How does the PPD (Purified Protein Derivative) test work?

How the PPD Test Works

The PPD test detects tuberculosis infection by injecting purified protein derivative from M. tuberculosis intracutaneously and measuring the delayed-type hypersensitivity immune response that produces induration at the injection site 48-72 hours later. 1

Mechanism of Action

The PPD test operates through a type IV delayed-type hypersensitivity reaction that occurs when the immune system has been previously exposed to M. tuberculosis antigens. 1

Immunologic Basis

• When PPD antigens are injected into the skin of someone previously infected with M. tuberculosis, memory T-cells recognize these antigens and migrate to the injection site 1
• These T-cells release cytokines (particularly interferon-gamma and IL-2) that recruit other immune cells, creating a localized inflammatory response 2
• The accumulation of immune cells produces a firm, raised area of induration that can be measured 1, 3
• In individuals never exposed to M. tuberculosis, no memory T-cells exist to recognize the antigens, so minimal or no reaction occurs 1

Administration Technique

Proper Injection Method (Mantoux Technique)

• 0.1 mL of PPD containing 5 tuberculin units (TU) must be injected intracutaneously into the volar or dorsal surface of the forearm 1, 3
• The injection should be placed just beneath the skin surface, not subcutaneously 1
• A successful injection produces a discrete, pale wheal measuring 6-10 mm in diameter immediately after administration 1, 3
• Failure to produce this wheal indicates improper technique and requires repeat testing 3

Reading and Interpretation

Timing and Measurement

• The test must be read by trained healthcare personnel between 48-72 hours after injection 1, 3
• Patient self-reading is unreliable and should never be accepted 1, 3
• Only the transverse diameter of induration (palpable, raised, hardened area) should be measured in millimeters 1, 3
• Erythema (redness) should be completely ignored in the measurement, as it does not indicate a positive result 1, 3

Risk-Stratified Interpretation Thresholds

The definition of a positive test varies based on the patient's risk profile, as the predictive value depends on the prevalence of TB infection in the tested population. 1

High-risk individuals (≥5 mm induration is positive): 1, 3

• HIV-infected persons
• Recent close contacts of active TB cases
• Persons with chest radiograph findings consistent with prior TB
• Patients receiving TNF-blocking agents or other immunosuppressive therapy 1

Moderate-risk individuals (≥10 mm induration is positive): 1, 3

• Foreign-born persons from high TB prevalence countries
• Healthcare workers and others with occupational TB exposure
• Residents of congregate settings (prisons, nursing homes, homeless shelters)
• Persons with medical conditions increasing TB risk (diabetes, chronic renal failure, malignancies)

Low-risk individuals (≥15 mm induration is positive): 1, 3

• Persons with no known TB risk factors

Sensitivity and Specificity Considerations

Test Performance

• The sensitivity of PPD testing in immunocompetent persons with previously treated TB is 95-98% 1
• However, the test is less than 100% sensitive and specific, and interpretation requires understanding of its limitations 1

False-Negative Results Occur In:

• Infants and young children 1
• Early infection (within 6-8 weeks of exposure) before the immune system develops memory T-cells 1
• Immunosuppressed individuals, including those with HIV infection, on high-dose corticosteroids, or receiving TNF inhibitors 1
• Persons with overwhelming or disseminated TB disease 1
• Recent viral infections or live viral vaccination 1
• Anergic patients who cannot mount delayed-type hypersensitivity responses 4

False-Positive Results Occur In:

• Previous BCG vaccination, though this should not prevent testing in individuals requiring screening 3
• Infection with non-tuberculous mycobacteria, which share antigens with M. tuberculosis 5
• Improper reading technique (measuring erythema instead of induration) 3

The Booster Phenomenon and Two-Step Testing

Why Two-Step Testing Is Necessary

• In persons with remote TB infection, the ability to react to tuberculin may wane over time 3
• An initial PPD test can "boost" or restore this waned reactivity, causing a larger reaction on subsequent testing 3
• Without two-step testing, this boosted reaction might be misinterpreted as a new infection (conversion), leading to unnecessary contact investigations and preventive therapy 3

Two-Step Testing Protocol

• Perform initial PPD test 3
• If negative, repeat PPD test 1-3 weeks later 3
• The second test result establishes the true baseline 3
• This method is essential for newly employed healthcare workers without documented negative PPD in the preceding 12 months 3

Clinical Applications

Primary Purpose

• The PPD test identifies latent TB infection (LTBI) in persons who would benefit from preventive therapy 3
• It does not diagnose active TB disease, which requires chest radiography and bacteriologic studies 1

Follow-Up Based on Results

Negative PPD (below threshold for patient's risk category): 3

• No further action required if test was properly administered and read
• Consider repeat testing in 8-10 weeks if exposure occurred within the past 8 weeks 3

Positive PPD without symptoms: 3

• Obtain chest radiograph to exclude active TB
• If chest radiograph is normal, diagnose LTBI and consider preventive therapy (typically isoniazid for 9-12 months) 3

Positive PPD with symptoms or abnormal chest radiograph: 3

• Evaluate for active TB disease with sputum examination for acid-fast bacilli and culture 3
• Initiate appropriate isolation precautions if active TB is suspected 1

Critical Pitfalls to Avoid

• Improper injection technique (subcutaneous instead of intradermal) causes false-negative results 3
• Reading outside the 48-72 hour window reduces accuracy 3
• Measuring erythema instead of induration leads to incorrect interpretation 3
• Accepting patient self-reading is unreliable and should never be done 1, 3
• Failing to use risk-stratified interpretation can lead to inappropriate clinical decisions 3
• Not performing two-step testing in appropriate populations (especially healthcare workers) can result in misclassification of boosted reactions as new infections 3
• Dismissing positive results in BCG-vaccinated individuals without proper evaluation, as BCG history should not prevent appropriate screening 3