Medication Guide App

Tuberculin, Purified Protein Derivative (Parenteral-Local )


VA CLASSIFICATION
Primary: DX300

Commonly used brand name(s): Aplisol; Aplitest; Tuberculin PPD TINE TEST; Tubersol.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Diagnostic aid (tuberculosis)—

Indications

Accepted

Tuberculosis (diagnosis)—Tuberculin, purified protein derivative (PPD) is indicated as a diagnostic aid in the detection of Mycobacterium tuberculosis infection. {29} It is also indicated when BCG vaccination or isoniazid prophylaxis is being considered. {01} {02} {03} {04} {06} {07} {19}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Tuberculin PPD is a sterile isotonic solution of tuberculin. It is obtained from a human strain of Mycobacterium tuberculosis grown on a protein-free synthetic medium and buffered with potassium and sodium phosphates {01} {02} {03} {04} {06} {07} {19}

Mechanism of action/Effect:

Intradermally injected tuberculin PPD causes a delayed (cellular) hypersensitivity reaction in individuals sensitized by mycobacterial infection. {01} {06} Following infection with mycobacteria, sensitization of T-cells {26} occurs primarily in the regional lymph nodes. {01} {06} Natural infection with M. tuberculosis usually initiates a cell-mediated immune response against mycobacterial antigens. T-cells proliferate in response to the infection and give rise to T-cells specifically sensitized to mycobacterial antigens. {01} {03} {04} {06} After several weeks, these T-lymphocytes enter the bloodstream and circulate for a long period of time. {01} {06} Subsequent restimulation of these T-lymphocytes with intradermal injection of tuberculin PPD evokes a local reaction mediated by these cells. {01} {03} {04} {06}

Onset of action:

5 to 6 hours after intradermal injection of tuberculin PPD. {01} {06} The reaction reaches its peak more than 24 (usually 48 to 72) hours after administration. {01} {06} {07}


Precautions to Consider

Pregnancy/Reproduction
Fertility—
Studies on effects of tuberculin PPD on fertility have not been done.

Pregnancy—
Studies have not been done in humans. It is not known whether tuberculin PPD can cause harm to the fetus when administered to a pregnant woman. However, during pregnancy known positive reactors may demonstrate a negative response to the PPD tine test. {33}

Studies have not been done in animals. {01} {02} {03} {04} {06}

FDA Pregnancy Category C. {01} {02} {03} {04} {06}

Breast-feeding

It is not known whether tuberculin PPD is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of tuberculin PPD have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.


Geriatrics


In geriatric patients, reactions may develop slowly and may not peak until after 72 hours. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Bacillus Calmette-Guérin (BCG) vaccine    (individuals previously given BCG vaccine will usually {29} show a positive reaction to tuberculin test {01} {06} {07} administered within 6 to 12 weeks after BCG vaccination; a few years after BCG vaccination, reaction to tuberculin tests may be either positive or negative; {06} a positive reaction to tuberculin PPD years after BCG vaccination suggests tuberculous infection {27})


Corticosteroids or
Immunosuppressive agents    (reactivity to the tuberculin test may be suppressed or enhanced {31} in patients receiving these medications {01} {06})


Vaccines, killed or live virus    (the reaction to tuberculin PPD may be suppressed if the test is given within 4 to 6 weeks following immunization with killed or live virus vaccines {01} {06})


Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With results of this test

Due to medical problems or conditions
Acquired immunodeficiency syndrome (AIDS) or{06}{07}{08}{09}{10}{11}{12}{13}{15}{18}{21}{22}{24}
Anergy or{01}{03}{06}{07}
Atopic dermatitis or sun-damaged skin or
Human immunodeficiency virus (HIV) infection or{06}{07}{08}{09}{10}{11}{12}{13}{15}{18}{21}{22}{24}
Illness that affects the lymphoid system (Hodgkin's disease, lymphoma, chronic lymphocytic leukemia) or{01}{03}{06}{07}
Pregnancy or
Stress, severe{06}    (may cause false-negative test results {06})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Known positive tuberculin reaction    (in highly sensitive persons the reaction at the test site can be severe, resulting in vesiculation, ulceration, or necrosis {01} {02})



Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Allergic reactions (skin rash or itching)
    
necrosis, ulceration, or vesiculation at the site of injection (redness, blistering, peeling, or loosening of the skin)



Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Erythematous reaction (redness at the site of injection)
    
granuloma (sores at and around the site of injection{06}{07})
    
pain
    
pruritus (itching)


Note: Discomfort and transient bleeding may be observed at the PPD tine puncture site. {33}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tuberculin, Purified Protein Derivative (PPD) Injection.

