preparing)for)the)arrival)of) ebolavirusintheutah ) · hemorrhagic fever, a clinical syn-drome that...

Preparing for the Arrival of Ebola Virus in the Utah

Bert K. Lopansri, MD Chief, Intermountain Division of Infec:ous

Diseases and Clinical Epidemiology Medical Director, Central Microbiology Lab

Conflicts of Interest

•  None related to this presenta:on

Learning Objec;ves

•  Understand the clinical characteris:cs of Ebola virus and how to iden:fy poten:al cases

•  Understand historical perspec:ve of Ebola and current outbreak

•  Understand key methods required to prevent spread to other persons including healthcare workers

Ques;on #1

•  21 year old man returned from West Africa (Kumasi, Ghana) with fever, chills, headache. No sick contacts during travel. What your assessment of risk for Ebola?

A.  High B.  Low C.  None D.  Not enough informa:on

Ques;on #2

•  What are the most appropriate precau:ons for preven:ng spread of Ebola?

A.  Airborne precau:ons only B.  Airborne and contact isola:on C.  Droplet isola:on D.  Droplet and contact isola:on E.  Hazmat

Ques;on #3

•  There is no treatment for Ebola.

A.  True B.  False

Agents of Viral Hemorrhagic Fever

VIRUS TRANSMISSION Es;mated annual cases

Filoviridae family Ebola Marburg

Human-‐to-‐human Current deaths: 4,922 All others: 1,590

Lassa virus Rodent urine Human-‐to-‐human

100,000-‐300,000

Crimean Congo Hemorrhagic Fever

Tick, infected animal blood and :ssue

4,000

Dengue Mosquito 500,000 Yellow Fever Mosquito 200,000

Ebola Virus

•  Enveloped, nega:ve sense RNA Virus

•  Characteris:c filamentous par:cles

n engl j med nejm.org

PERSPECTIVE

3

assumed that the new West Afri-can variant is not more virulent than previous Zaire ebolaviruses; a case fatality rate of about 70%, if confirmed, might even indicate lower virulence. The finding that the Guinea variant resides at a more basal position within the clade than previously known Zaire ebolaviruses1 argues against an in-troduction from Central Africa and instead supports the likeli-hood of distinct evolution in West Africa. These findings reinforce the hypothesis that ebolaviruses have a broader geographic distri-bution than previously thought.

There is currently no licensed prophylaxis or treatment for any ebolavirus or marburgvirus infec-tion; therefore, treatment is mere-ly supportive.2 Over the past decade, however, multiple counter-

measure options have shown promising efficacy in macaque models of filoviruses, and some of the approaches have complet-ed or are at least nearing phase 1 clinical trials in humans.4

The current front-runner for therapeutic intervention seems to be antibody treatment, which has been successful in macaques even when antibodies are admin-istered more than 72 hours after infection. Treatment approaches involving modulatory RNA (i.e., small interfering RNAs or phos-phorodiamidate morpholino olig-omers) are following close be-hind, along with a promising synthetic drug-like small mole-cule, BCX4430.5 The most prom-ising vaccine approaches are based on recombinant technolo-gies, such as virus-like particles

produced through plasmid trans-fection and replication-incompe-tent and -competent viral vectors.4

Among the latter, vesicular stoma-titis virus vectors have shown ef-ficacy within 24 to 48 hours after infection in rhesus macaques.

In the absence of effective in-tervention strategies, diagnosis becomes a key element in our re-sponse to ebolavirus infection.2Detection rests largely on mo-lecular techniques utilizing mul-tiple reverse-transcriptase–poly-merase-chain-reaction assays that can be used at remote outbreak sites. Antigen detection may be performed in parallel or serve as a confirmatory test for immedi-ate diagnosis, whereas assays for detection of antibodies (e.g., IgM and IgG) are secondary tests that are primarily important in sur-veillance. Molecular detection strongly depends on sequence con-servation, and established assays may fail when applied to new variants, strains, or viruses. There-fore, real-time sharing of infor-mation, particularly sequence data, is absolutely critical for our re-sponse capacity, since any delay could have disastrous conse-quences for public health. In ad-dition, diagnostics remain essen-tial for the time-consuming process of tracing contacts during an outbreak and for overcoming the obstacles to reintroducing sur-vivors into their community.

