Download Severe Acute Respiratory Syndrome

Severe Acute Respiratory
Syndrome (SARS)
David S. Stephens MD
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
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
- Legionnaire’s Disease - West Nile
Factors in Emergence and
Reemergence of Infections
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Microbial Mutation and Horizontal Recombination
–
–
–
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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
Severe Acute Respiratory
Syndrome (SARS)
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Emergence
Clinical Features
Pathogenesis
Transmission and Infection Control
Treatment
The Future
Severe Acute Respiratory
Syndrome (SARS)
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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).
PATIENT A
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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
Patient B
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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

On March 5th, 2003, seven healthcare workers
who had cared for the patient B in Hanoi also
became ill…
Spread from Hotel M
MMWR 2003; 52(12):241
Canada
Guangdong
Province,
China
F,G
A
F,G
18 HCW
11 close contacts
A
Hotel M
Hong
Kong
A
Hong Kong SAR
95 HCW
H,J
H,J
K
B
Ireland
K
0 HCW
I, L,M
C,D,E
I,L,M
>100 close contacts
B
C,D,E
Vietnam
Singapore
37 HCW
34 HCW
21 close contacts
37 close contacts
United
States
1 HCW
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)
SA (2)
Vietnam (63)
Thailand (8)
Taiwan (676)
Singapore (206)
Australia&NZ (6)
Total: 8404 cases; 779 deaths (~10%case fatality)
Donnelly, Lancet.com May 7, 2003
Masked shop owner in Amoy Gardens
complex
photo by Christian Keenan
Timeline of SARS Cases in Canada
NEJM 2003;348;1995
SARS cases by date of hospitalization, Singapore*—Feb
25–Mar 22, 2003
7
No. of cases
6
5
Tertiary(6)
Secondary(16)
Primary(19)
Index(3)
4
3
2
1
* Data provided by WHO
Date of onset
ar
19
-M
ar
17
-M
ar
15
-M
ar
13
-M
ar
11
-M
ar
9M
ar
7M
ar
5M
ar
3M
b
ar
1M
27
-F
e
25
-F
e
b
0
68 Reported Cases of Probable SARS, United States
through June 5, 2003
2
3
1
9
2
MA 2
1*
21*
1*
3
1
2
1
1
3*
2
2
2
1
1*
1
1
1
1
4
HI 2
CT 3
NJ 1*
SARS - Clinical Features
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Asymptomatic or mild respiratory illness
Moderate respiratory illness
– Temperature of >100.4º F (>38º 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
SARS – Clinical presentation
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Incubation period 2-7(10) days
Patients abruptly develop high fever (>38° 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.
Symptoms Commonly Reported By
Patients with SARS1-5
Symptom
Fever
Cough
Dyspnea
Chills/Rigor
Myalgias
Headache
Diarrhea
1.
Range (%)
100
57-100
20-100
73-90
20-83
20-70
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
SARS – Diagnostic evaluation
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Chest x-ray
O2 saturation
Blood cultures
Sputum Gram stain and culture
Testing for bacterial and viral respiratory
pathogens:
–
–
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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 (>21 days from
symptom onset)
SARS – Laboratory findings
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Hypoxemia
Leucopenia with lymphopenia
Thrombocytopenia
Transaminase elevation (ALT/AST 1-3 times
upper limit of normal)
CPK elevation
LDH elevation
Common Clinical Findings in Patients with
SARS1-5
Finding
Examination
Rales
Hypoxia
Laboratory
Leukopenia
Lymphopenia
Low platelet
Increased ALT
Increased LDH
Increased CPK
Range (%)
38-90
60-83
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
Radiographic Features of SARS
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Infiltrates present on chest radiographs in > 80%
of cases
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Infiltrates
– initially focal in 50-75%
– interstitial
– Most progress to involve multiple lobes, bilateral
involvement
NEJM Lee et al. 348 (20): 1986
Evolution of Radiographic
Findings
NEJM Lee et al. 348 (20): 1986
NEJM, Ksiazek et al.
