AHFS Class:

• Tuberculosis 36:84

Generic Name(s):

• Tuberculin Purified Protein Derivative

Tuberculin is a skin-test antigen preparation derived from culture media filtrates of a human strain of Mycobacterium tuberculosis .1,2 Tuberculin is commercially available as purified protein derivative (PPD).1,2

Tuberculin purified protein derivative (PPD) has the following uses

Tuberculin purified protein derivative (PPD) is used to perform a tuberculin skin test (TST) to determine whether a person is infected with Mycobacterium tuberculosis , the bacteria that causes tuberculosis (TB) infection.1,2 In the US, the prevalence of Mycobacterium tuberculosis infection and active disease varies for different segments of the population; however, the risk for M. tuberculosis infection in the overall population is low.2 The primary strategy for preventing and controlling TB is to minimize the risk of transmission by identifying and treating patients who have active infectious TB, finding and screening persons who have been in contact with active infectious TB patients, and screening high risk populations.2 The Centers for Disease Control and Prevention (CDC) has published guidelines on the diagnosis and treatment of TB infection and disease.1,3,4,5 Currentrecommendations can be accessed at [Web].

CDC recommends TB testing as part of routine healthcare in persons at increased risk for TB infection; these individuals include healthcare workers who care for patients with TB disease, individuals born in or who frequently travel to countries where TB disease is common, those with contact with persons known or thought to have infectious TB disease, and those who live or spend time in settings where TB is more common.4,5 There are 2 types of tests that can be used to detect TB infection: the TST and TB blood test (also called interferon-gamma release assay or IGRAs).3 Healthcare providers are encouraged to use newer TB blood tests to screeen for TB infection; however, test availability, costs, and reasons for testing may factor into the decision regarding the appropriate test to use.3,5 CDC states that TST is the recommended method for testing children younger than 5 years of age.3 In order to prevent false-positive reactions, the TB blood test is preferred for persons 5 years of age and older who were previously vaccinated with the bacille Calmette-Guerin (BCG) vaccine.3 The American Academy of Pediatrics (AAP) suggests the use of TST as the preferred test in children younger than 2 years of age, but states that many experts will use a TB blood test in children of any age, especially if the child has received a BCG vaccine but has no other significant risk factors other than foreign birth.6

Tuberculin reactivity may indicate latent infection, prior infection, and/or disease with M. tuberculosis and does not necessarily indicate the presence of active tuberculous disease; further diagnostic evaluation (e.g., medical history, physical exam, chest X-ray and other laboratory tests) is necessary to establish whether the infection has progressed to clinical tuberculosis.1 3,5 Treatment of latent TB infection is essential to reduce the risk of progression to TB disease.3,5

General

Tuberculin purified protein derivative (PPD) is available in the following dosage form(s) and strength(s):

Tuberculin PPD (Mantoux)(Tubersol^®): 5 mL multi-dose vials containing 5 Tuberculin Units (TU) per 0.1 mL for intradermal injection.1

Tuberculin PPD, diluted (Aplisol^®) is supplied as multi-dose vials containing 5 Tuberculin Units (TU) per 0.1 mL for intradermal injection.2

Administration

Administer by intradermal injection only; do not inject IV, IM, or subcutaneously.1,2 If subcutaneous injection occurs, the test cannot be interpreted.1

Store vials at 2-8ºC; do not freeze and protect from light.1,2 Vials in use for more than 30 days should be discarded due to possible oxidation and degradation which may affect potency.1,2

Inspect the vials for particulate matter and/or discoloration before use.1,2,3 If these conditions exist, do not administer the product.1,2 Use a separate syringe and needle for each injection.1,2

Administer by intradermal injection using the Mantoux method.1,2,3

Mantoux Test

The preferred site of the test is the volar aspect of the forearm.1,2 Avoid areas of the skin that are red or swollen.1,2 Avoid visible veins and areas with lesions.1,2

Clean the skin site with a suitable germicide (e.g., 70% alcohol) and allow to dry prior to injection of the antigen.1,2

The test should be performed by injecting 0.1 mL of tuberculin PPD with a tuberculin syringe.3

To administer the dose, insert the point of the needle into the most superficial layers of the skin with the needle bevel pointing upward and administer the dose by slow intradermalinjection.1,2 If the intradermal injection is performed properly, a pale bleb will rise at the needle point.1,2 This bleb will disperse within minutes; do not dress the site.1,2

A drop of blood may appear at the administration site following injection; this is normal.1,2 Use a gauze pad to gently remove the blood but avoid squeezing out the injected tuberculin test fluid.1,2

In the event of an improperly performed injection (i.e., no bleb formation), repeat the test immediately at another site, at least 2 inches from the first site and circle the second injection site as an indication that this is the site to be read.1,2

