Dengue Lecture Slides PDF

Dengue Dengue: The Virus Family of viruses called Falviviridae Dengue yellow fever West Nile virus Zika +ssRNA viruses Arbovirus - found primarily in arthropods (ticks and mosquitoes) Can infect humans all belong to a single genus - Flavivirus Dengue: The Virus 4 serotypes that are all genetically a...

Dengue Dengue: The Virus Family of viruses called Falviviridae Dengue yellow fever West Nile virus Zika +ssRNA viruses Arbovirus - found primarily in arthropods (ticks and mosquitoes) Can infect humans all belong to a single genus - Flavivirus Dengue: The Virus 4 serotypes that are all genetically and antigenically related DENV 1-4 Infection with one serotype provides immunity to that serotype only Enveloped, spherical viral particles Dengue: The Virus Genome encodes 10 proteins 3 structural proteins C protein – capsid M protein – membrane E protein - envelope Dengue: The Virus Genome encodes 10 proteins 7 non-structural (NS) Proteins NS1 NS2A NS2B NS3 NS4A NS4B NS5 Involved in viral replication and Packaging of new virus Dengue: The Virus sNS1 – is the key mediator or Dengue pathogenesis Dengue: Viral Replication ENTRY and UNCOATING DENV E protein binds to cellular receptor The cellular receptors have not been identified DENV undergoes endocytosis Acidification of endosome Change in E protein Fusion with endosomal membrane Release of virion capsid into cytoplasm Dengue: Viral Replication Translation and Amplification Uncoating of capsid occurs Host ribosomes translate (+) ssRNA into a single polypeptide Cellular and viral proteases cleave the polypeptide in to 10 proteins (see previous slide) Dengue: Viral Replication Repackaging and Exit New virus is assembled on intracellular membranes Bud into the ER Translocation through the Golgi apparatus where post translation modifications Vesicles fuse with cell membrane to release newly formed virus. Dengue: The Virus Note that some virus is release as fully mature membrane protein and can reinfect other cells Some virus is release with immature membrane protein and cannot infect other cells sNS1 can be secreted from cells directly or be associated with the surface of infected cells. Associated with vascular leakage Dengue: The Disease Dengue viruses are spread to people through the bite of an infected Aedes species (Ae. aegypti or Ae. albopictus) mosquito. Almost half of the world’s population, about 4 billion people, live in areas with a risk of dengue. Dengue is often a leading cause of illness in areas with risk. Each year, up to 400 million people are infected by a dengue virus. Approximately 100 million people get sick from infection, and 40,000 die from severe dengue. Dengue is caused by one of any of four related viruses: dengue virus 1, 2, 3, and 4. A person can be infected with dengue multiple times in their life. Dengue: The Disease Dengue viruses are spread to people through the bite of an infected Aedes species (Ae. aegypti or Ae. albopictus) mosquito. Almost half of the world’s population, about 4 billion people, are at risk of Dengue Dengue: The Disease Each year up to 400 million people are infected by a dengue virus. Approximately 100 million people get sick from infection 40,000 deaths from severe dengue. Cases of Dengue have been increasing in over the past 60 years. Dengue: The Disease First reported epidemics in 1779 –80 in Asia, Africa and North America. Considered a mild non fatal disease Epidemics every 10-40 years due to introduction of new serotype After World War II, pandemic of dengue which began in Southeast Asia, expanded geographical distribution, epidemics with multiple serotypes and emergence of DHF Dengue: The Disease resurgence 1980s: a second re-expansion of DHF in Asia with epidemics in India, Sri Lanka and Maldives, Taiwan, PRC; Africa and Americas Progressively larger epidemic WHY? Uncontrolled urbanisation and population growth à substandard housing, inadequate water, sewer and waste management Deterioration of public health infrastructure Faster and more accessible travel Ineffective mosquito control in endemic regions Hyperendemicity: prevalence of multiple serotypes Dengue: Pathophysiology Clinical Presentation Dengue can range from asymptomatic infection or mild illness to severe disease. 25% of infections are symptomatic - Commonly mild or febrile 5% of patients with dengue progress to severe dengue Dengue: Pathophysiology In 2009 the WHO replaced the old clinical classification of Dengue to : Dengue with or without warning signs (Dengue fever – febrile) 1997 or Severe Dengue (Dengue hemorrhagic Fever/Dengue Shock Syndrome) 1997 Dengue: Pathophysiology Dengue begins abruptly after a typical incubation period of 5–7 days, and the course follows 3 phases: febrile, critical, and convalescent. Febrile Phase Fever typically lasts 2–7 days and can be biphasic. signs and symptoms may include: severe headache retro-orbital eye pain muscle, joint, and bone pain macular or maculopapular rash minor hemorrhagic manifestations including: petechia ecchymosis purpura Nosebleeds bleeding gums blood in the urine + tourniquet test result. Dengue: Pathophysiology Dengue begins abruptly after a typical incubation period of 5–7 days, and the