Flaviviruses Notes

NOTES NOTES FLAVIVIRUSES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Single-stranded, ⊕-sense, enveloped RNA viruses ▪ AKA arboviruses ▪ > 40 types identified Replication ▪ Cell surface attachment → cytoplasm entry → viral protein translation → viral RNA genome replication → virion formation (encapsidation) → cellular release Transmission ▪ Primarily transmitted via arthropod bites RISK FACTORS ▪ Recent endemic area travel/residence ▪ Poor insect repellant use ▪ Improper skin coverage (e.g. long sleeve clothing) SIGNS & SYMPTOMS ▪ Mainly asymptomatic ▪ Others commonly have acute-onset flu-like symptoms ▪ Serious complications/sequelae commonly characterized by neurologic disease (e.g. seizure, encephalopathy) ▫ Fever, nausea/vomiting DIAGNOSIS LAB RESULTS ▪ Serology ▪ Time-dependent on infection course, immune response ▪ Reverse transcription polymerase chain reaction (RT-PCR) for viral antigens OTHER DIAGNOSTICS ▪ Endemic area travel/residence ▪ Presence of mosquito bite(s) TREATMENT ▪ No cure MEDICATIONS ▪ Variable vaccine availability ▫ Untenable mainly due to antigenic mutations, multiple genotypes OTHER INTERVENTIONS ▪ Fluid, electrolyte balance OSMOSIS.ORG 391

DENGUE VIRUS osms.it/dengue-virus PATHOLOGY & CAUSES ▪ Viral disease, mosquito transmission ▫ Characterized by febrile illness ▫ AKA break-bone fever ▪ Four serotypes ▫ DENV-1 through DENV-4 ▫ IgG response to specific type → lifetime immunity ▫ Limited, transient cross-protectivity across viral types ▪ Vector ▫ Primarily Aedes aegypti and A. albopictus Pathogenesis ▪ Aedes mosquito bite → dengue virus skin introduction → local infection, response → dissemination → viremia (2–6 days later) → circulating leukocyte infection (especially) monocytes → viral replication, release → fever RISK FACTORS ▪ Endemic area residence ▪ Recent travel COMPLICATIONS Severe dengue ▪ AKA dengue hemorrhagic fever ▪ Viremia → local hemorrhage → systemic hemorrhage → hemodynamic collapse → shock ▫ Dengue shock syndrome (rare complication—DENV-2 confers highest risk) ▪ Direct bone marrow infection → hematopoietic stem cell infection → ↓ megakaryocyte differentiation (among all other cell lines) → ↓ platelets formed ▫ ↓ Circulating lifetime: virus-antibody complex → circulating platelet adherence → complement destruction 392 OSMOSIS.ORG ▪ ▪ ▪ ▪ of virus-antibody complex → adherent platelet destruction Capillary leak ▫ Direct effect: viral endothelial cell infection → cellular dysfunction → tight junction widening → capillary leak ▫ Indirect: virus-infected monocytes, dendritic cells, mast cells → TNFalpha, IFN-gamma, IL-2, IL-8, vascular endothelial growth factor release, complement activation → ↑ capillary permeability Molecular mimicry ▫ Viral E protein antibody response → plasminogen cross-reaction → inefficient coagulation cascade → hemorrhage Liver failure ▫ Direct viral infection → Kupffer cells, hepatocytes → apoptosis → hepatocellular necrosis, Councilman bodies ▫ Sever disease → shock → liver hypoperfusion → hepatocellular injury, death Central nervous system (CNS) involvement ▫ Rare, direct viral infection of brain parenchyma SIGNS & SYMPTOMS ▪ High-grade fever (> 38.5°C/101.3°F) ▪ Generalized pain ▫ Abdominal pain/tenderness, headache, joint pain, muscle pain, eye/retro-orbital pain ▪ Nausea/vomiting ▪ Mucosal bleeding ▪ Rash Severe symptoms and signs ▪ Severe bleeding ▪ Fluid accumulation → respiratory distress ▫ Ascites, pleural effusion

