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The clinician frequently must determine whether a patient has tuberculosis. Part of the evaluation involves tuberculin skin testing. Two preparations of tuberculin are available for use in the United States: old tuberculin (OT) and purified protein derivative (PPD).
Although several techniques are available, the most widely used are the intradermal PPD skin test (Mantoux procedure), with antigens of various strengths, and the tine test. Except for epidemiologic screening of low-risk groups, an intradermal PPD skin test rather than a tine test is used to decrease the problem of false-negatives. Three concentrations of PPD antigens are available: first strength [1 tuberculin unit (1 TU)], intermediate strength (5 TU), and second strength (250 TU). Testing should begin with the intermediate-strength preparation; a first-strength PPD is rarely, if ever, indicated. Tuberculin protein is absorbed by plastic, and the detergent polysorbate 80 is added to the diluent to prevent this reaction. After 48 to 72 hours, the extent of induration, not erythema, is determined by palpation and measured in millimeters. In the past, an area of induration of 10 mm or more was considered evidence of past or present infection with Mycobacterium tuberculosis. Reactions measuring 5 to 9 mm in a normal host usually represent prior infection with atypical mycobacteria that cross-react with PPD-S (M. tuberculosis preparation; purified protein derivative-standard). Prior infection with atypical mycobacteria can be demonstrated by skin testing with a battery of atypical antigens (available only for investigational studies). A person’s largest reaction is to the infecting organism (dual skin test technique).
In 1990, the American Thoracic Society and the Centers for Disease Control revised the criteria defining a positive tuberculin skin test result in an effort to decrease the number of false-negatives in high-risk persons, such as those with HIV infection, and decrease the number of false-positives in low-risk groups. Three criteria were adopted for tuberculin reactivity based on risk factors for disease and the probability of having a true infection with M. tuberculosis:

A skin test reaction of 5 mm or more of induration is considered positive in persons likely to be infected with M. tuberculosis, such as persons with HIV disease, close contacts of infected patients, and those with chest roentgenographic findings consistent with old, healed tuberculosis.

A reaction of 10 mm or more of induration is considered positive in foreign-born persons from Asia, Africa, and Latin America; IV drug users; medically underserved, low-income groups; residents of long-term care facilities; and other immunosuppressed hosts, such as persons with silicosis, gastrectomy, chronic renal failure, diabetes mellitus, or underlying hematologic or other malignancies, or who are receiving high-dose corticosteroids or other cytotoxic therapy. Additionally, a reaction in employees of an institution where a person with tuberculosis would pose a risk to a large number of susceptible persons should be considered positive at 10 mm of induration. Also considered as a high-risk group are children less than 4 years of age.

A reaction of more than 15 mm of induration is positive in persons with no other risk factors (Table 65-1).

Table 65-1. Interpretation of purified protein derivative (PPD) tuberculin skin test results

About 80% of normal hosts with active tuberculosis have a positive reaction to a 5-TU PPD test. The result of a 5-TU PPD skin test will be negative in 20% of seriously ill patients with active tuberculosis when first seen. In the evaluation of patients with suspected tuberculosis for delayed hypersensitivity, a number of factors can be considered that can explain false-negative tuberculin reactions (Table 65-2). A battery of skin test antigens is used to assess delayed-type hypersensitivity. Control antigens commonly used include mumps, Candida, and tetanus toxoid. If any amount of induration, but not erythema, is considered a positive reaction, about 60% of normal adult control subjects will react positively to each of these antigens. If three skin antigens are selected, 90% of normal subjects will react to at least one antigen. In addition to the Mantoux-type procedure for administering antigens to test delayed-type hypersensitivity, a multiple-puncture device (tinelike) is available that uses seven antigens. This device has two disadvantages: the amount of antigen injected into the skin is variable because of technical factors related to administration, and it is expensive.

