# Presentation: 016415

## Severe Acute Respiratory Syndrome (SARS): What Every Clinician Should Know About Diagnosis and Management

- John A. Jernigan, MD, MS
- For the
- SARS Preparedness Task Force
**National Center for Infectious Diseases**

## Objectives

- Review the importance of early recognition
- Review the clinical presentation of SARS
- Review key epidemiologic features of SARS
- Describe a strategy for early recognition and management that combines clinical and epidemiologic features
- Before SARS activity is documented
- After SARS activity is documented

## Importance of Early Recognition

- Simple infection control measures can dramatically reduce transmission of SARS-CoV
- Delays in clinical recognition and isolation of SARS patients contributed to transmission
- Early case detection and isolation will be critical in controlling future outbreaks of SARS

## Clinical Aspects of Severe Acute Respiratory Syndrome (SARS)

**Incubation period 2-10 days**
**Median 4-6**
**Rarely up to 14 days?**
**Onset of fever, chills/rigors, headache, myalgias, malaise**
**Fever may resolve prior to respiratory symptoms**
**Diarrhea has been a prominent feature of early illness in some**** **
**Respiratory symptoms often begin 3-7 days after symptom onset, peak in second week**
**30% have respiratory symptoms at onset**

## Symptoms Commonly Reported By Patients Presenting with SARS

_**Symptom**_**	****	**_**Range (%)**_
- 	Fever 		   95-100
- 	Cough	 	   57-100
- 	Dyspnea 		   20-100
- 	Chills/Rigor	   73-90
- 	Myalgias		   20-83
- 	Headache		   20-70
- 	Diarrhea		   10-67
-      Nausea/Vomiting	    10-24

## Symptoms Commonly Reported By Patients Presenting with SARS

_**Symptom**__**	**_**	**_**Range (%)**_
- 	Fever 		   95-100
- 	Cough	 	   57-100
- 	Dyspnea 		   20-100
- 	Chills/Rigor	   73-90
- 	Myalgias		   20-83
- 	Headache		   20-70
- 	Diarrhea		   10-67
-      Nausea/Vomiting	    10-24
-      (Rhinorrhea)            5-25
-      (Sore Throat)           5-25

## Common Clinical Findings in Patients with SARS

| Finding | Range (%) |
| --- | --- |
| Physical Examination
     Rales/Rhonci
     Hypoxia | 
38-90
60-83 |
| Laboratory
    Leukopenia
    Lymphopenia
    Thrombocytopenia
    Prolonged aPTT
    Increased ALT
    Increased LDH
    Increased CPK | 
17-34
70-95
30-50
40-60
20-30
70-94
30-40 |

## Radiographic Features of SARS

**Infiltrates develop on chest radiograph in  nearly 100% of laboratory confirmed cases**
**At presentation, CXR normal in up to 30%**** **
**How soon do abnormalities appear?**
**66%   abnormal by day 3**
**97%   abnormal by day 7****	**
**100% abnormal by day 10**

**Wong. Radiology 2003;228:401-6.**
**Wang. Proceedings of International Science Symposium on SARS. Beijing, China, 2003**
**Xue****. ****Chin Med J 2003;116:819-822**
**Zhao. J Med Microbiol 2003;52:715-20.**
**Rainer. BMJ 2003;326:1354-8.**

## Radiographic Features of SARS

**Infiltrates**
**initially focal, often peripheral lower lobes**
**interstitial**
**75% progress to involve multiple lobes or both lungs**
**Computed tomography more sensitive than conventional radiography**
**Ground glass opacification**
**Peripheral lower lobes**

