Infectious Disease Case Conference

Case Presentation22 yo U.S. Army Active Duty male deployed to Afghanistan west of Kandahar presents with fever (102.5o F), headache, fatigue, chills, abdominal pain with non-bloody diarrhea (SEP 8, 2009)Symptoms progressing over the previous 4 days

Initially told he had a gastroenteritis at local clinicTreated with Cipro and immodium48 hour quarters

Returned the following day (SEP 9):Symptoms worsening, now with nausea/vomiting and lethargyTold he may have a viral syndromeReferred to Kandahar for observation

Case PresentationProgressively worsened over the next several hoursLethargy lead to somnolence Bloody diarrhea and bleeding gumsShortness of breath intubatedAnemic, low platelets, developing organ failure

Evacuated to LRMC with presumed diagnosis of pneumonia with septic shock (antibiotics started)

Case PresentationUpon arrival at the Landstuhl Regional Medical Center, he is found to be bleeding EVERYWHEREPetechiae everywhereLarge ecchymotic lesions at IV sitesExtremely sick

He requires emergent bronchoscopy for bleeding

The ICU staff raises the concern for viral hemorrhagic feverCase PresentationCo-located with Afghan army

Potential exposuresNumerous outdoor activities to include sleeping outsideRecent tick exposuresPatient and battle buddy both with recent bites within a week of illness onsetThis was a common occurrence (bragging rights)

Exposure to goat blood and undercooked goat meat

Blood sent to the Bernard Nocht Institute (BNI) in Hamburg within hours of admission

Blood run overnightSEP 10: PCR and IGM POSITIVE for CCHFInfectious diseases consulted just prior to test results

Within ~12 hours of diagnosis, treatment with oral ribavirin thru feeding tubeDose given to match the standard IV dose

Emergency IND approval for IV ribavirin from the FDA

IV ribavirin started 12 hours after oral treatment (48 hours of hospitalization)

Case Presentation6Renal and hepatic dialysis startedPatient appeared to be improving

However:SEP 14Patient had a asystolic/PEA arrestsDeclared brain deadAt time of death, viral load had declined and antibodies present

Case PresentationIn the ensuing investigation, 2 staff found to have seroconverted.Therefore, would like to make it so that doesnt happen to you.7Viral Hemorrhagic FeversCOL Art LyonsDCCS, DTHCPentagon, Washington, DC8Weve dealt with a fair number of potential exposures over timePeter asked me to put together some thoughts related to one in 2004Ill present the scenario and rather than go into detail on the response, I just want to raise some questions that weve wrestled with for consideration and discussionRecently cited in the news related to new laboratories being builtHistorically, weve erred on the side of cautionEven a paper cut in containment has to be taken seriouslyWe want to know if something happens in the lab, so we might be able to do something about it and prevent future potential exposures

Will Cover Some Steps to Avoid.

10

The Slammer11More of the slammer tourShow you what weve done

2 other facilities: Emory/CDC and Univ of Nebraska MC

1995 Kikwit Zaire ZEBOV OutbreakCourtesy of Don NoahOutlineVHFs in generalEpidemiologyClinical aspectsDiagnosisPreventive measuresTreatment

14Generally when one hears about VHFs, they often think of OutbreakJoke: Ted Cieslak lectures tomorrowHe is a very entertaining speakerIf he tells you he replaced Dustin Hoffman, youll know the truth:I replaced Dustin HoffmanTeds arrival drove Renee Russo to the CDC, much to my chagrinUnited State Army Medical Research Institute of Infectious Diseases (USAMRIID):

15Where I was chief of med divisionReturned yesterday after interlude at WRAMC

Work on biodefense and diseases requiring containmentPotential of VHFs for WeaponizationPROMany demonstrated as infectious by aerosol transmissionException is Dengue

Potentially high morbidity and mortalityReplicate well in cell cultureException are viruses in Bunyaviridae (e.g. CCHF)

Capability to overwhelm medical resourcesFrightening effects of illness / terror value

CONLack of treatment or vaccine to protect users own troopsMay not be deterrent for some countries / non-state actors

Possible entry into local vector / reservoir populationStabilizers must be used to enhance viability 16I became interested in these while at RIIDLess relavent for this specific course is: potential use as BW/BT.Aerosol transmission varies by virus.Some data experimental/some inferred from outbreaks, although all may not be proven in humans.exception is Dengue - not spread by aerosol.The Bunyaviridae, as a group and especially CCHF, do not replicate very well in cell-culture. Note: Soviets produced large quantities of Marburg & Ebola for weaponization- would argue that lack of a vaccine/treatment may not be a deterrent.Other Military Relevance: History of WeaponizationYellow fever and RVF were weaponized by the U.S. during their offensive program

Former Soviet Union produced large quantities of Ebola, Marburg, Lassa, Junin, and Machupo

Yellow fever may have been weaponized by North Koreans

The Aum Shinrikyo cult unsuccessfully tried to obtain Ebola virus to create biological weapons

Several studies have demonstrated ability to aerosolize Ebola, Marburg, Lassa, and some of the New World arenaviruses17Definition Viral hemorrhagic fever (VHF): Fever Malaise Myalgia prostration Bleeding diathesis Enveloped, single-stranded, RNA viruses

Hemorrhagic fever virus (HFV) is a term used to generically identify those agents that cause VHF.