The latest outbreak of Zaire ebolavirus in West Africa again has shown the limited ability of our public health systems to respond to rare, highly virulent communi-cable diseases. The medical and public health sectors urgently need to improve education and vigilance. And rapid, reliable di-agnostic procedures must be im-plemented in key regions within or closer to the areas where these

Ebola — A Growing Threat?

Polymerase

ssRNA

20 nmMatrix

Viral membrane

Glycoprotein spikes

Ebolavirus

Viral membraneViral membrane

Glycoprotein spikes

ssRNANucleocapsidNucleocapsidNucleocapsid

Structure of Ebolavirus.

Shown is an ebolavirus particle and its characteristic filamentous shape. The negative-strand RNA genome is found in the center of particles in an encapsidated form as the nucleocapsid, together with the polymerase complex. Embedded in the virus membrane are trimeric glycopro-tein spikes. Beneath the membrane is the matrix protein, which facilitates morphogenesis and budding of virus particles. The image is based on Protein Data Bank identifiers 3CSY and 1ES6 (www.rcsb.org) and Electron Microscopy Data Bank identifier EMD-2043 (www.emdatabank.org). The abbreviation ssRNA denotes single-stranded RNA.

The New England Journal of Medicine Downloaded from nejm.org by BERT LOPANSRI on September 15, 2014. For personal use only. No other uses without permission.

Copyright © 2014 Massachusetts Medical Society. All rights reserved.

Heinz Feldmann, Ebola-‐A growing threat? NEJM.

Distribu;on of Ebola Virus Infec;ons PERSPECTIVE

n engl j med nejm.org2

pathology and pathophysiology closely resemble those of ebola-virus infections in humans; im-munosuppression, increased vas-cular permeability, and impaired coagulation have been identified as hallmarks of the disease.2 Evidence of microscopic hemor-rhage is usually found, but the degree of bleeding ranges from undetectable to acutely visible. The recently introduced term “Eb-ola virus disease” may not con-vey the seriousness of a viral hemorrhagic fever, a clinical syn-drome that should trigger isola-tion guidelines that ensure ap-propriate case management and implementation of infection-con-trol measures.

Ebolaviruses are zoonotic pathogens purportedly carried by various species of fruit bats that are present throughout central and sub-Saharan Africa. In con-

trast to marburgvirus, whose reservoir has been identified as Rousettus aegyptiacus fruit bats,3 ebolaviruses have not yet been isolated from bats that have mo-lecular and seroepidemiologic evi-dence of infection. Introduction into humans most likely occurs through direct contact with bats or their excretions or secretions or through contact with other end hosts, such as the great apes. Since Reston ebolavirus has been discovered in pigs on the Philip-pine islands, the possibility that there may be interim or amplify-ing hosts should not be dis-missed, as we further elucidate ebolavirus ecology.

Human-to-human transmission leads to outbreaks, which are of-ten started by a single introduc-tion from the wildlife reservoir or another end host and involve virus variants with little genetic

diversity, as in the current out-break in West Africa.1 Some re-corded outbreaks, on the other hand, have stemmed from multi-ple introductions, which have re-sulted in greater genetic viral diversity among the subsequent distinct chains of human-to- human transmission. Within a given species, however, virus vari-ants have been shown to have low genetic diversity, often less than a few percent, as illustrated by the new variant isolated from patients in Guinea.1 Such limited diversity generally leads to neu-tralizing cross-reactivity within the species.

Biologic characterization of various Zaire ebolaviruses, their case fatality rates, and their virulence in animal models have so far failed to provide convincing evi-dence of obvious differences in pathogenicity. Thus, it should be

Ebola — A Growing Threat?

Lake Victoria marburgvirus

Sudan ebolavirus

Taï Forest ebolavirus

Zaire ebolavirus

Kenya

SouthSudan

Angola

GabonUganda

Ivory CoastLiberia

Guinea

Zimbabwe

Congo

DemocraticRepublic ofthe Congo

Liberia

Kenya

Bundibugyo ebolavirus

Region of current outbreaks offilovirus infections

Region of past and recent outbreaksof filovirus infections

Africa

Outbreaks or Episodes of Filovirus Infections.

