Severe Acute Respiratory Syndrome (SARS) David S. Stephens MD

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Severe Acute Respiratory Syndrome (SARS)David S.
Stephens MD

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Age of Aquarius

• One can think of the middle of the 20th century
  as one of the most important social revolutions
  in history- the elimination of the infectious
  disease as a significant factor in social life
• Sir Frank MacFarland Burnet 1962, 1960 Nobel
  Laureate for Medicine
• Infectious Diseases will be eliminated as a
  major threat to human health
• US Surgeon General 1967

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Microbial Evolution

• Ignored historical and ecological data that
  emergence and reemergence of infections have been
  common place in nature throughout evolution
• Plague - Hepatitis C - Diphtheria
• Anthrax - Dengue - Helicobacter
• HIV - EBOLA - Hantavirus
• Lyme - Legionnaires Disease - West Nile

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Factors in Emergence and Reemergence of Infections

• Microbial Mutation and Horizontal Recombination
• Rapid generation time and high copy number
• 3.8 billion years of microbial evolution and
  diversity
• The vast majority of microorganisms remain
  uncultured and unknown
• Urbanization and Land Use
• Globalization and Population Growth
• Environmental and Social Changes

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Severe Acute Respiratory Syndrome (SARS)

• Emergence
• Clinical Features
• Pathogenesis
• Transmission and Infection Control
• Treatment
• The Future

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Severe Acute Respiratory Syndrome (SARS)

• Atypical pneumonia/ARDS caused
• by a newly identified coronavirus
• First recognized in Hanoi, Vietnam
• on February 26th, 2003 by Dr Carlo Urbani.
• As of June 6th, WHO had received reports of 8404
  cases of probable SARS from China, Hong Kong
  Special Administrative Region of China, Canada,
  Vietnam, Singapore, Thailand, United States and
  22 other countries.
• Thus far 779 people have died and 5937 have
  recovered (11.6 mortality).

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PATIENT A

• Physician from Guangdong province China
• Onset of symptoms on February 15, 2003
• Visit to relatives in Hong Kong 21 February
• Stayed in Hotel M in Room 911
• Admitted to Hong Kong Hospital 22 February and
  died the next day
• 12 patients in Hotel M, 2 family members and 4
  Health Care Workers infected

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Patient B

• 47 YO Asian-American textile businessman stayed
  on 9th floor at Hotel M on 21 February
• On February 23rd traveled to Hanoi and became ill
  on February 26th was admitted to a hospital in
  Hanoi with high fever, dry cough, myalgias and
  mild sore throat. Over the next 4 days he
  developed increasing respiratory difficulties,
  thrombocytopenia and then ARDS.
• He was transferred to a hospital in Hong Kong but
  died on March 12th, 2003

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• On March 5th, 2003, seven healthcare workers who
  had cared for the patient B in Hanoi also became
  ill

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Spread from Hotel M MMWR 2003
52(12)241
Guangdong Province, China
A
A
Hotel MHong Kong
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SARS Cases Worldwide Reported to WHO as of June
6, 2003
Europe 8 countries (38)
Canada (219)
U.S. (68)
China (5329)
Hong Kong (1750)
Vietnam (63)
Taiwan (676)
SA (2)
Singapore (206)
Thailand (8)
AustraliaNZ (6)
Total 8404 cases 779 deaths (10case fatality)
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Donnelly, Lancet.com May 7, 2003
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Masked shop owner in Amoy Gardens complex
photo by Christian Keenan
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Timeline of SARS Cases in Canada
NEJM 20033481995
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SARS cases by date of hospitalization,
SingaporeFeb 25Mar 22, 2003
Data provided by WHO
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68 Reported Cases of Probable SARS, United
States through June 5, 2003
2
3
9
1
MA 2
2
1
1
2
1
CT 3
1
3
21
1
3
2
NJ 1
2
2
1
1
1
1
1
1
4
HI 2
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SARS - Clinical Features