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to tuberculin PPD
Other medical problems, especially known positive tuberculin reaction


Side/adverse effects
» Signs of potential side effects, especially allergic reactions and necrosis, ulceration, or vesiculation at the site of injection


General Dosing Information
Anergy to tuberculin among asymptomatic HIV-positive persons is common, making interpretation of tuberculin tests difficult. Therefore, the Centers for Disease Control (CDC) has produced guidelines for assessing delayed-type hypersensitivity in these patients. Concurrent administration of at least 2 other skin test antigens is recommended. The CDC suggests choosing from among mumps skin test antigen, candida antigen, and tetanus toxoid. The test antigens are given concurrently with the tuberculin skin test and the response is measured 48 to 72 hours later. Any amount of induration is considered evidence of delayed-type hypersensitivity; failure to elicit a response is considered evidence of anergy. HIV-positive persons and others at risk of anergy are considered to have a significant reaction to a standard Mantoux test if the induration reaction measures 5 mm or more in diameter, regardless of the reaction to the other antigens. It is very important to perform anergy testing in a population at increased risk of tuberculosis. {06} {07} {08} {09} {10} {11} {12} {13} {15} {18} {21} {22} {24}

Booster effect—The ability of persons who have TB infection to react to tuberculin may gradually wane. For example, if tested with tuberculin, adults who were infected during their childhood may have a negative reaction. However, the tuberculin could boost the hypersensitivity, and the size of the reaction could be larger on a subsequent test. This boosted reaction may be misinterpreted as a tuberculin test conversion from a newly acquired infection. Misinterpretation of a boosted reaction as a new infection could result in unnecessary investigations of laboratory and patient records in an attempt to identify the source of infection and in unnecessary prescription of preventive therapy for health care workers. Although this booster effect can occur among persons in any age group, the likelihood of the effect increases with the age of the person being tested. {01} {02} {06} {17} {20}

Two-step testing—When tuberculin testing of an adult is to be repeated periodically, 2-step testing can be used to reduce the likelihood that a boosted reaction will be misinterpreted as a new infection. Two-step testing should be performed on all newly employed health care workers who have an initial negative tuberculin test at the time of employment and have not had a documented negative tuberculin test result during the 12 months preceding the initial test. A second test should be performed 1 to 3 weeks after the first test. If the second test result is positive, this is most likely a boosted reaction, and the patient should be classified as previously infected. If the second test result is negative, the patient is classified as uninfected, and a positive reaction to a subsequent test is likely to represent a new infection with M. tuberculosis . {06} {27}

It is recommended that children at high risk for tuberculosis be given tuberculin skin tests annually by the Mantoux method. {33} Children considered at high risk include those from areas with a high prevalence of the disease; those from households with 1 or more cases of tuberculosis; black, Hispanic, Asian, native American, and native Alaskan children, and others who are socioeconomically deprived; children from Asia, Africa, the Middle East, Latin America, or the Caribbean and children of parents who have immigrated from these areas; and children with medical risk factors for tuberculosis. {06} {14} {25}

It is recommended that individuals with signs and/or symptoms suggestive of current tuberculous disease be given tuberculin skin test routinely by the Mantoux method. These individuals include persons who are recent contacts of known cases of clinical tuberculosis or are suspected of having tuberculosis; persons with abnormal chest radiographs compatible with past tuberculosis; persons with medical conditions that increase the risk of tuberculosis; HIV-infected individuals; immigrants from Asia, Africa, Latin America, and Oceania; inner-city and skid row populations. {06} {14} {25}

Tuberculin PPD is administered by intradermal injection (the Mantoux method) or by using a disposable multiple-puncture device. These 2 commonly used test methods are briefly described below.

