Tuberculin (Monograph)

Brand names: Aplisol, Tubersol
Drug class: Tuberculosis
- Cell-mediated Immunity Function
- Immunity Function, Cell-mediated
VA class: DX300

Introduction

Skin-test antigen for diagnosis of Mycobacterium tuberculosis infection.

Uses for Tuberculin

Diagnosis of Tuberculosis (TB) Infection

• Aids in identifying Mycobacterium tuberculosis-infected individuals at high risk for developing active TB who may benefit from treatment of latent TB infection.

• Treatment of latent TB infection previously referred to as “preventive therapy” or “chemoprophylaxis”.

• ATS and CDC recommend tuberculin testing in high-risk groups and generally discourage such testing in those at low risk to maximize use of resources and minimize false-positive results.

• ATS, CDC, and IDSA recommend tuberculin testing in the following high-risk individuals or groups:

• Close contacts (i.e., those sharing same household or other closed environment) of known cases of clinical TB or individuals suspected of having TB

• HIV-infected individuals; consider annual testing in such individuals at high risk of continued exposure to TB, beginning at 3–12 months of age

• Other individuals with medical conditions or factors that increase risk of latent TB infection progressing to active TB, including diabetes mellitus, chronic renal failure, certain hematologic or reticuloendothelial disorders (e.g., leukemias, lymphomas), certain other malignancies (e.g., head and neck or lung cancer), immunosuppression (e.g., organ transplant recipients, individuals receiving prolonged high-dose corticosteroid therapy, tumor necrosis factor, or other immunosuppressive agents), silicosis, weight >10% below ideal body weight, gastrectomy or jejunoileal bypass

• Illicit-drug users and other locally identified high-risk substance users (e.g., crack cocaine users); required in all individuals enrolled in methadone detoxification or maintenance treatment program

• Residents and employees of high-risk congregate settings (e.g., correctional facilities, nursing homes, mental institutions, other long-term residential facilities [e.g., for HIV-infected patients], homeless shelters); routine (at least annual) testing recommended

• Foreign-born individuals (e.g., legal immigrants and refugees with class B1 and B2 TB notification status), including children who recently arrived (≤5 years) from countries with high incidence or prevalence of TB and those adopted from outside US

• Certain medically underserved, low-income populations (e.g., migrant farm workers, homeless persons)

• Individuals with pulmonary fibrotic lesions on chest radiographs (consistent with healed TB)

• Children <5 years of age or infants, children, and adolescents exposed to adults in high-risk categories; annual testing recommended in high-risk pediatric patients (e.g., individuals from countries with high prevalence of TB, low-income groups, children infected with HIV, incarcerated adolescents)

• All health-care workers (baseline and postexposure screening); ongoing periodic screening recommended according to risk

• History of BCG vaccination does not rule out use of tuberculin testing to aid diagnosis of TB infection. (See False-positive Reactions under Cautions.)

Tuberculin Dosage and Administration

General

• Document test result in permanent medical record. Include name of preparation, manufacturer and lot number, administration technique (i.e., Mantoux method), date and dose administered, date of test reading, and extent of induration in mm (including 0). Recording result only as “negative” or “positive” is not adequate.

Administration

Intradermal Administration

Administer by intradermal injection using Mantoux method. Avoid administering by IV, IM, or sub-Q. Sub-Q injection lacks diagnostic value and may result in adverse reactions (e.g., general febrile reaction, acute inflammation around old tuberculous lesions) in highly sensitive individuals.

Use tuberculin syringe with short (0.25–0.5 inch) 26- or 27-gauge needle. Use a separate sterile, single-use disposable syringe and needle for each individual patient to prevent transmission of infectious agents (e.g., HIV, hepatitis virus). To avoid contamination of vial content (and subsequent transmission of infectious agents to other individuals), never use the same needle and/or syringe to re-enter multidose vial, even when used for the same individual.

