fluid requirement c.t Dengue Hemorrhagic fever


Hemorrhagic Manifestations

 Skin hemorrhages: Petechiae, purpura, ecchymoses


 Gingival bleeding
 Epistaxis
 Gastro-intestinal bleeding: hematemesis, melena
 Hematuria
 Increased bleeding per vaginum
 Intracranial bleed
DENGUE HEMORRHAGIC FEVER
Petechiae
PURPURA
Four Grades of DHF
 Grade 1
 Fever and nonspecific constitutional symptoms
 Positive tourniquet test is only hemorrhagic
manifestation
 Grade 2
 Grade 1 manifestations + spontaneous bleeding
 Grade 3
 Signs of circulatory failure (rapid/weak pulse, narrow
pulse pressure, hypotension, cold/clammy skin)
 Grade 4
 Profound shock (undetectable pulse and BP)
Tourniquet Test
 Inflate blood pressure cuff to a point midway between
systolic and diastolic pressure for 5 min

 Positive test: 20 or more petechiae / inch2 (6.25 cm2)

 In an epidemic situation, the test is positive in


 50% on the 1st day, and in
 80% by the end of the febrile phase.

Pan American Health Organization: Dengue and Dengue Hemorrhagic Fever: Guidelines for
Prevention and Control. PAHO: Washington, D.C., 1994: 12.
Positive Tourniquet Test
Endemic areas -WHO criteria

2 clinical observations
+
1 laboratory finding

OR

At least a rising hematocrit level


Thrombocytopenia (< 100,000 cells/mm3)
Hemoconcentration
 A rise in hematocrit levels > 20% of the baseline values can be
documented if hematocrit level is monitored regularly from early
stages of illness.

 A drop in hemoglobin or hematocrit > 20% following volume


replacement therapy can be taken as an indication of previous
hemoconcentration.
Clinical Case Definition for DSS
 4 criteria for DHF

 Evidence of circulatory failure


manifested indirectly by :

 Rapid and weak pulse


 Narrow pulse pressure ( 20 mm Hg) OR hypotension for age
 Cold, clammy skin and altered mental status

 Frank shock is direct evidence of circulatory failure


Hypothesis on DHF - DSS
 Neutralizing Ab
 type specific
 neutralize the homologous sub type

 Enhancing Ab
 Serotype independent
 Concentration dependent

 Subsequent infection with heterologous subtype


 causes immune complexes - target the mononuclear lineage for enhanced
viral replication
 Infected monocytes release vasoactive mediators causing vascular damage
Initial Immunogenecity
Immune Complexes
Risk Factors Reported for DHF

 Age – Bimodal ; Children > Adults


 Race – Whites > Black
 Host genetics
 Pre-existing anti-dengue antibody

 maternal antibodies in infants


 previous infection
Risk Factors for DHF (continued)
 Chronic infections

 Hyperendemic transmission

 Locations with 2 or more serotypes circulating


simultaneously at high levels
 Secondary infections

 Cross-reacting Flaviviral (IgM) Antibody


Hyperendemicity

Increased circulation Increased probability


of viruses of secondary infection

Increased probability of Increased probability of


occurrence of virulent strains immune enhancement

Increased probability of DHF

Gubler & Trent, 1994


Viral Risk Factors

 Virus strain (genotype)

 Epidemic potential: viremia level, infectivity

 Virus serotype

 DEN-2 > DEN-3 > DEN-4 > DEN-1


Risk Factors Reported for DSS

 Younger age at onset


 Altered sensorium
 Paralytic ileus
 Deranged Prothrombin time at
presentation
Clinical Evaluation in Dengue Fever
 Blood pressure

 Hydration status

 Tourniquet test

 Evidence of bleeding in skin or other sites

 Evidence of increased vascular permeability


DIFFERENTIAL DIAGNOSIS
 Falciparum malaria
 Gram-Negative septicemia
 Leptospirosis
 Rickettsiosis
 Typhoid fever
 Chikungunya Fever
Laboratory Tests
 In uncomplicated DHF cases

 Hematocrit and platelet counts are the only necessary tests

 In those at high risk of complicated DHF

 Blood grouping/cross matching


 Blood glucose
 Blood electrolyte (Na, Ca, K, CO2)
 Liver function test
 Renal function test (BUN, creatinine, uric acid)
 Blood gas
 Coagulogram (PTT, PT, TT)
 Complete Blood Count

-WBC (leukopenia with lymphocytosis)


-Platelet count <1,00,000

 Peripheral smear

 PCV (Hematocrit) rise 20% above baseline

 Coagulation profile to rule out DIC

 ABG : Metabolic Acidosis in prolonged shock

 Blood urea and S.Creatinine elevated in terminal stage of shock


Laboratory Tests (continued..)
 Serum electrolytes – Hyponatremia

 Urine--check for microscopic hematuria

 Liver function tests –Hypoproteinemia, SGOT>SGPT

 CXR – Pleural effusion (Right > Left )

 USS Abdomen – Hepatomegaly, Ascites and Gall bladder


thickening
Turk Reaction cell
 Transformed lymphocytes (Plasmacytoid )
 More than 20% Turk cells in buffy coat smear is
characteristic of DHF
Serological methods
 MAC-ELISA -> IgM

 Hemagglutination inhibition test -> IgG

 Complement fixation test

 Dot-Blot immunoassay
RT-PCR
 Early detection of dengue infection when antibodies are
not yet detectable.

 Less sensitive than viral isolation during early days of fever


 Rapid detection within 24 hours.
 But after 5 days of fever it is more sensitive than virus isolation.
 Able to detect the virus up to 7-8 days of fever.

 Epidemiological studies

 dengue serotypes could be identified without cross reactivity


with other flaviviruses
Virus isolation
 Mosquito cell lines

 Sensitivity of 50 %
 Culture done in cell line derived from A. albopictus cell.
 Can determine serotype of the infecting virus)
 For research and epidemiological studies.

 Mosquito inoculation technique

 Vertebral cell culture


Confirmed case - WHO definition

 Positive viral identification

AND/OR

 Positive serological test for HI antibody ≥ 1,280


OR

 Positive IgM/IgG ELISA test in the convalescence


Important points to evaluate are
 History

 Bleeding, abdominal pain, vomiting, appetite, fluid intake, and urine output

 Physical examination

 Vital signs, liver size and tenderness

 Blood counts

 WBC ≤ 5,000 cells/mm3 with lymphocytosis and increase in atypical lymphocytes


 Platelet counts ≤ 100,000 cells/cumm – indicates progression to critical phase.
 Rising Hct of 10-20% - indicates that the patient has progressed to the critical phase

 Liver function tests

 in every patient who shows a change in consciousness, restlessness, confusion and


irritability
Transmission of Dengue Virus
by Aedes aegypti
Mosquito feeds / Mosquito refeeds /
acquires virus transmits virus

Extrinsic Intrinsic
incubation incubation
period period
Viremia Viremia
0 5 8 12 16 20 24 28
DAYS
Illness Illness
Human #1 Human #2
Temperature, Virus Positivity and
Anti-Dengue IgM , by Fever Day
100

Dengue IgM (EIA units)


300
Temperature (degrees Celsius)

39.5
Percent Virus Positive

80
39.0 225
38.5 60
150
38.0 40
37.5 20 75

37.0
0 0
-4 -3 -2 -1 0 1 2 3 4 5 6
Fever Day
Mean Max. Temperature Virus Dengue IgM
Adapted from Figure 1 in Vaughn et al.,
J Infect Dis, 1997; 176:322-30.