EMERGING INFECTIOUS DISEASES: FOCUS ON SARS

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EMERGING INFECTIOUS DISEASESFOCUS ON SARS

• David Jay Weber, M.D., M.P.H.
• Professor of Medicine, Pediatrics Epidemiology
• UNC at Chapel Hill
• Revised 11 February 2004

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EMERGING INFECTIOUS DISEASES FOCUS ON SARSDavid
Jay Weber, M.D., M.P.H.Professor of Medicine,
Pediatrics and Epidemiology, UNC
SARS will knock you backward, it may even kill
you, but I can tell you SARS can kill the
economy, and all of us will be killed by the
collapsing economy Goh Chok Tong, Prime Minister
of Singapore
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SOURCES OF SLIDES

• Ralph Baric, PhD, Professor of Epidemiology, UNC
• Centers for Disease Control and Prevention (CDC)
• Nancy Cox, MD, Chief Influenza Branch, CDC
• Jeffrey Engel, MD, NC State Epidemiologist
• William Rutala, PhD, Professor of Medicine, UNC
• World Health Organization (WHO)

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CAUSES OF DEATH, WHO, 1996
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Infectious Disease Mortality in the United
States, 1980-1996
80
70
60
50
40
Crude ID Mortality Rate
Deaths per 100,000 population
30
20
10
0
Year
Source JAMA 1996275189-193 and unpublished CDC
data
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EMERGING INFECTIOUS DISEASESDEFINITION

• Emerging infectious diseases can be defined as
  infections that have newly appeared in the
  population, or have existed but are rapidly
  increasing in incidence or geographic range

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EMERGING INFECTIOUS DISEASES SINCE 1990

• 1993 (US) - Hantavirus pulmonary syndrome (Sin
  nombre virus)
• 1994 (US) Human granulocyte ehrlichiosis
• 1995 (Worldwide) - Kaposi sarcoma (HHV-8)
• 1995 (US) Cyclosporiasis from raspberries
• 1996 (England) Variant Creutzfeld-Jakob disease
  (vCJD)
• 1997 (Japan) Vancomycin-intermediate S. aureus
• 1998 (Malaysia) Nipah virus
• 1999 (US) - West Nile encephalitis (West Nile
  virus)
• 2001 (US) - Anthrax attack via letters
• 2001 (Netherlands) Human metapneumovirus
• 2002 (US) Vancomycin-resistant S. aureus
• 2003 (China ? worldwide) - Severe acute
  respiratory syndrome (coronavirus)
• 2003 (US) - Monkeypox
• 2004 (Asia) Avian influenza (H5N1)

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SUCCESS STORIES

• Vaccine Preventable
• Smallpox
• Polio
• Measles
• Rubella
• Invasive Haemophilus influenzae type b

• Other
• Toxic shock (S. aureus)
• Tooth decay
• Tuberculosis
• Rheumatic fever

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VACCINE PREVENTABLE DISEASES
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EMERGING DISEASE THREATS WORLDWIDE

• Multi-drug resistant P. falciparum (malaria)
• HIV-1, HIV-2 (AIDS)
• Multi-drug resistant tuberculosis
• Severe acute respiratory disease syndrome (SARS)

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SOURCES OF EXOTIC DISEASES

• Travel
• Animal exposure (zoonotic diseases)
• Exposure via travel, leisure pursuits (hunting,
  camping, fishing), occupation (farming), pets
• Bioterrorist agents
• Research
• Exposure via laboratory work or animal care

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U.S. PERSONS TRAVELING ABROAD, 1989-99
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Stiffen R, Ericsson CD. CID 200030809.
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FACTORS CONTRIBUTING TO EMERGENCE OF INFECTIOUS
DISEASES

• Societal events
• Health care
• Food production
• Human behavior
• Environmental change
• Public health infrastructure
• Microbial adaptation and change

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FACTORS CONTRIBUTING TO NEW DISEASES

• SOCIETAL EVENTS
• Economic impoverishment
• War or civil conflict
• Population growth and migration
• Urban decay
• Use of high-density facilities (e.g., prisons,
  day care)

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FACTORS CONTRIBUTING TO NEW DISEASES

• HEALTH CARE
• New medical devices
• Organ or tissue transplantation
• Drugs causing immunosuppression
• Widespread use of antibiotics

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FACTORS CONTRIBUTING TO NEW DISEASES

• FOOD PRODUCTION
• Globalization of food supplies
• Changes in food processing, packaging, and
  preparation

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FACTORS CONTRIBUTING TO NEW DISEASES

• HUMAN BEHAVIOR
• Travel
• Sexual behavior
• Drug use
• Diet
• Outdoor recreation
• Use of day care facilities

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Speed of Global Travel in Relation to World
Population Growth
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FACTORS CONTRIBUTING TO NEW DISEASES

