2/16/18 ARBOVIRUSES: CLINICAL FEATURES DISCLOSURES GENERAL ARBOVIRUS CLUES OVERVIEW. I do not have any relevant relationships with industry

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1 ARBOVIRUSES: CLINICAL FEATURES DISCLOSURES Iris Ahronowitz MD, FAAD Assistant Professor of Clinical Dermatology Keck School of Medicine University of Southern California I do not have any relevant relationships with industry U055 Arthropod-Borne Viruses: What Dermatologists Need to Know American Academy of Dermatology Annual Meeting February 18, 2018 OVERVIEW GENERAL ARBOVIRUS CLUES Dengue, Chikungunya, Zika and West Nile viruses: signs and symptoms morphology of rashes and associated features diagnostic methods management Epidemiology: recent travel to or residence in endemic area Exposure: mosquito bite, person-to-person (sexual, vertical), transfusion/transplant Symptoms: fever, rash, headache, myalgias ( nonspecific febrile illness"), arthralgias Signs: conjunctivitis, enanthem, altered mental status, meningismus 1

DENGUE: CLINICAL PRESENTATION DENGUE: SEQUENTIAL RASH Incubation period 3-14 days

retro-orbital pain Nausea, severe myalgias ( breakbone fever ) Rash (50-82%) Labs:

al. Indian J Dermatol. 2010;55(1):79-85.

Sunburn Subsequent rash: 3 to 5 days later Generalized morbilliform eruption

eu/generated/pubx/173/arboviruses/dengue.

2 DENGUE: CLINICAL PRESENTATION DENGUE: SEQUENTIAL RASH Incubation period 3-14 days Uncomplicated (classic) dengue - sudden onset of: Fever, severe headache, retro-orbital pain Nausea, severe myalgias ( breakbone fever ) Rash (50-82%) Labs: Thrombocytopenia Leukopenia, transaminitis, hyponatremia less specific Thomas EA et al. Indian J Dermatol. 2010;55(1): Initial rash: Within 24-48h of symptom onset Flushing erythema of face, neck, chest Sunburn Subsequent rash: 3 to 5 days later Generalized morbilliform eruption Petechiae and islands of sparing White islands in a sea of red DENGUE RASH: MORE EXAMPLES Thomas EA et al. Indian J Dermatol. 2010;55(1): Kenzaka T et al. BMJ Case Rep Nov 25;2013. Pincus LB et al. J Am Acad Dermatol Feb;58(2):

DENGUE: CLINICAL SYNDROMES SEVERE DENGUE Uncomplicated dengue (classic dengue fever) Severe dengue (dengue hemorrhagic fever) ~0.

serotype Antibody-dependent enhancement WHO.org www.etsu.edu/com/medicalmystery/dengue.aspx smallcapworld.files.wordpress.com/2010/10/dengue_fever2.jpg Joob B et al. J Indian Soc Periodontol.

DENGUE: DIAGNOSIS AND MANAGEMENT CHIKUNGUNYA: CLINICAL PRESENTATION Dx: serum RT-PCR (< 7 days) or IgM ELISA (>4d to ~6 mo), widely available Confirmatory testing at public health departments Usually

3 DENGUE: CLINICAL SYNDROMES SEVERE DENGUE Uncomplicated dengue (classic dengue fever) Severe dengue (dengue hemorrhagic fever) ~0.1% (500,000 per year) Capillary leak syndrome and coagulopathy Extensive purpura Bleeding from mucosa, GI tract, injection sites Dengue shock syndrome Prior immunity; new infection with a different serotype Antibody-dependent enhancement WHO.org smallcapworld.files.wordpress.com/2010/10/dengue_fever2.jpg Joob B et al. J Indian Soc Periodontol Jan;18(1):4. DENGUE: DIAGNOSIS AND MANAGEMENT CHIKUNGUNYA: CLINICAL PRESENTATION Dx: serum RT-PCR (< 7 days) or IgM ELISA (>4d to ~6 mo), widely available Confirmatory testing at public health departments Usually self-limited, mortality <1% (up to 20% in severe dengue) Supportive care (fluid resuscitation, analgesia) Avoid NSAIDs! (increased hemorrhage risk) Acetaminophen for analgesia, antipyretic Tetravalent vaccine - controversial Incubation 3-7 days Acute onset high fevers, chills, myalgias Nonspecific exanthem at ~3 days in 40-75% Symmetric polyarthralgias: One who walks bent over Fingers, wrists, ankles Labs: lymphopenia, AKI, AST/ALT Acute symptoms resolve within 7 10 days da Costa VG et al. Vaccine Jul 19. Thiboutot MM et al. PLoS Negl Trop Dis Apr 27;4(4):e623. 3

