DENGUE INFECTION

Presenters: Nurhaziqah bt Abdul Aziz 2008402436 Siti Nurulismah bt Che Haron 2008409704 Sharifah Nazeera bt Syed Anera 2008409684 Wan Ahmad Aizat b Wan Zaidi 2008402318 Supervisor: Prof Alam Sher Malik

CONTENTS
Case summary Introduction Etiology Clinical features Diagnosis Differentiation between DF and DHF Principle of management Complication Literature

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Case Summary

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CASE 1

Nur Hidayah, 9 y/o malay girl admitted to the ward on 2nd Aug 2010 with chief complaint of fever 7 days prior to admission. The fever was associated with vomiting, abdominal pain and diarrhea along with muscle and joint pain. Her family members mostly just recovered from fever and she live in dengue prone area. On physical examination, no significant findings.
Diagnosis: Dengue fever

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CASE 2

Aminuzzaman, 11y/o malay boy, 2nd admission due to dengue infection on 23rd July 2010 with chief complaint of fever 5 days prior to admission. He had also diarrhoea and vomiting. He did several blood test at KK before being referred to HSB and result showed down trendy platelet. On physical examination were petechial rashes on extremities up to thigh on both legs and decreased volume of radial pulse. Diagnosis: Dengue Hemorrhagic Fever
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INTRODUCTION

Definition: Dengue infection is a disease that

caused by four related viruses spread by a particular species of mosquito
[http://www.mayoclinic.com]

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EPIDEMIOLOGY
In Malaysia (2008),
Disease
Dengue Fever Dengue Hemorrhagic Fever

[HEALTH FACTS 2008 BY KKM]

*Incidence rate
167.76 10.16

*Mortality rate
0.02 0.38

*per 100 000 population

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23 September 2012

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ETIOLOGY
Viral infection cause by female Aedes mosquito. (aedes aegyti and aedes albopictus)

Occurs in tropical and sub-tropical regions and usually rise in the hot and humid months.
Classical Dengue fever also called break-bone fever

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Dengue virus
ss, RNA virus in flaviviridae family. 4 serotypes (DEN 1,2,3,4) All can involve in both classical dengue and dengue hemorrhagic fever (DHF). Each serotype provides specific lifetime immunity and short term cross immunity. Genetic variation within serotype, some genetic variants within each serotype appear to be more virulent or have greater epidemic potential.

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o Transmitted from human to human by mosquito bites. o Female aedes aegypti (primary vector) bites during day (daytime feeder). o Peak biting times are at dawn and dusk. o It is most efficient of mosquito vectors bacause of its domestic habit o After feeding on person with blood containing virus, the mosquito becomes infective approximately 7 days after it has bitten a person carrying the virus. This is the extrinsic incubation period, during which time the virus replicates in the mosquito and reaches the salivary glands to infect another host. o Once infected, mosquito host remain infected for life.
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Distributed throughout tropical regions of the world. More common in urban population in contrast to rural areas

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CYCLE OF DENGUE FEVER

1.Inoculation of virus

2. spread to reg. lymph nodes

4. Viraemia starts 3-7 days aftr infection

3. Spread more through reticuloendothelial sys.

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5.The mosquito ingests blood containing virus

6. Virus replicate in mosquito midgut, ovaries, nerve tissues. Later infect salivary gland

7. Replicate in salivary gland and when mosquito bites other human the cycle continues

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IMMUNITY
Antibody mediated After an acute phase of infection by particular dengue serotype, antibody will response to ALL 4 dengue serotypes. After infection by 1 serotypes, individual will be immune to other serotypes for 2-12 months In fact, it appears that infection with one serotype increase the risk of more severe disease if there is a subsequent infection with another serotype It is likely that the cross reacting antibody binds to the new serotype but does not neutralize it. There is then enhanced uptake of the antibody-coated virus in the macrophage and other mononuclear cells leading to accelerated viral replication. A similar phenomenon may occur in infants who have circulating maternal antibody
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CLINICAL SPECTRUM
Dengue infection