To prepare dose, wipe vial stopper with suitable germicide (e.g., 70% alcohol) and use aseptic technique to draw exact dose into syringe, taking care to exclude air bubbles. .

Prior to intradermal injection, cleanse administration site with 70% alcohol or other antiseptic and allow to dry. Usual injection site is volar (preferred) or dorsal surface of forearm, approximately 4 inches below elbow. Avoid hairy areas, areas with lesions, areas near veins, swollen or red areas, and areas without adequate subcutaneous tissue (e.g., concavities over tendon or bone).

Potential for a drop of blood when needle withdrawn from injection site. Remove any blood at injection site gently with gauze to avoid squeezing out tuberculin.

Avoid recapping needle following use; properly dispose of used needles and syringes.

Mantoux Method

With needle bevel pointing upward, insert needle into the most superficial layers of the skin and inject slowly.

A pale bleb about 6–10 mm in diameter should form at injection site. Bleb is absorbed within minutes; no dressing required.

If improperly administered (i.e., no bleb formed) or if dose leaks from injection site, repeat test immediately at another site at least 5 cm (2 inches) from original injection site; indicate site used for second test in patient’s record or by circling second site.

In individuals requiring routine periodic testing (e.g., health-care professionals, residents and workers in hospitals, nursing homes, mental institutions, prisons), perform 2-step testing method initially (using Mantoux method) to avoid misinterpreting a booster effect as a conversion. (See Booster Effect and Two-Step Testing under Dosage and Administration.) If a small or negative reaction is observed after the first test, administer second test 1–4 weeks later.

Examine test site 48–72 hours after administration. (See Interpretation of Tuberculin Reaction under Dosage and Administration.)

Interpretation of Tuberculin Reaction

Only trained health professionals should interpret tuberculin skin test; interpretation by untrained individuals or family member not reliable.

At 48–72 hours after administration, visually inspect and palpate test site to determine extent of induration. Disregard finding of erythema (no diagnostic value); in absence of induration, an area of erythema with diameter >10 mm indicates too deep an injection and requires retesting. Note and record presence and extent of necrosis and edema, although these findings have no diagnostic value.

Measure diameter of palpable induration transversely to long axis of forearm. Record in mm (including 0) and interpret reaction using guidelines from manufacturer, ATS, and CDC. (See Table 1.)

When of diagnostic importance, accept negative reaction as proof that sensitivity is absent only after normal reactivity to nonspecific irritants has been demonstrated. In individuals suspected of being TB positive who exhibit negative reaction to tuberculin testing, perform second test to exclude possibility of active TB. Individuals with negative reaction to initial and second test may be considered tuberculin negative.

To establish diagnosis of latent or active TB infection, rule out possible false-positive reaction (see False-positive Reactions under Cautions) and perform further medical and diagnostic evaluation (e.g., medical history, chest radiograph, sputum smear, culture examination).

A positive reaction may indicate latent infection, prior infection, and/or M. tuberculosis disease and may not indicate active TB; individuals with a positive reaction should be considered positive by current public health guidelines and referred for further medical evaluation.

A negative tuberculin skin test should not be used to exclude active TB in individuals with symptoms compatible with TB (see False-negative Reactions under Cautions).

Booster Effect and Two-Step Testing

If tuberculin sensitivity has waned (see Actions), initial testing will produce a small or negative reaction. Repeated testing may boost size of reaction (booster effect), which can be misinterpreted as a conversion (i.e., positive reaction indicative of recent infection with M. tuberculosis).

Therefore, individuals requiring routine periodic testing (e.g., health-care professionals, residents and workers in hospitals, nursing homes, mental institutions, prisons) should initially receive 2-step testing (i.e., a repeat tuberculin test after an initial negative reaction) to permanently document infectivity status (e.g., uninfected, previously infected). If first test is negative, use result of second test performed 1–4 weeks later to determine TB status. If reaction to second test is positive, individual is considered previously infected; if reaction is negative, individual is considered uninfected. In these uninfected individuals, a reaction size of ≥10 mm upon repeat testing within a 2-year period is considered a conversion.