2003;348: 1953
Coronaviruses
Single Strand RNA, nonsegmented, enveloped,
~31,000 bps
Order: Nidovirales
Family: Coronaviridae
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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
Relative Size of Coronaviruses
Compared to Other Microbes
NY Times 4/27/03
Structure of Coronavirus Virion
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The spike glycoproteins create corona, bind
and fuse with host cell membranes
Holmes, NEJM 2003;348: 1948
Coronavirus Biology and Disease: General
Themes
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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
Coronavirus Molecular Biology:
General Themes
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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
Coronaviruses, Hosts and Diseases
Antigenic
Group Virus
I
II
III
Host
Respiratory
HCoV-229E
TGEV
PRCoV
FIPV
FECoV
CCoV
human
pig
pig
cat
cat
dog
X
HCoV-OC43
MHV
RCoV
HEV
BCoV
human
mouse
rat
pig
cattle
X
X
X
X
X
IBV
TCoV
chicken
turkey
X
Enteric
Other
X
X
X
X
X
X
??
X
X
X
X
X
X
X
X
CDC
release
attachment
entry
translation
mRNA synthesis
replication
maturation
assembly
nucleus
M Denison,
Vanderbilt
Genome Organization
A
E
1a
1b
5,000
1
10,000
15,000
S
20,000
M
25,000
29,727 nt
N
30,000
B
20,001
25,000
30,000
X1
E
X3
M
S
X2
N
X4 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
CDC
SARS-CoV is similar in general genome organization
to other coronaviruses
SARS-CoV is genetically distinct from other known coronaviruses
–Structural
proteins are < 40% identical
–Replicase proteins are < 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.
Evidence that Urbani Coronavirus
is the Etiology of SARS
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Culture of novel coronavirus from SARS patients in
multiple sites worldwide
Identical Sequence
EM’s 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
CIVET CAT
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Nocturnal Animal
Related To Mongoose
Delicacy in Southern
China
NY Times 4/27/03
SARS ASSOCIATED NOVEL
CORONAVIRUS
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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?
Diagnosis
Confirmed Case
 Detection of antibody to SARS-CoV in
specimens obtained during acute
illness or >21 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
RT-PCR Urbani SARS Coronavirus
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Real Time PCR (Orf 1B)
Sputum 108 molecules/ml (DAY 9)
Plasma 100 molecules/ml (Day 9)
Feces + (Day 25)
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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
SARS-CoV Antibody Assays
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Very low or absent antibody in controls and
persons without acute SARS
Interpretation of results
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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
Transmission
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Animal to Human
Human to Human
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Large Respiratory Droplet Nuclei
Contact with objects contaminated with secretions
Airborne?, aerosol –generating procedures
Fecal Oral?
Super spreaders (sheaders?)
Other
Probable SARS cases by reported source
of infection,* --- Singapore
February 25--April 30, 2003
MMWR 2003;52:405
MMWR 2003;52:405
SARS – Travel History
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Thus far US patients have:
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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
SARS- Infection Control
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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
SARS – Infection Control
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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.
A thermal sensor checks passenger temperatures at an
airport in Guangdong province
NY Times 4/27/03
Selling masks near Vancouver airport
AP photo - Chuck
Stoody
Sars-Infection Control
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Isolation
– Hand hygiene
– Contact Precautions (gloves, gown)
– Eye protection
– Environmental cleaning
– Airborne Precautions (N-95 respirator, negative
pressure)
SARS
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RISKS FOR DISEASE SEVERITY
CO-INFECTIONS
TREATMENT
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Antiviral
Immune modulation
RISK FACTORS FOR
PROGRESSION OF SARS
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AGE >40, >>50 years
Underlying Disease (Diabetes, Heart Disease,
Lung Disease, Smoking?)
Hypoxia at Presentation <95%,<<90% O2
Saturation
Progressive Pulmonary Infiltrates
Elevated LDH >350 U/L, CPK >500U/L,
Decreased Platelet Count <150,000 cu3/ml
Co-Infections ?
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Paramyxovirus
Metapneumovirus
Rhinovirus
Chlamydia pneumoniae
SARS - Treatment
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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
SARS and RIBAVIRIN
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No in vitro activity or ribavirin, at 100 ug/ml or
greater concentrations, against SARS
coronavirus
Huggins et al
USAMRID
INTERFERON
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Intranasal interferon αA 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
OTHER SARS ANTIVIRALS?
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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
Immune Modulation
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Ribravirin??
Macrolides??
Steroids
–
–
–
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Broncholitis Obliterans Organizing Pneumonia (BOOP)
Acute Interstitial Pneumonia
ARDS
Gamma Globulin
Convalescent Immune Globulin
SARS Treatment
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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
SARS- The Present
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Transmissible respiratory infection with no
effective vaccine or drugs
Recognition and Interruption of transmission is key
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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
SARS- The Future
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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”