• ENVIRONMENTAL CHANGES
• Deforestation and/or reforestation
• Changes in water ecosystems
• Flood/drought
• Famine
• Global warming

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FACTORS CONTRIBUTING TO NEW DISEASES

• PUBLIC HEALTH INFRASTRUCTURE
• Curtailment or reduction in prevention programs
• Inadequate communicable disease surveillance
• Lack of trained personnel
• Epidemiologists
• Laboratory scientists
• Vector and rodent control specialists

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FACTORS CONTRIBUTING TO NEW DISEASES

• MICROBIAL ADAPTATION AND CHANGE
• Changes in virulence and toxin production
• Development of drug resistance
• Microbes as cofactors in chronic diseases

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BASIC CONCEPTS IN DISEASE EMERGENCE

• Emergence of infectious diseases is complex
• Infectious diseases are dynamic
• Most new infections are not caused by genuinely
  new pathogens
• Agents involved in new and reemergent infections
  cross taxonomic lines
• The concept of the microbe as the cause of
  disease is inadequate and incomplete
• Wilson ME. Emerging
  Infectious Diseases 1995139.

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BASIC CONCEPTS IN DISEASE EMERGENCE

• Human activities are the most potent factors
  driving disease emergence
• Social, economic, political, climatic,
  technologic, and environmental factors shape
  disease patterns and influence emergence
• Understanding and responding to disease emergence
  require a global prospective, conceptually and
  geographically
• The current global situation favors disease
  emergence

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WORLDWIDE DISTRIBUTION OF WEST NILE VIRUS
Campbell GL, et al. Lancet ID 20022519.
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MORTALITY AS A FUNCTION OF AGE
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LESSONS FROM WEST NILE

• Initial detection via the astute observer (not
  via a surveillance system)
• Once established diseases likely become endemic
• Geographic range likely to increase
• Unusual methods of transmission may occur (e.g.,
  via organ transplantation)
• Development of diagnostic tests key to
  containment
• Under ascertainment of mild (or asymptomatic
  cases)
• Public relations nightmare

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TRAVEL CRITERIA FOR SUSPECT OR PROBABLE U.S.
CASES OF SARS
CDC. Case Definition. 18 July 2003
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CUMULATIVE NUMBER OF PROBABLE CASES OF SARS (WHO)
March April May
June July August
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SARS CASES AND OUTCOME
WHO 26 September 2003
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Total SARS Cases and Healthcare Workers by
Country
HCW
Total No. SARS cases
HCW
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RECENT SARS CASES

• Recent community SARS cases (based on onset of
  illness)
• December 31, 2004 35 yo male, Guangdong
  Province, China
• December 25, 2003 20 yo female, Guangdong
  Province, China (restaurant worker)
• December 16, 2003 32 yo male, Guangdong
  Province, China
• Recent laboratory aquired SARS cases
• December, Taiwan, China
• September, 27 yo researcher, Singapore

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TRANSMISSION IN SINGAPORE

• Case 1
• Visit to Hong Kong stayed in Hotel M, Feb.
  20-25
• Feb. 25 Developed fever with dry cough
• March 1 Hospitalized Ward 5A TTSH (patchy
  infiltrate)
• March 4 Transferred to ICU
• March 6-11 Admitted to Ward 5A on isolation
• March 11 Transferred to Ward 8
• Case 1 linked to SARS infection in 21 persons (9
  HCWs, 12 family members or visitors)

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CASE DEFINITION, US

• April 16
• Suspected Case Fever, respiratory symptoms,
  exposure
• April 20
• Suspected case Fever, respiratory symptoms,
  exposure
• Probable case Fever, respiratory symptoms, and
  exposure plus pulmonary infiltrate or autopsy
  evidence of disease
• May 2 Laboratory criteria added
• Case definition refined
• May 20/23
• July 5, July 11, July 18
• November 3
• December

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CASE DEFINITION, USCLINICAL CRITERIA (December
2003)

• Early illness
• Presence of two or more of the following fever
  (might be subjective), chills, rigors, myalgia,
  headache, sore throat, rhinorrhea
• Mild to moderate respiratory illness
• Temperature of gt100.4 oF (gt38 oC), and
• One or more clinical findings of respiratory
  illness (cough, SOB)
• Severe respiratory illness
• Meets clinical criteria of mild to moderate
  respiratory illness, and
• One or more of the following
• Radiographic evidence of pneumonia, or
• Respiratory distress syndrome, or
• Autopsy findings consistent with pneumonia or
  ARDS without cause

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CASE DEFINITION, USEPIDEMIOLOGIC CRITERIA
(December 2003)

• Possible exposure to SARS-associated coronavirus
  (SARS-CoV)
• One of more of the following exposures in the 10
  days before onset of symptoms
• Travel to a foreign or domestic location with
  documented or suspected recent transmission of
  SARS-CoV, or
• Close contact with a person with mild to moderate
  or severe respiratory illness and with a history
  in the 10 days before onset of symptoms to a
  foreign or domestic location with documented or
  suspected recent transmission of SARS-CoV

