SUBJECT SEMINAR SUBJECT SEMINAR MANAGEMENT OF MANAGEMENT OF DENGUE FEVERDENGUE FEVER

PRESENTERPRESENTER : Dr.Mohan.T.Shenoy

CHAIRPERSONCHAIRPERSON: Dr.Nisarga

REFERENCESREFERENCES 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 Warning Signs for Dengue ShockShock

When Patients Develop DSS:• 3 to 6 days after onset of symptoms

When Patients Develop DSS:• 3 to 6 days after onset of symptoms

Initial Warning Signals• Disappearance of fever• Drop in platelets• Increase in hematocrit

Initial Warning Signals• Disappearance of fever• Drop in platelets• Increase in hematocrit

Alarm Signals:• Severe abdominal pain• Prolonged vomiting• Abrupt change from fever to hypothermia• Change in level of consciousness (irritability or somnolence)

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

Four Criteria for DHF• Fever• Hemorrhagic manifestations• Excessive capillary permeability• 100,000/mm3 platelets

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 FeverAdmission 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

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

DENGUE FEVERDENGUE FEVER

General measuresGeneral 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 supportNutritional 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)General measures (continued) SedationSedation is needed in some cases to restrain agitated child.

Chloral hydrate(12.5-50 mg/kg), orally or rectally recommended. Avoid Long-acting sedatives.

NCPAPNCPAP 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 treatmentOther 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 transfusionBlood and platelet transfusion

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 Platelets return to normal within 7-9 dayswithin 7-9 days. .

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

Fresh Whole blood / Packed red cell transfusionFresh Whole blood / Packed red cell transfusion

Role of SteroidsRole 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/DSSComplications of DF/DSS

DIC Myocardial dysfunction incl. Cardiomyopathy Hepatitis Reye-like syndrome Encephalitis ARDS Glomerulonephritis

Treatment of Treatment of complicationscomplications

Fluid overload Fluid overload

AVOID

Early IV fluid therapyEarly IV fluid therapy- in the febrile phase- in the febrile phase Excessive use of hypotonic solutionsExcessive use of hypotonic solutions Non-reduction in the rate of IV fluid after initial resuscitationNon-reduction in the rate of IV fluid after initial resuscitation Blood loss replaced with fluids in cases with occult bleedingBlood 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

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

every 6 hour

Large pleural effusions, ascitesLarge pleural effusions, ascites

Careful titration of intravenous fluids.

Avoid insertion of intercostal drains and tracheal intubation.

Large pleural effusions during recovery phase after 48 hoursfurosemide (0.25-0.5 mg/kg at 6 hours’ interval for 1 to 2 doses).

Electrolyte imbalance Electrolyte imbalance

Disseminated intravascular coagulationDisseminated 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 failureARDS & Hypotension with Respiratory failure

Nasal CPAP

Refractory shockRefractory 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.

The case fatality rate is high with shortage of experienced medical teams..

Criteria for Discharge of patientsCriteria 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 rashConvalescent confluent petechial rash

BETWEEN 8 –10th day of SICKNESS

Signs of recoverySigns 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 aboutCommon Misconceptions aboutDengue Hemorrhagic FeverDengue 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 DHFPoor 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 TRIALSUGGESTIONS FROM THE TRIAL

Vaccine has moderate, but improvable reactogenicity

High seroconversion rates against four serotypes of DEN virus

• 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

GLOBAL STATUS

BURDEN OF DISEASE IN S.E.ASIABURDEN OF DISEASE IN S.E.ASIA

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

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

CATEGORY-CCATEGORY-C (BHUTAN, NEPAL)

CATEGORY-DCATEGORY-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 aegyptiAedes aegypti Mosquito Mosquito

Day-biting urban thriving mosquito Day-biting urban thriving mosquito White bands or scale patterns on its legs and thorax. White bands or scale patterns on its legs and thorax.