The Mantoux test method: The test is performed by intradermally injecting exactly 0.1 mL of diluted tuberculin PPD. The result is read 48 to 72 hours later and only induration is considered in interpreting the test. Induration is a hard, raised area with clearly defined margins at, and around, the injection site. Erythema may develop at the injection site but has no diagnostic value. The test is performed as follows:    • The site of the test is usually the flexor surface of the forearm, about 4 inches below the elbow. Other skin sites may be used, but the flexor surface of the forearm is preferred. The site of the test should be free of lesions and away from the veins.
   • The skin at the injection site is cleansed with 70% alcohol or another suitable antiseptic agent {31} and allowed to dry.
   • The test material is administered with a tuberculin syringe (0.5 or 1.0 mL) fitted with a short (one-half-inch) 26- or 27- gauge needle.
   • The syringe and needle should be a sterile, disposable, single-use type or should have been sterilized by autoclaving, boiling, or the use of dry heat. A separate sterile unit should be used for each person tested.
   • The diaphragm of the vial-stopper should be wiped with 70% alcohol.
   • The needle is inserted through the stopper diaphragm of the inverted vial. Exactly 0.1 mL is added to the syringe, with care being taken to exclude air bubbles and to keep the lumen of the needle filled.
   • The point of the needle is inserted into the most superficial layers of the skin with the needle bevel pointed upward. As the tuberculin solution is injected, a pale bleb 6 to 10 mm in size will rise over the point of the needle. This is quickly absorbed, and no dressing is required. In the event that the injection is delivered subcutaneously (in this case no bleb will form) or if a significant part of the dose leaks from the injection site, the test should be repeated immediately at another site at least 5 cm (2 inches) removed from the first site.
   • The test site should be examined by trained personnel {27} 48 to 72 hours after the injection. The examination should be performed in good light with the arm slightly flexed at the elbow. The reaction should be measured and recorded in millimeters. Any induration reaction that measures {30} {31} {32} 5 mm or more in diameter is considered positive in persons who have had recent close contact with tuberculosis; persons who have chest radiographs consistent with tuberculosis (including stable lesions consistent with “inactive” tuberculosis); immunosuppressed persons (including HIV-infected persons and patients on immunosuppressive therapy); and persons with cancer (including leukemia or lymphoma), Hodgkin's disease, or end-stage renal disease. Induration of 10 mm or more is considered a positive reaction in foreign-born persons; substance abusers (alcoholics and intravenous drug users); residents and employees of correctional institutions and nursing homes; hospital employees; persons over age 70; low-income populations, including the homeless; and persons with medical conditions including diabetes mellitus, post gastrectomy, silicosis, prolonged corticosteroid therapy, and 10% or more below ideal body weight. Induration of 15 mm or more is considered a positive reaction in all other persons (general population with no known tuberculosis risk factors). {30} {31} {32}


The multiple-puncture (Tine) test method: Each test unit provides for the intradermal administration of 1 test-dose of tuberculin PPD. The test is performed as follows:    • The preferred site of the test is the flexor surface of the forearm about 4 inches below the elbow. Other suitable skin sites, such as the dorsal surface of the forearm, may be used. Areas without adequate subcutaneous tissue, such as skin over a tendon, as well as hairy areas, {33} should be avoided.
   • The skin at the test site should be cleaned with 70% alcohol or another suitable antiseptic agent such as acetone, ether, or soap and water {33} and allowed to dry thoroughly.
   • To expose the 4 impregnated tines, remove the protective cap while holding the plastic handle. {33}
   • The patient's forearm should be grasped firmly to stretch the skin taut at the test site and to prevent any jerking motion of the arm that could cause scratching with the tines.
   • The test unit should be applied firmly without twisting to the test area for approximately 1 second. Sufficient pressure should be exerted to ensure that all 4 tines have penetrated the skin.
   • Used units should be disposed of carefully to avoid accidents. Do not reuse.
   • The test site should be examined by trained personnel 48 to 72 hours after application of the test. The examination should be performed in good light with the arm slightly flexed at the elbow. The presence of vesiculation indicates a positive reaction to the test. The test reaction is negative if both induration and vesiculation are absent. Induration reactions less than 2 mm in diameter may be considered negative. However, unless vesiculation is present, individuals with any size induration reaction should be retested using a standard Mantoux test. {03} {04} {06} {07}The dose of tuberculin PPD introduced into the skin with currently available multiple-puncture devices cannot be precisely controlled. Therefore, this test should not be used for the periodic surveillance of individuals likely to be exposed to clinical tuberculosis or for the evaluation of individuals who are suspected of having tuberculosis or are contacts of persons with clinical tuberculosis. {31}