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CASE DEFINITION, USEPIDEMIOLOGIC CRITERIA
(December 2003)

• Likely exposure to SARS-associated coronavirus
  (SARS-CoV)
• One of more of the following exposures in the 10
  days before onset of symptoms
• Close contact with a confirmed case of SARS-CoV
  disease, or
• Close contact with a person with mild to moderate
  or severe respiratory illness for whom a chain of
  transmission can be linked to a confirmed case of
  SARS-CoV disease in the 10 days before onset of
  symptoms

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CASE DEFINITION, USLABORATORY CRITERIA
(December 2003)

• Detection of serum antibody to SARS-CoV by a test
  validated by CDC (e.g., EIA), or
• Isolation in cell culture of SARS-CoV from a
  clinical specimen, or
• Detection of SARS-CoV RNA by a RT-PCR test
  validated by CDC and with subsequent confirmation
  in a reference laboratory (CDC)

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CASE DEFINITION, USEXCLUSION CRITERIA (December
2003)

• An alternative diagnosis can explain the illness
  fully
• Antibody to SARS-CoV is undetectable in a serum
  obtained gt28 days after onset of illness
• The case was reported on the basis of contact
  with a person who was excluded subsequently as a
  case of SARS-CoV disease

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CASE DEFINITION, USCASE CLASSIFICTION (DECEMBER
2003)

• Reports in persons from areas where SARS in not
  known to be active
• RUI-1 Patients with severe illness compatible
  with SARS in groups likely to be first affected
  with SARS-CoV if
• Re

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SARS CASES AND OUTCOME, US
Schrag S, et al. EID 200410185
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Schrag S, et al. EID 200410185
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CLINICAL FEATURES
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CLINICAL FEATURES
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CLINICAL FEATURES
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CLINICAL FEATURES
H Vu. EID 200410334
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CLINICAL FEATURES
Low value Elevated value
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CLINICAL FEATURESRADIOGRAPHS

• In the early stages of the disease, a peripheral
  / pleural-based opacity may be the only
  abnormality
• Appearance may range from ground-glass to
  consolidation
• HRCT may reveal pulmonary lesions in the
  retro-cardiac area in SARS patients with normal
  radiographs
• In more advanced cases, there is widespread
  opacification which may be ground-glass
  consolidation affecting large areas
• May affect the lower zones first often bilateral
• Calcification, cavitation, pleural effusion or
  lymphadenopathy are not features of this disease

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CLINICAL FEATURESHIGH RESOLUTION CT (HRCT)

• Solitary or multiple patchy areas of
• Ground-glass opacification with or without
  thickening of the intra-lobular interstitium or
  interlobular interstitium
• Consolidation
• A combination of 1 2

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24-Year Old Symtomatic Female. Frontal View Shows
Vague Paraspinal Opacity in Left Lower Zone
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31-Year Old Healthcare Worker With 2 Day History
Of Fever, Chills And Myalgias
Time of diagnosisill-define Air space
opacification RLL
Day 3, partial resolution of RLL infiltrate but
new LLL infiltrate
Day 7, partial resolution of pulmonary changes
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52-Year Old Symptomatic Female From Virginia
On presentation
Day 4 following presentation
Day 5 following presentation
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24-Year Old Philipino Nursing Aid With One Week
History Of Fever, Dry Cough, and Myalgia
Day 7, bilateral infiltrates patient required
ventilation
Day 1, subtle LLL infiltrate
Day 5, LLL consolidation
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PEDIATRIC CASES
2-year old boy with convulsions and
cough Opacities in med and lower zones
5-year old girl with fever for 4 days Opacity in
left lower zone
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CLINICAL CHARACTERISTICS, US
Schrag S, et al. EID 200410185


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CLINICAL CHARACTERISTICS, US
Schrag S, et al. EID 200410185


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CLINICAL CHARACTERISTICS, US
Schrag S, et al. EID 200410185


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CLINICAL CHARACTERISTICS, US

• Reasons why US cases have a milder clinical
  course than cases described elsewhere
• Not SARS ascertained via a very broad case
  definition
• Altered virus
• Other

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CLINICAL DIAGNOSIS

• Clinical history Sudden onset flu-like prodrome,
  dry cough, non-respiratory symptoms (e.g.,
  diarrhea common)
• Clinical examination Does not correlate with
  chest radiography
• Bedside monitoring Hypoxia
• Hematology Low lymphocyte count
• Biochemistry Raised LDH
• Radiology CxR changes poorly defined, patchy,
  progressive changes
• Microbiology No other etiology identified