[Malaysia Pediatric Protocols]

Asymptomatic

Symptomatic

Undifferentiated fever

Dengue fever

Dengue hemorrhagic fever

Without hemorrhage

With unusual hemorrhage

No shock

Dengue shock syndrome

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CLINICAL FEATURES (SYMPTOMS)

Others: -Abdominal pain -Gastrointestinal hemorrhage -Headache -Obstructive jaundice

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Dengue infection

[http://www.cdc.gov/Dengue/]

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CLINICAL FEATURES (SIGNS)

High/low pulse rate High/low BP Narrow pulse pressure Abnormal capillary refill Pitting edema Cold extremities Cyanosis

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Dengue infection

[Malaysia Pediatric Protocols]

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CLINICAL FEATURES BASED ON AGE

UNDIFFERENTIATED FEVER INFANTS AND YOUNG CHILDREN

MACULAPOPULAR RASH

MILD FEBRILE SYNDROME OR CLASSIC INCAPITATING DISEASE WITH HIGH FEVER OF ABRUPT ONSET, SOMETIMES WITH PEAKS (SADDLE-BACKED) AGE SEVERE HEADHES OLDER CHILDREN AND ALDULTS PAIN BEHIND THE EYES PETECHIAE (UNCOMMON) NAUSEA AND VOMITING

MUSLE,BONE AND JOINT PAINS

RASH
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WHO

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CLINICAL FEATURES cont

Fever Abrupt onset, rising to 39.5-41.4C Accompanied by frontal or retro-orbital headache Lasts 1-7 days, then defervesce for 1-2 days Biphasic, recurring with second rash but not as high Rash Initial rash transient, generalized, macular, and blanching; occurs in first 1-2 days of fever Second rash occurring within 1-2 days of defervescence, lasting 1-5 days Second rash morbilliform, maculopapular, sparing palms and soles Occasionally desquamates Bone pain Absent in dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS) After onset of fever Increases in severity Not associated with fractures May last several weeks Most common in legs, joints, and lumbar spine eMedicine
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SIGNS OF INTRAVASCULAR VOLUME DEPLETION

A child with dengue hemorrhagic fever or dengue shock syndrome may present severely hypotensive with disseminated intravascular coagulation (DIC), as this severely ill PICU patient did. Crystalloid fluid resuscitation and standard DIC treatment are critical to the child's survival. Delayed capillary refill may be the first sign of intravascular volume depletion. Hypotension usually is a late sign in children. This child's capillary refill at 6 seconds was delayed well beyond a normal duration of 2 seconds.

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eMedicine

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LAB DIAGNOSIS
Full Blood Count 1) Platelet count 100, 000 mm3
2) - usually found between 3rd to 8th day of ilness

Homoconcentration (hematocrit 20%) - indicate plasma leakage 3) wbc count - onset of illness = lekopenia to mild leukocytosis - near the end of febrile phase = reduction in the no. of neutrophils - defervescence phase = relative lymphocytosis 4) Reduce serum complement levels particularly C3 Chest X- Rays Reveal plueral effusion

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WHO

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SEROLOGY TEST
1. Identification of DENV from serum or autopsy tissue samples by reverse transcriptase-polymerase chain reaction (RT-PCR), 2. seroconversion from negative to positive or a four-fold or greater change in anti-dengue antibody titer in paired serum samples taken in the acute- (<6 days after illness onset) and convalescent-phase (630 days after onset) of the illness, or 3. dengue viral antigen identification in autopsy tissue samples by immunofluorescence or immunohistochemical analysis.

