The Tuberculin, Purified Protein Derivative PPD TINE TEST® is a sterile, simple, multiple-puncture, disposable intradermal test device for the detection of tuberculin reactivity. These convenient devices are especially useful in mass tuberculosis screening programs.
Each test unit consists of a stainless steel disk attached to a light blue plastic handle. Projecting from the disk are four triangular-shaped prongs (tines) that are 2 mm long and approximately 4 mm apart. The tines have been mechanically dipped into a concentrated solution of Purified Protein Derivative (PPD). The PPD concentrate used is purified from culture filtrates of human-type strains (C, DT, and PN) of Mycobacterium tuberculosis grown in synthetic medium and precipitated with ammonium sulfate according to the Seibert Process. 1,2 It is stabilized with 7% acacia (gum arabic), 30% dextrose, and 5% glycerol as a humectant. The PPD concentrate for dipping is standardized against U.S. Standard Tuberculin, Purified Protein Derivative in sensitized guinea pigs. Following dipping, the tines are capped and the entire unit is sterilized by Cobalt 60 irradiation. No preservative has been added. The device is for single dose, single use.
PPD TINE TEST has been standardized by clinical evaluation in human subjects to elicit at least a 2 mm reaction or more in a person who responds with a 5 mm reaction or more to 5 TU (US tuberculin units) of Tuberculin, PPD administered intradermally in the Mantoux test. 3
Between 1953 and 1985, the number of cases of tuberculosis (TB) reported annually in the U.S. decreased by 74%, from 84,304 to 22,201 cases. 4-7 Between 1985 and 1992, there was a 20% increase in the number of reported TB cases, to 26,673 in 1992. This resurgence was attributed to the emergence of the human immunodeficiency virus (HIV) epidemic, increased immigration from countries with high TB prevalence, social factors such as homelessness and substance abuse, increased numbers of persons in institutionalized settings, and decreased resources allocated to TB control programs. 4-6 Between 1992 and 1995, the reported number of TB cases in the U.S. decreased by 4% to 6% annually. 5 This decline has been attributed to decreased transmission among persons in congregative settings (eg, hospitals, correctional facilities) and improvement in TB control measures. Despite the declining incidence, TB rates remain elevated in certain high-risk groups, such as immigrants, substance abusers, and the homeless.
The classic delayed-type tuberculin skin reaction is elicited in sensitive individuals by intradermal injection of tuberculoprotein antigens (purified protein derivative, old tuberculin). 3 Production of delayed skin reaction involves recognition of antigen by sensitized lymphocytes (T cells), immobilization of lymphocytes at the site, production and release of lymphocyte mediators, and accumulation of macrophages, with eventual destruction of antigen and resolution of the resolution of the reaction. 8 Fixed tissue macrophages and basophilic leukocytes, along with fibrin deposition and vessel permeability, are also found. 9 The result is an inflammatory response in the skin with the induration and erythema characteristic of a "positive" reaction.
Data were obtained from clinical studies with a total of 3,062 volunteer subjects (males and females), ranging in age from 4 to 96 years, of which 47.5% (1,443) were Mantoux positive (induration of 10 mm or larger).
The following test results for the Mantoux test and corresponding measurements of the PPD TINE TEST were considered positive: 5 - 9 mm induration Mantoux was equivalent to 2 mm PPD TINE TEST; 10 - 19 mm Mantoux was equivalent to 3 - 8 mm PPD TINE TEST; >20 mm Mantoux was equivalent to >9 mm PPD TINE TEST.
The PPD TINE TEST demonstrated a sensitivity of 93.8% (95% Cl: 92.7% - 94.9%), which corresponds with a false negative rate of 6.2%, and a specificity of 82.5% (95% Cl: 80.4% - 84.6%), which corresponds with a false positive rate of 17.5%. 10,11 Based on these results, the positive predictive value ranges from 37.2% to 97.9% as the prevalence of positive Mantoux PPD-T (Tween 80) tests varies from 10% to 90% in different populations. In the population studied, the positive accuracy, which correlates with the positive predictive value, was 89.1%. 11 It should be noted that these results are based on the accuracy of the Mantoux test in predicting the presence of TB infection; Mantoux test error rates have been reported to range from 2% to 10%. 11 In studies in which individual lots of PPD TINE TEST are standardized to elicit at least a 22 mm reaction or more in 50 persons who are known to test positive with the Mantoux test, the sensitivity of the PPD TINE TEST was at least 95%. 10
PPD TINE TEST reactions are measured at 48 to 72 hours. 3,11 Various factors may influence the time to maximum reaction or the possibility of a false-negative reaction, including waning sensitivity in older persons. 12 Among individuals with waning sensitivity to homologous or heterologous mycobacterial antigens, however, the stimulus of a tuberculin test may "boost" or increase the size of the reaction to a second test, even causing an apparent development of sensitivity in some cases. 13
The recommended frequency of repeated tuberculin tests depends on risk of exposure of the individual and on the prevalence of tuberculosis in the population group. The repeated testing of uninfected individuals does not sensitize to tuberculin.