Inform the patient of the need to return for the reading of the test by a trained healthcare professional.1 Self-reading may be inaccurate and is strongly discouraged.1 A patient who does not return within 72 hours will need to be rescheduled for another skin test.3

Interpretation of Test

The skin test should be read by a trained healthcare professional 48 to 72 hours after the injection.1,2,3 Skin test sensitivity is indicated by induration only; redness (erythema) should not be measured.1,2

Measure the diameter of induration transversely to the long axis of the forearm and record the measurement in millimeters (including 0 mm).1,2 Find the margins of the induration by drawing the index or middle finger lightly across the reaction.2 The tip of a ballpoint pen, gently pushed at a 45° angle toward the site of injection, will stop at the edge of induration.1,2

Tuberculin reactivity may indicate latent infection, prior infection and/or disease with M. tuberculosis and does not necessarily indicate the presence of active tuberculous disease.1,2

Classification of the tuberculin skin test reaction according to the Centers for Disease Prevention and Control (CDC) is as follows:3

Induration of 5 or more millimeters is considered positive in people living with HIV; recent contact of a person with infectious TB disease; people with chest x-ray findings suggestive of previous TB disease; people with organ transplants; or other immunosuppressed people (e.g., patients on prolonged therapy with corticosteroids equivalent to/greater than 15 mg per day of prednisone or those taking TNF-α antagonists).3

Induration of 10 or more millimeters is considered positive in people born in countries where TB disease is common, including Mexico, the Philippines, Vietnam, India, China, Haiti, and Guatemala, or other countries with high rates of TB; people who abuse drugs; mycobacteriology laboratory workers; people who live or work in high-risk congregate settings (e.g., nursing homes, homeless shelters, or correctional facilities); people with certain medical conditions that place them at high risk for TB (e.g., silicosis, diabetes mellitus, severe kidney disease, certain types of cancer, and certain intestinal conditions); people with a low body weight (<90% of ideal body weight); children younger than 5 years of a and infants, children, and adolescents exposed to adults in high-risk categories.3

Induration of 15 or more millimeters is considered positive in people with no known risk factors for TB.3

Negative reactions:Induration of less than 15 milimeters is considered negative in persons with no risk factors for TB.2 An individual who does not show a positive reaction to 5 TU on the first test, but is suspected of being TB positive, may be retested with 5 TU.1 Any individual who does not show a positive reaction to an initial injection of 5 TU, or a second test with 5 TU may be considered as tuberculin negative.1

False positive reactions: False positive tuberculin reactions can occur in individuals who have been infected with other mycobacteria, including vaccination with bacille Calmette-Guerin (BCG) vaccine.1,2,3 False-positive reactions also may occur from incorrect measurement or interpretation of the reacion or incorrect antigen used.3 A TB blood test is the preferred method of testing for people who have received the BCG vaccine in order to prevent false-positive reactions.3

False negative reactions:Some persons may not react to the TST even though they are infected with M. tuberculosis .3 The reasons for these false-negative reactions may include, but are not limited to, the following: anergy, recent TB infection (within the past 8 to 10 weeks), very young age (younger than 6 months), recent live-virus measles or smallpox vaccination, incorrect method or administration of the tuberculin skin test, or incorrect measurement or interpretation of the skin test reaction.3

Altered immune status: Impaired or attenuated cell mediated immunity (CMI) can potentially cause a false-negative tuberculin reaction.1 Many factors have been reported to cause a decreased ability to respond to the tuberculin test in the presence of tuberculous infection including viral infections (e.g., measles, mumps, chickenpox and HIV), live virus vaccinations (e.g., measles, mumps, rubella, oral polio and yellow fever), overwhelming tuberculosis, other bacterial infections, leukemia, sarcoidosis, fungal infections, metabolic derangements, low protein states, diseases affecting lymphoid organs, drugs (corticosteroids and many other immunosuppressive agents), and malignancy or stress.1 A tuberculin skin test should be deferred for patients with major viral infections or live-virus vaccination in the past month.1 Persons with the common cold may be tuberculin tested.1 Because skin test results in HIV-infected individuals are less reliable as CD4 counts decline, screening should be completed as early as possible after HIV-infection occurs.1

Boosted reaction: A boosted reaction occurs mainly in previously infected, older adults whose ability to react to tuberculin has decreased over time.3 When given a tuberculin skin test years after infection, these persons may have an initial negative reaction.3 However, the skin test may stimulate the immune system, causing a positive or boosted reaction to subsequent tests.3 Giving a second tuberculin skin test after an initial negative reaction is called two-step testing.3