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EPIDEMIOLOGIC CLUES

• Infection control Increase in hospital acquired
  pneumonia
• Nursing Pattern of deterioration in patients
  with pneumonia suggestive of SARS
• Occupational health HCWs with atypical pneumonia
• Radiographers Pattern of atypical pneumonia
• Hematologists Profile suggestive of atypical
  pneumonia
• Biochemists Profile suggestive of atypical
  pneumonia
• Microbiologists Increase in undiagnosed pneumonia

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CLINICAL MANAGEMENT

• Manage as community acquired pneumonia
• CBC with diff, platelets, PT/PTT, electrolytes,
  LFTs, renal function
• Pulse ox or ABGs
• Chest radiograph
• Blood cultures x 2
• Nasopharyngeal aspirate Rapid RSV and influenza
  A and B
• Labs for SARS (per CDC)
• Not available except through Health Department
• Treat as for community acquired pneumonia

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Peiris et al Lancet, May 24, 2003
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Peiris personal communication
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SARS DiagnosticsOther Respiratory Pathogens
rule-out testing
Other respiratory pathogens, U.S. SARS
surveillance, Mach-July, 2003.
Schrag SJ et al. SARS surveillance in the United
States during the Emergency Public Heath
Response, March-July, 2003. EID (In press).
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MORTALITY (WHO)

• Case fatality rate 14-15 (range, 0-50)
• Variation with age
• Age lt24 years lt1
• Age 25-44 6
• Age 45-64 15
• Age gt65 50
• Variation with locale
• Hong Kong 11-17
• Singapore 13-15
• Canada 15-19
• China 5-13

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PREDICTORS OF MORTALITY

• Hong Kong (Lee N, et al)
• Univariate analysis Advanced age, male gender,
  high CPK peak, high LDH on presentation, high
  initial absolute neutrophil count, low serum
  sodium
• Multivariate analysis Advanced age (OR 1.8 for
  every 10 years), high peak LDH (OR 2.1 for every
  100 U/l), and high absolute neutrophil count on
  presentation (OR 1.6)
• Toronto (Booth C, et al)
• Univariate analysis Advanced age, male gender,
  high initial absolute neutrophil count, elevated
  PT, low sodium, high urea, high creatinine, high
  CK
• Multivariate analysis Age gt60 y (OR 1.4),
  diabetes (OR 3.1), other comorbid diseases (OR
  2.5)

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TIME COURSE OF SARS
Vu B. EID 200410334
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SUMMARYEPIDEMIOLOGY

• SARS represents a global outbreak
• Origin of outbreak China
• Incubation period 2-10 days
• Transmission via close contact (direct contact
  and/or droplet)
• Major risk factors for acquisition Household
  contact, HCWs
• Some cases appears to be hyper-transmitters
• Contact plus airborne precautions prevent HCW
  acquisition

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SUMMARYCLINICAL FEATURES

• Initial symptoms
• Nonrespiratory prodrome lasting 2-7 days
  characterized by one or more of the following
  Fever, rigors, headache, malaise, myalgia,
  diarrhea
• Respiratory phase beginning 2-7 days after onset
  characterized by nonproductive cough, dyspnea,
  absence of upper respiratory symptoms

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SUMMARYCLINICAL FEATURES

• Laboratory findings
• Normal or low leukocyte count, lymphopenia,
  mildly depressed platelet count
• Elevated LDH, elevated CPK, elevated
  transaminases
• Prolonged PTT
• Radiographic findings
• Abnormal chest radiograph results in most
  patients be second week of illness
• Unilateral focal involvement 55, bilateral
  involvement 45

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SUMMARYCLINICAL COURSE

• No predilection for gender or age
• Requirement for ICU care 20 of hospitalized
  patients
• Mortality 10-15
• Risk factors of mortality Advanced age and
  markers of more severe disease (high LDH, low
  sodium, high CK, elevated PT)
• The presence of underlying medical conditions
  associated with worse clinical outcome
• No proven therapy

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Time-line NC Confirmed Case

• Toronto 5/15 to 5/18
• Work 5/19 to 5/23
• Ill 5/24
• Clinic 5/27, 5/28, 6/1, 6/3
• CXR positive 6/3
• Seroconversion from 6/3 to 6/4

• 2 workplace contacts investigated for atypical
  pneumonia
• 1 diagnosed with mycoplasma 6/13
• 1 died of pneumonia/ARDS 6/13

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SARS in Toronto, 2003
Orange County mans travel dates
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Index Case Physician Visits
May 24 (Saturday) IC develops febrile
illness May 27 IC presents to family physician
(FP), viral syndrome suspected May 30 1st
follow-up at FP, Rocky Mountain spotted fever
suspected and doxycycline begun June 2 2nd
follow-up, respiratory symptoms develop
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SARS in NC
June 3 3rd follow-up, suspect SARS,
Orange County Health Department notified June 3
Chest x-ray shows patchy infiltrates, probable
SARS June 3 and 6 Serology sent to CDC June 9
CDC detects seroconversion, notifies NC of
laboratory-confirmed SARS
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Index Case, June 8
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AIRCONDITIONING
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SARS Control Measures