The purple ovals indicate regions of past and recent filovirus activity (on the border between the Republic of the Congo and Gabon from 2000 to 2005 and on the border between the Democratic Republic of the Congo and Uganda in more recent years), and the red oval indicates the current outbreak of Zaire ebolavirus.



Heinz Feldmann. NEJM. May 7, 2014

Ebola Virus •  34 independent clusters, 24 outbreaks since 1976 •  Five Ebola subtypes –  Zaire ebolavirus (ZEBOV)

•  13 outbreaks, 47-‐100% mortality –  Sudan ebolavirus (SEBOV)

•  6 outbreaks, 36-‐65% mortality –  Taï Forest virus (TFV)

•  1 Case –  Bundibugyo ebolavirus (BEBOV)

•  2 outbreaks, 25-‐36% mortality –  Ebola-‐Reston (REBOV)

•  Asymptoma:c in humans

Pathophysiology •  Transmission: –  Infected reservoir animals –  Direct contact with infected blood or body fluids •  Minute skin lesions •  Mucosa •  Percutaneous injury

–  Nursing care for infected pa:ents

–  Burial prac:ces –  NO EVIDENCE FOR AIRBORNE TRANSMISSION

Pathophysiology •  Primary Target Cells:

–  Macrophages and dendri:c cells, fibroblasts

–  Apoptosis of “bystander” cells (T cells, NK cells)

•  Other Target Cells: Epithelial cells (Endothelial cells, adrenal cor:cal cells, hepatocytes)

•  Vascular dysfunc:on, hepa:c necrosis, adrenal insufficiency, DIC, shock

•  Prolonged shedding in semen (13 weeks)

From Mike Bray, and others. Int J Biochem and Cell Biology. 2005

Clinical Manifesta;ons

•  Incuba:on Period –  4-‐10 days (Range 2-‐21) – NOT INFECTIOUS

•  Early –  Emergence of viremia – lower in first 3 days –  Fever (38.5oC), chills, myalgias, nausea, vomi:ng, abdominal pain, diarrhea

– Maculopapular rash followed by desquama:on (days 5-‐7)

–  Sore throat, conjunc:vi:s

Clinical manifesta;ons: Current Outbreak

0 10 20 30 40 50 60 70 80 90

All

Death

Survive

Adapted from NEJM. 2014; 371:1481-‐1495

Hemorrhagic manifesta;ons: Current Outbreak

0

5

10

15

20

25

All

Death

Survive

*

* * *

Adapted from NEJM. 2014; 371:1481-‐1495 *More frequent in those who died.

Differen;al Diagnosis •  Malaria •  Typhoid fever •  Shigellosis •  Cholera •  Leptospirosis •  Plague •  Rickeosiosis •  Relapsing fever •  Meningi:s •  Hepa::s •  Other viral hemorrhagic fevers

Clinical Manifesta;ons

•  Late Stages •  Shock •  Mul:-‐organ failure •  Mucosal hemorrhages •  Convulsions •  Diffuse coagulopathy •  High viremia

•  Time of death 6-‐16 days aqer onset of symptoms

•  Lab findings •  Leukopenia (1000 cells/uL) •  Lymphopenia and

neutrophilia –  Leq shiq with atypical lymphocytes

•  Thrombocytopenia •  AST and ALT eleva:on •  Electrolyte abnormali:es

Clinical Management •  PREVENT SPREAD –  Strict barrier nursing procedures

•  BASIC SUPPORTIVE CARE –  Fluid and electrolyte management –  Other suppor:ve care as needed – Management of complica:ons during hospitaliza:on

•  Experimental agents –  Zmapp (LeafBio, Inc.) –  Convalescent sera –  Brincidofovir (Chimerix, Inc.) –  TKM-‐Ebola ( Tekmira, Inc.)

