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

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)

Emergence Clinical Features Pathogenesis Transmission and Infection Control Treatment The Future

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

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

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…

Hotel MHong Kong

Guangdong Province,

China A

A

H,J

A

H,J

Hong Kong SAR

95 HCW

>100 close contacts

United States

1 HCW

I, L,M

I,L,M

KIreland

0 HCWK

Singapore

34 HCW

37 close contacts

C,D,E

C,D,E

B

B

Vietnam

37 HCW

21 close contacts

F,G

Canada

18 HCWF,G

11 close contacts

Spread from Hotel M MMWR 2003; 52(12):241

SARS Cases Worldwide Reported to WHO as of June 6, 2003

China (5329)

Singapore (206)

Hong Kong (1750)

Vietnam (63)

Canada (219)

U.S. (68)

Europe:8 countries (38)

Thailand (8)

Taiwan (676)

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

Australia&NZ (6)

SA (2)

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

0

1

2

3

4

5

6

7

25-F

eb27

-Feb

1-M

ar3-

Mar

5-M

ar7-

Mar

9-M

ar11

-Mar

13-M

ar15

-Mar

17-M

ar19

-Mar

Date of onset

No

. of

case

s

Tertiary(6)

Secondary(16)

Primary(19)

Index(3)

* Data provided by WHO

68 Reported Cases of Probable SARS, United States through June 5, 2003

1*

CT 3

NJ 1*

MA 2

21*

9

1*

1*

1

12

2

12

1 1

2

3*

1

HI 2

3

1

2

32

1

1

4

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

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

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

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 Range (%)Examination Rales 38-90 Hypoxia 60-83Laboratory 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

Infiltrates present on chest radiographs in > 80% of cases

Infiltrates– initially focal in 50-75%– interstitial– Most progress to involve multiple lobes,

bilateral involvement

NEJM Lee et al. 348 (20): 1986

NEJM Lee et al. 348 (20): 1986

Evolution of Radiographic Findings

NEJM, Ksiazek et al.

2003;348: 1953

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

Relative Size of Coronaviruses Compared to Other Microbes

NY Times 4/27/03

Holmes, NEJM 2003;348: 1948

-

Structure of Coronavirus Virion

The spike glycoproteins create corona, bind and fuse with host cell membranes

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 DenisonVanderbilt

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

Antigenic Group Virus Host Respiratory Enteric Other

I HCoV-229E human X TGEV pig X

PRCoV pig XFIPV cat X X XFECoV cat XCCoV dog X

II HCoV-OC43 human X ??MHV mouse X X XRCoV rat X XHEV pig X XBCoV cattle X X

III IBV chicken X XTCoV turkey X

CDC

nucleus

attachmentattachment

maturation assembly

translation

replicationmRNA synthesis

releaserelease

entry

M Denison,Vanderbilt

CDC

X1

X2

X3

X4 X5

NME

20,001 30,00025,000

S

RNA 6

RNA 5

RNA 4

RNA 3

RNA 28.3 kb4.5 kb

3.4 kb

2.5 kb1.7 kb

S1b

1a

NM

EA

B

1 5,000 10,000 15,000 20,000 25,000 30,000

29,727 nt

Genome Organization

- Replicases (1a/1b) & structural genes (S,E,M,N)

- Multiple small genes (X1-X5)-these vary in number, location, and sequence in different coronaviruses

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

- 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

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

Nocturnal Animal Related To Mongoose Delicacy in Southern

China

NY Times 4/27/03

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

Confirmed CaseDetection 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-CoVProbable CaseSuspected Case

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

Viral Shedding in Nasopharyngeal Secretions Peiris J, et al. Lancet.com 5/9/03

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

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

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

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

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

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

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

pressure)

SARS

RISKS FOR DISEASE SEVERITY CO-INFECTIONS TREATMENT

– Antiviral– Immune modulation

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 ?

Paramyxovirus Metapneumovirus Rhinovirus Chlamydia pneumoniae

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

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

Huggins et alUSAMRID

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 alUSAMRID

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

Ribravirin?? Macrolides?? Steroids

– Broncholitis Obliterans Organizing Pneumonia (BOOP)– Acute Interstitial Pneumonia– ARDS

Gamma Globulin Convalescent Immune Globulin

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

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

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”