18Flaviviruses are single-stranded positive sensesAll others are negative: filos single-stranded2 separate segments for arenas; 3 for bunyas

Hemorrhage is actually a minor feature for many similar to other inflam conditions (e.g. septic shock), vascular permeability is a common feature brought about by mediators from infected cellsKnow Whats There and How You Can Get It

Courtesy of Mike Bray, NIAIDAlkhurma Lujo21

CCHF

CCHF

Overview of Etiologic Agents of VHFsFamilyGenusSpeciesFiloviridaeEbolavirus Zaire, Sudan, Ivory Coast, Reston, BundibugyoMarburgvirusLake Victoria marburgvirus ArenaviridaeArenavirusLassa, Lujo (Old World)Junin, Machupo, Guanarito, Sabia, (New World) BunyaviridaeNairovirusCrimean-Congo hemorrhagic fever PhlebovirusRift Valley feverHantavirusHantaan, Seoul, Puumala, Dobrava, Sin Nombre FlaviviridaeFlavivirusOmsk HFKyasanur forest disease (including Alkhurma)DengueYellow fever274 families of virusesDifferent epidemiologiesFiloviruses: 2 genera: Hemorrhagic manifestation consistently observed.Arenaviruses: Old World and New World: Hemorrhagic manifestations common.Bunyaviruses: 3 genera, Nairovirus, Phlebovirus and Hantavirus.Hantaviruses: Old World (HFRS) and NW (Respiratory).Flaviviruses: perhaps the better known.DF & YF - 2 of the most important infx dzs in the world. Hemorrhagic manifestation not common.Overview of Epidemiology of HFVsNatural OtherIncubationDisease (virus)DistributionHost/Sources (days)VectorFilovirusesEbola HFAfrica, Philippines (ER)Bats?Nosocomial2-21Marburg HFAfricaBats?Nosocomial5-10

ArenavirusesLassa fever and Lujo virusAfricaRodentNosocomial 5-16Argentine HF (Junin)South AmericaRodentNosocomial 7-14Bolivian HF (Machupo)South AmericaRodentNosocomial 9-15Venezuelan HF (Guanarito)South AmericaRodentNosocomial 7-14Brazilian HF (Sabia)South AmericaRodentNosocomial 7-14

BunyavirusesCCHFEurope, Asia, AfricaTickAnimal slaughter, Nos.3-12Rift Valley feverAfricaMosquitoAnimal slaughter2-6HFRS/HPS (Bunyaviridae)World-wideRodent9-35

FlavivirusesOmsk HFSoviet UnionTick2-9Kyasanur forest diseaseIndiaTick2-9Dengue HFAsia, Americas, AfricaMosquito3-15Yellow feverAfrica, tropical AmericaMosquito3-6Alkhumra HFSaudi Arabia, EgyptTick2-928With the exception of dengue all maintained in nature with a cycle in animalsDengue maintained in a human-mosquito-human cycle

The big issue for military (and hence their real importance for this course):Which ones endemic dz threats in military operations:More likely those transmitted by insect vectors:CCHF, YF, DFBut, historical importance of HFRS in KoreaPerhaps better equipped now with knowledge of epidemiology(ask whether Liberia malaria mentioned ad nauseum has anyone mentioned concern for Lassa?)

EXTRA:INCUBATION In some cases, range probably narrower than indicated(difficulty in determining when people actually become infected). In primates, incub. Depends on inoculum, species (cynomolgus vs rhesus), and viral agent.How are VHFs Spread?1 Inhaling or ingesting excretions/secretions from rodent hosts (urine, feces)

2 - Bite of an infected arthropod (tick, mosquito)

3 Nosocomial/lab transmission contact with human or animal blood/body fluids/tissue

4 - Artificially generated aerosols (biowarfare)

Crimean Congo Hemorrhagic FeverHow are VHFs spread?In NHPs possible airborne transmission between cages 3 meters apartLung tissue with documented virus

In NHPs and GPs: infective via airborne, conjunctival, oral exposure

Viremia 3-5 days1 day prior or simultaneous with clinical illness (D4-5)Virus recovered from nares, pharynx, conjunctivae, anus (days 7-10; limited numbers)Lancet 1995;346:1669-71. Arch Virol 1996(suppl);11:115-134. Arch Pathol Lab Med 1996;120: 140-5. Int J Exp Path 1995;76:227-36.