## Lee N. et al NEJM 4/7/03

**Lee N. et al NEJM 4/7/03**

## Lee N. et al NEJM 4/7/03

**Lee N. et al NEJM 4/7/03**

## Common Clinical Features of the 

| Presenting Symptoms
Non-Respiratory Prodrome lasting 2-7 days characterized by one or more of the following:
Fever
Rigors
Headache
Malaise
Myalgia
Diarrhea/Nausea/Vomiting
Respiratory phase beginning 2-7 days after onset  characterized by:
Non-productive cough
Dyspnea
Absence of upper respiratory symptoms |
| --- |
| Laboratory Findings
Normal or low total white blood cell count
Lymphopenia
Elevated lactate dehydrogenase levels
Elevated creatine phospokinase levels
Elevated transaminase levels
Prolonged activated partial thromboplastin time |
| Radiographic Findings
Abnormal chest X-ray in almost all patients by day 7 of illness  |

- Common Clinical Features of the
- Severe Acute Respiratory Syndrome

## Laboratory Diagnosis of SARS

**SARS CoV testing**
**RNA detection by RT-PCR or real time PCR**
**Serology**** **

## Laboratory Diagnosis of SARS

**Ability to detect SARS CoV early in illness limited**
**Low titer of virus in early specimens**
**< 50% positive by PCR 1****st**** week**
**Testing multiple specimens may improve ability to diagnose**
**Respiratory, stool, serum/plasma**
**Stool may be best**
**Antibody response can take up to 28 days**
**Detectable as early as 10-14 days**** **
**False positive PCR assays a concern**** **

## Currently, there are no specific clinical or laboratory findings which can distinguish with certainty SARS from other respiratory illnesses at the time of presentation

## Early recognition will depend on the astute clinician’s ability to combine clinical and epidemiologic features!

## Important Epidemiologic Features of SARS

## Important Epidemiologic Features of SARS

**Epidemiologic link to SARS-affected areas or other persons with SARS  **** **

## Important Epidemiologic Features of SARS

**Epidemiologic link to SARS-affected areas or other persons with SARS  **** **
**Case clustering**** **

## Important Epidemiologic Features of SARS

**Epidemiologic link to SARS-affected areas or other persons with SARS  **** **
**Case clustering**** **
**Association with healthcare **

## Key to Early Clinical Decision Making: Combining Clinical and Epidemiologic Features

**Requires assessment of both:**
**clinical compatibility with SARS **
**	****	****	****	**_**AND**_
**risk of exposure to SARS**
**depends upon level of SARS activity in the surrounding community and the world**
**No documented SARS transmission**
**Documented SARS transmission**

## Evaluating Patients When No SARS Transmission Documented Anywhere in the World

## Evaluating Patients When No SARS Transmission Documented Anywhere in the World

**Likelihood of SARS approaches zero unless presence of both the following:**** **
**Suggestive clinical presentation (i.e. severe unexplained pneumonia)**** **
_**AND**_
**Epidemiologic features suggesting possibility of exposure to SARS-CoV**
**Travel to previously affected area **_**OR**_** clustering **_**OR**_** healthcare association **

## When SARS Transmission Has Not Been Documented Anywhere in the World.....

**SARS should only be considered in patients who:**
**Are hospitalized for pneumonia of unknown etiology**
_**AND**_
**Have evidence of one of the following:**
**recent travel to a previously SARS-affected area or close contact with ill persons with a history of travel to such areas**
**Employment as a healthcare worker with recent direct patient contact**
**recent exposure to other persons with unexplained pneumonia **

## When SARS Transmission Has Not Been Documented Anywhere in the World.....

**If a patient hospitalized for pneumonia has at least one exposure risk factor, the clinician should:**
**Notify local health department**
**Use droplet precautions**
**Treat for common causes of community-acquired pneumonia**
**Perform diagnostic workup, including:**
**CBC with differential**
**Pulse oximetry**
**Blood cultures**
**Sputum Gram’s stain and culture**
**Testing for viral respiratory pathogens**
**Urinary antigen testing: legionella and pneumococcal **
**Other tests: CPK, transaminase levels, LDH, aPTT, C-reactive protein**
**If no alternative diagnosis within 72 hours, consider need for SARS testing in consulation with local health department**

