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

Diagnostic TestPathogen Rx Alternative Dx 0100 Probability of Specific Pathogen: No Test/Test Test/Treat Determining the Optimal Use of Diagnostic Tests for Patients with Acute Respiratory Infections XY 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 TestPathogen Rx Alternative Dx 0100 Probability of S. pneumoniae: No Test/Test Test/Treat Diagnostic Test Thresholds for Patients with Suspected Pneumococcal Pneumonia XY

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 PathogenAssaySensitivitySpecificity S. pneumoniaeUrine antigen 86%94% S. pneumoniaeGram stain60%85% InfluenzaSputum 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 Inpatients and Outpatients Inpatients Only Bacteremic Patients ICU Patients Pre-antibiotics Antibiotics

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 TestPathogen Rx Alternative Dx 0100 Probability of S. pneumoniae: No Test/Test Test/Treat Diagnostic Test Thresholds for Patients with Suspected Pneumococcal Pneumonia 214

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 Result - Result

PCR/EIAIntervention Alternative Dx 0100 Probability of SARS: No Test/Test Test/Treat Determining the Optimal Use of Diagnostic Tests for Patients with Suspected SARS XY

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