Chapter 73 Flaviviruses ▪ Neurologic impairment ▫ Lethargy, seizure, encephalopathy DIAGNOSIS LAB RESULTS ▪ Leukopenia ▪ Thrombocytopenia ▪ ↑ Hematocrit TREATMENT MEDICATIONS ▪ No antiviral therapy available ▪ Fever control ▫ Antipyretics OTHER INTERVENTIONS Antibody testing ▪ Antigen assay ▫ ⊕ < five days of infection ▪ IgM ▫ ⊕ ≧ three days of infection ▪ IgG ▫ ⊕≧ seven days of infection ▫ May be ⊕ due to prior infection OTHER DIAGNOSTICS Positive tourniquet test ▪ Blood pressure cuff insufflation → maintain pressure midway between systolic, diastolic → hold for five minutes → deflate → observe for petechiae ▫ Positive test:10+ petechiae in 2.5cm/1in ▪ Maintain adequate intravascular volume ▪ Shock ▫ Crystalloid fluid resuscitation ▪ Bleeding ▫ Platelet transfusion if severe thrombocytopenia and/or active, uncontrolled bleeding Prevention ▪ Mosquito control ▫ ↓ Standing water breeding sites ▫ Copepod use (organisms feed on mosquito larvae) ▫ Insecticides ▪ Personal protective measures ▫ Repellant use ▫ Permethrin-treated clothing (Na+ channel blockade → neurotoxicity → paralysis → death; low toxicity in humans) WEST NILE VIRUS osms.it/west-nile-virus PATHOLOGY & CAUSES ▪ Virus causing mosquito-borne, self-limited disease ▫ Characterized by flu-like symptoms ▫ Potential for severe neurologic sequelae ▪ Vector ▫ Culex mosquito Pathogenesis ▪ Culex mosquito bite → viral replication in skin’s dendritic cells → lymph node migration → further replication → enters bloodstream → visceral organ dissemination ▫ Complication arise when virus enters bloodstream → crosses blood-brain barrier Transmission ▪ Infected bird (amplifying host) → prolonged viremia → Culex mosquito blood meal → human/other vertebrate bite → blood meal, virus-laden saliva injected→ virus transmission ▪ Viral-load organ/blood donation ▪ Transplacental infection OSMOSIS.ORG 393

RISK FACTORS ▪ Elderly ▪ Immunosuppressed individuals ▪ Malignancy (especially hematologic malignancies) ▪ Chemokine receptor CCR5 deficiency ▫ Chemokine involved in viral infection immune response (especially brain parenchyma) COMPLICATIONS ▪ Neurological ▫ Meningitis, encephalitis, tremor, flaccid paralysis, Guillain–Barré syndrome ▪ Ocular ▫ Chorioretinitis, uveitis, optic neuritis ▪ Cardiac ▫ Myocarditis, cardiac arrhythmias ▪ Muscular ▫ Myositis, rhabdomyolysis ▪ Other ▫ Pancreatitis, orchitis, hepatitis, central diabetes insipidus SIGNS & SYMPTOMS ▪ Abrupt-onset fever, headache, myalgias ▫ Usual presentation is self-limited (AKA West Nile Fever) ▪ Abdominal pain, anorexia, nausea/vomiting, diarrhea, maculopapular rash Neurologic complications ▪ Motor ▫ Tremor, flaccid paralysis (Guillain-Barré complications) ▪ Meningoencephalitis ▫ Meningismus, altered mental status DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Neurologic sequelae → ↑ signal in T2 imaging 394 OSMOSIS.ORG Nerve action potentials ▪ Normal sensory conduction velocity ▪ Abnormally ↓motor neuron velocity, potentials LAB RESULTS ▪ Reverse transcription polymerase chain reaction (RT-PCR) ▪ Viral cultures ▪ Cerebrospinal fluid ▫ Severe cases ▫ If present in CSF → neuroinvasive disease likely ▫ Neutrophilic pleocytosis (<500 cells/ microL) → lymphocytic predominance as disease progresses ▫ ↑ Protein (<150mg/dl) ▪ Serology ▫ Enzyme-linked immunosorbent assay (MAC-ELISA) for IgM detection → positive 4-10 days after viremia detection OTHER DIAGNOSTICS ▪ Integument examination ▫ Maculopapular rash ▪ Neurological ▫ Meningismus (in severe cases) Electroencephalography (EEG) ▪ Generalized, continuous slowing prominent in frontal/temporal regions TREATMENT ▪ No cure OTHER INTERVENTIONS Prevention ▪ Personal protection measures ▪ Mosquito control programs ▪ Blood donor screening