Highly sensitive persons may respond to skin testing with vesicular or ulcerating local reactions. These reactions are interpreted as positive. Persons who are known to be tuberculin-positive generally should not be tested with PPD TINE TEST (see ). 14
There is no reliable method to distinguish a tuberculin reaction caused by vaccination with the bacille Calmette-Guerin (BCG) vaccine from those caused by natural mycobacterial infections. Therefore, a previously vaccinated person with a significant reaction to the PPD TINE TEST should be evaluated for the presence of TB disease and managed accordingly. 14 Previous BCG vaccination is not a contraindication to the use of PPD TINE TEST.
There are case reports of anaphylactic reactions to the PPD TINE TEST. Any individual with a known significant immediate-type hypersensitivity to tuberculin or any component of the PPD TINE TEST, including acacia (gum arabic), should not be tested with the PPD TINE TEST.
Tuberculin testing generally should not be administered to individuals with known active tuberculosis. Although activation of quiescent lesions is rare, if a patient has a history of occurrence of vesiculation and necrosis with a previous tuberculin test by any method, tuberculin testing should be avoided.
Skin testing is not to be used as the sole diagnostic factor and patients who have a positive reaction to PPD TINE TEST should be evaluated further with additional laboratory tests. Chest radiography is the preferred screening method for persons with current pulmonary TB. 12
Not all persons infected with M. tuberculosis will have a delayed-type hypersensitivity reaction to a tuberculin skin test. Factors which may cause a decreased ability to respond to tuberculin testing include: viral infections (eg, measles, mumps, chicken pox), live virus vaccinations (eg, measles, mumps, rubella, polio), overwhelming tuberculosis or other bacterial infections, drugs (eg, corticosteroids, immunosuppressive agents), metabolic derangements, nutritional factors, age (eg, newborns, elderly), and stress (eg, surgery, burns, mental illness, graft-host reactions). 14-16 Anything that impairs or attenuates cell-mediated immunity potentially can cause a false negative reaction (eg, viral infections, particularly HIV; live viral vaccines; protein malnutrition; lymphoma; leukemia; sarcoidosis, use of glucocorticoid and other immunosuppressive drugs). Reactivity to the test also may be suppressed in individuals who are anergic.
As with any biological product, allergic reactions including anaphylaxis may occur. Before administration of PPD TINE TEST, the healthcare professional should take all known precautions for prevention of allergic or any other reactions. This includes a review of the patient' history for possible sensitivity to this or similar products or to any component of PPD TINE TEST, including acacia. Epinephrine injection (1:1,000) and other appropriate agents used for control of immediate allergic reactions should be available for immediate use. The healthcare professional should also obtain information about the patient' previous immunization history, including immunization with the BCG vaccination.
The utility of the tuberculin skin test depends on the prevalence of M. tuberculosis infection and the relative prevalence of cross-reaction with nontuberculous mycobacteria.
The reactivity of the PPD TINE TEST may be suppressed or depressed in persons who recently received live virus vaccines, who have had a viral infection, or who are receiving corticosteroids or immunosuppressive agents. 14-16
Antituberculous chemotherapy should not be instituted solely on the basis of a single positive PPD TINE TEST unless vesiculation occurs, in which case management of the patient is the same as that for one classified as positive to the Mantoux test.
Tuberculin, Purified Protein Derivative PPD TINE TEST units must never be reused. The units should be discarded into an impenetrable sharps container with recapping.