31Where we have been able to test..Lung tissue with virus suggests airborne route of inoculationViremia occurs 1D prior or simultaneous with clinical symptoms

[EXTRA NOTES:Airborne exposure - 400pfu by inhalationOral/conjunctival exposure 5.2log/ml(3/4 oral, 4/4 conjunctival)In EBO-Reston, 4/6 caretakers seroconverted (IFA Ab+)-Spread rapidly in monkey house42/284 handlers with imported NHP contact are IFA+VHF Human-to-human transmissionOnly dengue and yellow fever virus have adapted to efficient human-to-human transmission (via mosquitoes).For other HF viruses, humans are dead-end hosts.

Typical story for nosocomial transmission:Uncertain how first human/NHP is infectedPatient enters the health care facilityVHF is not recognized or infection control procedures are not followedUnrecognized nosocomial spread from blood/body fluid contactHealth care personnel among the victimsVictims carry infection to the community

Close family members and those doing burial rites facilitate further spread

No proven human to human respiratory transmission

32How are VHFs Spread Person to Person?Usually spread during patient care without appropriate barrier precautionsContact with blood/tissue/body fluidsIncludes re-use of syringes/needles

Epidemiologically, VHFs not readily transmitted person-to-person by airborne routeA possibility in only rare circumstances

Highest risk in later stages, when having vomiting, diarrhea, shock, hemorrhageNot reported during incubation period (before fever)MMWR 1995;44(25):475-79.33Despite the cache, the reality

Know What They Can do

Model of Filoviral Pathogenesis in Primates165432361 Infx of dendritic cells and macrophages2 these sentinel cells serve as sites of replication (unusual)3 Macrophages migrate to lymph nodes4 virions released into lymphatics or bloodstream5 dissemination of virus to fixed macrophages in the liver, spleen, or other tissuesDirect effect: necrosis of virus-infected macrophages, dendritic cells, organs, such as liver6 macrophages release proinflammatory cytokines and chemokines (massive systemic release:TNF alpha, IL6, Macrophage inflame protein, INF alpha, RANTESAlso see INF beta, IL18, NO in plasmaThese bring out circulatory failure vascular leak, vasodilation7 Indirect effect: lymphocyte apoptosis early loss of NK cells, then CD8, CD4 T cellsLeads to impairment of host adaptive immune response/ VP24 and VP35 suppress Type 1 INF response8 Indirect effect: unregulated expression of cell surface tissue factor (Factor VII) triggers extrinsic coagulation pathway and ultimately DIC. rapid depletion of other coagulation factors (protein C)This is the reason for early increase in D-dimer.9 -further loss of coagulation factors due to liver dysfunction, vasodilation, impairment of endothelial function (anti-thrombotic & anti-inflammatory functions), DIC, circulatory shock, and multi-organ failure.VHF: Spectrum of Clinical PresentationsVariety of presentationsProdromeHigh fever, Headache, Malaise, Arthralgias, MyalgiasNausea, Abdominal pain, Non-bloody diarrhea

Early signsFever, Tachycardia, Tachypnea, Conjunctivitis, PharyngitisFlushing, Skin Rash

Late BP, Hemorrhagic diathesis, Petechiae, Mucous membraneConj. hemorrhage, Hematuria, Hematemesis, Melena

Major ManifestationsDIC, Circulatory Shock, CNS dysfunction37Rapid-onset of symptoms

Final common pathway of late manifestations

38Palatal petechiae

Argentine Hemorrhagic Fever (Junin virus New World Arenavirus )Gingival hemorrhage39Argentine Hemorrhagic Fever - gingival bleeding in human.

Oral epithelial necrosis and ulceration occurs in primate models.Ref: Current Science/Current Medicine (Peters CJ, Zaki SR, Rollin PE). Viral hemorrhagic fevers. In: Fekety R, vol ed. Atlas of Infectious Diseases, p10.1-10.26, Volume VIII, 1997.

Bolivian Hemorrhagic Fever(Machupo virus New World Arenavirus)Conjunctival injection & subconjunctival hemorrhage40Conjunctival and subconjunctival hemorrhage. Conjunctivits and photobia occurs in primate models.

