Arboviruses: group of viruses that are transmitted by arthropod vectors (ARthropod-BOrne virus)

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1 Arboviruses Timothy P. Endy MD, MPH Infectious Disease Division, SUNY Upstate Medical University, Syracuse, NY Contemporary Issues in Emergency Medicine, April 22, 2015

2 Financial Disclosure Chair, Science Advisory Board, Dengue Vaccine, Sanofi- Pasteur Chair, DSMB and Advisory Board, Dengue Vaccine, Merck Pharmaceuticals Chair, DSMB for Ebola Vaccines, Veristat Advisory Board, Dengue Therapeutics, Visterra, Inc Study Section, National Institute of Health Grant Recipient, National Institute of Health and Department of Defense

3 Arboviruses: group of viruses that are transmitted by arthropod vectors (ARthropod-BOrne virus) Aedes aegypti Ixodes scapularis (deer tick)

4 Lecture Objectives Virus Families. RNA Viruses. Concepts of Transmission. Clinical Presentation Summary.

8 RNA Viruses Majority of the highly pathogenic viruses that produce encephalitis, severe febrile illnesses. All arboviruses (transmitted by ticks, mosquitoes). Many have an animal reservoir or animal amplification transmission with humans as an incidental host. Many are endemic with periods of epidemics.

12 Anatomy of the Mosquito

13 Clinical Syndromes of the Arboviruses Systemic Febrile Illness Chikungunya, O nyong-nyong, Ross River, Dengue. Fever with Arthritis Chikungunya, Ross River, O nyong-nyong. Encephalitis Japanese encephalitis, West Nile virus, Venezuelan equine encephalitis, Eastern equine encephalitis, Western equine encephalitis, Murray Valley encephalitis, Powassan, TBE. Hemorrhagic Fever Yellow Fever, Dengue, Rift Valley Fever, Chikungunya.

14 Case 64 year old white male who presents in August with fever, headache, mental status changes and neck stiffness.

15 Travel History Patient had no travel in the preceding year outside of NY State. Lives in Cicero, NY with a house bordering on Cicero Swamp.

16 Syracuse, NY Cicero Swamp

18 Clinical Data CBC demonstrated a leukopenia. CSF: WBC 120 (90% lymphocytes), Protein 100, Glucose of 30.

19 MRI

20 Your diagnosis?

21 What type of viral encephalitis did he have? A. West Nile Encephalitis B. St. Louis Encephalitis C. Powassan encephalitis D. Eastern equine encephalitis E. None of the above.

22 EEE Cases in the United States

23 Eastern Equine Encephalitis Virus Neuroinvasive Disease Cases Reported by State, New York: 5 cases (1971, 1983, 2009, 2010, 2011)

24 EEE in New York

25 Culiseta melanura

27 EEE Virology EEE is in the Togaviridae family in the genera alphavirus. Positive ssrna enveloped viruses of 60-65nm in diameter. Alphavirus genus contains 4 encephalitic viruses which produce encephalitis; EEE, WEE, VEE and Everglades. Focal epidemics of EEE have occurred in the Eastern USA, WEE is endemic in the Western USA, VEE is endemic in South America and N. America. Clinical manifestations vary from an inapparent to influenza like illness to the syndrome of encephalitis. Probability of developing encephalitis varies widely: highest for the EEE and lowest for VEE. Mortality rate varies from 5% for WEE, 35% for VEE to 50% for EEE.

28 Case 64 year old white male who presents in February with fever, headache, mental status changes and neck stiffness.

29 Travel History Patient had traveled to Thailand 2 weeks before his illness. Lives in Cicero, NY with a house bordering on Cicero Swamp.

30 Syracuse, NY Cicero Swamp

31 Clinical Data CBC demonstrated a leukopenia. CSF: WBC 120 (90% lymphocytes), Protein 100, Glucose of 30.

32 MRI

33 What type of viral encephalitis did he have? A. West Nile Encephalitis B. Japanese Encephalitis C. Powassan encephalitis D. Eastern equine encephalitis E. None of the above.