## Evaluating Patients Following Documented SARS Transmission Anywhere in the World

** **

## Evaluating Patients Following Documented SARS Transmission Anywhere in the World

**Risk of exposure to SARS CoV varies based on presence of epidemiologic link to settings in which current SARS activity has been documented**

## Evaluating Patients Following Documented SARS Transmission Anywhere in the World

**No exposure to settings with current SARS activity**
**Very low risk**
**Higher threshold for clinical suspicion of SARS**
**Hospitalized for pneumonia **
_**plus**_
**travel to *****previously***** SARS-affected area, clustering, or healthcare association**
**Exposure to settings with documented SARS activity**
**Significant risk**
**Lower threshold for clinical suspicion of SARS**
**e.g. Fever *****OR***** respiratory illness**

## After SARS Transmission Documented Anywhere in the World...

**SARS should be considered among patients with both:**
**Early clinical features compatible with SARS (i.e. fever *****OR***** respiratory symptoms) **** **
_**AND**_
**Evidence suggesting potential exposure to SARS CoV **
**Exposure to areas *****currently***** affected by SARS (foreign or domestic)**
**	****OR **
**close contact to a suspected SARS case **

## After SARS Transmission Documented Anywhere in the World...

**Any patient with either fever OR respiratory symptoms should be asked about:**
**Recent exposure to a SARS-affected area or close contact with ill persons with exposure to such areas (foreign or domestic)**
**Recent exposure to a person suspected of having SARS**

## After SARS Transmission Documented Anywhere in the World...

**If fever OR respiratory symptoms AND has at least one risk factor for exposure to SARS CoV:**
**Begin SARS isolation precautions**
**Notify local health department**
**Diagnostic workup**
**Chest X-ray**
**CBC with differential**
**Pulse oximetry**
**Blood cultures**
**Sputum Gram’s stain and culture**
**Testing for viral respiratory pathogens**
**If pneumonia, then urinary antigen testing: legionella and pneumococcal **
**Other tests: CPK, transaminase levels, LDH, aPTT, C-reactive protein **
**Follow management algorithm......**

## Draft- Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

**Draft- Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- Radiographic Evidence
- Of Pneumonia

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- Radiographic Evidence
- Of Pneumonia

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions

## Using Alternative Diagnosis to “Rule Out” SARS
Based on test with high positive predictive value
Clinical course consistent
No evidence of clustering
No strong epidemiologic link

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- Radiographic Evidence
- Of Pneumonia

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions

- Using Alternative Diagnosis to “Rule Out” SARS
- Based on test with high positive predictive value
- Clinical course consistent
- No evidence of clustering
- No strong epidemiologic link

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- Radiographic Evidence
- Of Pneumonia

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

- No Radiographic Evidence of
- Pneumonia

**- CXR**

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- Radiographic Evidence
- Of Pneumonia

**+ CXR**

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

- No Radiographic Evidence of
- Pneumonia

- No Alternative Diagnosis

- Continue SARS isolation and re-evaluate
- 72 hours after initial evaluation

**- CXR**

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- Radiographic Evidence
- Of Pneumonia

**+ CXR**

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

- No Radiographic Evidence of
- Pneumonia

- No Alternative Diagnosis

- Continue SARS isolation and re-evaluate
- 72 hours after initial evaluation

- Symptoms
- improve
- or resolve

**- CXR**

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- Radiographic Evidence
- Of Pneumonia

**+ CXR**

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions

- Consider D/C
- SARS isolation
- precautions

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

- No Radiographic Evidence of
- Pneumonia

- No Alternative Diagnosis

- Continue SARS isolation and re-evaluate
- 72 hours after initial evaluation

- Persistent fever or
- unresolving respiratory symptoms

-  Perform SARS test
-  Continue SARS isolation for additional
-    72 hours.  At the end of the 72
-    hours, repeat clinical evaluation
-    including CXR

- Symptoms
- improve
- or resolve

**- CXR**

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- Radiographic Evidence
- Of Pneumonia

