Mantoux Test (Tuberculin Skin Test) - Detailed Clinical Note

1. Historical Background

• Park's Textbook of Preventive & Social Medicine, p.217
• Fitzpatrick's Dermatology, p.2889

2. Immunological Basis

• Following primary infection with M. tuberculosis, sensitized T lymphocytes are generated.
• On re-exposure to tuberculin antigens, these memory T cells are activated and release cytokines (especially IFN-γ), recruiting macrophages and other inflammatory cells to the injection site.
• This produces the characteristic induration, which begins 5-6 hours after placement, peaks at 48-72 hours, then subsides over several days.
• Tuberculin sensitivity typically develops 2 to 10 weeks after infection and persists throughout life, though it may wane with age.
• Important caveat: Tuberculin sensitivity (skin reactivity) is NOT equivalent to immunity; sensitivity and immunity do not always parallel each other.
• Fitzpatrick's Dermatology, p.2889
• Murray & Nadel's Respiratory Medicine, p.932
• Andrews' Diseases of the Skin, p.381
• Robbins & Cotran Pathologic Basis of Disease, p.1849-1852

3. Tuberculin - The Antigen

Types of Tuberculin

• PPD is standardized in tuberculin units (TU) based on biological reactivity.
• A standard 5 TU dose of PPD-S = delayed skin activity in 0.1 μg/0.1 mL of PPD-S.
• 1 TU of PPD-RT 23 = 5 TU of PPD-S (more potent on a per-unit basis).
• Tween 80 is added to tuberculin preparations as a surfactant/detergent to prevent adsorption to glass or plastic surfaces.
• In India: PPD-RT 23 with Tween 80 is used. The recommended strength for standard Mantoux testing in India is 1 TU.
• In the USA and Canada: 5 TU of PPD-S is the standard dose.
• Park's Textbook of Preventive & Social Medicine, p.217
• Andrews' Diseases of the Skin, p.381

PPD vs. Old Tuberculin

4. Technique of Mantoux Test

Equipment

• Tuberculin syringe (1 mL capacity)
• 25-26 gauge, short bevel needle
• PPD tuberculin of appropriate strength

Site

• Volar (flexor) surface of the left forearm, midway between the elbow and wrist.

Procedure - Step by Step

1. Draw 0.1 mL of tuberculin (containing the appropriate TU dose) into the tuberculin syringe.
2. Clean the site with an alcohol swab and allow to dry.
3. Hold the syringe nearly parallel to the skin (at approximately 10-15°) with the bevel facing upward.
4. Insert the needle intradermally (bevel up, into the dermis itself - not subcutaneous tissue).
5. Inject 0.1 mL of PPD slowly.
6. A pale wheal of 6-10 mm diameter should appear at the injection site if the technique is correct.
7. If no wheal appears, or if the wheal is less than 5 mm, the injection was likely subcutaneous - repeat at a different site at least 5 cm away.
8. Do not massage or bandage the site.
9. Advise the patient to return for reading.

• Park's Textbook of Preventive & Social Medicine, p.217

Common Technical Errors to Avoid

• Injecting subcutaneously (no wheal formed) - most common error
• Using wrong concentration of PPD
• Allowing PPD to sit in syringe for prolonged period (adsorption reduces potency)
• Injecting into a hairy, tattooed, or blemished area
• Injecting too large a volume

5. Reading the Test

Timing

• Results are read after 48-96 hours.
• Ideal reading time: 72 hours (3rd day).
• In clinical practice, 48-72 hours is the standard window.
• If the TST cannot be read within 48-72 hours, repeat testing should be performed.