Table 65-2. Reasons for false-negative tuberculin reactions

A negative reaction to an intermediate-strength PPD skin test in patients who are not anergic does not exclude tuberculosis. It was found in one study that one third of patients with active tuberculosis who had a negative 5-TU PPD skin test result were not anergic. The question should be pursued further with a second-strength (250-TU) PPD skin test. A negative PPD (250-TU) test result and a positive result with one or more of the controls (anergy battery) constitute powerful evidence against tuberculosis. If the result of the 250-TU PPD test is negative and the result with the anergy battery is also negative, the possibility of tuberculosis still exists. A positive 250-TU PPD test result is less helpful, as it may signify nonspecific cross-reactivity to the atypical mycobacteria or a false-positive reaction resulting from the high concentration of tuberculin protein.
Another problem is to distinguish between a positive tuberculin reaction in a person who has received a bacille Calmette-Guérin (BCG) vaccination and one caused by an injection of M. tuberculosis. Tuberculin skin reactions caused by BCG vaccination wane with time, and large reactions are likely to indicate an infection with M. tuberculosis. In an adult who was given BCG vaccine as an infant, a tuberculin reaction of more than 10 mm of induration is unlikely to be caused by the BCG vaccine. It is more difficult to interpret the size of a tuberculin skin test reaction in an adult who received BCG vaccine after infancy.
Repeated tuberculin skin testing can also increase the reaction size from 5 to 9 mm to more than 10 mm. This boosting reaction can occur with skin tests performed from 1 to several weeks apart. In elderly subjects, the size of the tuberculin reaction decreases with age because of a waning of cell-mediated immunity to the tuberculin antigen. When elderly subjects are tested twice in a 3-week interval, a positive reaction may be detected on the second skin test as a result of immunologic recall. This must not be interpreted as a recent skin test conversion but as a false-negative skin test result on the initial tuberculin test. Progressive increase in the size of the tuberculin skin test reaction has been noted when a third and a fourth boosting test are used. Although the American Thoracic Society and Centers for Disease Control suggest that an increase of more than 10 mm of induration likely represents the occurrence of infection, in one study in the elderly, large increases were noted that did not indicate true conversions. Better tests are needed to identify persons at an increased risk for development of active disease. Rarely, an atypical mycobacterial infection will cause a reaction to the PPD-S skin test antigen that is larger than 10 mm.
A positive tuberculin skin test result in patients with suspected active tuberculosis together with negative results on acid-fast smears provides indirect evidence for the diagnosis pending cultures. A negative result on a properly performed tuberculin skin test, along with appropriately reacting controls, is evidence against the diagnosis in a normal host. (N.M.G.)
Advisory Committee for Immunization Practices. Use of BCG vaccines in the control of tuberculosis: a joint statement by the ACIP and the Advisory Committee for Elimination of Tuberculosis. MMWR Morb Mortal Wkly Rep 1988;37:663.
A positive skin test result in a BCG-immunized person need not be attributed to M. tuberculosis infection if the person is not in a high-risk group and has no history of exposure.
American Thoracic Society and Centers for Disease Control. Diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990;142:725.
Guidelines for tuberculin skin testing and interpretation.
Buoros D, et al. Palpation vs. pen method for the measurement of skin tuberculin reaction (Mantoux test). Chest 1991;99:416.
Use either the palpation or pen method to measure tuberculin skin test reactivity.
Centers for Disease Control. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. MMWR Morb Mortal Wkly Rep 1994;43(RR13):1–132.
Guidelines for interpreting tuberculin skin test results and methods to decrease transmission.
Centers for Disease Control. Anergy skin testing and preventive therapy for HIV-infected persons: revised recommendations. MMWR Morb Mortal Wkly Rep 1997; 46(RR15):1–10.