course follows 3 phases: febrile, critical, and convalescent. Critical Phase The critical phase of dengue begins once the fever subsides and typically lasts 24–48 hours. Most patients clinically improve during this phase. However patients with substantial plasma leakage can, within a few hours, develop severe dengue as a result of a marked increase in vascular permeability. Patients may appear to be well despite early signs of shock. However, once hypotension develops, systolic blood pressure rapidly declines, and irreversible shock and death may ensue despite resuscitation. Patients can also develop severe hemorrhagic manifestations, including: vomiting blood, bloody stool, or menorrhagia, especially if they have been in prolonged shock. Dengue: Pathophysiology Dengue begins abruptly after a typical incubation period of 5–7 days, and the course follows 3 phases: febrile, critical, and convalescent. Convalescent Phase As plasma leakage subsides, the patient enters the convalescent phase and begins to reabsorb extravasated intravenous fluids and pleural and abdominal effusions. As a patient’s well-being improves, hemodynamic status stabilizes (although he or she may manifest bradycardia), and diuresis ensues. The patient’s hematocrit stabilizes or may fall because of the dilutional effect of the reabsorbed fluid, and the white cell count usually starts to rise, followed by a recovery of platelet count. The convalescent-phase rash may scale or flake and become itchy. Laboratory findings commonly include leukopenia, thrombocytopenia, hyponatremia, elevated aspartate aminotransferase and alanine aminotransferase, and a normal erythrocyte sedimentation rate. Dengue: Diagnosis and Testing Diagnostic Tests for Dengue and Specimens Diagnostic Test ≤7 Days After Symptom Onset (Acute Phase) >7 Days Post Symptom Onset (Convalescent Phase) Specimen Types Molecular Tests (RT_PCR) ✓ — Serum, plasma, whole blood, cerebrospinal fluid* Dengue Virus Antigen Detection (NS1) ✓ — Serum Serologic Tests ✓ ✓ Serum, cerebrospinal fluid* Tissue Tests ✓ ✓ Fixed tissue * Testing cerebrospinal fluid is recommended in suspect patients with central nervous system clinical manifestations such as encephalopathy and aseptic meningitis. Dengue: Diagnosis and Testing Molecular Testing Nucleic Acid Amplification Test (NAAT) or RT-PCR Commercially available kit multiplex assay – can test for all for DENV 1-4 serotypes a positive test confirms dengue infection a negative test does not rule out infection Should be confirmed by IgM antibody testing Dengue: Diagnosis and Testing Dengue Virus Antigen Detection NS1 detection NS1 is secreted into the blood during dengue infection Commercially available serum antibody test kits a positive test confirms dengue infection but not serotype a negative test does not rule out infection Should be confirmed by IgM antibody testing Dengue: Diagnosis and Testing Serologic Tests IgM Antibody ELISA Antigens used for assay are derived from the envelope proteins of the DENV 1-4 serotypes IgM antibodies are detectable 4-5 days after onset of symptoms Can be detected reliably up to ~12 weeks Need to combine with NAAT or NS1 testing Can cross-react with other flaviviruses Dengue: Diagnosis and Testing Tissue testing Testing for dengue virus in specific tissues Requires biopsy or autopsy specimen NAAT or RT_PCR IHC (Immunohistochemistry) on fixed tissue Most often only used for forensic or retrospective pathology studies. Not an immediate diagnostic tool Dengue: Treatment No treatment: No specific antiviral agents exist for dengue. Supportive care is advised: Patients should be advised to stay well hydrated and to avoid aspirin (acetylsalicylic acid), aspirin-containing drugs, and other nonsteroidal anti-inflammatory drugs (such as ibuprofen) because of their anticoagulant properties. Fever should be controlled with acetaminophen and tepid sponge baths. Febrile patients should avoid mosquito bites to reduce risk of further transmission. Patients with fluid loss due to capillary leakage should be given intravenous fluids and monitored Hematocrit levels should be constantly monitored. Prophylactic platelet transfusions in dengue patients are not beneficial and may contribute to fluid overload Dengue: Vaccines BioDrugs (2022) 36:325–336 https://doi.org/10.1007/s40259-022-00531-z Dengue: Vaccines DengVaxia Only vaccine approved by the US FDA tetravalent live attenuated recombinant vaccine (DENV1-4), based on a previous yellow fever vaccine (backbone) 3 doses, 6 months apart Starting 2022 Children and adoslescents 9-16 years old who have laboratory confirmed previous dengue infections living in endemic dengue areas May increase risk to sever Dengue if administered to seronegative individuals who subsequently are infected with Dengue. Dengue: Vaccines QDenga Approved by European Medicines Agency (2022) for use in endemic countries tetravalent live attenuated vaccine (DENV 1-4) 2 doses, 3 months apart Starting 2022 Adults, adolescents and children > 4 years of age. Shown to be effective in 4-16 year olds Has varying efficacy against different serotypes (highest to DENV2 and lowest to DENV4) Effectiveness wanes after 3-5 years Booster studies are needed.