What to Measure

• Induration (not erythema) is measured.
• Erythema alone (without induration) is not significant.
• Measure the transverse (horizontal) diameter of the area of induration using a transparent plastic ruler or calipers, in millimeters.
• The "ballpoint pen method" (Sokal method): draw lines toward the induration from both sides; the point at which resistance is felt marks the edge of induration.
• Murray & Nadel's Respiratory Medicine, p.932-933
• Park's Textbook of Preventive & Social Medicine, p.217

6. Interpretation - Criteria for Positivity

Standard 3-Tier Classification (CDC / ATS / Park's)

Indian/Park's Classification

• Negative: <6 mm
• Doubtful: 6-9 mm (may represent M. tuberculosis or atypical mycobacteria)
• Positive: ≥10 mm
• If no induration: record as 0 mm

Additional Note on Sensitivity Analysis (Andrews')

• TST >6 mm detects 89% of latent TB cases
• TST >10 mm detects 75% of latent TB cases
• TST >15 mm detects only 47% of latent TB cases
• At least 7% of patients with latent TB will have a completely negative TST
• Park's Textbook of Preventive & Social Medicine, p.217-218
• Andrews' Diseases of the Skin, p.381
• Murray & Nadel's Respiratory Medicine, p.932-933

7. Clinical Significance of Reaction Size

• Strong reactors (≥20 mm induration) have a greater chance of developing active tuberculosis than those showing 10 mm induration.
• Paradoxically, those with <5 mm induration also have more risk than 6-9 mm reactors.
• Studies indicate ~92% of new TB cases occur in persons who are already tuberculin reactors, illustrating prognostic significance.
• In patients with established tuberculous skin disease and high levels of skin sensitivity, the number of bacteria within lesions is small (inverse correlation between skin sensitivity and bacterial burden in skin lesions).
• An increase in skin sensitivity in a patient with clinical tuberculosis usually indicates a favorable prognosis.
• Park's Textbook of Preventive & Social Medicine, p.217
• Fitzpatrick's Dermatology, p.2889

8. False-Positive Reactions

Causes of False-Positive TST

• BCG immunization leads to a positive tuberculin result.
• In immunized children, this reaction usually does not persist beyond 10 years.
• Repeated BCG immunization or BCG given after age 2 years is more likely to produce a persistently positive TST.
• BCG given in the first year of life has limited effect on TST specificity (immune response is less vigorous).
• BCG-induced tuberculin reactivity wanes over time: positive reactions 10 or more years after vaccination should not be attributed to BCG.
• In a meta-analysis of 11 studies, pooled specificity of TST was lower among BCG-vaccinated individuals compared to unvaccinated (59% vs. 97%).

• NTM infections account for ~1-5% of all positive TST results.
• More important in areas with very low TB prevalence and high NTM prevalence (e.g., southern United States).
• Many intermediate TST responses (6-14 mm) may represent cross-reaction with atypical mycobacteria.

• Booster effect from repeat testing can produce a larger reaction, potentially misinterpreted as conversion (see Two-Step Testing).
• Andrews' Diseases of the Skin, p.381
• Murray & Nadel's Respiratory Medicine, p.935-936
• Robbins & Cotran Pathologic Basis of Disease, p.1852
• Meta-analysis: PMID 42203236 - BCG-induced false positivity TST: global meta-analysis of 242 studies (Eur Respir Rev, 2026)

9. False-Negative Reactions

Clinical Causes of False-Negative TST

• Andrews' Diseases of the Skin, p.381-382
• Park's Textbook of Preventive & Social Medicine, p.218
• Murray & Nadel's Respiratory Medicine, p.933-934
• Robbins & Cotran Pathologic Basis of Disease, p.1852

10. The Booster Effect and Two-Step Testing

Booster Effect

• Some individuals infected with TB long ago may have a waned immune response and test negative initially.
• The initial TST injection, though negative, may stimulate (boost) the ability to react to tuberculin in subsequent tests.
• A positive reaction on a subsequent test may be misinterpreted as a new infection (conversion) when it is actually a boosted response to an old infection.

Two-Step Testing Protocol

1. Administer first TST.
2. Read at 48-72 hours.
3. If positive → consider the person infected.
4. If negative → administer a second TST 1-3 weeks after the first injection.
5. Read second test at 48-72 hours.
6. If second test positive → consider the person previously infected (boosted reaction, not new infection).
7. If second test negative → consider the person truly uninfected.

