# Presentation: 547862

## Clinical Approach to the Diagnosis of SARS

- Joshua P. Metlay, MD, PhD
- VA Medical Center
- Division of General Internal Medicine
- Center for Clinical Epidemiology and Biostatistics
- Philadelphia, PA

**CCEB**

## Overview of Talk

- Clinical approach to the diagnosis of acute respiratory tract infections
- Case example:  Evaluation of diagnostic tests for pneumococcal pneumonia
- Implications for the development and application of SARS diagnostic tests

## Applications of Diagnostic Testing 

- Physician Perspective:
- Determining need for antimicrobial Rx
- Targeting antimicrobial Rx
- Risk stratification for site of care

- Public Health Perspective:
- Disease surveillance
- Infection control
- Clinical studies

## Characteristics of Diagnostic Tests 

- Physician perspective:
- Rapid  detection
- Bedside capability
- Examples:
- Antigen assays
- DNA amplification

- Public Health perspective:
- Time insensitive
- Centralized testing
- Examples:
- Micro cultures
- Serology

## Determining the Optimal Use of Diagnostic Tests 

- Diagnostic Test

- Pathogen Rx

- Alternative Dx

**0**

**100**

- Probability of Specific Pathogen:

- No Test/Test

- Test/Treat

**Determining the Optimal Use of Diagnostic Tests **
**for Patients with Acute Respiratory Infections**

**X**

**Y**

***Adapted from Pauker and Kassirer.  NEJM.  1980***

## Calculating the No Test/Test Threshold

- _(1-Specificity) x R_
- ((1-Specificity) x R) + (Sensitivity x B)

- Where R=Risk and B=Benefit of Treatment

## Calculating the Test/Treatment Threshold

- _Specificity x R_
- (Specificity x R)+((1-Sensitivity) x B)

- Where R=Risk and B=Benefit of Treatment

## Diagnostic Test Thresholds for Patients 

- Diagnostic Test

- Pathogen Rx

- Alternative Dx

**0**

**100**

- Probability of *S. pneumoniae*:

- No Test/Test

- Test/Treat

**Diagnostic Test Thresholds for Patients **
**with Suspected Pneumococcal Pneumonia**

**X**

**Y**

## Factors Influencing the Clinical Decision to Use a Diagnostic Test

- Pretest probability of disease
- Test costs  (clinical and financial)
- Test sensitivity and specificity
- Treatment risks and benefits

## Pretest Probability

- Population based estimates
- Modified for individual patient characteristics
- Presenting symptoms
- Presenting signs
- Modified for temporal and geographic trends

## Estimating the probability of pneumonia in patients with acute cough illness

## Pretest Probability

- Population based estimates
- Modified for individual patient characteristics
- Probability of pneumonia
- Probability of pneumococcal pneumonia
- Modified for temporal and geographic trends

## Identifying Pneumonia based on Signs and Symptoms

## Identifying the Pathogen based on History and Physical Exam

- Once the diagnosis of pneumonia is established, the H&P is of little value in targeting antimicrobial therapy
- Both IDSA and ATS guidelines advise against targeted therapy based on H&P
- Clinical associations of signs and symptoms are rarely sufficient to guide therapy

## Pretest Probability of Specific Pathogens in Patients with ARIs

- 30 million cough visits per year in the US
- 5% of patients with ARIs will have CAP
- 30% - 50% of patients with CAP have *S. pneumoniae** *
- 1% of cough patients have pneumococcal pneumonia

## Factors Influencing the Clinical Decision to Use a Diagnostic Test

- Pretest probability of disease
- Test costs  (clinical and financial)
- Test sensitivity and specificity
- Treatment risks and benefits

## Accuracy of Rapid Diagnostic Tests

| Pathogen | Assay | Sensitivity | Specificity |
| --- | --- | --- | --- |
| S. pneumoniae | Urine antigen | 86% | 94% |
| S. pneumoniae | Gram stain | 60% | 85% |
| Influenza | Sputum antigen | 85% | 95% |

## Estimating the Risks and Benefits of Treatment

- For most antimicrobial drugs, placebo controlled data on efficacy is missing
- For most antimicrobial drugs, premarketing information on risk is limited

## Mortality Assessment in Pneumonia

**Notes:**
I have attempted to explicity compare mortality outcoms for patients with pneumococcal pneumonia before and after the introduction of antibiotic therapy.  This is certainly not an entirely fair comparison given a number of differences in these two time periods including differences in diagnostic accuracy, other medical treatments, and validity of outcomes measurement.  

Nevertheless, this slide makes the point that while antibiotic therapy has almost certainly reduced mortality from pneumococcal pneumonia, the relative reduction is definitely less than 100%. Indeed there are high risk patients today whose mortality exceeds that of the general population with pneumococcal pneumonia before the introduction of antibiotics.

I have made this comparision in part because it is one approach to understanding the maximum worsening in health outcomes that could be attributed to complete antibiotic resistance among pneumococcal pneumona.  Iin fact, as I have suggested, the actual impact on mortality will almost certainly be far less.

## Testing thresholds for Pneumococcal Detection using Gram Stain

- Treatment benefit 10-15%
- Treatment risk 1%
- No Test/Test threshold: 2%
- Test/Treat threshold: 14%

## Diagnostic Test Thresholds for Patients 

- Diagnostic Test

- Pathogen Rx

- Alternative Dx

**0**

**100**

- Probability of *S. pneumoniae*:

- No Test/Test

- Test/Treat

**Diagnostic Test Thresholds for Patients **
**with Suspected Pneumococcal Pneumonia**

**2**

**14**

## Lessons learned from the pneumococcal pneumonia example

- Until the pretest probability is > 1%, diagnostic testing is unlikely to be indicated in routine practice
- Unless the diagnostic test has excellent operating characteristics, the testing window will be narrow.
- Effective treatments for high risk illnesses have low thresholds unless treatment risk is high.

## Identifying the Optimal Clinical Settings for a Diagnostic Test

**PreTest Probability**

**PostTest Probability**

**0**

**100**

**0**

**100**

**+ Result**

**- Result**

## Determining the Optimal Use of Diagnostic Tests 

- PCR/EIA

- Intervention

- Alternative Dx

**0**

**100**

- Probability of SARS:

- No Test/Test

- Test/Treat

**Determining the Optimal Use of Diagnostic Tests **
**for Patients with Suspected SARS**

**X**

**Y**

## SARS Case Definition: A potential population for diagnostic testing

- Severe respiratory illness:
- Cough illness with fever
- Pneumonia/ARDS on CXR
- Exposure history
- Travel
- Close contact

## SARS Diagnosis in Primary Care

- We must emphasize importance of local surveillance and disease reporting.
- Absent local cases, diagnostic testing will not be supported without epidemiological exposures
- Given competing respiratory pathogens, it is unlikely that signs and symptoms will further modify pretest probability