Left arm. Ecchymosis, diffuse, severe. (1 week after clinical onset)

CCHFPhoto credit: Robert Swaneopoel, PhD, DTVM, MRCVS, National Institute of Virology, Sandringham, South Africa.42

DENGUE

CCHF

KOREAN HEMORRHAGIC FEVER (HANTAAN)

DENGUE

BOLIVIAN HEMORRHAGIC FEVER (MACHUPO)

KOREAN HEMORRHAGIC FEVER (HANTAAN)

CCHF

CCHF

DENGUE

Photo credit: Martini GA, Knauff HG, Schmidt HA, et. al. Ger Med Mon. 1968:13:457-470. Marburg Infection HumanMaculopapular rash52Clinical Features - VHF

Courtesy of Drs. Zaki & Peters53This slide came from a paper by Zaki and CJ Peters.Not all VHFs are alike distinct clinical featuresVHF: Spectrum of Laboratory AbnormalitiesLeukopeniaLassa with leukocytosis (WBC inc.)

AnemiaHemoconcentrationThrombocytopeniaElevated liver enzymesMay have renal dysfunctionCoagulation abnormalities

54VHF: Spectrum of Laboratory AbnormalitiesCoagulation abnormalitiesProlonged bleeding timeProthrombin timeActivated PTT fibrin degradation fibrinogenUrinalysisProteinuriaHematuriaOliguria Azotemia

55VHFs With Known Nosocomial SpreadFiloviruses Ebola and MarburgArenaviruses Lassa, Junin/Machupo (rare)Bunyaviruses CCHF, Andes virus (a cause of hantavirus pulmonary syndrome)Flaviviruses dengue (rare from blood splash)

Lassa most common imported VHF (if dengue not included)The Deadly VHFsVIRUSMortality RateEbola Zaire75-90%

Marburg 25-90% Lassa 15-20% of hospitalizedCCHF 3-70% (typically 20-30%)

Rift Valley fever50% of patients with hemorrhagic form57Not too many dzs give you high mortality rates like theseRates here are higher in more severe casesUnlike EBO/Marburg figures-everyone is severePotential distinguishing featuresJaundice/icterusYF,RVF, CCHF, filoviruses (rare)

Renal failureHantaan/hantaviruses, YF

EncephalopathySouth American HFs, Filoviruses, YF, Omsk, Kyasanur

RashDengue, filoviruses, LassaHow to Diagnose

Differential Diagnosis

Distribution of CCHF

Distribution of RVF

Distribution of Malaria60OTHER MOSQUITO BORNE DISEASES, SUCH AS MALARIA, HAVE SIMILAR GEOGRAPHIC DISTRIBUTION AS VIRAL HEMORRHAGIC FEVERS.

Lets look at CCHF and RVF, specificallyDistribution of CCHF

Distribution of RVF

Distribution of JuninAntiviral Res 2008:132-39.61Take your pick one virus for every region of the world

Junin photo - Antiviral Res 2008:132-39.

Differential Diagnosis of VHFClinical presentation: Fever, hemorrhage/purpura, thrombocytopenia, CNS signs, elevated LFTs, leukopenia, thrombocytopenia, DIC, multisystem / multi-organ failure

MalariaTyphoid fever Rocky Mountain Spotted Fever (Rickettsia rickettsii) & other rickettsiosesLeptospirosisMeningococci Q fever (Coxiella burnetti)PlagueInfluenza Viral meningitis / encephalitis (e.g. henipaviruses)HIV / co-infectionHemorrhagic smallpoxVasculitis (i.e. autoimmune diseases)Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS)

62Clinically, these dzs could look like VHF

NOTE: Histologically RMSF causes a profound vasculitis w/ endothelial damage not seen in the HFVs.Diagnosis - Clinical PathologyThrombocytopenia or abnormal platelet functionLeukopenia (exception is Lassa, which has a leukocytosis)Some patients have anemiaMost have elevated liver enzymes (ALT / AST)Bilirubin is elevated in RVF and YFProthrombin time, activated partial thromboplastin time (APTT) and bleeding time are prolonged Some have disseminated intravascular coagulation (DIC); those that have DIC have elevated d-dimers (FDPs) and decreased fibrinogenThese are not hard and fast rules. There will be overlap with many of these infections.63Diagnosis - Laboratory ConfirmationGold Standard - Virus isolation from blood, serum or tissue biopsyBSL-4 Lab

Electron microscopyReverse transcription - polymerase chain reaction (RT-PCR)Increasingly important tool64RT-PCR - can increase sensitivity to as little as 4500 organisms per ml of serum.