Individuals whose second test is negative, but whose reaction is positive after one year, are considered to have newly acquired TB infection and should be managed accordingly.

Dosage

Each dose (0.1 mL) is bioequivalent to 5 US units (TU) of the US reference standard (PPD-S).

Pediatric Patients

Diagnosis of TB Infection

Intradermal

0.1 mL.

Adults

Diagnosis of TB Infection

Intradermal

0.1 mL.

Cautions for Tuberculin

Contraindications

• Known hypersensitivity or previous severe reaction (e.g., anaphylaxis, vesiculation, ulceration, necrosis, blistering) to tuberculin or any ingredient in the formulation.

• Individuals with previous positive reactions; severe reactions (vesiculation, ulceration, necrosis) may occur in these patients.

• Individuals with documented active TB or a history of treatment for TB infection or disease.

• Individuals with extensive burns or eczema.

• Defer testing for patients with major viral infections or live-virus vaccination (e.g., measles, mumps, rubella, oral polio, yellow fever) in previous month; common cold is not contraindication to test (see False-negative Reactions under Cautions).

Warnings/Precautions

Warnings

Previous Severe Reaction

Risk of severe reaction at test site in individuals who previously experienced a severe reaction (e.g., vesiculation, ulceration, necrosis). Use not recommended in such individuals. (See Contraindications under Cautions.)

False-negative Reactions

Possible decreased ability to respond to test (resulting in false-negative reaction) in individuals with any condition that impairs or attenuates cell-mediated immunity, including viral infections (e.g., HIV, infectious mononucleosis, influenza, measles, mumps, rubella, varicella), overwhelming TB or tuberculous pleurisy, other bacterial infections (e.g., brucellosis, leprosy, pertussis, typhoid fever, typhus), fungal infections (e.g., blastomycosis), diseases affecting lymphoid organs (e.g., Hodgkin's disease, chronic leukemia, lymphoma, sarcoidosis), or malignancy.

Possible temporarily decreased ability to respond to test (resulting in false-negative reaction) caused by live virus vaccines (e.g., measles, mumps, rubella, oral polio, yellow fever). Administer skin test and vaccine at separate sites when tuberculin screening required at same time as live-virus vaccine. Delay tuberculin skin test for ≥4–6 weeks after live virus vaccination if live virus vaccine recently administered.

Possible decreased ability to respond to test (resulting in false-negative reaction) in individuals with metabolic derangements (e.g., chronic renal failure), low protein states, malnutrition, stress (e.g., surgery, burns, mental illness, graft-versus-host reactions), or with immunosuppressive therapy. (See Interactions.)

Reactivity to test possibly depressed or suppressed for 5–6 weeks following viral infections, immunization with certain live virus vaccines, or discontinuance of corticosteroid or immunosuppressive therapy. (See Interactions.)

Possible decreased ability to respond to test (resulting in false-negative reaction) in newborns and geriatric patients. (See Specific Populations under Cautions.)

In HIV-infected individuals, test becomes less reliable as CD4⁺ T-cell count declines; therefore, perform tuberculin testing as soon as possible after HIV infection develops.

Possible false-negative reaction if performed too soon after infection with M. tuberculosis. (See Actions.)

False-positive Reactions

Possible false-positive reaction in individuals infected with nontuberculous mycobacteria or in individuals previously vaccinated with BCG vaccine.

Cannot reliably distinguish between reactions caused by BCG vaccination and those caused by natural mycobacterial infections. In individuals with prior BCG vaccination, indurations ≥20 mm in diameter not likely caused by BCG vaccination.

Test reaction of ≥10 mm probably attributable to M. tuberculosis infection in a BCG-vaccinated individual from a country with a high prevalence of TB or who is in close contact with another person with infectious TB (especially if contact has spread M. tuberculosis to others) or if individual continually exposed to groups with a high TB prevalence.