• Park's Textbook of Preventive & Social Medicine, p.218

11. Approach to TST-Positive Patients with Prior BCG

• BCG-vaccinated individuals with positive TST should be regarded as true positives, without modification of the standard TST positivity criteria.
• However, clinicians should be aware that BCG is a common cause of false-positive TST.
• If doubt exists about whether a TST-positive BCG-vaccinated individual has true LTBI, IGRA testing is preferred to clarify.
• Dual testing (TST + IGRA) is not routinely recommended but may be considered in certain situations.
• Murray & Nadel's Respiratory Medicine, p.935, Fig 42.1

12. Screening Indications for TST (Who to Test)

1. Screen asymptomatic individuals for LTBI
2. Guide empirical treatment decisions for active TB in symptomatic individuals with negative microbiological results

High-risk groups requiring screening (Target Populations):

• Close contacts of untreated infectious TB cases
• Immigrants from TB-endemic areas (<5 years)
• Healthcare workers
• Residents/employees of congregate settings (prisons, shelters, nursing homes)

• HIV infection
• Severe immunosuppression (organ transplant, chemotherapy, TNF-α inhibitors)
• Certain malignancies (hematologic, head/neck)
• Silicosis
• End-stage renal disease
• Radiographic evidence of prior granulomatous disease
• Children <5 years with positive TST

• Diabetes mellitus
• Underweight (>10% below ideal body weight)
• Heavy tobacco use
• Heavy alcohol use
• Children 5-14 years

• Murray & Nadel's Respiratory Medicine, p.931-932

13. TST vs. IGRA - Comparative Summary

• Murray & Nadel's Respiratory Medicine, p.932-944
• Andrews' Diseases of the Skin, p.381-382
• Fitzpatrick's Dermatology, p.2889-2890
• Meta-analysis [PMID 36184056]: IGRA vs TST positive rates in LTBI detection - 200,000 head-to-head tests (Clin Immunol, 2022)
• Meta-analysis [PMID 34606768]: Novel skin-based in vivo tests vs PPD vs IGRA (Lancet Infect Dis, 2022)

14. Dermatological Relevance of Tuberculin Sensitivity

• In tuberculosis verrucosa cutis and other forms of cutaneous tuberculosis, the degree of skin sensitivity correlates inversely with the bacterial load within the lesion.
• High skin sensitivity = fewer organisms in the lesion (paucibacillary disease).
• In scrofuloderma and other forms where there is active dissemination from a deeper focus, TST is often strongly positive.
• In acute miliary tuberculosis (with cutaneous involvement), TST may be negative due to overwhelming immune suppression.
• Lupus vulgaris: Strongly positive TST (high hypersensitivity form of cutaneous TB).
• Tuberculids (e.g., lichen scrofulosorum, papulonecrotic tuberculid, erythema induratum of Bazin): TST is strongly positive as these are hypersensitivity reactions to haematogenously spread mycobacterial antigens in a highly sensitized host.
• Leprosy overlap: In leprosy patients, TST can be positive, reflecting mycobacterial cross-reactivity.
• Fitzpatrick's Dermatology, pp.2889-2890

15. Limitations of the Mantoux Test

1. Two visits required for completion (injection + reading)
2. Technical competence-dependent (reading and administration)
3. Booster effect from repeat testing can create false-positive conversions
4. False-positive results in BCG-vaccinated individuals (significant problem in countries with universal BCG vaccination)
5. Sensitivity is only ~77% for active TB
6. Cannot differentiate between LTBI, past infection, and active disease
7. Cannot distinguish between M. tuberculosis infection and NTM infection
8. Negative result does not rule out TB, especially in immunocompromised patients
9. In high BCG coverage countries (like India), it has lost its value as an epidemiological indicator of "true" prevalence of infection.

16. Recent Evidence (2022-2026)

Summary Mnemonic: "MANTOUX"

• M - Measure induration (NOT erythema), transverse diameter
• A - Antigen = PPD (purified protein derivative); 1 TU in India, 5 TU in USA
• N - Needle bevel UP, near-parallel angle, intradermal, left forearm
• T - Time to read: 48-72 hours (ideal 72 hours); up to 96 hours acceptable
• O - Old tuberculin replaced by PPD; Old infections may produce booster effect
• U - Uninterpretable/negative in immunosuppressed, miliary TB, recent live vaccines
• X - X-reactivity with BCG and NTM causes false positives; IGRA avoids this