Rapid ELISA techniques most easily employedAntigen capture detectionIgM (test of choice for Hantaviridae, yellow fever, & Dengue) or IgG antibody capture

Serology on paired sera (acute and convalescent)Immunohistochemistry (IHC) & in situ hybridization (ISH) of infected tissues Formalin-fixed tissue CDC has developed a skin biopsy procedure for detection of EBOV using IHCDiagnosis - Laboratory Confirmation65Know How to Protect Yourself and Others

Prevention / ControlYELLOW FEVERLicensed 17D vaccine, highly efficaciousLive virus vaccineReports of vaccine associated deathsCannot be used in persons with egg allergy

Junin Candid 1 ARGENTINE HFLive, attenuatedSafe and efficaciousProtects monkeys against Bolivian HFNOT AVAILABLE IN THE UNITED STATES67Prevention / Control:None LicensedRift Valley Fever Formalin-inactivatedsafe but requires 3 shots, intermittent boosterlimited supply

Live, attenuated MP-12Phase II testing

EbolaAdenovirus vectored +/- DNA primeVEE repliconsVSV vectoredVirus-like particles (VLP)

MarburgRecent NHP study at USAMRIID: 100% survival following challenge w/ lethal dose of MBGV and then post-exposure treatment w/ recombinant VSV-GP Marburg vaccine

68VHF Spread Summary lack of spread1967 Marburg no airborne transmission1975 2 pts, Marburg in S. Africa1/35 HCWs infected when barrier precautions not used

1979 34 pts, Ebola in Southern Sudan29 cases direct contact0 cases of 103 who had no direct contact

1994 1 pt, Ebola1/70 contacts infected (no airborne precautions)

1996 2 pts, Ebola0/300 contacts infected

VHF Spread Summary evidence of spread1995 316 infected with Ebola in DRC3 HCPs infected after barrier precautions1 non-adherent1 needlestick1 uncertain - ? Rubbed eyes with glove

No household non-physical contacts infected

2000 224 deaths, Ebola in Uganda14/22 (64%) infected after infx controlUncertain why this happenedCouldnt rule out airborne transmission

Conclusion:Preponderance of evidence: Cant r/o airborne transmission, but appears to be a minor mode if it exists

Transmission rarely, if ever occurs prior to onset of signs/symptomsNumber of infected health care workers declined after barrier nursing practices were begun during the Ebola HF outbreak in Kikwit, DRC, 1995.

Critical Care Clinics (2005) 21:765-783.Back to the initial case18 healthcare providers identified as being HIGH risk exposuresOffered oral ribavirin post-exposure prophylaxis2 individuals had more significant symptoms to medsBoth were found to have developed antibodies to the CCHF virus

1995 Kikwit Zaire ZEBOV OutbreakCourtesy of Don Noah

Outbreak Management:IsolationBarrier precautions74CDC Recommendations - when to go hotStandard Precautions in initial assessmentsPrivate room upon initial hospitalizationBarrier precautions including face shields, surgical masks, eye protection within 3 feet of patient

Negative pressure room not required initially, but should be considered early to prevent later need for transfer

Airborne precautions if prominent cough, vomiting, diarrhea, hemorrhageE.g. HEPA masks, negative pressure isolationMMWR 1988;37(S-3):1-16. MMWR 1995;44(25):475-79. 75Upon hospitalization:equivalent to droplet precautions + contact-i.e. when illWe planned for graded infx control barriers while asx

www.cdc.gov/ncidod/dvrd/spb/mnpages/vhfmanual.htm76Standard Precautions for All PatientsIdentify a minimum level of Standard Precautions Establish routine hand washingEstablish safe handling and disposal of used needles and syringesBe prepared to intensify Standard Precautions and include VHF isolation precautionsIdentify a VHF coordinator to oversee and coordinate activities associated with VHF isolation precautionsWHO VHF Africa ManualUse VHF Isolation PrecautionsIsolate the patientWear protective clothing:Scrub suit, gown, apron, two pairs of gloves, mask, headcover, eyewear, rubber boots

Clean/disinfect spills, waste, and reusable safety equipment, soiled linens, and laundry safelyUse safe disposal methods for non-reusable supplies and infectious wasteCounsel staff about the risk of VHF transmissionProvide information to families and the community about VHF prevention and care of patientsWHO VHF Africa ManualSelection Site for Isolation Area (if isolation area not available)Single room with adjoining toilet or latrineSeparate building or ward for VHF patients onlyAn area in a larger ward that is separate and far away from other patientsAn uncrowded corner of a large room or hallAny area that can be separated from the rest of the health facilityWHO VHF Africa ManualInfection ControlSingle room with adjoining anteroom as only entranceChanging area/protective equipmentDisinfection solutions0.5% sodium hypochlorite, 2% glutaraldehyde, phenolic disinfectants (0.5%-3.0%), soaps and detergents

Hand washing stationsChemical toilets

WHO VHF Africa Manual80risk for person-to-person transmission of HFV highest during the latter stages of illnessno evidence that HFV can be transmitted via sewage systems, but as an added precaution use chemical toilets or autoclave waste.In the 1995 Zaire outbreak, some instances of Ebola virus transmission within a few days after onset of fever were reported; however, other symptoms in the source patients and the level of exposure to body fluids among these secondary cases were unknown (CDC, unpublished data, 1995). In studies involving three monkeys experimentally infected with Ebola virus (Reston strain), fever and other systemic signs of illness preceded detection of infectious virus in the pharynx by 2-4 days, in the nares by 5-10 days, in the conjunctivae by 5-6 days, and on anal swabs by 5-6 days (P. Jahrling, U.S. Army Medical Research Institute of Infectious Diseases, unpublished data, 1995).