Dosage

Diagnosis of Tuberculosis (TB) Infection

Each dose (0.1 mL) is bioequivalent to 5 US units (TU) of the US reference standard (PPD-S).1,2

A test dose of 0.1 mL is the standard strength used for intradermal (Mantoux) testing.1,2

Contraindications

• Patients with known hypersensitivity or allergy to tuberculin PPD or any of its components.1,2,3
• Manufacturer of Tubersol^® states that the tuberculin skin test should not be administered to persons with documented active tuberculosis or a clear history of treatment of TB infection or disease, and to persons with extensive burns or eczema.1

Warnings/Precautions

Hypersensitivity

A hypersensitivity or allergic reaction may occur following use of tuberculin PPD even in persons with no prior history of hypersensitivity to the product components.1,2 The tuberculin skin test should not be administered to persons who previously experienced a severe reaction (e.g., vesiculation, ulceration, necrosis) at the test site.1,2 Epinephrine must be immediately available in case an anaphylactoid or acute hypersensitivity reaction occurs.1,2

Syncope

Syncope (fainting) can occur in association with administration of injectable medicines, including tuberculin PPD.1 Procedures should be in place to avoid falling injury and to restore cerebral perfusion following syncope.1

Diagnostic Limitations

The predictive value of the tuberculin skin test depends on the prevalence of infection with M. tuberculosis and the relative prevalence of cross-reactions with nontuberculous mycobacteria.2

False positive or false negative tuberculin skin test reactions may occur in some individuals.1,2 False positive tuberculin reaction tests occur in individuals who have been infected with other mycobacteria, including vaccination with BCG.1,2 Not all infected persons will have a delayed hypersensitivity reaction to a tuberculin test.1,2 Many factors have been reported to cause a decreased ability to respond to the tuberculin test such as the presence of infections, viral infections (measles, mumps, chickenpox, HIV), live virus vaccinations (measles, mumps, rubella and other live vaccines), bacterial infections (typhoid fever, brucellosis, typhus, leprosy, pertussis, overwhelming tuberculosis, tuberculous pleurisy), fungal infections (South American blastomycosis), drugs (corticosteroids and other immunosuppressive agents), metabolic derangements (chronic renal failure), low protein states (severe protein depletion, afibrinogenemia), age (newborns, elderly patients with waned sensitivity), stress (surgery, burns, mental illness, graft-versus-host reactions), diseases affecting lymphoid organs (Hodgkin's disease, lymphoma, chronic leukemia, sarcoidosis), and malignancy.1,2

Any condition that impairs or attenuates cell mediated immunity potentially can cause a false negative reaction, including aging.2

Tuberculin skin test results are less reliable in HIV-infected individuals as CD4 counts decline.2

Administration Precautions

Avoid injecting tuberculin subcutaneously; if this occurs, no local reaction develops, but a general febrile reaction and/or acute inflammation around old tuberculous lesions may occur in highly sensitive individuals.1,2

A separate, sterile, single-use disposable syringe and needle should be used for each individual patient to prevent possible transmission of serum hepatitis virus and other infectious agents from one person to another.1,2 Special care should be taken to ensure that the product is injected intradermally and not into a blood vessel.1,2

Before administration of tuberculin PPD, review the patient's history with respect to possible immediate-type hypersensitivity to the product, determination of previous use of tuberculin PPD, and the presence of any contraindications.1,2

Epinephrine should be immediately available in case an anaphylactoid or acute hypersensitivity reaction occurs.1,2

Failure to store and handle tuberculin PPD as recommended may result in a loss of potency and inaccurate test results.2

Specific Populations

Pregnancy

Animal reproduction studies have not been conducted with tuberculin PPD.1,2 It is also not known whether the drug can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.1,2 Tuberculin PPD should be given to a pregnant woman only if clearly needed.1,2

Lactation

It is not known whether tuberculin PPD is excreted in human milk.1 Because many drugs are excreted in human milk, caution should be exercised when tuberculin PPD is administered to a nursing woman.1

Pediatric Use

There is no contraindication to tuberculin skin testing of infants and children.1,2 Young children (e.g., infants <6 months ofage) who are infected with M. tuberculosis may not react to tuberculin PPD.1,2,6 The American Academy of Pediatricians (AAP) recommends that only children who have a risk factor for TB infection or are at risk for progressing to disease, are suspected of having TB disease, or who have immunosuppressive disease or about to start immunsuppressive therapy should be tested with either a tuberculin skin test (TST) or a TB blood test.6

Geriatric Use

Once acquired, tuberculin sensitivity tends to persist, although it often wanes with time and advancing age.2 In geriatric patients, the reaction may develop more slowly and may not be maximal until after 72 hours.2 A number of factors have been reported to cause a decreased ability to respond to the tuberculin test, such as elderly patients with waned sensitivity.2 Any condition that impairs or attenuates cell mediated immunity potentially can cause a false negative reaction, including aging.2