Prior to administration of this product, the healthcare professional should inform the patient, parent, guardian, or other responsible adult, of the benefits and risks of tuberculin skin tests. The healthcare professional should inform the patient that pain, pruritus, and discomfort may occur at the injection site. Patients, parents or guardians should be instructed to report vesiculation, ulceration or necrosis which may appear at the test site in highly sensitive patients, and any adverse experience to their healthcare professional.
The patient should be given oral instructions regarding how to read the test, the importance of reading the skin test reactions at 48 hours, and the importance of returning the induration indicator card to the healthcare professional. The induration indicator card is an important health record.
Reactivity to the test may be suppressed in patients who are receiving corticosteroids or immunosuppressive agents, or those who have recently been immunized with live vaccines such as Measles-Mumps-Rubella vaccine (MMR) and oral polio vaccine. If tuberculin skin testing is indicated, it should be done preceding, or at the time of such immunization, and read 48 to 72 hours later. If the test is not administered in the time suggested, an interval of 4 to 6 weeks should be allowed between tuberculin skin testing and immunization with live measles vaccine or MMR to prevent suppression of tuberculin reactivity. 3,6,13,19 The effect of live-virus varicella and yellow-fever vaccines on tuberculin skin testing is not known. 19
PPD TINE TEST has not been evaluated for its carcinogenic or mutagenic potential or its potential to impair fertility.
Pregnancy Category C.
Animal reproduction studies have not been conducted with Tuberculin, Purified Protein Derivative PPD TINE TEST. It is also not known whether PPD TINE TEST can cause fetal harm when administered to a pregnant woman or affect reproduction capacity.
Pregnancy is known to cause physiologic suppression of cell-medicated immunity. 20 Several studies on tuberculin testing have been conducted during pregnancy. 21-25 Earlier studies suggested that a negative response to tuberculin may occur late in pregnancy while tests prior to pregnancy had been positive. 21-23 However, a well-controlled study and a study in which women who tested positive during pregnancy were retested in the postpartum period showed no indication that pregnancy affected the level of tuberculin sensitivity. 24,25
The Advisory Council for the Elimination of Tuberculosis of the Centers for Disease Control and Prevention (CDC) considers tuberculin skin testing valid and safe throughout pregnancy. 12
Because of the possibility that a false negative response may occur during pregnancy, further diagnostic procedures should be considered if tuberculosis is suspected clinically. The clinical judgment of the healthcare professional should prevail at all times.
The American Academy of Pediatrics (AAP) and the Advisory Council for the Elimination of Tuberculosis of the CDC recommend focusing tuberculosis skin testing on children who are at increased risk of acquiring TB infection or disease. 12,26 Children without risk factors who reside in low-TB-prevalence areas, including those under 1 year of age, do not require routine TB skin testing. The AAP states that children who have no risk factors, but who reside in high-prevalence regions, and children whose histories for risk factors are incomplete or unreliable should be considered for tuberculin (Mantoux) skin testing at 4 to 6 and 11 to 16 years of age. Family investigation is implicated whenever a tuberculin skin test result of a parent or child converts from negative to positive (indicating recent infection). Children with HIV infection and those living with HIV-infected persons should receive annual tuberculin (Mantoux) skin testing. 26 Healthcare professionals in their own judgement may decide to administer tuberculin skin testing to specific children at earlier ages, if circumstances warrant.
Because TB case rates increase with age among all racial and ethnic groups and both sexes, screening for TB in facilities providing long-term care to the elderly is recommended. The incidence of disease is two to seven times higher among nursing home residents in some areas than among demographically similar persons in other settings. Studies indicated that unsuspected transmission of M. tuberculosis in nursing homes/facilities presents a risk to residents and workers. 12
Data obtained from clinical studies with a total of 3,062 volunteer subjects (males and females), ranging in age from 4 to 96 years, of which 47.5% (1,443) were Mantoux positive clearly demonstrate that PPD TINE TEST, when used as a screening test to determine tuberculin reactivity, is associated with very little, if any, adverse reactivity. Other than the skin test reaction itself, modest or mild vesiculation and ulceration were the only adverse experiences reported. The modest or mild vesiculation was equally divided between the two tests (PPD TINE TEST, 54/3062, 1.78%; and PPD-T Mantoux, 55/3062, 1.81%). The slight ulceration observed with one subject at 72 hours was associated with the PPD TINE TEST site.