Other Isolation PrecautionsLimit health facility staff and visitors in the patients roomDevelop and post an authorized list for entryProvide a guard with the list

Limit use of invasive procedures and reduce injectable medicinesWHO VHF Africa Manual

82Medical ManagementFirst Aid for ExposuresAnticipate in advance be preparedWash / irrigate wound or site immediately within 5 minutes of exposure

Mucous membrane (eye, mouth, nose)continuous irrigation with rapidly flowing water or sterile saline for > 15 minutes

Skinscrub for at least 15 minutes while copiously soaking the wound with soap or detergent solutionfresh Dakin's solution (0.5% hypochlorite)83Scrub for at least 15 minutes; soak with soap or detergent solution.Swab, irrigate deeps wounds

Dakin's solution should be swabbed into the wound for >5 minutes. The 1995 MMWR on VHF recommends a 1:100 dilution of hypochlorite for disinfection.(Note: the hypochlorite solution will cause burning and discomfort when applied to the wound.)3 Levels of RiskCasual contacts:Remote contact (same airplane/hotel)No surveillance indicated

Close contacts:Housemates, nursing personnel, shaking hands, hugging, handling lab specimensPlace under surveillance when diagnosis confirmedRecord temperatures twice daily x 3 wksNotify for temperature >=101MMWR 1988;37:1-1684From the CDC guidelines-for contact with infected individuals3 Levels of RiskHigh-risk:Mucous membrane contact (kissing, sex) or needle stick or other penetrating injury involving blood/body fluidPlace under surveillance as soon as diagnosis is consideredImmediately isolate for temperature >= 101

MMWR 1988;37:1-1685From the CDC guidelinesKnow What to Do for Yourself and Others

Medical ManagementThe foundation of treatment is supportive care

Hemodynamic resuscitation & monitoringCareful management of fluid and electrolytes, blood pressure, and circulatory volume Use of colloidHemodialysis or hemofiltration as neededEsp. HFRS patients

Vasopressors and cardiotonic drugs (some cases do not respond to i.v. fluids)Cautious sedation and analgesia

87Medical ManagementDisseminated Intravascular Coagulation (DIC) may be important in some VHFs (RVF, CCHF, filoviruses)

Coagulation studies and clinical judgment as guideReplacement of coagulation factors / cofactorsPlatelet transfusions

No aspirin, NSAIDs, anticoagulant therapies, or IM injections

88Primary insult hematologic-appropriate to monitor hematological parameters closelyMedical ManagementAntiviral TherapyRibavirin Investigational drug, compassionate use Contraindicated in pregnancy Arenaviridae (Lassa, AHF, BHF) Bunyaviridae (HFRS, CCHF) not RVF NO UTILITY FOR FILOVIRUSES OR FLAVIVIRUSES

Immune (convalescent) plasma Arenaviridae (AHF & BHF; ?Lassa) Passive immunoprophylaxis post-exposure? Experimental studies in animals have not proven efficacy against filovirus infection NOT READILY AVAILABLE89Documented laboratory-acquired case of Sabia virus in a virologist as the result of a lab accident (centrifuge), survived with early treatment w/ Ribavirin.

Convalescent plasma and passive immunization has been used extensively in many VHF outbreaks with limited success. Junin and Machupo viruses seem to be most responsive to plasma therapy, so much so that this is the treatment of choice in many areas of Argentina and Bolivia.

Medical Management For Arenavirus & BunyavirusRibavirin Treatment30 mg/kg IV single loading dose 16 mg/kg IV q 6 hr for 4 days8 mg/kg IV q 8hr for 6 days

Prophylaxis500 mg PO q 6 hr for 7 days (different regimens)

Note: Parenteral (Rx) and oral Ribavirin (PEP) are investigational and available only through human use protocols (ahem.contact USAMRIID through ID consult)Borio L, et al. JAMA 287(18):2391-2405, 2002McCormick JB et. al. N Eng J Med 314(1):20-26, 1986Jahrling PB et al. J Infect Dis 141:580-589, 198090Protocols for the use of Ribavirin as an IND exist through the CDC and USAMRIID