34 Japanese Encephalitis

35 Virus Description Family Flaviviridiae, positive sense single-stranded RNA JEV circulates as a single serotype (Vaccine efficacy ramifications) Molecular phylogeny 5 genotypes I: Northern Thailand, Cambodia, Korea II: Southern Thailand, Malaysia, Sarawak, Australia, Indonesia III: Japan, China, Taiwan, Viet Nam, Philippines, Sri Lanka, India, Nepal» Four subgroups IV: Indonesia V: Singapore

Transmission cycle Vector Culex tritaeniorhynchus Night feeders on large domestic animals and birds Rice fields, Marshes, Small collections of water around fields Rainy season marks highest

36 Transmission cycle Vector Culex tritaeniorhynchus Night feeders on large domestic animals and birds Rice fields, Marshes, Small collections of water around fields Rainy season marks highest transmission Irrigation allows year round transmission Vertical infection and overwinter is possible Sexual transmission b/w mosquitoes Natural Host Pig Prolonged and high titer viremia, asymptomatic. Production of numerous uninfected offspring Viral replication Migrating birds and domestic fowl Accidental Humans and horses

Enzootic cycle Culex mosquitoes are primary vectors C. tritaeniorhyncus, C. vishnui (India) C. gelidus and fuscocephala (India, Malaysia, Thailand) C. annulus (Taiwan), C.

37 Enzootic cycle Culex mosquitoes are primary vectors C. tritaeniorhyncus, C. vishnui (India) C. gelidus and fuscocephala (India, Malaysia, Thailand) C. annulus (Taiwan), C. annulirostris (Guam) Transmission patterns Seasonal transmission (Large epidemics) Japan, China, Taiwan, Korea, northern Viet Nam and Thailand Northern India, Nepal Year round transmission (Sporadic cases) Southern Viet Nam, Thailand, India, Indonesia, Malaysia, Philippines, and Sri Lanka

39 Epidemiology 50,000 cases each year, 10,000 deaths each year Underreported JE endemic areas Infection is common with high seroprevalence rates Annual incidence as high as 10 to 20 per 100,000 Increasing in India, and Nepal. Inapparent to apparent infections = :1

40 Clinical Features Incubation period 6 to 16 days Spectrum: Febrile headache Aseptic meningitis Encephalitis (<1%) Prodrome (2-3 days) Headache, fever, chills, anorexia, N/V, dizziness Acute (3-4 days) High fever and seizures Dull flat mask-like facies, Unblinking eyes, Tremor, Hypertonia, Rigidity Abnormal behavior, Acute flaccid paralysis Subacute (7-10 days) and Convalescent (4-7 weeks) Tremors, Paresis, Incoordination, Pathologic reflexes, Lip smacking Rapidly changing CNS signs Poor prognosis Respiratory dysfunction, Prolonged seizures and fever, Albuminuria, Infectious virus in CSF Low IgM in CSF

41 Two Vaccines Available: JE is a Preventable Disease JE-Vax, Biken, distributed by Connaught Laboratories, Inc: mouse-brain derived vaccine consisting of JE E- protein of Nakayama strain. 3 shot series results in longterm immunity. Serious side-effect is an anaphylactic-like reaction (delayed and rare). Production has stopped. IXIARO, Novartis Pharmaceuticals Inactivated Vero cell derived from JEV strain SA Virus suspension is treated with protamine sulfate to remove contaminating DNA and proteins. Purified virus is inactivated by formaldehyde treatment. Administered in two doses 28 days apart

42 Case 50 year old white male, high school football coach in Northern Syracuse who presents in August with fever, headache, and neck stiffness.

43 Travel History Patient had no travel in the preceding year outside of NY State. Lives in North Syracuse. Gave a history of walking in his barn and may have been bitten by a bat 3 weeks prior to symptoms. Very active outside and also recalls several ticks about the same time as the bat exposure.

44 Clinical Data CBC demonstrated a leukopenia. CSF: WBC 120 (90% lymphocytes), Protein 100, Glucose of 30.

45 What type of viral encephalitis did he have? A. West Nile Encephalitis B. Rabies Encephalitis C. Powassan encephalitis D. Eastern equine encephalitis E. None of the above.

46 Powassan Virus Tick transmitted flavivirus in the Tick-borne encephalitis family. Endemic in the Northeast and Great Lakes region. Signs and symptoms include fever, headache, neck stiffness, vomiting, seizures and confusion.

48 Powassan virus neuroinvasive disease cases reported by year,

49 Powassan virus neuroinvasive disease cases reported by state,

51 Case Presentation. A 56 year old woman is admitted to the hospital with 7 days of fever, headache and myalgia. On the day she is admitted develops a maculopapular rash. She has leukopenia and thrombocytopenia. She has been healthy with no other medical problems. His travel history is significant for having just returned from a 2 week trip to Key West, Florida. No other significant travel history. 51

52 Physical Findings Petechiae on chest wall. 52

53 Petechiae on soles of feet. Petechiae on the arm. 53

54 Laboratory Findings White blood cell count 2,000. Hematocrit 52%. Platelet count 68,000. Liver function tests, SGOT 300 and SGPT of 400.

55 What infection do you think caused this patient s illness? A) Plasmodium falciparum malaria B) Bacterial sepsis C) Dengue virus D) Influenza E) None of the above.