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http://www.cdc.gov/dengue/clinicalLab/diagnosticProcess.html

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Laboratory criteria for diagnosis include one or more of the following: 1. Isolation of the dengue virus from serum, plasma, leukocytes, or autopsy samples 2. Demonstration of a 4-fold or greater change in reciprocal immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody titers to one or more dengue virus antigens in paired serum samples 3. Demonstration of dengue virus antigen in autopsy tissue via immunohistochemistry or immunofluorescence or in serum samples via enzyme immunoassay (EIA) 4. Detection of viral genomic sequences in autopsy tissue, serum, or cerebral spinal fluid (CSF) samples via polymerase chain reaction (PCR)

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CDC

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DIFFERENTIATION BETWEEN DENGUE FEVER AND DENGUE HEMORRHAGIC FEVER

WHO

DENGUE FEVER CLINICAL FEATURES 1. Nonspecific febrile syndrome 2. Epitaxis and gum bleeding 3 .General body pain 4. Vomiting 5. Maculopapular rash 1. Fever for 2-7 days 2. Mild hemorrhagic manifestation 3 . Arthralgia, myalgia and bone pain 4. Vomiting 5. Maculopapular rash 1. Trombocytopenia (<100,000 mm3) 2. Leukocytopenia 3. Positive IgM antibody test for dengue virus

DENGUE HEMORRHAGIC FEVER 1. Biphasic Fever 2. Severe hemorrhagic manifestations 3. Ascites 4. Abdominal pain & decrease vocal fermitus 5. Hepatomegaly 1. Biphasic Fever 2. Severe hemorrhagic manifestations 3. Peritoneal effusion 4. Plueral effusion 5. Hepatomegaly

CLINICAL DIAGNOSIS

LAB DIAGNOSIS

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1. Trombocytopenia (<100,000 mm3) 2. Leukocytopenia 3. Positive IgM antibody test for dengue virus 4. Hemoconcentration (hematocrit 20% relative to baseline) 5. Plueral effusion seen in chest X29 ray -

PRINCIPLES OF MANAGEMENT FOR DENGUE FEVER AND DENGUE HEMORRHAGIC FEVER

by Sharifah Nazeera Syed Anera 2008409684

MONITORING OF SUSPECTED DENGUE PATIENTS IN WARDS

Hydration

mucosal and skin turgor oral fluid intake urine volume, and other fluid losses such as vomiting or diarrhoea.

Haemodynamics
skin perfusion temperature of extremities capillary refill time, pulse volume heart rate blood pressure pulse pressure level of consciousness.

Body Temperature
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MANAGEMENT OF DENGUE FEVER

Dengue fever is usually a self-limited illness, and only supportive care is required. In febrile phase of dengue fever :
Bed rest Antipyretic : paracetamol to reduce the fever (not more than 4 times in 24 hours) according to age for fever above 39C.
Age < 1 year 1-4 years >5 years mg/dose 60 60-120 240

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DENGUE FEVER

Oral rehydration therapy is recommended for patients with moderate dehydration caused by vomiting and high temperature. 50ml/kg bodyweight during the first 4-6 hrs. After correction of dehydration, the child should be given maintenance fluids orally at the rate of 80-100ml/kg bodyweight in the next 24 hrs . Do not give Aspirin because it can cause gastritis or bleeding. Do not give antibiotics as these do not help. Food should be given according to appetite.

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DENGUE FEVER

In afebrile/critical phase :
Bed rest Check platelets and haematocrit level Oral fluids

Convalescent phase :
Normal diet with no restriction

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DENGUE HEMORRHAGIC FEVER

Clinical courses
Febrile phase - very high body temperature, sometimes exceeding 40oC. Critical phase - starts with defervescence which is towards the end of the febrile phase, and lasts for 24 to 48 hours. Convalescent / resorption phase - plasma that has leaked into pleural and peritoneal surfaces is reabsorbed.

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DENGUE HEMORRHAGIC FEVER

MANAGEMENT OF THE ACUTE PHASE

1. Fluid management - Fluid therapy has to be adjusted according to: haematocrit level (pre-existing anaemia, severe haemorrhage, and capillary leakage can affect haematocrit levels) urine volume 0.5 to 1.0 ml/kg/hour vital signs and tissue perfusion
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DENGUE HEMORRHAGIC FEVER

For children with signs of shock, two fluid therapy lines should be established:

1.

first fluid line

- for replacement of fluid lost in the plasma leakage in decompensated shock, rapid bolus of normal saline based on 20ml/kg body weight should be given in compensated shock, normal saline based on 10-20 ml/kg body weight should be given over 30-60 minutes volume and infusion rate has to be adjusted every 2-6 hours based on clinical assessment and haematocrit of the patient.