The Heaf test method: The test is performed using the Heaf multiple-puncture apparatus. The result is read 3 to 10 days later and only induration is considered in interpreting the test.    • The site of the test is usually the volar surface of the left forearm. The skin at the test site is cleansed with alcohol or another suitable antiseptic agent and allowed to dry. The undiluted tuberculin is transferred using a syringe needle or loop and smoothed over a circular area of about 1 cm in diameter.
   • The needle points of the apparatus are placed on the forearm to give a puncture of 1 mm (for children under 2 years of age) or 2 mm (for older children and adults).
   • With the apparatus held at a right angle to the skin, the end plate is placed firmly and evenly in the center of the film of tuberculin and the handle pressed to release the needles. No dressing need be applied. It is very important that the apparatus be properly sterilized after each application or that a disposable end plate be used.
   • A positive result should be recorded only when there is palpable induration around at least 4 puncture points. The induration is best felt by passing the finger lightly over the punctures. If no resistance is felt, a negative result should be recorded.
   • Four grades of positive response are recognized:

• Grade 1—At least 4 small indurated papules.


• Grade 2—An indurated ring formed by confluent papules.


• Grade 3—A solid induration 5 to 10 mm wide.


• Grade 4—Induration over 10 mm wide. {34}



For treatment of adverse effects
Recommended treatment consists of the following:

   • If strongly positive reactions, including vesiculation, ulceration, or necrosis, occur, cold packs or topical steroid preparations may be used for symptomatic relief of the associated pain, pruritus, and discomfort. {06}


Parenteral Dosage Forms

TUBERCULIN (Purified Protein Derivative [PPD] Injection) USP

Usual adult and adolescent dose
Tuberculosis (diagnosis)
Intradermal, 5 U.S. units (tuberculin units [TU]).


Note: The 1-TU-per-test-dose preparation is used for individuals suspected of being highly sensitized, since larger initial doses may result in severe skin reactions. The preparation containing 250 TU per test dose should be used exclusively for the testing of individuals who fail to react to a previous injection of 5 TU; under no circumstances is it to be used for the initial injection. {01} {06}


Usual pediatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


1 U.S. unit (TU) per test dose (0.1 mL) (Rx) [Tubersol]


5 U.S. units (TU) per test dose (0.1 mL) (Rx) [Aplisol] [Tubersol]


250 U.S. units (TU) per test dose (0.1 mL) (Rx) [Tubersol]

Canada—


1 U.S. unit (TU) per test dose (0.1 mL) (Rx) [Tubersol]


5 U.S. units (TU) per test dose (0.1 mL) (Rx) [Tubersol]


250 U.S. units (TU) per test dose (0.1 mL) (Rx) [Tubersol]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Protect from light. {01} {02} {05}

Additional information:
Vials of tuberculin PPD that have been opened should be discarded after 1 month of use, since oxidation and degradation may have reduced the potency. {01}


TUBERCULIN (Purified Protein Derivative [PPD] Multiple-Puncture Device) USP

Usual adult and adolescent dose
Tuberculosis (diagnosis)
Intradermal, equivalent to or more potent than {33} 5 U.S. units (tuberculin units [TU]).


Usual pediatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


Equivalent to or more potent than{33} 5 U.S. units in individually capped test units (Rx) [Aplitest] [Tuberculin PPD TINE TEST]

Canada—
Not commercially available.

Packaging and storage:
Store below 30 °C (86 °F). Do not refrigerate. {03} {04} {05}



