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Dengue fever Update
Dengue fever Update
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  1. 1. Dengue can be defined as a debilitating viral disease of the tropics and subtropics that gets transmitted by mosquitoes, and causing sudden fever and acute pains in the joints.
  2. 2. Dengue: • Infection of tropical and subtropical regions • Nonspecific febrile illness to fatal hemorrhagic disease • Infection caused by 4 closely related virus and spread by an insect vector – Aedes mosquito
  3. 3. Dengue virus • Flavi viruses: RNA • Arbovirus group • 4 serotypes – DENV 1, DENV- 2, DENV-3, DENV-4 • Cycle involves humans and mosquitos • Infection with one virus gives immunity to that specific serotype only
  4. 4. Vector for Dengue • Aedes aegypti, Aedes albopictus less commonly • Domestic day biting mosquito • Prefers to feed on humans • Breeds in stored clean water • Have short flight range • May bite several people in same household
  5. 5. Dengue: History • It is said that the four serotypes of virus were originated from monkeys and then transmit to humans in Southeast Asia and some parts of Africa about 100 - 800 years ago • First reported epidemics in 1779 –80 in Asia, Africa and North America. • Until the second world war, DF was restricted to some countries of the world (Southeastern Asia and Africa) • But with beginning of the 2nd world war, transportation of Aedes mosquitoes by cargo could play an important factor for dissemination of the viruses around the world.
  6. 6. •After World War II, pandemic of dengue which began in Southeast Asia and Africa, expanded geographical distribution and then epidemics with multiple serotypes and emergence of DHF starts globally •Epidemics every 10-40 years due to introduction of new serotype •In 1980s a second re-expansion of DHF in Asia with epidemics in India, Sri Lanka and Maldives, Taiwan, PRC; Africa and Americas
  7. 7. Dengue: Current Global Scenario • Climate changes can have a significant effect on the incidence and prevalence rate of Dengue infection. • Progressively larger epidemics • Primarily affects urban areas • In many of tropical and subtropical countries, dengue is endemic and disease occurs every year, when rainfall is optimal for breeding • Now, dengue is endemic in at least 100 countries in Asia (more in South-east), Africa, the Americas, and the Caribbean islands.
  8. 8. Reasons for resurgence • Uncontrolled urbanization and population growth  substandard housing, inadequate water, sewer and waste management • Deterioration of public health infrastructure • Dengue fever is one of the most rapidly emerging infectious diseases in the world, and due to faster international and domestic air travel it continues to spread as a travel-related infection. • Ineffective mosquito control in endemic regions • Hyperendemicity: prevalence of multiple serotypes
  9. 9. Dengue in India • First isolated in Calcutta in 1945 • Extensive epidemics since 1963 • DHF, DSS epidemics over last 4 decades • Severe epidemic in Delhi in 1996, 2006,2012,2019; In Lucknow in 1998, 2003, 2006 • All 4 serotypes are prevalent • Viruses prevalent all over except Himalayan region & Kashmir
  10. 10. Dengue Fever : Clinical Features • Incubation period 2-7 days • Sudden fever 40 degree Celsius -41 degree Celsius • Nonspecific constitutional symptoms • Severe muscle aches, retro-orbital pain • Hepatomegaly • Rash • Facial flush • Fever subsides in 2-7 days, may be biphasic
  11. 11. Laboratory findings in Dengue • CBC: Thrombocytopenia • HIA (Hemagglutinin Inhibition assay): test antibody against hemagglutinin spike of virus. • FAT (Fluorescence antibody test): detects virus antigen using virus specific antibody • MAC-ELISA (IgM capture ELISA): detects Dengue specific IgM can distinguish primary infection from secondary infection. In primary infection ratio of IgM to IgG is greater than 1.5 • Neutralization test: detect antibody against dengue • Virus isolation: mosquito cell line culture with patient serum. • Nucleic acid detection: RT-PCR is used to detect virus
  12. 12. DDx • Respiratory Infections • Measles • Rubella (German measles) • Malaria • Meningoencephalitis • Pyelonephritis • Septicemia
  13. 13. WHO case definition for DF: Acute Febrile illness with 2 or > of the following: • Headache • Retro-orbital pain • Myalgia • Arthralgia • Rash • Hemorrhagic manifestations • Leukopenia • Hepatomegaly common
  14. 14. Pathogenesis of dengue fever •Dengue virus after entering in the body invades the local macrophages and multiply there. •Infected local cells then migrate from site of infection to lymph nodes, where monocytes and macrophages are recruited, which become targets of infection. •Consequently, infection is amplified and virus is disseminated through the lymphatic system. As a result of this primary viremia, several cells of the mononuclear lineage, including blood-derived monocytes •Viremia develops within 24 hours. During this period, virus travels throughout the body. •Bone marrow cells have also been shown to be susceptible to infection with DENV •In severe case, viral load is very high and many vital organs are affected. •Virus infected macrophages produces a number of signaling proteins such as interferons, cytokines, chemokines, TNF, other mediators which are responsible for many symptoms such as flue like syndrome and pain.