Common Adverse Effects

Induration at the tuberculin PPD injection site is the expected reaction for a positive skin test; however, strongly positive reactions incuding vesiculation, ulceration, necrosis, or scarring may occur.1,2 Immediate erythematous or other reactions also may occur at the injection site.1,2

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Reactivity to the tuberculin skin test may be depressed or suppressed in persons who are receiving corticosteroids or immunosuppressive agents.1,2 Reduced reactivity may be present for as long as 5-6 weeks after discontinuation of therapy.1,2

Reactivity to tuberculin PPD may be temporarily depressed by certain live virus vaccines (measles, mumps, rubella, oral polio, yellow fever, and varicella).1,2,3 If a parenteral live attenuated virus vaccine has been administered recently, tuberculin testing should be delayed for >1 month after vaccination.1

When tuberculin screening is required at the same time as a measles-containing vaccine or other parenteral live attenuated virus vaccine, simultaneous administration of tuberculin PPD and the vaccine at separate sites is the preferred option.1

Actions

Mechanism of Action

Tuberculin PPD is a sterile aqueous solution of a purified protein fraction for intradermal administration.1,2

Tubersol^® is prepared from a large master batch (Connaught tuberculin CT68) and is a cell-free purified protein fraction obtained from a human strain of M. tuberculosis grown on a protein-free synthetic medium and inactivated.1 The purified protein fraction of Aplisol^® is isolated from culture media filtrates of a human strain of M. tuberculosis by the method of F. B. Seibert.2

After a person becomes infected with mycobacteria, T lymphocytes proliferate in response to the antigenic stimulus and become sensitized.1,2 After 3-8 weeks, these sensitized T cells enter the bloodstream and circulate for months or years.1 This sensitization process occurs principally in the regional lymph nodes.1,2 Once acquired, tuberculin sensitivity tends to persist, although it often wanes with time and advancing age.2 The injection of tuberculin PPD into the skin stimulates the lymphocytes and activates the series of events leading to a delayed-type hypersensitivity response.2

Delayed hypersensitivity reactions to tuberculin typically begin at 5 to 6 hours, are maximal at 48 to 72 hours and subside over a period of days.1,2 The resultant immune response consists of induration due to cell infiltration and occasionally vesiculation and necrosis.1 Clinically, a delayed hypersensitivity reaction to tuberculin is a manifestation of previous infection with M tuberculosis or a variety of non-tuberculosis bacteria.1 In most cases sensitization is induced by natural mycobacterial infection or by vaccination with BCG Vaccine.1

Advice to Patients

• Prior to administration of tuberculin PPD, review the patient's current health status and medical history.1,2 The patient's immunization history should also be reviewed for possible sensitivity to components of the product.1,2
• Inform the patient of the need to return for the reading of the PPD test.1,2 Self-reading of the test has been shown to be inaccurate and unreliable.1,2
• The healthcare provider should give the patient a permanent personal record.1 In addition, the healthcare provider should record the testing history in thepermanent medical record of each patient.1 This permanent record should contain the name of the product, date given, dose, manufacturer, and lot number, as well as the test result in millimeters of induration (including 0 mm, if appropriate).1 Reporting results only as negative or positive is not satisfactory.1

Additional Information

AHFS first Release^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Only references cited for selected revisions after 1984 are available electronically.

1. Sanofi Pasteur. Tubersol^® (tuberculin purified protein derivative [Mautoux]) diagnostic antigen prescribing information. Swiftwater, PA; 2021 Oct.

2. Par Pharmaceuticals. Aplisol^® (tuberculin purified protein derivative, diluted [stabilized solution]) diagnostic antigen prescribing information. Chestnut Ridge, NY; 2017 Oct.

3. US Department of Health and Human Services Centers for Disease Control and Prevention (CDC). Tuberculin skin testing-information for health care providers. Updated Sept 2020. From CDC website. [Web]

4. Caruso E, Mangan JM, Maiuri A, Bouwkamp B, DeLuca N. Tuberculosis Testing and Latent Tuberculosis Infection Treatment Practices Among Health Care Providers — United States, 2020-2022. MMWR Morb Mortal Wkly Rep 2023;72:1183-1189.

5. US Department of Health and Human Services Centers for Disease Control and Prevention (CDC). Questions and answers about tuberculosis.

6. Nolt D, Starke JR. Tuberculosis Infection in Children and Adolescents: Testing and Treatment. Pediatrics. 2021 Dec 1;148(6):e2021054663. doi: 10.1542/peds.2021-054663. PMID: 34851422.