Developed: 08/01/1995



References
  1. Tubersol package insert (Connaught—US/Canada), Rec 7/94.
  1. Aplisol package insert (Parke-Davis—US), Rev 2/94, Rec 7/94.
  1. Tuberculin PPD TINE TEST package insert (Lederle—US), Rev 7/89, Rec 48/94.
  1. Aplitest package insert (Parke-Davis—US), Rev 9/93, Rec 7/94.
  1. The United States pharmacopeia. The national formulary. USP 22nd revision (January 1, 1990). NF 17th ed (January 1, 1990). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1990: 1433.
  1. McEvoy GK, editor. AHFS Drug information 94. Bethesda, MD: American Society of Hospital Pharmacists, 1994: 1631-6.
  1. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 30th ed. London: The Pharmaceutical Press, 1993: 779-80.
  1. Selwyn PA, Sckell BM, Alcabes P, Friedland GH, Klein RS, Schoenbaum EE. High risk of active tuberculosis in HIV-infected drug users with cutaneous anergy. JAMA 1992; 268(4): 504-9.
  1. Graham NMH, Nelson KE, Solomon L, Bonds M, Rizzo RT, Scavotto J, et al. Prevalence of tuberculin positivity and skin test anergy in HIV-1-seropositive and -seronegative intravenous drug users. JAMA 1992; 267(3): 369-73.
  1. Moreno S, Baraia-Etxaburu J, Bouza E, Parras F, Prez-Tascn M, Miralles P, et al. Risk for developing tuberculosis among anergic patients infected with HIV. Ann Intern Med 1993; 119(3): 194-8.
  1. Markowitz N, Hansen NI, Wilcosky TC, Hopewell PC, Glassroth J, Kvale PA, et al. Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Ann Intern Med 1993; 119(3): 185-93.
  1. Blatt SP, Hendrix CW, Butzin CA, Freeman TM, Ward WW, Hensley RE, et al. Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients. Ann Intern Med 1993; 119(3): 177-84.
  1. Skin test responses as predictors of tuberculous infection and of progression in HIV-infected persons [editorial]. Ann Intern Medicine 1993; 119(3): 241-3.
  1. Prevention and control of tuberculosis in correctional institutions: recommendations of the advisory committee for the elimination of tuberculosis. MMWR Morb Mortal Wkly Rep 1989; 38(18): 313-20.
  1. Zoloth R, Safyer S, Rosen J, Michaels D, Alcabes P, Bellin E, et al. Anergy compromises screening for tuberculosis in high-risk populations. Am J Public Health 1993; 83(5): 749-51.
  1. Menzies R, Vissandjee B, Rocher I, Germain YS. The booster effect in two-step tuberculin testing among young adults in Montreal. Ann Intern Med 1994; 120(3): 190-8.
  1. Rosenberg T, Manfreda J, Hershfield ES. Two-step tuberculin testing in staff and residents of a nursing home. Am Rev Resp Dis 1993; 148(6 pt 1): 1537-40.
  1. Higgins SP, Bradbeer CS, Bateman NT. Tine testing in HIV positive patients. Thorax 1993; 48(8): 831-4.
  1. Rose DN, Schechter CB, Sacks HS. Preventive medicine for HIV-infected patients: an analysis of isoniazid prophylaxis for tuberculin reactors and for anergic patients. J Gen Intern Med 1992; 7(6): 589-94.
  1. Gordin FM, Perez-Stable EJ, Reid M, Schecter G, Cosgriff L, Flaherty D, et al. Stability of positive tuberculin tests: are boosted reactions valid? Am Rev Resp Dis 1991; 144(3 pt 1): 560-3.
  1. Purified protein derivative (PPD)-tuberculin anergy and HIV infection: guidelines for anergy testing and management of anergic persons at risk of tuberculosis. MMWR Morb Mortal Wkly Rep 1991; 40(RR-5): 27-32.
  1. Johnson MP, Coberly JS, Clermont HC, Chaisson RE, Davis HL, Losikoff P, et al. Tuberculin skin test reactivity among adults infected with human immunodeficiency virus. J Infect Dis 1992; 166(1): 194-8.
  1. Schutze GE, Rice TD, Starke JR. Routine tuberculin screening of children during hospitalization. Pediatr Infect Dis J 1993; 12(1): 29-32.
  1. Martin-Casabona N, Ocana RI, Vidal PR, Codina GG, Cayla JA, Gonzalez FT. Diagnosis of mycobacterial infection in acquired immunodeficiency syndrome (AIDS) patients and HIV carriers. J Hyg Epidemiol Microbiol Immunol 1992; 36(3): 293-302.
  1. Cantwell MF, Snider DE, Cauthen GM, Onorato IM. Epidemiology of tuberculosis in the United States, 1985 through 1992. JAMA 1994; 272(7): 535-9.
  1. Panel Comment, 11/94.
  1. Panel Comment, 11/94.
  1. Panel Comment, 11/94.
  1. Panel Comment, 11/94.
  1. Reviewer Comment, 12/94.
  1. Panel Comment, 11/94.
  1. Panel Comment, 11/94.
  1. Reviewer Comment, 1/95.
  1. Gilian Walker, editor. ABPI Data sheet compendium, 1994-95. London: Datapharm Publications Ltd., 1994: 521.
  1. Panel Comment, 11/94.
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