CHIKUNGUNYA: LONG TERM SEQUELAE Rheumatoid-like arthritis (seronegative): up to 59% of pts >20% severe joint pains a year after initial presentation Several recent studies suggest MTX may be best

4 CHIKUNGUNYA: LONG TERM SEQUELAE Rheumatoid-like arthritis (seronegative): up to 59% of pts >20% severe joint pains a year after initial presentation Several recent studies suggest MTX may be best treatment Case fatality ratio ~ 1: 1000 Most deaths in newborns, elderly, debilitated Bandyopadhyay D et al. Int J Dermatol Nov;47(11): Rampal et al. J Assoc Physicians India Nov;55: Amaral, JK et al. Arthritis Care Res. Accepted. doi: /acr CHIKUNGUNYA: DIAGNOSIS CHIKUNGUNYA: MANAGEMENT Serum studies RT-PCR in first 7-8 days of illness Serology: IgM, IgG, neutralizing antibodies IgM positive ~5 days after symptom onset 3-4 months Now available at many commercial and DPH labs Confirmatory testing is by CDC Treatment is supportive Evaluate for and treat coinfections Dengue, malaria, bacterial infections If considering dengue in ddx, avoid NSAIDs New vaccine in development (phase 2 trials) Chang LJ et al. Lancet Aug 14. pii: S (14)

2/16/18 Z IK A VIRU S: C LIN IC AL PRESEN TATIO N Z IK A VIRU S EX AN TH EM Incubation: 3 12 days 80% asymptomatic, 20% mild

if present) Labs: +/- leukopenia, thrombocytopenia, mild transaminitis He A et al. Am J Clin Dermatol. 2017 Apr;18(2):231-236.

5 2/16/18 Z IK A VIRU S: C LIN IC AL PRESEN TATIO N Z IK A VIRU S EX AN TH EM Incubation: 3 12 days 80% asymptomatic, 20% mild illness lasting up to 1 week Exanthem (90% of symptomatic patients): small discrete papules, trunk lower body, appears day 3-4, lasts ~6d pruritus a major feature! 50-80%, can be intense Arthralgias (65%) Nonpurulent conjunctivitis (55%) Other: headaches, palatal petechiae, fever (low grade if present) Labs: +/- leukopenia, thrombocytopenia, mild transaminitis He A et al. Am J Clin Dermatol Apr;18(2): Farahnik B et al. J Am Acad Dermatol Jun;74(6): Z IK A : EX AN TH EM + AC RA L ED EM A Derrington SM et al. JAMA Dermatol Jun 1;152(6): Farahnik B et al. J Am Acad Dermatol Jun;74(6):

ZIKA: MUCOSAL MANIFESTATIONS ZIKA VIRUS: COMPLICATIONS Guillain-Barre syndrome Acute disseminated encephalomyelitis, meningitis Congenital Zika syndrome (a TORCHZ infection) Microcephaly

6 ZIKA: MUCOSAL MANIFESTATIONS ZIKA VIRUS: COMPLICATIONS Guillain-Barre syndrome Acute disseminated encephalomyelitis, meningitis Congenital Zika syndrome (a TORCHZ infection) Microcephaly Arthrogryphosis Cardiac anomalies Miscarriages 10% of US confirmed Zika infections in pregnancy had associated defects (15% in 1 st T) Derrington SM et al. JAMA Dermatol Jun 1;152(6): Bryson Y. Curr Opin Pediatr Dec 23. Reynolds MR, et al. MMWR Morb Mortal Wkly Rep 2017;66: ZIKA VIRUS AND MICROCEPHALY Definition: HC at birth <3 rd percentile for gestational age and sex Microcephaly is associated with: Developmental delay Hearing, vision, and motor deficits Seizures Increased mortality Viral particles detected in brains of microcephalic babies Viral proteins NS4A, NS4B hijack autophagy of neurons Promote viral replication in neuronal stem cells Diverts resources from neuronal differentiation, growth and maturation Washingtonpost.com Qiming Liang et al. Cell Stem Cell, August