  15. 15. •These mediators affects hemostatic system of body. •Fluid from blood vessels starts to leak out so that the blood volume decreases resulting in low blood pressure. •Decrease in blood pressure causes insufficient supply of blood and Oxygen to vital organs such as brains. •Dengue also infects bone marrow, so that bone marrow cannot produces sufficient platelets. •Since platelets are needed for blood clotting, dengue infection causes blood clotting defect and increase the risk of bleeding.
  16. 16. Types of Dengue infection Primary infection: •Primary infection is characterized by fever, break bone fever, retro- orbital pain and flue like syndrome. •The person who is not previously infected with any Flavivirus is termed as primary infection. •In primary infection ratio of Dengue specific IgM to IgG is high. Secondary infection: •Dengue infection in host who is immunologically sensitized to dengue or other flavivirus is termed as secondary infection. •Secondary infection is characterized by rise in antibody titer. The ratio of IgM to IgG is low.
  17. 17. Symptomatic dengue includes, classical dengue fever, Dengue haemorrhagic fever (DHF) and Dengue shock syndrome (DSS). I. Classical dengue fever: • It is characterized by fever, rashes, severe headache, pain behind eyes, pain in muscle and joints, enlarged lymph nodes, • Fever lasts for 2-7 days • Myalgia and break bone fever ( deep bone pain) is the characteristic of Dengue fever • Classical dengue fever is self-limited. • Mostly adults and older children are affected
  18. 18. II. Dengue hemorrhagic fever (DHF): •DHF is marked by bleeding from skin and mucus membrane. •DHF has four major clinical manifestation- High fever, hemorrhagic phenomenon, hepatomegaly and circulatory failure. •In early stage of infection DHF resembles classical dengue fever. •Usually occurs in children •About 23% of children with DHF develops circulatory failure with haemo-concentration and a marked decrease in platelets counts leading to severe hemorrhage.