• Hospital Infection Control
• Early detection
• Containment Proper infection control,
  environmental cleaning
• Protection of personnel PPE, hand hygiene
• Community
• Active Surveillance
• Disease Investigation
• Isolation and Quarantine

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RECOMMENDATIONSHEALTHCARE SETTINGS

• Isolation (universal respiratory hygiene)
• Contact (gloves, gowns), airborne (mask, eye
  protection, private room)
• Wear an N95 respirator as part when entering the
  room of a patient with known or suspected SARS
• Once in the presence of a SARS patient, the N95
  should be considered potentially contaminated and
  touching the outside avoided
• Upon leaving the room, dispose of the N95
  followed by hand hygiene
• Exclusion for visitors
• Exclude close contacts with SARS cases who have
  fever or respiratory symptoms
• Screen contacts

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RECOMMENDATIONSHEALTHCARE SETTINGS

• Surveillance HCWs
• Active surveillance for fever and respiratory
  symptoms following unprotected exposure
• Passive surveillance (occupational health
  records) of all HCWs in a facility with a SARS
  patients
• Exclusion from duty for exposed HCWs
• Fever or respiratory symptoms if they develop
  within 10 days of unprotected exposure to a SARS
  patient
• No exclusion if well

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RECOMMENDATIONSHEALTHCARE SETTINGS

• If a sufficient supply of respirators is not
  available, consider reuse of the respirators as
  long as not damaged or soiled
• Consider wearing a loose-fitting barrier (e.g.,
  surgical mask) over the respirator
• Remove the mask upon leaving the patients room
  and perform hand hygiene discard the surgical
  mask
• Remove the respirator and store properly
• If respirators are not available, consider use of
  a surgical mask

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RISKS FOR ACQUIRING SARS, RNs, TORONTO

• Activities increasing risk (plt0.5)
• Intubation OR 4.20
• Suctioning before intubation OR 4.20
• Nebulizer treatment OR 3.24
• Manipulation oxygen mask OR 9.00
• Activities decreasing risk
• N95 or surgical mask OR 0.23
• 
  Loeb M. EID 200410251

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EFFICACY OF PPE

• Taiwan (4/14/2003) - 23 probable cases, 120
  possible cases
• Healthcare worker
• 32 year old physician cared for the wife of the
  initial case
• On 3/14, physician had performed chest ultrasound
  (duration30 min)
• On 3/17, physician had supervised intubation
  (duration1 hr)
• PPE N95 mask, eyeglasses without goggles,
  gloves x 2, 2 gowns
• 3/21, developed symptoms (met criteria of
  probable SARS, PCR)
• Precautions
• Airborne isolation room PPE (N95, gloves x 2,
  gown x 2, goggles)
• No other infection in HCWs (N525)
  Twu S-J. EIDE 20039718

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EFFICACY OF PPE

• Report from Toronto
• Index case 54 year old physician
• April 1-2 Exposure (did not wear PPE)
• April 4 Symptoms developed
• April 8 Admitted
• April 13 Transferred to ICU intubated after 2
  hours
• April 15-21, nine HCWs developed suspect or
  probable SARS
• PPE worn during intubation gown, gloves, masks,
  goggles
• Room met airborne isolation requirements (no
  anteroom)
• No formal respiratory protection program (i.e.,
  no fit testing)
• CDC.
  MMWR 200352433

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EFFICACY OF PPE
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Effectiveness of Precautions

• Study Design case-control study in 5 Hong Kong
  hospitals
• Staff (241 non-infected, 13 infected) surveyed
  about use of mask, gloves, gowns, and handwashing
• Results 69 staff who reported all four measures
  were not infected all infected staff omitted at
  least one measure. Fewer staff who wore masks
  (N95 and surgical masks), gowns, and washed their
  hands became infected compared to those who did
  not.
• Conclusion practice of Contact and Droplet
  Precautions is effective in reducing risk of
  infection after exposure.
• WH Seto et al. Lancet 20033611519-1520

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ENVIRONMENTAL SURVIVAL

• Feces
• Room temperature gt1-2 days
• Diarrheal stool gt4 days
• Urine
• Room temperature gt1-2 days
• Cell-culture supernatant
• 4 oC and 80 oC gt21 days
• 56 oC (10,000 units) 15 min

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Stability of SARS Coronavirus

• Virus is stable in feces and urine at RT for at
  least 1-2 d
• Virus survival in cell-culture supernatant
• Minimal reduction in virus conc after 21 days at
  4oC and 80oC
• 1 log reduction at RT for 2 days
• Heat (56oC) kills SARS coronavirus
• Virus loses infectivity after exposure (lt5 min)
  to 2 phenol, 75 ethanol, 110 Clorox
• WHO Laboratory Network. May 2003.