7 THE ZIKA CRISIS ZIKA VIRUS DIAGNOSIS Feb 1, 2016, WHO declares Zika a Public Health Emergency of International Concern Never before in history has there been a situation when a bite from a mosquito can result in such a devastating scenario. - Dr. Tom Frieden, CDC Director RT-PCR: acute (<= 7 days from onset) Serum, saliva, urine (also semen, amniotic fluid, CSF) Higher viral loads, longer duration of positivity in urine than serum IgM serology (Zika MAC-ELISA) subacute to chronic (> 4 days - ~12 wks) Testing now widely available at commercial labs Confirmatory testing conducted by DPH labs ZIKA VIRUS MANAGEMENT Supportive treatment only; drug target: NS2B/NS3 serine protease Vaccine in development (Zika purified inactivated virus, phase 2 trials) Prevention is key: Primary prevention: Avoidance of bites/vector control Pregnancy prevention in endemic areas and post-exposure (2 months) Secondary prevention: Avoidance of mosquito bites by infected patients Use of barrier contraception (virus detected in semen for up to 6 months) Lee H et al. Antiviral Res Dec 26. Abbasi J. JAMA Dec 27;316(24):2588. WEST NILE VIRUS: CLINICAL PRESENTATION Incubation 2-14 days, up to 21 days if immune compromised 75% of patients are asymptomatic 25% of patients develop West Nile Fever Fever, headache, myalgias, arthralgias, rash <1% of patients develop neuroinvasive disease Meningitis, encephalitis mortality as high as 10% Many patients who survive have longstanding neurologic deficits (esp memory) Mukhopadhyay S et al. Science Oct 10;302(5643):248. Petersen LR, Brault AC, Nasci RS. JAMA Jul 17;310(3):

WEST NILE VIRUS: RASH WEST NILE VIRUS: RASH Rash seen in ~50% of patients Appears on day 5-12 of illness, lasts ~7 days Mostly described as maculopapular or morbilliform Generalized distribution

8 WEST NILE VIRUS: RASH WEST NILE VIRUS: RASH Rash seen in ~50% of patients Appears on day 5-12 of illness, lasts ~7 days Mostly described as maculopapular or morbilliform Generalized distribution Symptoms: 33% pruritus, 27% tingling/burning Generally nonspecific Ferguson DD et al. Clin Infect Dis Oct 15;41(8): Ferguson DD et al. Clin Infect Dis Oct 15;41(8): WEST NILE VIRUS: DX AND TX WNV: ANOTHER ZIKA? Diagnostic testing: WNV-specific IgM (serum or CSF) - turns positive day 3-8, stays positive 30+ days Confirmatory test: neutralizing antibody test (acute and convalescent specimens) RT-PCR or culture from serum, CSF, tissue Treatment: supportive No vaccine yet New study demonstrates that WNV can infect human placental tissue cause fetal demise in pregnant mice Birth outcomes study: 77 US woman with WNV acquired in pregnancy: 4 miscarriages 7 with significant congenital defects (microcephaly, lissencephaly, aortic coarctation, polydactyly) Is this another unrecognized TORCH infection? Not enough data yet. Platt D, Smith A, et al. Science Translational Medicine 31 Jan 2018: Vol. 10, Issue 426, eaao7090 O'Leary DR, Kuhn S, et al. Pediatrics Mar;117(3):e

hemorrhage shock severe arthralgias, high fever headache, arthralgias, conjunctivitis, less fever fever, headache, arthralgias ----------------------- maculopapular rash ------------------- arthritis

9 THE KEY POINTS CDC CLINICIAN INFORMATION CENTER CDC.GOV/TRAVEL/PAGE/CLINICIAN- INFORMATION- CENTER Symptoms Skin Complications Diagnosis Dengue Chikungunya Zika West Nile retro-orbital pain, myalgias, fever biphasic rash white islands, sea of red hemorrhage shock severe arthralgias, high fever headache, arthralgias, conjunctivitis, less fever fever, headache, arthralgias maculopapular rash arthritis PCR if < 7 days, IgM if > 4 days microcephaly Guillain-Barre PCR, IgM send serum + urine meningitis, encephalitis,?congenital PCR, IgM 2º route vertical transmission, blood transfusions, organ transplants Other risks sexual transmission Treatment supportive Adjunctive avoid NSAIDS avoid NSAIDS unless dengue ruled out COINFECTIONS POSSIBLE! CDC ARBONET DISEASE MAPS: DISEASEMAPS.USGS.GOV/MAPVIEWER THANK YOU! Contact: Iris.Ahronowitz@med.usc.edu 9