•  Post-‐discharge preventa:ve measures –  No unprotected Intercourse for 3 months

Proven Methods to Stop Ebola Outbreaks

•  Early Diagnosis •  Contact Tracing •  Infec:on Control – Pa:ent Isola:on – Avoid contact with body fluids – Safe Burial Prac:ces

Situa;on as of Oct. 25, 2014 Suspected and confirmed cases

Deaths N (%)

Guinea 1553 926 (60%) Liberia 4665 2705 (58%) Sierra Leone 3896 1281 (33%) Nigeria 20 8 (40%) Senegal 1 0 Mali 1 1 Spain 3a 2 U.S. 9b 1 (13%)c TOTAL 10,148 4924 (49%)

www.cdc.gov a.  2 repatriated, 1 secondary transmission b.  5 repatriated cases, 2 secondary transmissions; 1 currently in treatment. c.  Excludes 1 in treatment

Current Situa;on •  Nigeria and Senegal – cleared •  U.S. Cases – 2 Travel associated cases – 1 death, 1 in treatment – 2 Secondary transmissions – cured – 5 Repatriated Ci:zens – all survived, cured –  Ini:al exposures to index case under observa:on cleared with no infec:ons

– 8/9 received convalescent sera and experimental an:viral medica:ons •  Brincidofovir (Chimerix) •  TKM-‐Ebola (Tekmira, Inc.)

Why is EVD Uncontrolled in Current Outbreak?

•  Delayed recogni:on •  Inadequate supply of PPE •  Porous borders •  Delayed global response •  Inadequate contact tracing •  Cri:cal shortage of HCWs, hospital beds and treatment facili:es –  As of Sept 5, 2014 – 610 treatment beds available in Liberia, Guinea, Sierra Leone

•  Hospital care by family members •  Cultural barriers (tradi:onal healing, delay in seeking healthcare, burial prac:ces)

Guinea Forest Region

gence of the virus from the forest, butclearly the sociopolitical landscape dictateswhere it goes from there—an isolated caseor two or a large and sustained outbreak.

The effect of a stalled economy andgovernment is 3-fold. First, poverty drivespeople to expand their range of activitiesto stay alive, plunging deeper into theforest to expand the geographic as well asspecies range of hunted game and to findwood to make charcoal and deeper intomines to extract minerals, enhancing theirrisk of exposure to Ebola virus and otherzoonotic pathogens in these remote cor-ners. Then, the situation is compoundedwhen the unlucky infected person presentsto an impoverished and neglected health-care facility where a supply of gloves, cleanneedles, and disinfectants is not a given,leaving patients and healthcare workersalike vulnerable to nosocomial transmis-sion. The cycle is further amplified aspersons infected in the hospital return totheir homes incubating Ebola virus. Thisclassic pattern was noted in Guinea, whereearly infection of a healthcare worker inGueckedou triggered spread to surround-ing prefectures and eventually to the

capital, Conakry [1]. Lastly, with anoutbreak now coming into full force,inefficient and poorly resourced govern-ments struggle to respond, as we are seeingall too clearly with this outbreak of Ebolavirus disease in West Africa, which is nowby far the largest on record. The responsechallenge is compounded in this case byinfected persons crossing the highly porousborders of the three implicated countries,requiring intergovernmental coordination,with all the inherent logistical challenges inremote areas with poor infrastructure andcommunication networks and, in this case,significant language barriers.

Guinea, Liberia, and Sierra Leone,sadly, fit the bill for susceptibility to moresevere outbreaks. While the devastatingeffects of the civil wars in Liberia andSierra Leone are evident and well docu-mented, readers may be less familiar withthe history of Guinea, where decades ofinefficient and corrupt government haveleft the country in a state of stalled or evenretrograde development. Guinea is one ofthe poorest countries in the world, ranking178 out of 187 countries on the UnitedNations Development Programme Hu-

man Development Index (just behindLiberia [174] and Sierra Leone [177]).More than half of Guineans live below thenational poverty line and about 20% livein extreme poverty. The Guinea forestregion, traditionally comprised of smalland isolated populations of diverse ethnicgroups who hold little power and poselittle threat to the larger groups closer tothe capital, has been habitually neglected,receiving little attention or capital invest-ment. Rather, the region was systemati-cally plundered and the forest decimatedby clear-cut logging, leaving the ‘‘GuineaForest Region’’ largely deforested (Fig-ure 3).