Filovirus Prophylaxis/TreatmentA number of therapies have been shown to protect NHPs when begun shortly after filovirus exposure.Vaccination (recombinant VSV)Immunomodulators (rNAPc2 and rhAPC)Antivirals (siRNA and antisense molecules)Monoclonal antibodies

Pre-exposure prophylaxis with some vaccine platforms have demonstrated protection in NHPsVSV, Adenovirus vectored (with/without DNA prime)Virus-like ParticlesVEE replicon

None is approved for human use

91No licensed treatments for filovirusesNeutralizing human monoclonal antibodiesEffective as pre and immediate (1 h) postexposure prophylaxis in guinea pigs (failed at 6 h postchallenge)

Equine IgG ineffective for monkeys (on day 0)Delay in viremia, but still diedSecond dose on day 5 no added benefitJID 1999;179(Suppl1):S224-34 J Virol 2002;76:6408-12 Lancet 2003;362:1953-58.92Potential Options - EbolaNo consensus on utility of use of immune convalescent plasmaMost case reportsNot readily available, safe source

Humans limited data with blood transfusion from convalescent patients from Kikwit 7/8 survive with Ebola c/w case fatality rate of 80%Survivors received better supportive care?Late in the epidemic, thus decreased virulence?

JID 1999;179(Suppl1):S18-23JAMA 2002;287(18):2391-2405.93All seriously ill, with asthenia, -4 with hemorrhagic manifestations; -2 became comatoseWhole blood usedAt least one improved prior to transfusion

[Note: 5/8 received 2nd wk of illness; -4/7 tested already had EBO IGM/G before transfused]11 others (6 in Kikwit, 5 prior) received transfusions only 1 survived2 others treated in Europe survived (one had transfusion)Medical Management of Hemorrhagic SyndromePotential of Activated Protein C (Xigris)VHFs grouped by syndrome they produce not by agentActivated protein C (rhAPC / Xigris) targets the syndrome.

rhAPC labeled for use in syndrome, not as a specific antiviral chemotherapeutichas no anti-EBOV activity in vitro.

Serves as:an exogenous source of activated protein Canti-thromboticpro-fibrinolyticanti-inflammatory effects

Hensley et. al.: In publication 2007.94Medical Management of Hemorrhagic SyndromePotential of Activated Protein C (Xigris)DIC a common manifestation in several VHFs, especially filoviridae;rapid and significant depletion of endogenous protein C

Significant declines in protein C levels also reported in patients with Argentine hemorrhagic fever.

Recent study at RIID: rhAPC (Xigris) had beneficial effects in most NHPs (including survival in 2) challenged w/ lethal dose of ZEBOV

Hensley et. al.: In publication 2007.95Medical Management of Hemorrhagic SyndromePotential of XigrisApproved Xigris dose in humans for severe sepsis is 24 g/kg/hr for 96 hrs. Highest NOAEL* (No Observed Adverse Event Level ) from toxicology studies in monkeys and in phase 1 studies is 48 g/kg/hr.

Disadvantages of Xigris: Administered by continuous I.V. infusionShort high-lifeExpensive (AND NO LONGER PRODUCED BY COMPANY)Potential for development of immune antibodies against recombinant product

Not the magic bullet, but one possible component in combination therapy protocols for various VHFs.

Hensley LE, et. al.: In publication 2007.96Ebola virus induces overexpression of the pro-coagulant tissue factor in primate monocytes and macrophages

Inhibition of the tissue-factor pathway could ameliorate the effects of Ebola hemorrhagic fever

THE LANCET Vol 362 December 13, 200397Thanks to Todd Gleeson for some of these slides:There was some fanfare with this article came out.After all going from 100% CFR to 33% is a big step

33% (3/9) survival rate in each treatment group (injection of rNAPc2 either 10 min or 24 hr post lethal Ebola exposure)All but 1 control animal diedTHE LANCET 362 December 13, 200398Mean survival 11.7 ds (6 rNAPc2 treated macaques)Vs 8.3 ds for controlsNo difference in survival or delay of death whether treated 10 mins or 24 hours after challenge (1/3 vs 2/6 survived)BACKUP:Rx was 30 ug/kg QD vs saline for up to 14 ds (shorter if died)1000 PFUs EBO-Zaire challenge doseGoal: forming PMO: mRNA duplexBlocks translation of viral mRNA and inhibiting viral replication

Mice fully protected at 500 g, with dose response at lower doses

Guinea pigs with best response at 96 hr postchallenge

Nonhuman primates 3/4 survive after combination of oligomers used (VP24, VP35, L) one dies of bacterial infection