Chapter 73 Flaviviruses YELLOW FEVER VIRUS osms.it/yellow-fever-virus PATHOLOGY & CAUSES ▪ Virus that causes mosquito-borne illness in endemic, tropical areas (Africa, South America) ▫ Characterized by hemorrhagic fever, coagulopathy, shock (most severe cases) ▪ Seven major genotypes, conserved in each specific endemic region ▫ Only one serotype that has remained antigenically conserved ▪ Vector ▫ Aedes, Haemagogus mosquitoes Pathogenesis ▪ Female Haemagogus mosquito bite → viral transmission → skin dendritic cells infected→ lymphatic spread → monocyte/ macrophages, histiocytes in lymph node → replication → lymphatic, hematogenous spread throughout body ▫ 3–6 day incubation period until symptoms appear Transmission ▪ Infected monkey → Haemagogus mosquito bite → human bite → blood meal, viral transmission ▪ During epidemics/urban spread ▫ Aedes mosquito feeds on infected humans → infected Aedes mosquito → feeds on another human → viral transmission COMPLICATIONS ▪ Hepatic injury → viral hepatitis ▫ Councilman bodies (hepatocytes characterized by eosinophilic degeneration with condensed nuclear chromatin) present on histology ▫ Jaundice results ▫ Severe disease → ↓ vitamin ▪ ▪ ▪ ▪ ▪ K-dependent coagulation factors → hemorrhagic diathesis Shock ▫ Due to cytokine dysregulation ▫ ↑ IL-1, IL-6, TNF-alpha, IFN-10 Renal failure ▫ Hypotension/hepatorenal syndrome → eosinophilic degeneration, renal parenchyma fatty change Hemorrhage Secondary bacterial infection Myocardial infection Neurological ▪ Delirium, convulsions, coma SIGNS & SYMPTOMS ▪ Infection period (3–4 days) ▫ Acute-onset headache, fevers, chills, myalgia ▫ Photophobia, restlessness, anorexia, vomiting ▪ Remission period (up to 48 hours) ▫ Afebrile ▫ No other symptoms Severe yellow fever ▪ Intoxication period (3–6 days after infection onset) ▪ Nausea/vomiting, fever, oliguria → anuria, epigastric tenderness, jaundice ▪ Hemorrhage ▫ Coffee-ground emesis, melena, hematuria, petechiae, ecchymoses ▪ Myocardial injury ▫ Cardiac enlargement, conduction abnormalities ▪ Neurological dysfunction ▫ Altered mental status, convulsions, delirium OSMOSIS.ORG 395

OTHER DIAGNOSTICS DIAGNOSIS LAB RESULTS ▪ Renal dysfunction ▫ Azotemia, proteinuria, creatinine (3–-8x normal value) ▪ PCR ▫ Viral genome ▪ CSF analysis ▫ ↑ opening pressure, ↑ protein, ⊝ cells Serology ▪ Enzyme-linked immunosorbent assay (ELISA) ▫ IgM antibodies ▪ Reverse-transcriptase loop-mediated isothermal amplification (RT-LAMP) ▫ Field test for quick diagnostics ▫ Easy-to-read visual test, good sensitivity ECG ▪ Cardiac conduction abnormalities ▪ ST-T abnormalities TREATMENT OTHER INTERVENTIONS ▪ Fluid management, resuscitation ▪ Bleeding diathesis reversal ▫ Fresh frozen plasma ▪ Adequate nutrition Prevention ▪ Live attenuated vaccine ▫ Recommended for individuals > nine months old residing in/traveling to endemic areas ▫ Contraindication in children < six months old ▪ Passive maternal immunization ▫ Safest immunoglobulin transfer ZIKA VIRUS osms.it/zika-virus PATHOLOGY & CAUSES ▪ Mosquito-borne virus ▫ Characterized by mild disease in infected individuals, serious neurologic sequelae in developing fetus ▪ Vector ▫ Aedes aegypti/albopictus mosquitoes Pathogenesis ▪ Aedes mosquito bite → dendritic cell infection, replication → bloodstream → dissemination ▪ Maternal infection → placental injury → fetus infection → neuronal progenitor cell infection → neuronal cell death Transmission ▪ Human-to-human close contact 396 OSMOSIS.ORG ▫ E.g. sexual contact ▫ Possible transmission via other bodily secretions (e.g. tears, sweat) in individuals with very high viral loads ▪ Blood transfusion ▪ Organ transplantation ▪ Maternal-fetal spread COMPLICATIONS ▪ Microcephaly in developing newborns ▪ Greatest risk for sequelae estimated to occur with first, second trimester infection ▫ Serious neurological, intellectual deficits ▫ Seizures ▫ Vision, hearing problems ▪ Neurological sequelae ▫ Guillain–Barré syndrome ▫ Myelitis

Chapter 73 Flaviviruses ▫ Meningoencephalitis SIGNS & SYMPTOMS ▪ ▪ ▪ ▪ Mild fever Maculopapular rash Nonpurulent conjunctivitis Joint, muscle pain DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Pregnant individuals ▫ Microcephaly, growth retardation evaluation LAB RESULTS ▪ RT-PCR ▫ If < 14 days from symptoms onset ▫ Confirmatory testing with plaque reduction neutralization test (PRNT) ▫ PRNT: measure of antibodies that neutralize virus-specific antigens Serology ▪ IgM against Zika virus ▫ If > 14 days from onset of symptoms TREATMENT ▪ No cure MEDICATIONS ▪ Antipyretics OTHER INTERVENTIONS Mother ▪ Rest ▪ Fluid management, resuscitation Newborn ▪ Nutritional support ▪ Physical therapy ▪ Specialty referral (especially neurology) Prevention ▪ No vaccine available ▪ Personal protective measures in endemic areas ▪ Consultation with physician prior to travel for pregnant individuals ▪ Safe sexual practice ▫ Biologically-male individuals wait at least six months after endemic-area travel for unprotected sex ▫ Biologically-female individuals wait at least eight weeks after endemic-area travel for unprotected sex ▪ Blood donation ▫ Do not donate for at least six months after endemic-area travel OSMOSIS.ORG 397

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