The forest region also shares borderswith Sierra Leone, Liberia, and Coted’Ivoire, three countries suffering civilwar in recent decades. Consequently, theregion has found itself home to tens ofthousands of refugees fleeing these con-flicts, adding to both the ecologic andeconomic burden. A United Nations HighCommission for Refugees census of campsin the forest region in 2004 registered59,000 refugees. Although the formalrefugee camps have now been dismantled

Figure 4. Scenes of the degraded infrastructure of the Guinea forest region. A. Once-paved, but now deteriorated road; B, C, and D.Street views of the dilapidated town of Gueckedou, the epicenter of the Ebola virus disease outbreak. Photos credit: Frederique Jacquerioz.doi:10.1371/journal.pntd.0003056.g004

PLOS Neglected Tropical Diseases | www.plosntds.org 4 July 2014 | Volume 8 | Issue 7 | e3056

Daniel G. Bausch, Lara Schwartz. PLOS NTDS. July 2014. Vol 8(7).

Emergence of Zaire Ebola Virus Disease in Guinea

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med nejm.org2

Frontières had been working on a malaria project in Guéckédou since 2010.) In Guéckédou, eight patients were hospitalized; three of them died, and additional deaths were reported among the families of the patients. Several deaths were reported in Macenta, including deaths among hospital staff members. A team sent by the health ministry reached the outbreak region on March 14 (Fig. 1). Médecins sans Frontières in Europe was notified and sent a team, which arrived in Guéckédou on March 18. Epidemiologic investigation was initiated, and blood samples were collected and sent to the biosafety level 4 laboratories in Lyon, France, and Hamburg, Germany, for virologic analysis.

Me thods

PatientsBlood samples were obtained from 20 patients who were hospitalized in Guéckédou, Macenta, and Kis-sidougou because of fever, diarrhea, vomiting, or hemorrhage. Demographic and clinical data for the patients were provided on the laboratory request forms. Clinical data were not collected in a system-atic fashion. This work was performed as part of the public health response to contain the outbreak in Guinea; informed consent was not obtained.

Diagnostic Assays

Viral RNA was extracted from 50 to 100 µl of undiluted plasma and 1:10 diluted plasma with the use of the QIAmp viral RNA kit (Qiagen). Nucleic acid amplification tests for detection of filoviruses and arenaviruses were performed with the use of commercially available kits and published primers and probes5-11 (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).

Viral SequencingFragments amplified by filovirus L gene–specific primers were sequenced with the use of poly-merase-chain-reaction (PCR) primers. Complete EBOV genomes were sequenced directly with the use of RNA extracted from serum obtained from three patients with high levels of viral RNA, as measured on real-time reverse-transcriptase–PCR (RT-PCR) analysis. The genome was ampli-fied in overlapping fragments with the use of EBOV-specific primers. The fragments were se-quenced from both ends with the use of conven-tional Sanger techniques. The sequence of the contigs was verified by visual inspection of the electropherograms.

Viral IsolationAbout 100 µl of all serum samples was used to inoculate Vero E6 cells maintained in 25-cm2

flasks in Dulbecco’s modified Eagle’s medium containing 2 to 5% fetal-calf serum and penicil-lin–streptomycin. Cells and supernatant were passaged several times. Virus growth in the cells was verified on immunofluorescence with the use of polyclonal mouse anti-EBOV–specific anti-bodies in the serum of mice challenged with EBOV or on the basis of an increase in viral levels in the cell-culture supernatant over several orders of magnitude, as measured on real-time RT-PCR.

Electron MicroscopySpecimens from two patients were prepared for electron microscopy with the use of a convention-al negative-staining procedure. In brief, a drop of 1:10 diluted serum was adsorbed to a glow-dis-charged carbon-coated copper grid and stained with freshly prepared 1% phosphotungstic acid (Agar Scientific). Images were taken at room tem-perature with the use of a Tecnai Spirit electron microscope (FEI) equipped with a LaB6 filament and operated at an acceleration voltage of 80 kV.

Sierra Leone

Guinea

MamouFaranah

Macenta

Nzérékoré

Liberia

Kissidougou

Guéckédou

Kindia

Conakry

100 kmMali

ivorycoast

Senegal

Guinea Bissau

Figure 1. Map of Guinea Showing Initial Locations of the Outbreak of Ebola Virus Disease.