2.

second fluid line

- to administer maintenance fluids 5% Dextrose saline with or without KCl, in the maintenance volume according to the childs weight for height-centile-for-age most children with DSS will be physiologically stressed, and some may not be able to handle the glucose load. Blood glucose should be checked regularly and if found to be high, dextrose should be omitted or infusion rate reduced.

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DENGUE HEMORRHAGIC FEVER

If patient is still in shock, a second rapid normal saline bolus dose should be administered If still no improvement, rapid fluid bolus should be repeated with colloids or blood/blood products depending on whether there is a rise or fall in haematocrit When patient improves (patient is warm and has a good pulse volume), the fluid therapy is reduced to maintenance, and tapered off, finally discontinuing IV therapy, usually 24 to 48 hours after the start of plasma leakage. This is to avoid fluid overload and pulmonary oedema which may be fatal For obese patients, the weight adjusted to height-centile-for-age should be closely followed to avoid fluid overload. The use of albumin and plasma is not recommended.

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DENGUE HEMORRHAGIC FEVER

During rapid fluid therapy, the following need to be frequently assessed to determine the physiologic status: heart rate pulse volume and pulse pressure peripheral colour temperature capillary refill time blood pressure

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DENGUE HEMORRHAGIC FEVER

Management of the Acute Phase cont.

2. Blood transfusion - Significant haemorrhage should be recognised early, and prompt transfusion of fresh whole blood administered at 10 to 20 ml/kg. - The fresh whole blood is preferable because of plasma loss from plasma leakage. - A delay in blood transfusion and continued infusion of crystalloids or non-blood colloids (such as FFP and platelets) will give rise to more plasma leakage and a poor outcome.
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DENGUE HEMORRHAGIC FEVER

MANAGEMENT OF THE CONVALESCENT PHASE

Indicators of patients being in the convalescent phase:
Stable vital signs - wide pulse pressure, strong pulse, no tachycardia Return of haematocrit to baseline values. Increase in urine output (may be delayed if tense ascites is present) Confluent petechial rash with multiple small, white, round areas among the rash over the extremities Improvement in general condition with gradual return of appetite Afebrile state (unless nosocomial infection is present)

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DENGUE HEMORRHAGIC FEVER

Treatment
Discontinuation of intravenous fluids (to avoid pulmonary oedema) Hypokalaemia may occur during the diuretic phase. A check should be carried out for evidence of ileus arising from hypokalaemia that may occur with diuresis. This can be corrected with fruits and fruit juices. Potassium chloride supplementation should be considered if patient refuses or is unable to take these. Invasive procedures such as dental extractions or intramuscular injections are not advisable during this period
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COMPLICATIONS OF DENGUE SHOCK SYNDROME

Shock either persistent or recurrent Pleural effusion and ascites Bleeding , usually gastrointestinal Hepatic dysfunction may result from dengue viral hepatitis or shock Encephalopathy, usually occurs early before onset of plasma leakage Beware of fluid overload and cardiac failure during the reabsorption phase.
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The PDVI Dengue

VACCINE Portfolio
Partner Approach

Vaccines in Commercial Development Developer

WRAIR Acambis NIH

Live Attenuated GSK sanofi Pasteur Biological E Butantan Panacea Vabiotech InViragen Sub-Unit

Cell culture passage Yellow fever-Dengue chimera YDengue 4 - dengue chimeras and gene deletion

CDC

Dengue 2 - dengue chimeras

HBI

Hawaii Biotech Inactivated GSK & Fiocruz

Envelope + NS1 recombinant

WRAIR
23 September 2012

Purified / Inactivated
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