**+ CXR**

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions

- Consider D/C
- SARS isolation
- precautions5

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

- No Radiographic Evidence of
- Pneumonia

- No Alternative Diagnosis

- Continue SARS isolation and re-evaluate
- 72 hours after initial evaluation

- Persistent fever or
- unresolving respiratory symptoms

-  Perform SARS test
-  Continue SARS isolation for additional
-    72 hours.  At the end of the 72
-    hours, repeat clinical evaluation
-    including CXR

- Symptoms
- improve
- or resolve

**- CXR**

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- + CXR

- Radiographic Evidence
- Of Pneumonia

**+ CXR**

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions

- Consider D/C
- SARS isolation
- precautions

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department

- No Radiographic Evidence of
- Pneumonia

- No Alternative Diagnosis

- Continue SARS isolation and re-evaluate
- 72 hours after initial evaluation

- Persistent fever or
- unresolving respiratory symptoms

-  Perform SARS test
-  Continue SARS isolation for additional
-    72 hours.  At the end of the 72
-    hours, repeat clinical evaluation
-    including CXR

- No radiogrpahic evidence of
- pneumonia

- Symptoms
- improve
- or resolve

**- CXR**

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- + CXR

- Radiographic Evidence
- Of Pneumonia

**+ CXR**

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions

- Consider D/C
- SARS isolation
- precautions

## Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS

- Begin SARS isolation precautions, initiate preliminary work up and notify Health Department2

- No Radiographic Evidence of
- Pneumonia

- No Alternative Diagnosis

- Continue SARS isolation and re-evaluate
- 72 hours after initial evaluation

- Persistent fever or
- unresolving respiratory symptoms

-  Perform SARS test
-  Continue SARS isolation for additional
-    72 hours.  At the end of the 72
-    hours, repeat clinical evaluation
-    including CXR

- No radiogrpahic evidence of
- pneumonia

- Symptoms
- improve
- or resolve

**- CXR**

**Draft-Algorithm to Work Up and Isolate Symptomatic Persons who may have been Exposed to SARS**

- + CXR

- Radiographic Evidence
- Of Pneumonia

**+ CXR**

- Perform SARS testing

- Laboratory evidence
- of SARS-CoV or
-  No alternative diagnosis

- Alternative diagnosis
- confirmed3

- Continue SARS isolation until
- 10 days following resolution of
- fever given respiratory
- symptoms are absent or
- resolving

- Consider D/C
- SARS isolation
- precautions5

- Alternative diagnosis
- confirmed3

- Consider D/C
- SARS isolation
- precautions5

- Consider D/C
- SARS isolation
- precautions5

## Additional Considerations

**Community outbreaks**
**Nosocomial SARS**
**Elderly and underlying chronic illness**
**Pediatrics**

## Importance of Communication with Public Health Authorities

**clinicians must have frequent updates regarding location of SARS activity **** **
**mechanisms for rapid communication between clinicians and public health agencies must be in place**** **
**communication important in rapid identification of emerging areas of SARS activity**

## Treatment of Patients with SARS

**No proven effective therapy**
**Optimize supportive care**
**Treat for other potential causes of community-acquired pneumonia of unknown etiology**

## Treatment of Patients with SARS

**Potential therapies requiring further investigation**
**Cystine proteinase inhibitors**
**Interferons**
**Immunomodulatory agents**
**Corticosteriods**
**SARS-CoV specific immune globolin**
**Others?**

## Summary 

**Early recognition of patients with SARS is critical to successful control of future outbreaks.**
**Clinical features alone cannot reliably distinguish SARS from other respiratory illnesses**
**Currently available SARS CoV tests unlikely to be helpful in early clinical decision making **** **
**Epidemiologic features are the key to early recognition and clinical decision making**
**Importance of rapid communication between clinicians and public health authorities**** **
**The approach to early recognition will vary depending upon the level of SARS activity in the surrounding community and the world**