SARS: An Emerging Infectious Disease

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SARS An Emerging Infectious Disease

• June 11, 2003
• Edward L. Goodman, MD

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Emerging Infectious DiseasesInstitute of
Medicine Definition

• New, reemerging or drug-resistant infections
  whose incidence in humans has increased within
  the past two decades.

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Major Factors Contributing to EID

• Human demographics and behavior
• Technology and industry
• Economic development and land use
• International travel and commerce
• Microbial adaptation and change
• Breakdown of public health measures

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Emerging Infectious Diseases USA 1996 - 2003

• Ebola in non human primates, Texas
• Racoon rabies, Ohio
• Cyclospora gastroenteritis, multiple states
• Non imported Malaria, Georgia and Florida
• E coli 0157H7 in apple juice, multiple states
• West Nile Virus 1999, NY and now nationwide
• Anthrax 2001 Fla., NYC, DC, NJ
• Monkeypox Prairie Dogs to Humans 2003 Wisc

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Goals of todays presentation

• Show the power of epidemiology
• Case definition/revisions
• Descriptive epidemiology
• Geographic Variation
• Clinical findings
• Infection Control Recommendations
• Even before knowing an etiology
• Show the extent of modern microbiology
• Virology
• Gene detection technology
• Serology

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Epidemiology

• The science of studying diseases in populations
• Examples
• Cholesterol and CAD
• Smoking and lung cancer
• Tampons and TSS before Staph identified
• Defined risk groups for AIDS before HIV
  identified
• Draws conclusions on transmission and control
  even when etiology not known

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Epidemiologic Investigation of an Apparent
Outbreak

• Preliminary Case Definition
• Compare Features of Cases to Non-cases
• Refine Case Definition
• Case-control studies
• Refine Case Definition multiple times
• Investigate Etiology in refined definition group
• Define Clinical Features
• comparing proven to unproven cases

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Case Report
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Radiology of typical caseLee NEJM 4/7/04
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Initial signs of a worldwide outbreak

• February 11, 2003
• Respiratory illness in Guangdong province, China
• 305 cases, 5 deaths since November 16, 2002
• February 26March 12, 2003
• Disease spreads to large number of health care
  workers in Hong Kong and Vietnam
• March 12, 2003
• Global alert for Severe Acute Respiratory
  Syndrome (SARS)
• CDC offers assistance to the WHO

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Preliminary Case DefinitionMarch 19, 2003
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Epidemics Within Epidemics

• HIV
• Predominantly MSM/IVDU in US and Europe
• Predominantly heterosexual in Africa
• Lyme Borreliosis
• Predominantly joint disease in US
• Disproportionately CNS disease in Europe

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Epidemics within Epidemics

• SARS
• Asia and Canada
• Healthcare Workers and families
• USA
• Mostly imported from Asia
• Little transmission

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The Hong Kong connectionHotel M
February
March
A B C D E F G H I J K L M
Onset of symptoms
Stayed at Hotel M
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The Hong Kong connectionHotel M
February
March
A B C D E F G H I J K L M
Onset of symptoms
Stayed at Hotel M
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The Hong Kong connectionHotel M
February
March
A B C D E F G H I J K L M
Onset of symptoms
Stayed at Hotel M
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Spread from Hotel M Reported as of March 28, 2003
Guangdong Province, China
A
A
Hotel MHong Kong
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Epidemic Curve Hong Kong
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Clinical Features Hong Kong
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Estimated Mortality Hong Kong

• Patients lt 60 years old 13.2 (9.8-16.8)
• Patients gt 60 years old 43.3 (35.2-52.4)
• By comparison, the mortality from Influenza in
  1918 was 1!
• Lancet on line. May 7, 2003

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SARS in CanadaPoutenan et al. NEJM May 15, 2003
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Timeline linked Candadian cases
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SARS in Greater Toronto AreaJAMA June 4, 2003
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Epidemic Curve Worldwide
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Epidemic Curve USA May 30363 cases
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CDC Update June 4, 2003

