DENGUE

INTRODUCTION
It is an acute febrile illness caused by arthropod born viruses of

flaviridae family, is characterised by biphasic fever, myalgia, arthralgia, rash, leucopenia & lymphadenopathy
Dengue hemorrhagic fever is a severe, often fatal, febrile disease

caused by dengue viruses & characterized by increased capillary permeability, abnormalities of hemostasis, & in severe cases, a protein losing shock syndrome (dengue shock syndrome), which is thought to have an immunopathologic basis.

EPIDEMIOLOGY
Dengue is the most rapidly spreading mosquito-borne viral disease in

the world. In the last 50 years, incidence has increased 30-fold with increasing geographic expansion to new countries and, in the present decade, from urban to rural settings In recent past several major and minor outbreaks have been reported from various parts of India. It is estimated that during outbreaks about 150-200 mild infections occur in community for each case of severe dengue infection. Therefore only minority of individuals ( 3%) infected with DV develop severe Dengue fever. All 4 serotypes are found in India.

World distribution of dengue 2013

Dengue is the most rapidly spreading mosquito-borne

viral disease in the world. In the last 50 years, incidence has increased 30-fold with increasing geographic expansion to new countries and, in the present decade, from urban to rural settings All 4 serotypes are found in India.

Prevalent from centuries

Highly prevalent now

Distribution of Dengue in India

EPIDEMIOLOGICAL TRIAD
AGENT

HOST

ENVIRONMENT

ENVIRONMENT
VECTOR
Aedes aegypti mosquito and some outbreaks have also been attributed to

Aedes albopictus, Aedes polynesiensis and several species of the Aedes scutellaris complex. Tropical and subtropical region and widely distributed around the world, Habitats They live around human habitation, lays eggs and produces larvae mostly in stored water in artificial containers, e.g. Flower Vases, Automobile tires etc. Female mosquito bites and spread the infection. Day time biters. Extrinsic incubation period- 7days People, rather than mosquitoes, rapidly move the virus within and between communities.

The most common epidemic vector of dengue in the world is the Aedes aegypti mosquito. It can be identified by the white bands or scale patterns on its legs and thorax.

Transmission of Dengue Virus

Blood meal Released in circulation

Viral Replication

WBC and Lymphatics

Replication in the salivary gland

Viral replication in midgut

Female mosquito ingests infected blood

Transmission of Dengue Virus

AGENT
Dengue virus (DEN) is a small single-stranded RNA virus comprising four

distinct serotypes (DEN-1 to -4). Belongs to the genus Flavivirus, family Flaviviridae. Composed of three structural protein genes, which encode the nucleocapsid or core (C) protein, a membrane-associated (M) protein, an enveloped (E) glycoprotein and seven non-structural (NS) proteins. Distinct genotypes or nucleotide sequence have been identified within each serotype, is genetic variability of the dengue serotypes. DHF risk is greatest for DEN-2, followed by DEN -3,DEN-4,and DEN-1 Sequence of infection Serotype 1 followed by serotype 2 is more dangerous then serotype 4 followed by 2 .

HOST
Humans are main amplifying host of virus
Incubation period 3-14 days Most of the infections are asymptomatic or subclinical.

Longlife protective immunity to the infecting serotype.

However protected from clinical illness with a different serotype within 2--3 months of the primary infection but with no long-term cross-protective immunity. Secondary heterotypic infection is a risk factor for severe dengue however it can also occur during primary infection of infants born to dengue immune mother.

Target Organs of Dengue Virus in Human Body

Grade 1: fever, non specific constitutional symptoms; (+) TT- only hgic manifestation Grade 2: Grade 1 manifestation + spontaneous bleeding Grade 3: signs of circulatory failure (rapid weak pulse, narrow pulse pressure, hypotension, cold clammy skin)

Grade 4: profound shock with undetectable pulse and BP

Criteria
Dengue hemorrhagic Fever Fever Hemorrhagic manifestation Thrombocytopenia(100000/mm3) Hematocrit increased by 20% Increase capillary permiability Serosal effusion or hypoalbuminemia Dengue Shock Syndrome Criteria for DHF + hypotension or narrow pulse pressure(20 mmHg)

Grading of Severity of DHF/DSS

Grade 1: Fever, non specific constitutional symptoms; (+) TT - any hemorhagic manifestation

Grade 2: Grade 1 manifestation + spontaneous bleeding.