Sensitivity gradually wanes with time (period of years) but may be boosted/prolonged by periodic tuberculin testing. (See Booster Effect and Two-Step Testing under Dosage and Administration.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactic/anaphylactoid reactions manifested by angioedema, upper respiratory stridor, dyspnea, rash, generalized rash and/or urticaria reported within 24 hours after injection; manifestations resolved following treatment with epinephrine, diphenhydramine, and/or corticosteroids. Allergic reactions may occur in individuals with no prior history of hypersensitivity to tuberculin skin test components.

Ensure immediate availability of epinephrine and other appropriate agents in case of anaphylactic/anaphylactoid or acute hypersensitivity reaction.

Major Toxicities

Strongly Positive Reactions

Possible vesiculation, ulceration, or necrosis in highly sensitive individuals; may result in scarring at test site.

ATS recommends using a dry dressing to prevent secondary infection.

Some manufacturers recommend using cold packs or topical corticosteroid preparations for symptomatic relief of pain, pruritus, and discomfort at injection site. However, topical 1% hydrocortisone ointment shown to be ineffective in reducing extent or rate of resolution of induration reaction.

General Precautions

Improper Storage and Handling

Possible loss of potency and inaccurate test results if improperly stored or handled. (See Storage under Stability.)

Specific Populations

Pregnancy

Category C. Tuberculin skin testing considered valid and safe throughout pregnancy. Weigh benefit against risk, particularly in high-risk groups.

Pediatric Use

Due to an immature immune system, infants <6 weeks of age infected with M. tuberculosis may not react to test. In older infants and children, tuberculin sensitivity develops 2–12 weeks (median: 3–6 weeks) after initial infection.

Very young children infected with M. tuberculosis at increased risk for active tuberculosis. During contact investigations, give high priority to skin testing and treatment in young children and infants exposed to individuals with active TB.

Geriatric Use

Skin test sensitivity may wane with advancing age; skin test reaction may develop slowly and not be maximal until >72 hours.

Common Adverse Effects

Erythema, pain, pruritus, discomfort at test site. (See Major Toxicities under Cautions.)

Occasionally, localized redness or rash (without induration) within 12 hours of skin test; reaction does not indicate TB infection. (See Major Toxicities under Cautions.)

Drug Interactions

Specific Drugs

Tuberculin Pharmacokinetics

Absorption

Onset

In sensitive individuals, delayed hypersensitivity reaction is evident within 5–6 hours and is maximal within 48–72 hours.

In geriatric individuals or first-time recipients, reaction develops more slowly and may not be maximal until after 72 hours.

Duration

In tuberculin-sensitive individuals, delayed hypersensitivity reaction subsides over a period of days. Positive reaction may persist for up to 1 week.

Stability

Storage

Parenteral

Injection

2–8°C; do not freeze. Protect from light. Due to possible oxidation and degradation (which may affect potency), discard vials in use for ≥30 days.

Actions

• Purified protein fraction isolated from a human strain of M. tuberculosis.

• Produces delayed hypersensitivity response (e.g., local vasodilation, edema, infiltration of leukocytes) in individuals with tuberculin sensitivity (e.g., those infected with M. tuberculosis or other mycobacteria, those with history of BCG vaccination). Test not specific for M. tuberculosis; other nontuberculous mycobacteria may cross-react.

• Delayed hypersensitivity develops 2–12 weeks (median: 3–4 weeks) following infection and manifests as palpable induration (and occasional vesiculation and necrosis) at injection site.

• Tuberculin sensitivity generally persists throughout life but may gradually diminish or disappear with time (over a period of years) or advancing age. Upon initial testing after sensitivity has waned, reactivity may be small or absent. (See Booster Effect and Two-Step Testing under Dosage and Administration.)

Advice to Patients

• Risk of pain, pruritus, and discomfort at injection site. Importance of informing clinician if vesiculation, ulceration, or necrosis occurs.

• Importance of patient returning to clinician 48–72 hours after skin test administration for interpretation of test.

• Importance of maintaining personal immunization record.

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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