• WHO reports 8402 cases from 29 countries
• November 1, 2002 June 4, 2003
• 772 deaths (9.2 CFR)
• US and PR Cases 373, no deaths
• 67 probable, 306 suspect
• 65/67 attributed to international travel
• One each HCW and household contact

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Clinical Characteristics of Suspect SARS Cases
United States, 2003
Characteristics N100 Median Fever
( Range) 101.60F (100.4-104.50F) Cough 94
Shortness of Breath 40 Documented
Pneumonia 29 Hospitalized gt24
hours 39 Acute Respiratory Distress
Syndrome 1 Ventilated 1
Died 0

Denominators may vary due to missing information
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Finding the Pathogen

• Pathology
• Virology
• Gene detection
• Classification
• Diagnostics

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What are Coronaviruses?

• Taxonomy
• Order Nidovirales
• Family Coronaviridiae
• Genus Coronavirus
• Structure large, enveloped, positive-stranded
  RNA
• Genome 30,000 nucleotides, the largest of any
  RNA virus

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Structure
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More than you want to know!

• Group 1 and 2 are mammalian
• Group 3 are avian
• Major veterinarian pathogens
• Infectious bronchitis virus
• Feline infectious peritonitis virus
• Transmissible gastroenteritis virus

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Enough already!

• Human coronavirus infections
• Group 1 and 2
• 30 of common cold viruses
• SARS human coronavirus (SARS-CoV)
• Urbani strain, named after Italian physician who
  succumbed to this virus
• Distinct from other CoV

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Relatedness to other Coronaviruses
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Clinical Aspects of Severe Acute Respiratory
Syndrome (SARS)

• Incubation period 2-10 days
• Onset of fever, chills/rigors, headache,
  myalgias, malaise
• Respiratory symptoms often begin 3-7 days after
  symptom onset

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Symptoms Commonly Reported By Patients with
SARS1-5

• Symptom Range ()
• Fever 100
• Cough 57-100
• Dyspnea 20-100
• Chills/Rigor 73-90
• Myalgias 20-83
• Headache 20-70
• Diarrhea 10-67

1. Unpublished data, CDC. 2. Poutanen SM, et al.
NEJM 3/31/03. 3. Tsang KW, et al. NEJM. 3/31/03
4. Peiris JSM, et al. Lancet 4/8/03 5. Lee N. et
al NEJM 4/7/03
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Symptoms Reported by Patients With Diagnostic
SARS-CoV Laboratory Testing, United States, 2003
Symptom Coronavirus Positive (n6) Coronavirus Negative (n28)
Fever 100 96
Cough 100 93
Dyspnea 100 61
Myalgias 83 75
Chills/Rigor 83 68
Headache 67 68
Diarrhea 67 25
Coryza 17 43
Sore Throat 17 43
p.07
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Common Clinical Findings in Patients with SARS1-5
Finding Range ()
Examination Rales/Rhonci Hypoxia 38-90 60-83
Laboratory Leukopenia Lymphopenia Low platelet Increased ALT Increased LDH Increased CPK 17-34 54-89 17-45 23-78 70-94 26-56
1. Unpublished data, CDC. 2. Booth CM, et al.
JAMA 5/6/03. 3. Tsang KW, et al. NEJM. 3/31/03
4. Peiris JSM, et al. Lancet 4/8/03 5. Lee N. et
al NEJM 4/7/03
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Clinical Findings in Patients With Diagnostic
SARS-CoV Laboratory Testing, United States, 2003
Symptom Coronavirus Positive (n6) Coronavirus Negative (n28)
Examination Rales/rhonci 83 23
Hypoxia 83 29
Infiltrates 100 30
Laboratory Leukopenia 17 5
Lymphopenia 83 53
Low platelets 17 5
Increased ALT 60 17
plt.05
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Radiographic Features of SARS

• Infiltrates present on chest radiographs in gt
  80 of cases
• Infiltrates
• initially focal in 50-75
• interstitial
• Most progress to involve multiple lobes,
  bilateral involvement