• Asymptomatic or mild respiratory illness
• Moderate respiratory illness
• Temperature of gt100.4º F (gt38º C), and
• One or more clinical findings of respiratory
  illness (e.g., cough, shortness of breath,
  difficulty breathing, or hypoxia).
• Severe respiratory illness
• Fever and respiratory symptoms as above and
• radiographic evidence of pneumonia, or
• respiratory distress syndrome, or
• autopsy findings consistent with pneumonia or
  respiratory distress syndrome without an
  identifiable cause

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SARS Clinical presentation

• Incubation period 2-7(10) days
• Patients abruptly develop high fever (gt38 C),
  chills and rigors and other and flu-like symptoms
  including headache, myalgias followed in 3-7 days
  by symptoms of respiratory illness including
  cough, shortness of  breath and hypoxia.
• Radiographic findings can be initially normal or
  those of patchy pneumonia which may progress to
  bilateral infiltrates and ARDS.

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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

• 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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SARS Diagnostic evaluation

• Chest x-ray
• O2 saturation
• Blood cultures
• Sputum Gram stain and culture
• Testing for bacterial and viral respiratory
  pathogens
• Influenza A and B and RSV
• Legionella, C. pneumoniae, mycoplasma, etc
• Save clinical specimens for possible additional
  testing
• Respiratory, Blood, Serum
• Acute and convalescent sera (gt21 days from
  symptom onset)

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SARS Laboratory findings

• Hypoxemia
• Leucopenia with lymphopenia
• Thrombocytopenia
• Transaminase elevation (ALT/AST 1-3 times upper
  limit of normal)
• CPK elevation
• LDH elevation

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Common Clinical Findings in Patients with SARS1-5

• Finding Range ()
• Examination
• Rales 38-90
• Hypoxia 60-83
• Laboratory
• Leukopenia 17-34
• Lymphopenia 54-89
• Low platelet 17-45
• Increased ALT 23-78
• Increased LDH 70-94
• Increased CPK 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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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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NEJM Lee et al. 348 (20) 1986
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Evolution of Radiographic Findings
NEJM Lee et al. 348 (20) 1986
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NEJM, Ksiazek et al. 2003348 1953
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Coronaviruses

• Single Strand RNA, nonsegmented, enveloped,
  31,000 bps
• Order Nidovirales
• Family Coronaviridae
• Torovirus and Coronavirus Grp I, Grp II, Grp
  III
• 229E and OC43 in humans cause 1/3 of common
  colds , reinfections common
• May remain viable for several hours after drying
  on surfaces

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Relative Size of Coronaviruses Compared to Other
Microbes
NY Times 4/27/03
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Structure of Coronavirus Virion
-
The spike glycoproteins create corona, bind and
fuse with host cell membranes
Holmes, NEJM 2003348 1948
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Coronavirus Biology and Disease General Themes

• Recurrent / repeated infections
• Prolonged or persistent virus shedding
• Direct viral and immune mediated disease
• loose species barrier cross infections
  (natural or experimental)

M Denison Vanderbilt
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Coronavirus Molecular Biology General Themes

• High mutation rate 104 per template per
• replication (3 changes per genome)
• RNA-RNA homologous recombination
• Result rapid adaptation, recovery from
  deleterious mutations, mechanisms to acquire and
  regain virulence.

M Denison, Vanderbilt
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Coronaviruses, Hosts and Diseases

• Antigenic
• Group Virus Host Respiratory Enteric
  Other
• I HCoV-229E human X
• TGEV pig X
• PRCoV pig X
• FIPV cat X X
  X
• FECoV cat X
• CCoV dog X
• II HCoV-OC43 human X ??
• MHV mouse X X
  X
• RCoV rat X X
• HEV pig X X
• BCoV cattle X X
• III IBV chicken X X
• TCoV turkey X