The area of the outbreak is highlighted in red. The main road between the outbreak area and Conakry, the capital of Guinea, is also shown. The map was modified from a United Nations map.



Sylvain Baize, and others. NEJM. Sept 19, 2014

What are the global implica;ons?

Marcello F.C. Gomes, and others. PLOS Current Outbreaks. Sept 2, 2014

Risk of EVD Case Importa;on

Fig. 3: Risk of EVD case importation

Top 16 countries at risk of EVD case importation in the short term: (top) 1 September and (bottom) 22 September 2014. The risk is assessed as the probability that a country will experience at least one case importation by the corresponding date, conditional on not having imported cases prior to 21 August 2014. The dark blue and light blue bars represent the minimum and maximum probability estimates, respectively, according to different models of case detection during travel (see text). The orange area corresponds to the probability maximum assuming the Nigerian outbreak starts to follow the same dynamic of the other West African countries affected by the EVD epidemic. We report the rank of Nigeria as well, which has experienced already a case importation on 20 of July and indeed it ranks among the countries with the larger probability of case importation.





6PLOS Currents Outbreaks

↓↓

↓ ↓

EVD Preparedness at Intermountain Healthcare

•  RESOURCES heps://my.intermountain.net/Ebola/Pages/home.aspx

•  RECOGNITION –  Obtain travel history

•  COMMUNICATION –  Contact Public Health Officials (800 EPI-‐UTAH) –  Infec:ous Diseases and Infec:on Control –  Clinical lab –  Hospital administra:on

•  INFECTION CONTROL –  AVOID CONTACT WITH BLOOD AND BODY FLUIDS! –  Appropriate disposal of medical waste

EVD Case Defini;on •  PERSON UNDER INVESTIGATION: – Fever >38.0oC, severe headache, myalgias, vomi:ng, diarrhea, abdominal pain, unexpected hemorrhage

•  Epidemiologic risk factors within the past 21 days before onset of symptoms – Travel to Guinea, Liberia, Sierra Leone – Resolved risk in Nigeria and Senegal – NO RISK FOR TRAVEL TO SPAIN OR DALLAS!!

Epidemiologic Risk Factors

•  HIGH RISK CONTACT: –  Percutaneous or mucous membrane exposure to blood or body fluid of EVD pa:ent

–  Direct skin contact with or exposure to blood or body fluids without appropriate PPE

–  Processing blood/body fluids of confirmed EVD pa:ent without appropriate PPE

– Direct contact with dead body without PPE in outbreak country

•  LOW RISK CONTACT: –  Household contact, other close contact in health care facili:es or community sevngs or direct brief contact without wearing PPE

Infec;on Control Measures for Suspected Ebola

•  If available, admit to nega:ve pressure room –  IF HIGH RISK, TRANSFER TO INTERMOUNTAIN MEDICAL CENTER

•  PPE –  Fluid impermeable gowns with head cover

–  Leg covering with vomi:ng or diarrhea

–  Double glove –  Face shield and mask –  ADD Full body suite for confirmed cases with large amounts of diarrhea and vomi:ng

Infec;on Control Measures for Suspected Ebola

•  ASYMPTOMATIC, EXPOSED – Contact Utah Department of Health for monitoring

– Standard precau:ons

Laboratory Tes;ng in Pa;ents with Suspected EVD

•  HIGH RISK: Limit lab tes:ng to only tests cri:cal for pa:ent care that can be performed at bedside –  iSTAT – Malaria thin smear and RDT –  Blood culture – Manual WBC and Platelet Count –  Specimens must be labeled appropriately and hand delivered to the lab

•  EXPOSED, ASYMPTOMATIC: – No restric:ons on lab tes:ng

Summary •  As the situa:on worsens the probability that cases will be imported to neighboring countries and globally increases.

•  Awareness of a possible case and communica:on in a mul:disciplinary manner is cri:cal to recognizing and preven:ng spread.

•  Strict adherence to barrier precau:ons is essen:al to prevent secondary infec:ons in HCWs –  Training with PPE use essen:al

preparing)for)the)arrival)of) ebolavirusintheutah ) · hemorrhagic fever, a clinical syn-drome that...

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