Highly domesticated tropical mosquito, lives around human habitationHighly domesticated tropical mosquito, lives around human habitation Single infective mosquito may cause an outbreakSingle infective mosquito may cause an outbreak

Transmission CycleTransmission Cycle

Intrinsic Incubation Period: 3-14 days

Viraemia & Fever: 5-7 days

VectorHumidity: Rainfall & Temp.

Susceptible hosts,(population)

Source patients

ExtrinsicIncubation Period: 8-10 days

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: DISTRIBUTIONDENGUE ILLNESS: DISTRIBUTION

Population

Infection

Clinical Cases

DHF/DSS

AsymptomaticInfection

DF(non-DHF)

survive Death

24%

3%

0.8%

76%

97%

99.2%

Rates in dengue model by Shepard et al. Vaccine. 2004, 22:1275-1280.

SPECTRUM OF DENGUE INFECTIONSPECTRUM OF DENGUE INFECTION

Clinical FeaturesClinical 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 FLUSHERYTHEMATOUS FLUSH

Suffused + Swollen face with purplish lips, injected eyesReddened malar regions and ear lobules

Dengue fever with unusual hemorrhageDengue 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 ManifestationsHemorrhagic 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 DHFFour 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 TestTourniquet 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 TestPositive Tourniquet Test

Endemic areas -WHO criteria Endemic areas -WHO criteria

2 clinical observations

+

1 laboratory finding

OR

At least a rising hematocrit levelAt 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 DSSClinical 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 - DSSHypothesis 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 ImmunogenecityInitial Immunogenecity

Immune ComplexesImmune Complexes

Risk Factors Reported for DHFRisk 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)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 circulationof viruses

Increased probabilityof secondary infection

Increased probability ofoccurrence of virulent strains

Increased probability ofimmune enhancement

Increased probability of DHF

Gubler & Trent, 1994

Viral Risk FactorsViral Risk Factors

Virus strain (genotype)

Epidemic potential: viremia level, infectivity

Virus serotype

DEN-2 > DEN-3 > DEN-4 > DEN-1

Risk Factors Reported for DSSRisk Factors Reported for DSS

Younger age at onset Altered sensorium Paralytic ileus Deranged Prothrombin time at

presentation

Clinical Evaluation in Dengue FeverClinical Evaluation in Dengue Fever Blood pressure

Hydration status

Tourniquet test

Evidence of bleeding in skin or other sites

Evidence of increased vascular permeability

DIFFERENTIAL DIAGNOSISDIFFERENTIAL DIAGNOSIS

Falciparum malaria Gram-Negative septicemia Leptospirosis Rickettsiosis Typhoid fever Chikungunya Fever

Laboratory TestsLaboratory 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 TestsLaboratory 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

Transformed lymphocytes (Plasmacytoid ) More than 20% Turk cells in buffy coat smearbuffy coat smear is

characteristic of DHF

Turk Reaction cellTurk Reaction cell

Serological methodsSerological methods

MAC-ELISA -> IgM

Hemagglutination inhibition test -> IgG

Complement fixation test

Dot-Blot immunoassay

RT-PCRRT-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 Virus isolation

Mosquito cell linesMosquito 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 techniqueMosquito inoculation technique

Vertebral cell cultureVertebral cell culture

Confirmed case - WHO definitionConfirmed 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 VirusTransmission of Dengue Virusby by Aedes aegyptiAedes aegypti

Viremia Viremia

Extrinsic incubation

period

DAYS0 5 8 12 16 20 24 28

Human #1 Human #2

Illness

Mosquito feeds /acquires virus

Mosquito refeeds /transmits virus

Intrinsicincubation

period

Illness

Temperature, Virus Positivity and Anti-Dengue IgM , by Fever Day

Dengue IgMMean Max. Temperature Virus

Adapted from Figure 1 in Vaughn et al.,J Infect Dis, 1997; 176:322-30.

Fever Day

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20

40

60

80

100

Per

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iru

s P

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39.5

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Tem

per

atu

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deg

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Den

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