CDC
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nucleus
M Denison, Vanderbilt
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Genome Organization
A
E
1a
29,727 nt
S
1b
N
M
1
5,000
10,000
15,000
20,000
25,000
30,000
B
20,001
30,000
25,000
X1
X3
E
N
M
X2
X4
S
X5
8.3 kb
RNA 2
4.5 kb
RNA 3
3.4 kb
RNA 4
RNA 5
2.5 kb
1.7 kb
RNA 6
- Replicases (1a/1b) structural genes
(S,E,M,N) - Multiple small genes (X1-X5)-these
vary in number, location, and sequence in
different coronaviruses
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• SARS-CoV is similar in general genome
  organization
• to other coronaviruses
• SARS-CoV is genetically distinct from other known
  coronaviruses
• Structural proteins are lt 40 identical
• Replicase proteins are lt 70 identical
• SARS-CoV nsps are not homologous to known
  proteins
• Specific RT-PCR assays will allow the rapid and
  sensitive
• detection of the virus, aiding in control

CDC Enterovirus Reference Laboratory
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• - Distinct from other known coronaviruses
• Neither a mutant nor recombinant
• Previously unknown, probably from a nonhuman
  host, has acquired the ability to infect humans.
  

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Evidence that Urbani Coronavirus is the Etiology
of SARS

• Culture of novel coronavirus from SARS patients
  in multiple sites worldwide
• Identical Sequence
• EMs from BAL and lung showing coronavirus
• PCR finding novel coronavirus nucleic acid
• Antibody response specific to novel coronavirus,
  sera from other human coronaviruses show no
  reaction
• Infection re-produced in primate animal model

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CIVET CAT

• Nocturnal
  Animal
• Related To Mongoose
• Delicacy in Southern
  China

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NY Times 4/27/03
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SARS ASSOCIATED NOVEL CORONAVIRUS

• Previously unrecognized coronavirus
• Genetically distinct from human (229E)or known
  animal coronaviruses
• Phylogeny between bovine coronavirus and avian
  infectious bronchitis virus
• Animal reservoir, civets other animals?

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Diagnosis

• Confirmed Case
• Detection of antibody to SARS-CoV in specimens
  obtained during acute illness or gt21 days after
  onset, or
• Detection of SARS-CoV RNA by RT-PCR confirmed by
  a second PCR assay, or
• Isolation of SARS-CoV
• Probable Case
• Suspected Case

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RT-PCR Urbani SARS Coronavirus

• Real Time PCR (Orf 1B)
• Sputum 108 molecules/ml (DAY 9)
• Plasma 100 molecules/ml (Day 9)
• Feces (Day 25)
• Drosten et al. NEJM April 10, 2003

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Viral Shedding in Nasopharyngeal Secretions
Peiris J, et al. Lancet.com 5/9/03
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SARS-CoV Antibody Assays

• Very low or absent antibody in controls and
  persons without acute SARS
• Interpretation of results
• Single positive sera indicative of acute
  infection
• Acute sera may be positive as early as 6 days
  after onset of symptoms
• Convalescent sera should be positive by 21-28
  days after onset

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Transmission

• Animal to Human
• Human to Human
• Large Respiratory Droplet Nuclei
• Contact with objects contaminated with secretions
• Airborne?, aerosol generating procedures
• Fecal Oral?
• Super spreaders (sheaders?)
• Other

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Probable SARS cases by reported source of
infection, --- Singapore February 25--April 30,
2003 MMWR 200352405

• MMWR 200352405

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SARS Travel History

• Thus far US patients have
• A history of travel to Hong Kong, Taiwan,
  People's Republic of China, Toronto, Singapore,
  Hanoi within ten days of symptom onset.
• Close contact with persons with respiratory
  illness having the above travel history. (Close
  contact includes having cared for, having lived
  with, or having had direct contact with
  respiratory secretions and body fluids of a
  person with SARS).
• Community Transmission, not in US

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SARS- Infection Control

• Most HCW transmission occurred without proper
  barrier precaution
• Early recognition and isolation is key
• Heightened suspicion
• Triage procedures
• Transmission may occur during the early
  symptomatic phase, ? before both fever and
  respiratory symptoms develop

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SARS Infection Control

• Put a surgical mask on the patient and place on
  respiratory (negative pressure room and use of
  N-95 respirator masks for anyone entering the
  room) and contact precautions (gown, gloves,
  goggles for contact with the patient). Hand
  hygiene
• In some settings ninety percent of the most
  recent cases have been among healthcare workers.
• Hospital epidemiology and infectious diseases
  should be notified immediately.