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Lee N. et al NEJM 4/7/03
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Lee N. et al NEJM 4/7/03
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Clinical Outcome of Patients with SARS, 2003
n Progression to Resp. Failure ()
U.S.1 6 17
Canada2 144 14
Hong Kong3 10 20
Hong Kong4 50 38
Hong Kong5 138 14
Singapore1 178 12
1. Unpublished data, CDC. 2. Booth CM SM, et al.
JAMA 5/6/03. 3. Tsang KW, et al. NEJM. 3/31/03 4.
Peiris JSM, et al. Lancet 4/8/03 5. Lee N. et al
NEJM 4/7/03
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Clinical Outcome of Probable SARS Cases, 2003
n Case Fatality Proportion()
U.S. 65 0
Canada 146 15
Hong Kong 1654 12
Singapore 178 13
http//www.who.int/csr/sarscountry/2003_05_07/en
/
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Clinical Features Associated with Severe Disease

• Older Age
• Underlying illness
• ? Lactate dehydrogenase levels
• ? Severe lymphopenia

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Transmission

• Probable major modes of transmission
• Large droplet aerosolization
• Contact
• Direct
• Fomite
• Airborne transmission cannot be ruled out
• ? Role of aerosol-generating procedures
• ? Fecal-oral
• Transmission efficiency may vary among individuals

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SARS Virus Survival

• Survive on plastic surfaces up to 48 hours
• Survival in feces 2 days (solid) 4 days
  (loose)
• Survival in urine at least 24 hours
• Source WHO May 5, 2003

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Diagnostic Approach to Patients with Possible SARS

• Consider other etiologies
• Diagnostic workup
• Chest radiograph
• Blood and sputum cultures
• Pulse oximetry
• Testing for other viral pathogens (e.g.
  influenza)
• Consider urinary antigen testing for Legionella
  spp. and Streptococcus pneumoniae

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Diagnostic Approach to Patients with Possible SARS

• Diagnostic workup (continued)
• Save clinical specimens for possible additional
  testing
• Respiratory
• Blood
• Serum
• Acute and convalescent sera (gt21 days from
  symptom onset) should be collected
• Contact Local and State Health Departments for
  SARS-CoV testing

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Treatment of Patients with SARS

• Most effective therapy remains unknown
• Optimize supportive care
• Treat for other potential causes of
  community-acquired pneumonia of unknown etiology

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Treatment of Patients with SARS

• Potential Therapies Requiring Further
  Investigation
• Ribavirin
• ?other antiviral agents
• Immunomodulatory agents
• Corticosteroids
• Interferons
• Others?

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Infection Control

• Early recognition and isolation is key
• Heightened suspicion
• Triage procedures
• Transmission may occur during the early
  symptomatic phase
• Potentially before both fever and respiratory
  symptoms develop

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Infection Control

• Isolation
• Hand hygiene
• Contact Precautions (gloves, gown)
• Eye protection
• Environmental cleaning
• Airborne Precautions (N-95 respirator, negative
  pressure)

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Why Such Variation in Epidemiology and Outcome?

• Viral variation?
• Genetic host susceptibility?
• Prevalence of smoking?
• In adequate Infection Control Measures?

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Isolation

• Major thrust of Infection Control at PHD
• Constant education
• Intranet updates
• Constant surveillance
• Categories
• Standard Precautions
• Airborne
• Respiratory
• Contact

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Standard Precautions

• Default category
• All patients assumed to have a blood borne
  pathogen
• Gloves for contact with body fluids, excretions
• No special signs or equipment except gloves
  available

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Airborne Precautions

• Droplet nuclei travel long distances
• Proper size to be deposited in alveoli
• Tuberculosis, Varicella or disseminated Zoster,
  Smallpox and now SARS (4/03)
• Negative pressure rooms
• N 95 respiratory masks for HCW
• Fit tested to each individual
• Standard surgical masks for patients when out of
  room