PLoS Pathogens 2006;2(1):0005-0013.99Antisense oligomers: -sequence homology near AUG translational start siteFor NHPs Rx 2 ds prior - 9 ds after -dosed either 12.5mg or 100mg each dayIM virus challenge; Rx was IP

[EXTRA: 19 Kb genomes; 7 genes with open reading frames:NP, GP, Viral proteins (VP24, 30,35,40)RNA polymerase(L)Be on alert for emerging infectionsLujo hemorrhagic fever (Zambia, South Africa)4 out of 5 patients diedThe lone survivor received ribavirin

Alkhurma hemorrhagic fever (Saudi Arabi)Case fatality rate ~30%Considered to be tick bornHemorrhagic fever +/- encephalitis (similar to Kyasanur Forest Disease)

Novel bunyaviruses (likely tick borne)Severe Fever with Thrombocytopenia Syndrome virus (China)Heartland virus (2 cases, no deaths; found in Missouri)

Avian influenzaH5N1 (case fatality rates ~30-60%)H7N9 (case fatality rate ~33% as of 11 AUG 2013)

Middle East Respiratory Syndrome Coronavirus (MERS-CoV)48% case fatality rate (as of 1 AUG 2013)

Be on alert for emerging infections (not VHFs)HenipavirusesNipah virusInfects pigsCase fatality rate ~60-90%Movie Contagion based on this virusFlu-like respiratory illness with CNS involvement

Hendra virusInfects horsesCase fatality rate ~60%Flu-like respiratory illness with CNS involvement

Be on alert for emerging infections (not VHFs)Final ThoughtsMaintain an index of suspicionBYOP (Bring your own PPE):Masks, gowns, gloves, goggles, caps

Have an exit strategyDont let anyone use a non-sterile needle on youRodent/bat controlGet WHO guidelines

HEPA FilterIn-line Air

Ear PlugsAir FlowAir Flow

Positive PressureExhaust ventsDouble GlovesFor which of the following viral infections would you not use ribavirin?CCHFJunin (Argentine HF)LassaEbolaHantaan (HFRS)For which of the following viral infections would you not use ribavirin?CCHFJunin (Argentine HF)LassaEbolaHantaan (HFRS)Questions1) Which of the following diseases should be considered in the differential diagnosis of a viral hemorrhagic fever:a) malariab) smallpoxc) typhoid feverd) leptospirosise) all of the aboveQuestions1) Which of the following diseases should be considered in the differential diagnosis of a viral hemorrhagic fever:a) malariab) smallpoxc) typhoid feverd) leptospirosise) all of the aboveQuestions2) What is the primary mechanism of human to human transmission that has occurred in outbreaks of viral hemorrhagic fevers?

a) inhaled small droplet nuclei (respiratory aerosols)b) percutaneous or mucus membrane contact with blood or body fluids of a victimc) contact with urined) sharing the same householde) inhaled large dropletsQuestions2) What is the primary mechanism of human to human transmission that has occurred in outbreaks of viral hemorrhagic fevers?

a) inhaled small droplet nuclei (respiratory aerosols)b) percutaneous or mucus membrane contact with blood or body fluids of a victimc) contact with urined) sharing the same householde) inhaled large dropletsQuestions3) What is the most important aspect for preventing spread of viral hemorrhagic fevers in an outbreak?

a) isolating patients in a negative pressure roomb) caregivers use basic barrier methods (gloves, masks, gowns, goggles)c) place the patient in a separate facility a minimum of 20 foot distance from the primary care aread) rapid treatment with an effective antiviral medicatione) vaccination of all close contactsQuestions3) What is the most important aspect for preventing spread of viral hemorrhagic fevers in an outbreak?

a) isolating patients in a negative pressure roomb) caregivers use basic barrier methods (gloves, masks, gowns, goggles)c) place the patient in a separate facility a minimum of 20 foot distance from the primary care aread) rapid treatment with an effective antiviral medicatione) vaccination of all close contactsMatch the virus with the sequelaa)Lassab)Rift Valley Feverc)HFRSd)Yellow Fever__Retinitis__Deafness__Icterus/Jaundice__Renal failureMatch the virus with the sequelaa)Lassab)Rift Valley Feverc)Hantaand)Yellow Feverb_Retinitisa_Deafnessd_Icterus/Jaundicec_Renal failureMatch the virus with the Countermeasurea)Ebolab)Lassa c)Junind)Yellow Fever

__Licensed vaccine__Immune plasma__Ribavirin__Supportive CareMatch the virus with the countermeasurea)Ebolab)Lassa c)Junind)Yellow Fever

d_Licensed vaccinec_Immune plasmab_Ribavirina_Supportive careQuestions?Thanks to:

COL Mark Kortepeter, MD, MPHDirector, Infectious Disease Clinical Research Program