  19. 19. DHF: Pathogenesis • Secondary infection with another serotype leads to ‘antibody mediated enhancement’ • Heterotypic antibodies are non protective and fail to neutralize the virus • Virus-antibody complexes taken up by monocytes • Virion multiplication in human monocytes is promoted • Activation of CD4+ and CD8+ lymphocytes  release of cytokines • Complement system activated with depression of C3 & C5
  20. 20. Hypothesis on Pathogenesis of DHF  In a subsequent infection, the pre-existing heterologous antibodies form complexes with the new infecting virus serotype, but do not neutralize the new virus
  21. 21. Hypothesis on Pathogenesis of DHF (Part 3)  Antibody-dependent enhancement is the process in which certain strains of dengue virus, complexed with non-neutralizing antibodies, can enter a greater proportion of cells of the mononuclear lineage, thus increasing virus production
  22. 22. DHF: Pathophysiology  Activation of complement  Increased vascular permeability loss of plasma from vascular compartment  hemoconcentration & shock  Disorder of haemostasis involving thrombocytopenia, vascular changes and coagulopathy  Severe DHF with features of shock : DSS
  23. 23. DHF: WHO Criteria for diagnosis Often occurs with defervescence of fever, swelling All of the following must be present:  Fever  Hemorrhagic tendencies:  +ve tourniquet test  Petichiae, ecchymosis or purpura  Bleeding from other sites  Thrombocytopenia (<=100,000/cu mm)  Evidence of plasma leak  Rise in hematocrit > 20% above average  Drop in Hct  Pleural effusion/ascites/hypoproteinemia
  24. 24. III. Dengue shock syndrome (DSS): •DSS is serious form of DHF. •All serotypes of Dengue are associated with DHF and DSS. •The cause of DSS is not clearly understood. But it is assumed due to antibody dependent enhancement (ADE). •Pre-existing heterologous antibody against particular dengue serotype binds with the new infected virus serotype by its Fab region and Fc region of antibody binds to receptor on macrophage. So this pre-existing antibody increases virus infection to healthy macrophages. •From recent outbreak information of DHF, patients infected with DEN-2 after primarily infected with other serotypes can leads to DSS. •DSS is characterized by circulatory failure, rapid pulse, abnormal pain, severe bleeding from GI tract and other organs. •Usually occurs in children
  25. 25. DSS: WHO Criteria for diagnosis All of the above + evidence of circulatory failure:  Rapid, weak pulse  Narrow pulse pressure < =20 mm hg  Cold clammy skin  Restlessness Often present with abdominal pain; mistaken for acute abdominal emergency
  26. 26. Grading of DV infection DF/DHF Grade Symptoms Lab DF Fever with 2 or > of: headache/retro-orbital pain, myalgia, arthralgia Leukopenia, occasionally thrombocytopenia, no evidence of plasma leak DHF I Above symptoms + Positive tourniquet test Platelets < 100,000, Hct rise > 20% DHF II Above symptoms + spontaneous bleeding ,, DHF III/DSS Above symptoms + symptoms of circulatory failure ,, DHF IV/DSS Profound shock with undetectable BP and pulse ,,
  27. 27. WHO Lab Criteria for Dengue infection: • Probable Case: o CF + Supportive Serology: Acute HI titre > 1280, comparable IgG ELISA or +ve IgM o or occurrence at same location & time as other confirmed cases • Confirmed case: o isolation of virus from serum/ autopsy specimen o Demonstration of dengue virus antigen in serum/ CSF/ Autopsy tissue o Detection of dengue virus genome by PCR
  28. 28. Management: DF • No specific Tt • Analgesics/antipyretics • Avoid agents which may impair platelet function eg aspirin
  29. 29. Management: DHF: • Hospitalize • Closely monitor for shock; repeated hematocrit measurements • If Hct rising by >20%, IV fluids as 5% deficit • Start with DNS 6-7 ml/kg/hr. • Improves  reduce gradually over 24-48 hrs. • No improvement   upto 15 ml/kg/hr  colloid solution
  30. 30. Revised WHO classification (2009) Probable dengue Warning signs Severe dengue Live in/travel to endemic area Abdominal pain or tenderness Severe plasma leak Fever + 2 of : Persistent vomiting Shock Nausea, vomiting Clinical fluid accumulation Fluid accumulation with respiratory distress Rash Lethargy/ restlessness Severe bleeding Aches & pains Liver enlargement > 2 cm Severe organ involvement Tourniquet test +ve Laboratory increase in HCT concurrent with rapid decrease in platelet count Liver ALT or AST >=1000 Leucopenia Impaired consciousness Any warning sign Heart or other organs
  31. 31. Prevention  1. Anti-mosquito measures  Avoid open stagnant water in and around home  Bed nets  Long sleeved clothing  In house spraying  Mosquito repellants
  32. 32. 2. Dengue vaccine •Dengvaxia vaccine is licensed and available in some countries for people ages 9-45 years old. The World Health Organization recommends that the vaccine only be given to persons with confirmed prior dengue virus infection. •The vaccine manufacturer, Sanofi Pasteur, announced in 2017 that people who receive the vaccine and have not been previously infected with a dengue virus may be at risk of developing severe dengue if they get dengue after being vaccinated.