DENGUE

DENGUE

DENGUEINTRODUCTIONIt 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. EPIDEMIOLOGYDengue 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 settingsIn 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

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 settingsAll 4 serotypes are found in India.

Prevalent from centuriesHighly prevalent now

Distribution of Dengue in India

EPIDEMIOLOGICAL TRIAD AGENT

HOST ENVIRONMENTENVIRONMENTVECTOR 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- 7daysPeople, 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.

1. The virus is inoculated into humans with the mosquito saliva.

2. The virus localizes and replicates in various target organs, for example, local lymph nodes and the liver.

3. The virus is then released from these tissues and spreads through the blood to infect white blood cells and other lymphatic tissues.

4. The virus is then released from these tissues and circulates in the blood.

Blood mealViral ReplicationWBC and LymphaticsReleased in circulationTransmission of Dengue Virus

5.The mosquito ingests blood containing the virus.

6.The virus replicates in the mosquito midgut, the ovaries, nerve tissue and fat body. It then escapes into the body cavity, and later infects the salivary glands.

7.The virus replicates in the salivary glands and when the mosquito bites another human, the cycle continues.

Replication in the salivary glandViral replication in midgutFemale mosquito ingests infected bloodTransmission of Dengue Virus

AGENTDengue 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-1Sequence of infection Serotype 1 followed by serotype 2 is more dangerous then serotype 4 followed by 2 .

HOST Humans are main amplifying host of virusIncubation period 3-14 daysMost 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 FeverFeverHemorrhagic manifestationThrombocytopenia(100000/mm3) Hematocrit increased by 20% Increase capillary permiability Serosal effusion or hypoalbuminemia

Dengue Shock SyndromeCriteria 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 BLOODHumoral immunity cellular immunityFormation of neutralising antibodiesFormation of memory T- cellsActivation of CD4+ &CD8+ lymphocytesClearance of viremiaContinue Secondary infection with other serotype Non neutralizing ,cross reacting Ab comes into playFacilitates entry into Fc receptor bearing cellsBinds to epitopes on surface of heterologous virusHigh viral burdenReduce I/V 3ml/kg/hrCrystalloid duration 6-12 hrsReduce I/V 3ml/kg/hrCrystalloid duration 6-12 hrsMarked immune response plasma leakageRelease of inflammatory cytokines, inflammatory mediator & activation of complementsEndothelial cell activation

Model of Antibody Dependent Enhancement of Dengue Infection

Mechanisms of bleedingThey are multifactorialVasculopathyPlatelet abnormalityCoagulation defectsModel of Antibody Dependent Enhancement of Dengue InfectionThis occurs when preexisting antibodies present in the body from primary Dengue virus infection bind to an infecting DENV particle during a subsequent infection with a different dengue serotype. The antibodies from the primary infection cannot neutralize the virus. Instead, the Ab-Complex attaches to resceptor called Fcy receptor(FcyR) on circulating monocytes more effeciently. The outcome is an increase in the overall replication of the virus and a higher risk of severe dengue.

The cytotoxic T cell do not effectly clear the virus and release excess quantity of cytokines which produces serious inflammation and tissue damage such as leakage from capillaries leads to severe dengue diseaseThrobocytopenia develops due to presence of cross reacting antibodies to platelets.Dysfunction of Bone Marrow due to infection of stromal cells leads to reduced no. of platelets, which are necessary for effective blood clotting, resulting increased risk of bleeding manifestations.Increased apoptosis and endothelial cell dysfunction may also contribute to its pathogenesis.Dengue virus infection in infants may cause increased morbidity due to the pre existing maternal antibodies in endemic areas. Certain strains of dengue virus in South East Asian may be inherently capable of supporting severe antibody enhanced infection than the virus in other geographic areas 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.

A. Rising hematocrit ~ 50% Evidences of plasma leakage in DHF(Rt. lateral decubitus position)Rt pleural effusionAscites36COURSE OF ILLNESSDengue 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 PhaseSudden onset high grade fever that may last for 2-7 days.Facial flushing, skin erythmaTransient macular, generalized rash that blanches under pressure seen during 1st 24-48 hrsFrontal or retro orbital pain Myalgia, arthralgia , headache, Severe back pain(BREAK BONE FEVER) Anorexia, Nausea , VomitingGeneralized lymphadenopathy, cutaneous hyperasthesia 1-2 days after defervescence a generalized,maculopapular rashes appears that spares the palms and solesRarely there may be edema over the palms and solesThis time again along with rashes fever again rises and demonstrates characteristic biphasic pattern.Progressive decrease in total WBC and Platelet count.Febrile PhaseSudden onset high grade fever that may last for 2-7 days.Facial flushing, skin erythmaTransient macular, generalized rash that blanches under pressure seen during 1st 24-48 hrsFrontal or retro orbital pain Myalgia, arthralgia , headache, Severe back pain(BREAK BONE FEVER) Anorexia, Nausea , VomitingGeneralized lymphadenopathy. 1-2 days after defervescence a generalized,maculopapular rashes appears that spares the palms and solesThis time again along with rashes fever again rises and demonstrates characteristic biphasic pattern.Progressive decrease in total WBC and Platelet count.Critical PhaseIn 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 (90Onset of symptom (Days)08060

Interpretation of dengue diagnostic tests [adapted from Dengue and Control (DENCO) study] Highly suggestive Confirmed One of the following: One of the following: 1. IgM + in a single serum sample 1. PCR +2. IgG + in a single serum sample with a HI titre of 1280 or greater 2. Virus culture +3. IgM seroconversion in paired sera4. IgG seroconversion in paired sera or 4 fold IgG titer increase in paired seraDiagnostic methodDiagnosis of acute infectionTime to resultSpecimenTime of collection after onset of symptomViral isolation & serotype identificationConfirmed1-2 wksWhole blood , serum ,tissues1-5 daysNucleic acid detectionConfirmed1-2 daysTissue , whole blood , serum , plasma1-5 days

Antigen detectionConfirmed1 day Serum1-6 daysIgM ELISAIgM Rapid testProbable1-2 days30 minSerum , plasma , whole bloodAfter 5 daysIgG (paired sera )by ELISA,HI or neutralization testConfirmed7 days or moreSerum , plasma , whole bloodAcute sera , 1-5 days ;Convalescent after 15days ,Other laboratory featuresPancytopenia, 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 -ShockRaised liver enzymes-Hepatic Injury

X ray findings.The Ultrasound findings in early Milder form of DFGB wall thickening,Pericholecystic fluid, Minimal Ascites, Pleural effusion, Pericardial effusion and Hepatosplenomegaly. Severe formsFluid collection in the perirenal and pararenal region,Hepatic and Splenic subcapsular fluid,Pericardial effusion, Pancreatic enlargement.

MANAGEMENTMost childrens can be managed at homedo not have any of the warning signswho are able to tolerate adequate volumes of oral fluids pass urine at least once every six hoursGive 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 improvementDeterioration around the time of defervescenceSevere abdominal pain, persistent vomitingCold and clammy extremitiesLethargy or irritability/restlessnessBleeding (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