56 Before a definitive diagnosis can be confirmed, which medical therapies will you initiate? A) Antimalarial treatment B) Exchange transfusion. C) Intravenous fluids. D) Ribavirin treatment. E) None of the above.

57 Dengue Fever and Dengue Hemorrhagic Fever

58 Dengue Overview Dengue infection is caused by one of the four serotypes of dengue virus (DENV). Transmitted by mosquitoes (A.aegypti and A. albopictus ) Sequential infections put people at greater risk for more severe forms of disease: dengue fever (DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Global Health Problem: Dengue is endemic in over100 countries. 100 million infections, 500,000 DHS/DSS, 30,000 deaths per year. Emerged disease with a 30 fold global increase in disease over last 50 years. 58

phylogenetics 3-5 DEN-1 genotypes 5-6 DEN-2 genotypes 4 DEN-3 genotypes 2

59 Dengue Viruses Genus Flavivirus & Family Flaviviridae Four serotypes DEN-1, -2, -3, and -4 Antigenically distinct Genetic diversity and phylogenetics 3-5 DEN-1 genotypes 5-6 DEN-2 genotypes 4 DEN-3 genotypes 2 DEN-4 genotypes Variations in virus virulence RNA virus mutations Recombination events

60 History of United States Dengue Epidemics 1780 Epidemic in Philadelphia described by Dr. B. Rush. August-September febrile exanthem. Confined to persons residing along the Delaware River. Known as Break Bone Fever s Numerous US Coastal cities suffer epidemics Texas has 29 cases, 7 locally acquired Hawaiian Islands report 119 cases of DF. Majority of cases are imported or in returning travelers.

65 65

66 Aedes aegypti Life Cycle

67 Characteristics of Aedes aegypti Urban mosquito breeds in standing water (flower pots, tires, bottles). Daytime feeder. Humans preferred host for blood meal. Multiple probing for single blood meal.

68 Global Spread of Dengue Multiplication and spread of the vector, Aedes aegypti: Urbanization Transport of used tires and infected persons. Global warming. Population growth.

69 Thailand

70 Reported Cases of Dengue Hemorrhagic Fever in Thailand from 1958 to Cases Year Source: Division of Communicable Diseases, Thai Ministry of Public Health

71 Age -Specific Rates of DHF in Thailand

72 Dengue Serotypes at Bangkok Children's Hospital From 1973 to 2001

73 Clinical Spectrum of Dengue Infection DSS: Rapid weak pulse, narrow pulse pressure, hypotension. DHF: Grades I, II, III, IV. Bruising, bleeding, hemoconcentration, thrombocytopenia, DIC. DF: Fever with headache, myalgia, arthralgia, rash, leukopenia. Subclinical Infection 73

74 74

75 Clinical Manifestations: Dengue Hemorrhagic Fever (Secondary Dengue) Hemorrhagic manifestations include petechiae, epistaxis, intestinal bleeding, menorrhagia, and a positive tourniquet test. Myocarditis may occur and neurologic disorders (encephalopathy, peripheral mononeuropathy, polyneuritis, and Bell's palsy). Reye's syndrome has also been reported to follow dengue infection. Prolonged convalescence may occur with generalized weakness, depression, bradycardia, and ventricular extrasystoles.

76 Time Course of Clinical Signs and Symptoms Clinical Signs/Symptoms Dengue Fever DHF/DSS Shock Thrombocytopenia Petechiae /bruising Rash Fever Headache/Myalgia Viremia Clinical Illness Day 76

77 Petechiae on chest wall in child with DHF. Subcutaneous hemorrhage in child with DHF.

78 Petechiae on soles of feet in child with DHF. Showering of petechiae following blood pressure cuff inflation in child with DHF.

79 Melena Gastric Bleeding

80 Shock Syndrome Shock syndrome is the severe form of viral hemorrhagic fever and results from: intravascular volume depletion from plasma leakage into the third space and/or blood loss. cardiovascular collapse.

81 Plasma leakage the hallmark for dengue hemorrhagic fever.

82 Clinical Treatment Of DHF

83 CDC s Arbonet

88 Key Points Arboviral diseases are important human pathogens and responsible for many emerging and emerged global health problems. Diagnosis requires awareness of the potential endemic and imported arboviral diseases and recognition of the clinical presentation. 88

KILLER BITES: Mosquito-Borne Viruses Jon Mark Hirshon, MD, MPH, PhD

KILLER BITES: Mosquito-Borne Viruses Jon Mark Hirshon, MD, MPH, PhD Professor, Department of Emergency Medicine University of Maryland School of Medicine Disclosures Conflicts of Interest: Pfizer consultant