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MANAGEMENT OF SARS IN HEALTHCARE FACILITIES, CDC

• Basis of Response
• Community prevalence Low, high, secondary
  transmission
• Hospital prevalence Low, high, secondary
  transmission
• Communication
• Identification
• Signs at entrances in English and Spanish (/-
  HCW/guard)
• Hot line
• Triage
• Home
• Outpatient facility

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Hospital-based SARS surveillance Options for
Enhanced Surveillance
Facility with no SARS cases
Be alert for clusters of pneumonia among HCWs
Monitor HCWs taking care of SARS patients daily
for fever, cough or SOB
Screen all visitors
Fever, cough, or shortness of breath? SARS Risk
Factors?
Monitor daily healthcare workers
inpatients
Facility with unlinked nosocomial transmission
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MANAGEMENT OF SARS IN HEALTHCARE FACILITIES

• Infection control
• Identify outpatient, inpatient, ICU rooms
• Anterooms
• Airborne isolation
• PPE Use sitters
• Lock down procedures
• Personnel
• Laboratory capability

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Rationale for Limiting SARS-CoV TestingIn
setting of no or limited SARS activity
IF Sensitivity of detecting SARS in clinical
specimen 50 Specificity of test 95
Prevalence 50 PPV 95
PPV
Prevalence 1 PPV 9
Prevalence of SARS among persons tested
PPVpositive predictive value
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RECOMMENDATIONSHUMAN REMAINS

• PPE for autopsies and postmortem exams
• Surgical scrub suit, surgical cap, impervious
  gown or apron with full sleeve coverage, eye
  protection, shoe covers and double surgical
  gloves with an interposed layer of cut-proof
  synthetic mesh gloves
• N-95 or N-100 respirator or powered air-purified
  respirators (PAPR) equipped with HEPA filter
• Standard measures to prevent sharp injuries
• Autopsy suite should meet airborne precaution
  requirements (gt12 air exchanges, negative
  pressure, exhausted to the outside)
• 
  CDC
  25 March 2003
  

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QUARANTINABLE COMMUNICABLE DISEASES

• Viruses
• Smallpox, yellow fever, viral hemorrhagic fevers
  (Lassa, Marburg, Ebola, Crimean-Congo, South
  American, and others)
• SARS
• Bacteria
• Cholera, diphtheria, infectious tuberculosis,
  plague
• 
  Executive Order 12542, 4 April 2003

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CORONAVIRUSES

• Size and shape 120-160 nm, pleomorphic
• Genome Single-stranded, linear, positive-sense
  RNA
• Enveloped Yes
• Reservoirs Humans, multiple animal species
• Syndromes
• Common colds Account for up to 50 of upper
  respiratory tract infections
• Gastroenteritis
• SARS

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NIDOVIRALES ORDER
Coronaviridae -Group 1 TGEV HCV229E -Group
2 MHV BCV SARS? -Group 3 IBV
TGEV

• Important Pathogen of Swine
• Enteropathogen and Causes Gastroenteritis and
  Diarrhea, Usually in Newborn Piglets
• Transmitted by Fecal-Oral route, nursing, and
  aerosols from the Respiratory Tract
• 100 Fatal in Piglets under 10 Days of Age

• MHV
• Animal model for human disease
• Model for transcription, replication, entry, host
  range and persistence

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CORONAVIRUSES
Linear, plus polarity ssRNA genome (27,000-32,000
nucleotides in length)
Group 1, 2 and 4 coronaviruses lack the HE
glycoprotein, .
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MHV GENOME ORGANIZATION
PLP12-Papain like proteases 3clPro-poliovirus
like protease Pol-polymerase Hel-helicase
Potential target for drug development
TGEV lacks p30 and HE
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CORONAVIRUSES(Ksiazek et al., 2003)
CPE in Vero E6 Cells

• Evidence for etiology
• EM from lung samples
• Isolation in cell culture from clinical samples
• PCR amplification from clinical samples
• Seroconversion in ill patients
• Novel virus (new to humans)
• Other agents that have jumped species boundaries
  HIV (from SIV), vCJD (BSE from sheep scrapie)
• Found in respiratory tract and feces, some
  pathology in liver although it is not clear if
  virus replication is occurring at this site

FA Convalescent Sera
SARS Virus
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SARS GENOME ORGANIZATIONCoronavirus Nested Set
Structure
Target for Virus attenuation
How is E expressed? IBV like organization of
SxxEMxxxN Genes. Novel Conserved Intergenic
Sequence TAAACGAAC Upstream of each Gene.
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SARS PHYLOGENY
123
HALLMARK FEATURES OF CORONAVIRUS Replication