Postmarketing, voluntary reports of adverse events temporally associated with PPD TINE TEST have been received for which an association with the product is unknown. The following local reactions have been reported: rash, pain or discomfort, induration, pruritus, transient bleeding at the puncture site, petechiae, cellulitis, and skin necrosis in highly sensitive persons. Systemic reactions have also be reported. These reactions include fever, urticaria, lymphangitis and allergic reactions, including anaphylactoid reactions. However, there is no indication as to the frequency and severity of reaction relating to these reports.
Healthcare professionals should report suspected adverse events after administration of PPD TINE TEST to the Center for Biologics Evaluation and Research of the Food and Drug Administration by submitting a MedWatch form. 27
The volar surface of the upper one third of the forearm, over the fleshly portion of a muscle is the preferred site. Hairy areas, and areas without adequate subcutaneous tissue, eg, concavities over a tendon or bone, should be avoided.
Alcohol, acetone, ether, or soap and water may be used to cleanse the skin. The area must be clean and thoroughly dry before application of the PPD TINE TEST.
Expose the four coated tines by removing the protective cap while holding the plastic handle. Grasp the patient' forearm firmly, since the sharp momentary sting may cause the patient to jerk his or her arm, resulting in scratching. Stretch the skin of the forearm tightly and apply the disk with the other hand. Hold at least 1 second. Sufficient pressure should be exerted so that the four puncture sites and circular depression of the skin from the plastic base are visible. Release tension grip on forearm. Withdraw the PPD TINE TEST unit.
After administration of the test, local care of the skin is not necessary.
Tuberculin, Purified Protein Derivative PPD TINE TEST units must never be reused. The units should be discarded into an impenetrable sharps container without recapping.
Reading Reactions: Tests should be read at 48 to 72 hours. Vesiculation or the extent of induration are the determining factors. The size of any erythema or necrosis, if present, should be recorded, although not used in the interpretation of the test. Readings should be made in good light with the forearm slightly flexed. The size of the induration in millimeters should be determined by inspection, measuring, and palpation with gentle finger stroking. Identification of the application site is usually easy because of the distinct four-point pattern. The diameter of the largest single reaction around one of the puncture sites should be measured. With pronounced reactions, the areas of induration around the puncture sites may coalesce.
With a positive reaction, further diagnostic procedures must be considered. These may include X-ray of the chest, microbiological examination of sputa and other specimens, and confirmation of the positive PPD THE TEST reaction (except vesiculation reactions) using the Mantoux method. In general, the PPD TINE TEST does not need to be repeated.
When vesiculation occurs, the reaction is to be interpreted as strongly positive and a repeat test by the Mantoux method is not required. 14,17
The PPD TINE TEST has been standardized by clinical evaluation in human subjects to elicit at least a 2 mm reaction or more in a person who responds with a 5 mm reaction or more to 5 TU of Tuberculin, PPD administered intradermally in the Mantoux test. 3 However, there are certain high-risk populations in whom this reaction would not be considered positive including: 12
Appropriate diagnostic procedures, such as the Mantoux test, should be utilized for retesting individuals who display at 2 mm or greater reaction to PPD TINE TEST. For interpretation of the Mantoux test in various population groups, the healthcare professional should refer to the recommendations of the Advisory Council for the Elimination of Tuberculosis of the CDC. 12
Induration less than 2 mm. Persons who are contacts of TB patients or who have clinical evidence of disease should be screened by the Mantoux test or chest radiography, even if they have demonstrated a negative reaction to PPD TINE TEST.
Induration indicator cards illustrating typical reactions are enclosed and are considered an important health record. They should be used to record reactions, and become a permanent part of the patient' file. Patients should be instructed to complete and return the card to the healthcare professional.
Tuberculin, Purified Protein Derivative (PPD) TINE TEST is supplied as follows:
NDC 0005-2720-25 25 individual tests
NDC 0005-2720-28 100 individual tests
STORE AT CONTROLLED ROOM TEMPERATURE 15°C to 30°C (59°F to 86°F). DO NOT REFRIGERATE.
Manufactured by:
LEDERLE LABORATORIES
Division American Cyanamid Company
Pearl River, NY 10965 USA
US Govt. License No. 17
Marketed by:
WYETH LEDERLE VACCINES and PEDIATRICS
Philadelphia, PA 19101
Cl 6127-1 Issued March 15, 2000
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