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Respiratory

• Larger particles travel short distance
• Trapped in upper airway, mucociliary defense
• Meningococci, Mycoplasma, Measles
• Standard surgical masks
• Regular rooms

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Contact Isolation

• Draining wounds not covered by dressings
• Environmentally stable organisms
• Clostridum difficile (spores)
• VRE
• Multi-drug resistant bacteria
• MRSA
• VRE environmentally stable
• ESBL producing GNR
• Epidemiologically important apparent clusters
• Group A Strept infections (Clinical Inf Dis Dec
  2002)

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Contact - continued

• Components
• Gloves upon entering room
• Hand washing prior to leaving room
• Gowns for
• Contact with excreta/secretions
• Environmentally stable (VRE, C. diff.)
• Many institutions require gowns for all Contact
  Isolation
• Computerized tracking for future readmissions

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Infection Control
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Outpatient Infection Control
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Home Measures
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A Word About Quarantine

• Complex legal process
• Poorly understood by lay public
• Rarely invoked
• Hard to enforce

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Every medication has 2 effects. . .

1. The one you dont want

1. The one you want

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Quarantine/Isolation
Individual liberties Economic loss Social
isolation Social Stigma
Limit transmission
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Quarantine/Isolation unintended consequences?
Limiting transmission
Maintaining transmission e.g., HIV, leprosy
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EXECUTIVE ORDER 13295 REVISED LIST OF
QUARANTINABLE COMMUNICABLE DISEASES

• Cholera Diphtheria infectious Tuberculosis
  Plague Smallpox Yellow Fever and Viral
  Hemorrhagic Fevers
• (Lassa, Marburg, Ebola, Crimean-Congo, South
  American,
• and others not yet isolated or named).
• (b) Severe Acute Respiratory Syndrome (SARS),
  which is a disease associated with fever and
  signs and symptoms of pneumonia or other
  respiratory illness, is transmitted from person
  to person predominantly by the aerosolized or
  droplet route, and, if spread in the population,
  would have severe public health consequences.

President George W. Bush April 4, 2003
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What Next

• Rapid Diagnostic Tests (at present only at CDC)
• Antigen detection
• Gene detection PCR
• Serology (ELISA and IFA)
• Seroepidemiology
• Prevalence of antibody in healthy persons 0
• Is there asymptomatic seroconversion?
• Does antibody confer immunity?

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What Next?

• Expect epidemic curve to peak and die out
• Warmer weather should reduce transmission
• Fewer susceptibles in community
• Likely another epidemic in 2004
• Since genome sequenced
• Expect progress on determining protective
  epitopes, thus leading to
• Candidate Vaccine trials

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Therapy

• Supportive
• Antimicrobial
• Treat treatable causes of CAP
• IDSA 2000 Guidelines
• Broaden the diagnostic work up of suspect cases
• No proven effective anti-viral therapy
• Ribavirin used in uncontrolled studies
• Steroids used in uncontrolled studies

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Summary
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In Memory
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Bibliography

• http//www.cdc.gov/ncidod/sars/
• http//www.who.int/csr
• Donnelly CA et al. Epidemiological determinants
  of spread of causal agent of SARS in Hong Kong.
• Lancet on line May 7, 2003
• Ksiazek T. G. et al. A Novel Coronavirus
  Associated with Severe Acute Respiratory
  Syndrome. NEJM 2003 www.nejm.org. Apr 10, 2003

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• Lee N. et al. A Major Outbreak of Severe Acute
  Respiratory Syndrome in Hong Kong. N Engl J Med
  2003 published at www.nejm.org on Apr 7, 2003
• Rota PA, Oberste MS et al.Characterization of a
  Novel Coronavirus Associated with Severe Acute
  Respiratory Syndrome. Science Online 30 April
  2003.
• Seto W H, D Tsang et al. Effectiveness of
  precautions against droplets and contact in
  prevention of nosocomial transmission of severe
  acute respiratory syndrome (SARS). Lancet
  20033611519-20.