• High rates of mutation (10-4 3.2
  mutations/round of template replication) and RNA
  recombination frequency (20)
• Genome size, discontinuous transcription, RNA
  recombination rate increases from 5 to 3 end of
  the genome (more template for strand switching)
• New emerging Nidoviruses with epidemic potential
• Cross species transmission events occur with
  relative ease only a few mutations in the S
  glycoprotein gene are necessary for altering host
  species specificity, tissue tropism,
  pathogenesis, transmission strategy and
  virulence. (BCV and HCVOC43 are virtually
  indistinguishable)

124
Coronavirus Cross Species Transmission Mechanisms

• Two distinct mutational pathways for MHV host
  range expansion
• Persistent murine infection leads to genome
  mutations that expand host range via altered
  receptor usage
• -MHV variants that grow to 107 infectious units
  in human cells
• Mixed culture passage leads to evolution of
  expanded host range mutants (MCF 7 Variants)
• Cross species transmission occurs via recognition
  of human orthologues of the murine receptor
• Genetic basis of cross species transmission?

125
Lessons from the PastNidovirus Pandemics Since
1978

• 1978 Porcine epidemic diarrhea virus (PEDV)
  emerged in Belgium and the UK . The most
  important viral intestinal pathogen of swine in
  Europe and Asia
• Sequence more akin to HCV 229E
• 1984 Porcine Respiratory Coronavirus (PRCV)
  (respiratory pathogen) evolved from TGEV
  (enteric) pathogen.
• Single amino acid change or a deletion(224 amino
  acids) in S1 regulates enteric or respiratory
  tropism (Also removes two antigenic sites)
• Worldwide distribution, PRCV cross protection
  against TGEV, TGEV prevalence is declining

Tropism Change
PRCV
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Lessons from the PastNidovirus Pandemics

• 1987-90 Porcine Respiratory and Reproductive
  Disease Syndrome (PRRSV) emerged simultaneously
  in the US and Europe (Origin is unknown)
• Germany 1990-All of Europe by 1991
• Most important swine pathogen worldwide
  (pneumonia and fetal loss)(Arterivirus)
• 1993 Respiratory Bovine Coronavirus-Shipping
  Fever Pneumonia
• Changes in pol1a and S glycoprotein gene (single
  change) likely responsible for change in
  tropism/virulence from enteric (BCV) to
  respiratory disease (RBCV)
• BCV and HCV-OC43 are virtually indistinguishable
• SARS?
• Common Theme
• Crowding, stressful conditions favor changes in
  virus spread and tropism. In each case, losses
  continue despite widespread use of modern
  management and vaccination programs

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ORIGIN OF SARS

• Hong Kong, May 2001 (Zheng B. EID 200410176)
• Random selection of subjects
• Assay Immunofluorescence
• 17/938 (1.8) positive
• Guangdong, China, Sring 2003 (Guan Y. Science
  2003302276)
• Animal traders 8/20 (40) positive
• Persons who slaughter animals 3/15 (20)
  positive
• Vegetable traders 1/20 (5) positive

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ORIGIN OF SARS

• Similar but not identical virus found in the
  following animals
• Palm civet (SZ16)
• Raccoon dog (SZ13)
• Animal infection
• Cats No illness
• Macaques Mild illness
• Mice No illness
• Ferrets Severe disease

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Common Palm Civet
Delicacy in China SARS first seen in exotic
animal handlers in Guandong Province
Coronavirus isolated RNA sequence
nearly identical to SARS-CoV Did an animal CoV
jump species to humans?
130
(Guan Y. Science 2003302276)
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SARS GENOME ORGANIZATIONCoronavirus Nested Set
Structure
Target for Virus attenuation
How is E expressed? IBV like organization of
SxxEMxxxN Genes. Novel Conserved Intergenic
Sequence TAAACGAAC Upstream of each Gene.
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Coronavirus Vaccine Challenges

• Human coronavirus infection elicits short-lived
  immunity. SARS?
• Live-attenuated, inactivated and subunit based
  vaccines resulted in immune enhancement and
  increased pathogenicity following FIPV infection
  (Antibodies against S)
• Killed vaccines less effective than live
  attenuated vaccines
• Live-attenuated IBV and TGEV vaccines are
  somewhat effective.
• SARS Vaccines? Animal data is encouraging!
• People recover from infection
• Neutralizing antibody
• Cellular Immune responses
• Primate model (macaques)

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VACCINE APPROACHES

• Traditional Approaches
• Inactivated viruses (killed vaccines)
• Blind serial passage in tissue culture
  (attenuation)
• Rationale Approaches for Vaccine Design
• Coronavirus infectious cDNAs
• Coronaviruses as heterologous vaccine vectors
• Coronavirus gene order rearrangements
• Coronavirus replicase mutants
• VEE recombinant virus vaccines

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SARS CoV Vectored Vaccines
Vaccine Target Antigens S glycoprotein
neutralizing antibody T Cell
epitopes Receptor blockade antibodies Block
cell to cell spread N protein T cell
epitopes One report of neutralizing antibody?
Live Attenuated Vaccine Issues Safety
Issues Licensing Issues Manufacturing
Concerns Recombinant Virus Vaccine
Platforms Alphavirus Vectors Paramyxovirus
Vectors Vaccinia Vectors
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SARS UNKNOWNS

