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Severe Acute Respiratory Syndrome (SARS) David S. Stephens MD. Age of Aquarius. “ One can think of the middle of the 20 th century as one of the most important social revolutions in history- the elimination of the infectious disease as a significant factor in social life”

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age of aquarius
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
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
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
severe acute respiratory syndrome sars
Severe Acute Respiratory Syndrome (SARS)
  • Emergence
  • Clinical Features
  • Pathogenesis
  • Transmission and Infection Control
  • Treatment
  • The Future
severe acute respiratory syndrome sars1
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).
patient a
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
patient b
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
slide12
On March 5th, 2003, seven healthcare workers who had cared for the patient B in Hanoi also became ill…
slide13
Canada

18 HCW

F,G

F,G

11 close contacts

Ireland

0 HCW

K

K

A

Hong Kong SAR

95 HCW

H,J

I, L,M

H,J

B

C,D,E

I,L,M

>100 close contacts

C,D,E

B

United States

1 HCW

Vietnam

37 HCW

Singapore

34 HCW

21 close contacts

37 close contacts

Spread from Hotel M

MMWR 2003; 52(12):241

Guangdong Province, China

A

A

Hotel MHong Kong

slide15
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)

SA (2)

Taiwan (676)

Singapore (206)

Thailand (8)

Australia&NZ (6)

Total: 8404 cases; 779 deaths (~10%case fatality)

sars cases by date of hospitalization singapore feb 25 mar 22 2003
SARS cases by date of hospitalization, Singapore*—Feb 25–Mar 22, 2003

* Data provided by WHO

68 reported cases of probable sars united states through june 5 2003
68 Reported Cases of Probable SARS, United States through June 5, 2003

2

3

9

1

MA 2

2

1*

1

2

1

1*

CT 3

3

21*

1

3*

2

NJ 1*

2

2

1

1*

1

1

1

1

4

HI 2

sars clinical features
SARS - Clinical Features
  • 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
SARS – Clinical presentation
  • 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 sars 1 5
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
sars diagnostic evaluation
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 (>21 days from symptom onset)
sars laboratory findings
SARS – Laboratory findings
  • 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 sars 1 5
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

radiographic features of sars
Radiographic Features of SARS
  • Infiltrates present on chest radiographs in > 80% of cases
  • Infiltrates
    • initially focal in 50-75%
    • interstitial
    • Most progress to involve multiple lobes, bilateral involvement
slide34
Evolution of Radiographic Findings

NEJM Lee et al. 348 (20): 1986

slide38
NEJM, Ksiazek et al.

2003;348: 1953

coronaviruses
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
structure of coronavirus virion
Structure of Coronavirus Virion

-

The spikeglycoproteins create corona, bind and fuse with host cell membranes

Holmes, NEJM 2003;348: 1948

slide44
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

slide45
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

coronaviruses hosts and diseases
Coronaviruses, Hosts and Diseases

Antigenic

Group Virus HostRespiratoryEntericOther

IHCoV-229E human X

TGEV pig X

PRCoV pig X

FIPV cat X X X

FECoV cat X

CCoV dog X

IIHCoV-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

slide47
release

attachment

entry

translation

mRNA synthesis

maturation

assembly

replication

nucleus

M Denison,

Vanderbilt

genome organization
CDC

A

Genome Organization

E

1a

29,727 nt

1b

S

M

N

5,000

10,000

15,000

20,000

25,000

30,000

1

B

20,001

25,000

30,000

X1

E

X3

M

N

S

X2

X4

X5

8.3 kb

RNA 2

4.5 kb

RNA 3

3.4 kb

RNA 4

2.5 kb

RNA 5

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

slide49
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

slide50
- Distinct from other known coronaviruses
  • Neither a mutant nor recombinant
  • Previously unknown, probably from a nonhumanhost, has acquired the ability to infect humans.
evidence that urbani coronavirus is the etiology of sars
Evidence that Urbani Coronavirus is the Etiology of SARS
  • 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
CIVET CAT
  • Nocturnal Animal
  • Related To Mongoose
  • Delicacy in Southern China
sars associated novel coronavirus
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?
diagnosis
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
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
sars cov antibody assays
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
transmission
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
slide60
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
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
sars infection control
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
sars infection control1
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.
a thermal sensor checks passenger temperatures at an airport in guangdong province
A thermal sensor checks passenger temperatures at an airport in Guangdong province

NY Times 4/27/03

sars infection control2
Sars-Infection Control
  • Isolation
    • Hand hygiene
    • Contact Precautions (gloves, gown)
    • Eye protection
    • Environmental cleaning
    • Airborne Precautions (N-95 respirator, negative pressure)
slide70
SARS
  • RISKS FOR DISEASE SEVERITY
  • CO-INFECTIONS
  • TREATMENT
    • Antiviral
    • Immune modulation
risk factors for progression of sars
RISK FACTORS FOR PROGRESSION OF SARS
  • 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
Co-Infections ?
  • Paramyxovirus
  • Metapneumovirus
  • Rhinovirus
  • Chlamydia pneumoniae
sars treatment
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
sars and ribavirin
SARS and RIBAVIRIN
  • No in vitro activity or ribavirin, at 100 ug/ml or greater concentrations, against SARS coronavirus

Huggins et al

USAMRID

interferon
INTERFERON
  • 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
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
immune modulation
Immune Modulation
  • Ribravirin??
  • Macrolides??
  • Steroids
    • Broncholitis Obliterans Organizing Pneumonia (BOOP)
    • Acute Interstitial Pneumonia
    • ARDS
  • Gamma Globulin
  • Convalescent Immune Globulin
sars treatment1
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
sars the present
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
sars the future
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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