ADDITIONAL SLIDES OTHER ARBOVIRUSES (WITH RASHES) TO WATCH Crimean-Congo hemorrhagic fever tick-borne, livestock, recent outbreaks in Middle East and Asia, 40% mortality Mayaro virus mosquito-borne,

10 ADDITIONAL SLIDES OTHER ARBOVIRUSES (WITH RASHES) TO WATCH Crimean-Congo hemorrhagic fever tick-borne, livestock, recent outbreaks in Middle East and Asia, 40% mortality Mayaro virus mosquito-borne, brief dengue-like illness with rash, Central and South America Powassan virus tick-borne, neurotropic, also can infect placental tissue and cause fetal demise in rats Oropouche virus mosquito-borne, nonspecific febrile illness Ross River virus mosquito-borne, associated polyarthritis, Australia CDC ZIKA TESTING ALGORITHM IN THE UNITED STATES Only test if patient has exposure history AND is symptomatic Dengue: No known local transmission in US Chikungunya: First case acquired in US: Florida, 7/16/ imported cases in US as of Jan new US cases in 2017 (none locally acquired) Zika: First local transmission in US: Florida 7/29/ : 418 US cases, 4 locally acquired from mosquitoes (FL, TX), 5 sexually transmitted West Nile: Arrived in East Coast 1999, now endemic in all 50 U.S. states 10

annually 40% of world s population is at risk ~80% asymptomatic carriers Alphavirus (ssrna) Mosquito-borne, same vectors as dengue Large outbreaks in non-immune populations Until 2010: only in

11 DENGUE VIRUS CHIKUNGUNYA VIRUS Flavivirus (ssrna), mosquito-borne (Aedes aegypti, A. albopictus) 5 serotypes (DEN 1-5), 4 widely recognized Most common febrile illness in travelers from Caribbean, S America, SE Asia No known local transmission in US million infected worldwide annually 40% of world s population is at risk ~80% asymptomatic carriers Alphavirus (ssrna) Mosquito-borne, same vectors as dengue Large outbreaks in non-immune populations Until 2010: only in Africa, Southeast Asia, India Late 2013: local transmission in Americas First case acquired in US: Florida, 7/16/ imported cases in US as of Jan new US cases in 2017 (none locally acquired) McCarthy M. BMJ Jul 18;349:g4706. Mukhopadhyay S et al. Structure Jan;14(1): CDC/Arbonet data ZIKA VIRUS Flavivirus (ssrna): closely related to: yellow fever, dengue, West Nile Transmitted by Aedes aegypti mosquitoes (and potentially A. albopictus) First isolated near Zika Forest in Uganda, 1947 First outbreak: Micronesia and spread to SE Asia, 2007 Reaches Latin America (Brazil, May 2015) First local transmission in United States (Florida 7/29/16) 2017: 418 US cases, 4 locally acquired from mosquitoes (FL, TX), 5 sexually transmitted CDC/ArboNET data WEST NILE VIRUS Flavivirus, transmitted by Culex mosquitoes Also: blood transfusions, organ transplants, vertical transmission (rare) Arrived in East Coast 1999, now endemic in all 50 U.S. states Incubation period: 2-14 days, as long as 21 days if immune compromised 25% of infected patients develop West Nile Fever <1% of patients develop neuroinvasive disease Meningitis, encephalitis mortality as high as 10% Many patients who survive have longstanding neurologic deficits Mukhopadhyay S et al. Science Oct 10;302(5643):248. Petersen LR, Brault AC, Nasci RS. JAMA Jul 17;310(3):

Public Health Image Library. CDC/ Cynthia Goldsmith. Image #

Public Health Image Library. CDC/ Cynthia Goldsmith. Image # Zika Virus Fredrick M. Abrahamian, D.O., FACEP, FIDSA Clinical Professor of Medicine UCLA School of Medicine Director of Education Department of Emergency Medicine Olive View-UCLA Medical Center Sylmar,