Grade 3: Signs of circulatory failure (rapid weak pulse, narrow pulse pressure, hypotension, cold clammy skin) Grade 4: Profound shock with undetectable pulse and BP

PATHOPHSIOLOGY
DENGUE VIRUS ENTER BLOOD

Humoral immunity

cellular immunity

Formation of neutralising antibodies

Activation of CD4+ &CD8+ lymphocytes Formation of memory Tcells

Clearance of viremia

Continue
Secondary infection with other serotype

Non neutralizing ,cross reacting Ab comes into play Binds to epitopes on surface of heterologous virus Facilitates entry into Fc receptor bearing cells High viral burden

Marked immune response

Release of inflammatory cytokines, inflammatory mediator & activation of complements Endothelial cell activation plasma leakage

Model of Antibody Dependent Enhancement of Dengue Infection

Mechanisms of bleeding
They are multifactorial Vasculopathy Platelet abnormality Coagulation defects

 The major pathological changes that determine the

severity of disease and differentiate it from Dengue infection are:Plasma leakage into third space. Abnormal hemostasis leading to rising hematocrit values. Moderate to marked thrombocytopenia. Bleeding manifestations.

COURSE OF ILLNESS
Dengue infection is a systemic and dynamic disease.
After the incubation period, the illness begins abruptly

and is followed by the three phases

Febrile Critical Recovery

Febrile Phase
Sudden onset high grade fever that may last for 2-7 days. Facial flushing, skin erythma Transient macular, generalized rash that blanches under

pressure seen during 1st 24-48 hrs Frontal or retro orbital pain Myalgia, arthralgia , headache, Severe back pain(BREAK BONE FEVER) Anorexia, Nausea , Vomiting Generalized lymphadenopathy. 1-2 days after defervescence a generalized,maculopapular rashes appears that spares the palms and soles This time again along with rashes fever again rises and demonstrates characteristic biphasic pattern. Progressive decrease in total WBC and Platelet count.

Critical Phase
In between 3-7 days after onset of fever when defervescence

sets in. Bleeding manifestation and shock with fall in Platelet count and increase in Hematocrit. Capillary leakage in the form of puffiness, edema, ascites and pleural effusion specially in right side. Restlessness, cold calmy extremities. Rapid thready pulse, low blood pressure with narrow pulse pressure (<20 mm Hg) Delayed Capillary refill time and oliguria. Severe Hapatitis, encephalitis, myocarditis

Recovery Phase
If the patient survives the 2448 hour critical phase, a gradual

reabsorption of extravascular compartment fluid takes place in the following 4872 hours. General well being improves. Appetite returns, GI symptoms resolves. Hemodynamic status stabilizes and diuresis ensues, Desquamation and marked itching of extremities, palm and soles. PCV stabilizes or may become lower due to dilution. White blood cell count usually starts to rise soon after defervescence but the recovery of platelet count is typically later than that of white blood cell count. Respiratory distress from massive pleural effusion and ascites will occur at any time if excessive intravenous fluids have been administered. During the critical and/or recovery phases, excessive fluid therapy is associated with pulmonary oedema or congestive heart failure.

Primary infection

Primary infection

Secondary infection

Dengue infection is defined as primary if the IgM/IgG OD ratio is greater than 1.2 (using patients sera at 1/100 dilution) or 1.4 (using patients sera at 1/20 dilutions). The infection is secondary if the ratio is less than 1.2 or 1.4.

DIFFERENTIAL DIAGNOSES DURING FEBRILE PHASE

DIFFERENTIAL DIAGNOSES DURING CRITICAL PHASE

LABORATORY DIAGNOSIS
Virus isolation
Viral nucleic acid Antigens

Antibodies

 Before day 5 of illness, during the febrile period, dengue infections may be

diagnosed by virus isolation in cell culture, by detection of viral RNA by nucleic acid amplification tests (NAAT), or by detection of viral antigens by ELISA or rapid tests. Nucleic acid detection assays may identify dengue viral RNA within 2448 hours. NS1 antigen may be detected in some patients for a few days after defervescence. After day 5, dengue viruses and antigens disappear from the blood with the appearance of specific antibodies. Low levels of a detectable dengue IgM response or the absence of it in some secondary infections reduces the diagnostic accuracy of IgM ELISA tests. A four-fold or greater increase in antibody levels measured by IgG ELISA or by haemagglutination inhibition (HI) test in paired sera indicates an acute or recent flavivirus infection.