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A thermal sensor checks passenger temperatures at
an airport in Guangdong province
NY Times 4/27/03
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Selling masks near Vancouver airport
AP photo - Chuck Stoody
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Sars-Infection Control

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

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SARS

• RISKS FOR DISEASE SEVERITY
• CO-INFECTIONS
• TREATMENT
• Antiviral
• Immune modulation

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RISK FACTORS FOR PROGRESSION OF SARS

• AGE gt40, gtgt50 years
• Underlying Disease (Diabetes, Heart Disease, Lung
  Disease, Smoking?)
• Hypoxia at Presentation lt95,ltlt90 O2 Saturation
• Progressive Pulmonary Infiltrates
• Elevated LDH gt350 U/L, CPK gt500U/L, Decreased
  Platelet Count lt150,000 cu3/ml

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Co-Infections ?

• Paramyxovirus
• Metapneumovirus
• Rhinovirus
• Chlamydia pneumoniae

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SARS - Treatment

• A variety of antiviral (ribavirin, neuraminidase
  inhibitors, etc), antimicrobials (levoquin,
  ceftriaxone, azithromycin, doxycycline, etc) as
  well as corticosteroids have been used.
  Immunoglobulin preparation from convalescent
  patients

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SARS and RIBAVIRIN

• No in vitro activity or ribavirin, at 100 ug/ml
  or greater concentrations, against SARS
  coronavirus

Huggins et al USAMRID
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INTERFERON

• Intranasal interferon aA administered to people
  prior to infection with coronavirus 229E reduced
  the severity of illness and viral replication
  Higgins PG, 1983. No studies have evaluated
  systemic interferon.

Huggins et al USAMRID
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OTHER SARS ANTIVIRALS?

• Other compounds that have shown activity against
  selected coronavirus strains by in vitro or in
  vivo animal studies include hygromycin B,
  monolaurin, 7-thia-8-oxoguanosine,
  cyclopentenylcytosine, and cystatin A and D
  Macintyre G, 1991 Hierholzer JC, 1982 Higgins
  PG, 1991 Smee DF, 1990 Smee DF, 1990 DeClercq
  F, 1991 Collins AR, 1998 Collins AR, 1991.
• None of these compounds have formulations that
  would be available for use soon and further
  evaluation would be needed regarding their
  specific activity against coronaviruses and
  potential toxicity

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Immune Modulation

• Ribravirin??
• Macrolides??
• Steroids
• Broncholitis Obliterans Organizing Pneumonia
  (BOOP)
• Acute Interstitial Pneumonia
• ARDS
• Gamma Globulin
• Convalescent Immune Globulin

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SARS Treatment

• No control data regarding therapy
• No specific therapy has been shown to be
  effective
• No in vitro activity of ribravirin against SARS
  coronavirus
• Interferon beta may have activity
• Immunomodulation of uncertain benefit
• Cover for typical and atypical causes of
  pneumonia

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SARS- The Present

• Transmissible respiratory infection with no
  effective vaccine or drugs
• Recognition and Interruption of transmission is
  key
• Identify and isolate infected persons
• Has potentially to become endemic
• Aggressive and sustained infection control
• Voluntary isolation and quarantine are
  inconvenient, but have the potential to save
  lives and they will work to control spread

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SARS- The Future

• Rapid Diagnostic Test, Sensitive RT-PCR
• Antiviral Therapy, cysteine proteinase
  inhibitors?
• Identification of Super spreaders, transmission
  routes, period of infectiousness
• Spectrum of Disease influenza, co-infections
• Vaccine
• Understanding why species jump occurred

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