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 Test Pathogen RxAlternative 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 Pathogen RxAlternative 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

Diagnosis % of Total Annual # Visits (in millions)

Acute Bronchitis 40 4.2 URI 19 1.9 Sinusitis 10 1.0 Asthma 7 0.7 Pneumonia 4 0.4 Pharyngitis 2 0.2

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

0 10 20 30 40 50 60 70 80 90 100

Revised Probability

Tachycardia

Fever

Crackles

Dullness to Percussion

Cough only with normal vital signs

Cough, Fever, Tachycardia, and Crackles

Ex

am

ina

tio

n F

ind

ing

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 PneumoniaMortality Assessment in Pneumonia

0

10

20

30

40

50

60

70

Inpatientsand

Outpatients

InpatientsOnly

BacteremicPatients

ICUPatients

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 Test Pathogen RxAlternative 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

Po

stT

es

t P

rob

ab

ility

0 100

01

00

+ Result

- Result

PCR/EIA InterventionAlternative 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