Interpretation of dengue diagnostic tests [adapted from Dengue and Control (DENCO) study]
Highly suggestive One of the following: 1. IgM + in a single serum sample 2. IgG + in a single serum sample with a HI titre of 1280 or greater 1. PCR + 2. Virus culture + 3. IgM seroconversion in paired sera Confirmed One of the following:

4. IgG seroconversion in paired sera or 4 fold IgG titer increase in paired sera

Other laboratory features

Pancytopenia, Leucopenia, Thrombocytopaenia(1ooooo) is

usually observed in the period between day 3 and day 8 following the onset of illness.
Haemoconcentration, as estimated by an increase in

haematocrit of 20% or more is suggestive of hypovolaemia due to increase vascular permeability and plasma leakage.
Total protein & albumin low -Shock
Raised liver enzymes-Hepatic Injury

 X ray findings.
The Ultrasound findings in early Milder form of DF GB wall thickening, Pericholecystic fluid, Minimal Ascites, Pleural effusion, Pericardial effusion and

Hepatosplenomegaly. Severe forms Fluid collection in the perirenal and pararenal region, Hepatic and Splenic subcapsular fluid, Pericardial effusion, Pancreatic enlargement.

MANAGEMENT

 Most childrens can be managed at home do not have any of the warning signs who are able to tolerate adequate volumes of oral fluids pass urine at least once every six hours Give paracetamol for high fever.Do not give aspirin or

ibuprofen as these drugs aggrevates bleeding. Encourage oral intake of oral rehydration solution (ORS), fruit juice and other fluids containing electrolytes and sugar to replace losses from fever and vomiting. Check the hematocrit daily if possible.

 Counsel the parents to bring the child back for daily

follow up but to return immediately if any of the following occurs: No clinical improvement Deterioration around the time of defervescence

Severe abdominal pain, persistent vomiting

Cold and clammy extremities Lethargy or irritability/restlessness Bleeding (e.g. black stools or coffee-ground vomiting) Not passing urine for more than 46 hours.

 The goals of fluid resuscitation include improving central and peripheral circulation (decreasing tachycardia, improving blood pressure, pulse volume, warm and pink extremities, and capillary refill time <2 seconds) and improving end-organ perfusion i.e. stable conscious level (more alert or less restless), urine output 0.5 ml/kg/hour, decreasing metabolic acidosis.

Assessment of improvement should be based on : Mental status Heart rate Blood pressure Respiratory rate Capillary refill time Peripheral blood volume Extremities Urine Output

SEVERE DENGUE WITHOUT SHOCK

BLEEDING,THROMBOCYTOPENIA ,HEMATOCRIT RISE. VITAL SIGNS-STABLE

Intiate I/V Therapy 7ml/kg/hr Crystalloid solution for 1-2 hrs

Improvement Reduce I/V 5ml/kg/hr Crystalloid duration 1 hrs Further Improvement Reduce I/V 3ml/kg/hr Crystalloid duration 24-48 hrs Discontinue IVfluid

No Improvement Increase I/V 10ml/kg/hr Crystalloid for 1 hr

Improvement

No Improvement Vitals unstable

Reduce I/V to 6ml/kg/hr crystalloid with further reduction to 3 ml/kg/hr. discontinue after 24-48 hrs.

Hematocrit rise

Hematocrit falls

IV colloid(dextran 40) 10ml/kg for 1 hr

Blood transfusion 10ml/kg for 1 hr

No Improvement

Improvement

Consider adding Dopamine

Look for anaemia, Acidosis, myocardial dysfunction

IV therapy by crystalloid successively reduce the flow from 10 to 6,6 to 3ml/kg/hr. Discontinue after 24-48 hrs

SEVERE DENGUE WITH SHOCK

VITAL SIGNS-UNSTABLE URINE OUTPUT FALLS SIGNS OF SHOCK Intiate I/V therapy 20 ml/kg crystalloid solution over 1 hr

Improvement
Reduce I/V therapy by crystalloid from 20 to 10 , 10 to 6 ml/kg over 6 12 hrs Further Improvement Discontinue IV fluid after 24-48 hrs

No Improvement
Check Hct

Hematocrit ed

Hematocrit ed

I/V Colloid(dextran 40) or plasma 10ml/kg over 1 hr as intravenous bolus (repeat if necessary)

Blood transfusion 10ml/kg for 1 hr

Improvement*

IV therapy by crystalloid successively reduce the flow from 10 to 6,6 to 3ml/kg/hr. Dsicontinue after 24-48 hrs *Consider adding Dopamine