• Contagious period
• Prior to symptoms
• Duration post-onset
• Transmission routes
• Attack rate
• Relative frequency
• Asymptomatic infection rate
• Risk factors for infection, severe disease, death
• Treatment (No efficacious drugs have been
  identified)
• Does infection produce protective immunity?
• Evolution of new SARS strains (fecal-oral,
  respiratory spread)

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INFECTION CONTROL UNKNOWNS

• Environmental survival of SARS agent
• Coronaviruses are generally very stable at low
  and moderate temperature in liquids (days), less
  stable after desiccation and on surfaces (hrs)
  not clear how stable in sputum, fecal and
  salivary samples SARS stability is unknown
• Enveloped viruses are generally less stable than
  naked viruses in the environment
• Transmission (relative contributions)
• Via droplet spread
• Via direct control
• Via mucosal surfaces
• Via airborne spread?

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RISK OF DYING (US, per year)

• Major risks
• Heart disease 1 in 400
• Cancer 1 in 600
• Stroke 1 in 2,000
• Flu pneumonia 1 in 3,000
• MVA 1 in 7,000
• Being shot by a gun 1 in 10,000
• USA Today October 16, 2001
• Influenza hospitalizations 114,000
• Influenza deaths 36,000

• Other risks
• Falling down 1 in 20,000
• Crossing the street 1 in 60,000
• Drowning 1 in 75,000
• House fire 1 in 100,000
• Bike accident 1 in 500,000
• Commercial plane crash 1 in 1 million
• Lightening strike 1 in 3 million
• Shark attack 1 in 100 million
• Roller coaster accident 1 in 300 million

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Emerging Diseases Worst Case Scenario ( Historic
Perspective Respiratory Pathogen)

• 1918 Spanish Influenza-3 waves of infection
  occurring in the spring of 1918 (mild), fall of
  1918 (excessive mortality) and a 3rd wave in 1919
  (excessive mortality).
• Most of the human population was immunologically
  naive (elderly populations were least
  susceptible), 2.5 mortality rates in most
  populations, 70 in some isolated populations,
  Morbidity ranged from 20-50
• 30 million deaths worldwide in about 6 months
  (10,000 deaths/wk in some US cities/675,000
  deaths in 1918 in the US), 40 million by 1919.
• In one army camp, hospital admissions jump from
  80 to gt1,000 day in 8 days
• Average life expectancy in the US is depressed by
  more than 10 years
• Economic Paralysis, High mortality in health care
  workers, Hospitals swamped
• Human Population in 2003 is about 8X that of
  1918, SARS mortality is hovering around 5.6. Do
  the Math, the potential economic and social
  consequences are horrific!
• Unknowns asymptomatic rate vs.
  misclassification, aerosol transmission?,
  evolution of new pathogenic strains with
  altered/increased transmissibility? Will SARS
  cause the next great pandemic or will it
  disappear?

139
Projected Health Impact of the Next Flu Pandemic
on the U.S.

• Estimated Averages
• Deaths . . . . . . . . . . . . . . . . . . . . .
  . . . . . . . . . . . . . . . . . . . . 89,000
  - 207,000
• Hospitalizations . . . . . . . . . . . . . . . .
  . . . . . . . . . .. . 314,00 - 734,000
• Outpatient Clinic Visits . . . . . . . . . .
  18 - 42 million
• Sick at Home . . . . . . . . . . . . . . . . . .
  . . . . . . . . . . . . . . . . . 20 47 million

Mortality rate of 0.1 equals 250,000 deaths
in the US Spanish Flu mortality rates hovered
around 2.5 in 1918.
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REFERENCES

• www.cdc.gov/ncidod/sars/ CDC SARS page
• http//www.who.int/csr/sars/en/ WHO SARS
  page
• Poutanen SM, et al. Identification of severe
  acute respiratory syndrome in Canada. NEJM
  (electronic)
• Lee N, et al. A major outbreak of severe acute
  respiratory syndrome in Hong Kong. NEJM
  (electronic)
• Ho W. Guideline on management of severe acute
  respiratory syndrome (SARS). Lancet (electronic)

141
REFERENCES

• Drosten C, et al. Identification of a novel
  coronavirus in patients with severe acute
  respiratory syndrome. NEJM (electronic)
• Ksiazek TG, et al. A novel coronavirus
  associated with severe acute respiratory
  syndrome. NEJM (electronic)
• Pennis JSM, et al. Coronavirus as a possible
  cause of severe acute respiratory syndrome.
  Lancet (electronic)
• Twu S-J, et al. Control measures for severe
  acute respiratory syndrome (SARS) in Taiwan. EID
  20039