Hemorrhagic Complications
Patients at risk of major bleeding are those who:

prolonged/refractory shock; hypotensive shock and renal or liver failure and/or severe and persistent metabolic acidosis given non-steroidal anti-inflammatory agents pre-existing peptic ulcer disease anticoagulant therapy any form of trauma

Treatment of Hemorrhagic Complications

Blood transfusion is life-saving and should be given as soon as

severe bleeding is suspected or recognized Do not wait for the haematocrit to drop too low before deciding on blood transfusion Blood transfusion if with bleeding 5-10 ml/kg of PRBC or 10-20 ml/kg FWB repeat if with further blood loss or no rise in hematocrit after transfusion Little evidence to support transfusion of platelet concentrate and FFP If massive bleeding not managed by FWB/PRBC -Possibility of DIC.

 Blood transfusion is indicated Significant clinical bleeding Persistent shock despite adequate fluid replacement Platelet concentrates 50000 with bleeding 20000 without bleeding

Causes of fluid overload

Excessive and/or too rapid intravenous fluids.

Incorrect use of hypotonic rather than isotonic crystalloid

solution. Inappropriate use of large volumes of intravenous fluids in patients with unrecognized severe bleeding. Inappropriate transfusion of fresh-frozen plasma, platelet concentrates and cryoprecipitate . Continuation of intravenous fluids after plasma leakage has resolved [24-48 hours from defervescence] Co-morbid conditions such as congenital or ischemic heart disease, chronic lung disease and renal disease.

Early clinical features of fluid overload

Respiratory distress, difficulty in breathing
Rapid breathing Chest wall indrawing

Wheezing rather than crepitating rales

Large pleural effusions Tense ascities Increased jugular pressure Hypertension

Management of Fluid Overload

Oxygen therapy Stop IVF When to discontinue IVF: stable blood pressure, pulse and peripheral perfusion; haematocrit decreases with the presence of a good pulse volume; afebrile for more than 2448 days (without the use of antipyretics); resolving bowel/abdominal symptoms; improving urine output If necessary, give oral or intravenous furosemide 0.10.5 mg/kg/dose If the patient has stable haemodynamic status but is still within the critical phase, reduce the intravenous fluid accordingly. Avoid diuretics during the plasma leakage phase Patients who remain in shock with low or normal haematocrit levels but show signs of fluid overload may have occult haemorrhage. Careful fresh whole blood transfusion Repeated small boluses of a colloid solution

Other Supportive Measures

Renal replacement therapy- renal failure best managed with

veno-venous hemodialysis. Vasopressor and Inotropic therapy- if no improvement in Blood pressure with adequate fluid replacement. Management of :- Severe hepatic involvement. - Encephalopathy or Encephalitis. - Cardiac conduction abnormalities. - Fluid and electrolyte imbalance. Broad spectrum Antibiotics if superadded bacterial infections.

Criteria for Discharge

Clinical
No fever for 48 hours. Improvement in clinical status (general well-being, appetite, haemodynamic status, urine output, no respiratory distress).

Laboratory
Increasing trend of platelet count. Stable haematocrit without intravenous fluids.

Vector Control measures

Antilarval measures Environmental control Chemical control Biological control Anti adult measures Residual sprays Space sprays Genetic control Protection against mosquito bites Net Repellents screening.

Vaccine For Dengue Virus

Dengue vaccines have been under development since the

1940s, but a tetravalent vaccine which simultaneously provides long-term protection against all DV serotypes is a challenge. No licensed vaccine is available, several vaccine candidates are currently being evaluated in clinical studies. A live attenuated tetravalent vaccine based on chimeric yelow fever dengue virus (CYD-TDV), has progressed to phase III efficacy studies. Result from phase II b efficacy study in Thailand have been published in September 2012.
.

PROGNOSIS
The prognosis of dengue fever may be adversely affected

by passively acquired antibodies . Death has occurred in 4050% of patients with shock, but with adequate intensive care deaths should occur in <1% of cases. Survival is directly related to early and intense supportive treatment.

Take Home Message

Fluid resucitation is of outmost importance . Vital sign & hematocrit should be assess regularly .

Vector control measures are the best policy to avoid

upcoming epidemic contingency . The disease should be notified.

REFERENCES
Dengue,guidelines for diagnosis,treatment,prevention &

control by WHO IMNCI manual Nelson textbook of pediatrics, 19th edition Harrisons internal medicine, 18th edition Essential pediatrics by O.P.Ghai, 8th edition Parks Textbook of PSM ,21th edition

THANK YOU