Guidelines for anergy testing. Anergy testing is no longer recommended as a routine component of screening for tuberculosis among HIV-infected persons.
Centers for Disease Control. Tuberculin skin test survey in a pediatric population with high BCG vaccination coverage Botswana, 1996. MMWR Morb Mortal Wkly Rep 1997;46:846–851.
A tuberculin skin test of ³10 mm of induration is likely to be a consequence of tuberculous infection and not previous BCG vaccination.
Comstock GW, Woolpert SF. Tuberculin conversions: true or false. Am Rev Respir Dis 1978;118:215.
Describes the use of two tuberculin tests given at least 1 week apart to detect true but not necessarily recent conversions resulting from the booster phenomenon.
Doto IL, Furcolow ML, MacInnis FE. Size of tuberculin reaction. Arch Environ Health 1971;23:392.
The probability that reactivation tuberculosis will develop increases with the size of the skin test reactions.
Edwards PQ. Tuberculin negative? N Engl J Med 1972;286:373.
The causes of false-negative test results include anergic states, faulty antigenic material, improper administration, and errors in reading the reaction.
Ferebee SH, Mount FW. Evidence of booster effect in serial tuberculin testing. Am Rev Respir Dis 1963;88:118.
Because of “anamnestic recall,” the area of induration may be increased on a repeated skin test.
Franz ML, Carella JA, Galant SP. Cutaneous delayed hypersensitivity in a healthy pediatric population: diagnostic value of diphtheria-tetanus toxoids. J Pediatr 1976;88:975.
Diphtheria toxoid (concentration 1:1,000) is useful for the assessment of delayed hypersensitivity.
Galant SP, et al. Relationship between cutaneous delayed hypersensitivity and cell-mediated immunity in vitro responses assessed by diphtheria and tetanus toxoids. J Allergy Clin Immunol 1977;60:247.
Cutaneous delayed hypersensitivity can be assessed with tetanus toxoid intradermally.
Grabau JC, Burrows DJ, Kern ML. A pseudo-outbreak of purified protein derivative skin-test conversions caused by inappropriate testing materials. Infect Control Hosp Epidemiol 1997;18:571–574.
False-positive tuberculin skin test results were caused by erroneously using a second-strength (250-TU) PPD skin test.
Harrison BDW, Tugwell P, Fawcett IW. Tuberculin reaction in adult Nigerians with sputum-positive pulmonary tuberculosis. Lancet 1975;1:421.
Lack of reaction to tuberculin skin test correlates with low serum albumin levels (5 mm induration at 48 hours) with mumps (68%), Candida (63%), and Trichophyton (62%) antigens; 89% of patients reacted to at least one of these antigens.
Palmer DL, Reed WP. Delayed-hypersensitivity skin testing. II. Clinical correlates and anergy. J Infect Dis 1974;130:138.
Anergy was associated with old age, immunosuppressive medications, malignancy, azotemia, leukocytosis, anemia, and fever.
Present PA, Comstock GW. Tuberculin sensitivity in pregnancy. Am Rev Respir Dis 1975;112:413.
Pregnancy has no effect on the tuberculin test.
Reichman LB, O’Day R. The influence of a history of a previous test on the prevalence and size of reactions to tuberculin. Am Rev Respir Dis 1977;115:737.
On retesting, a history of a positive tuberculin skin test result was confirmed in only 42% of patients. Severe reactions to the repeated test (“slough”) were not a problem.
Rhoades ER, Bryant RE. The effect of injection technique upon the size of the tuberculin reaction. Am Rev Respir Dis 1973;107:1089.
The route of administration (intradermal or subcutaneous) has little effect on reaction size.
Robertson JM, et al. Delayed tuberculin reactivity in persons of Indochinese origin: implications for preventive therapy. Ann Intern Med 1996;124:779–784.
Some patients (26%) had a negative tuberculin skin test result at 48 to 72 hours that became positive at 6 days. This delayed response can be detected with the booster technique.
Rooney JJ, et al. Further observations on tuberculin reactions in active tuberculosis. Am J Med 1976;60:517.
Of patients who were seriously ill, 20% had a negative intermediate PPD skin test result. The majority (94%) reacted after the protein depletion was corrected.
Sepkowitz KA, et al. Benefit of two-step PPD testing of new employees at a New York City hospital. Am J Infect Control 1997;25:283–286.
Without use of the two-step testing technique, 10% of new employees would have been classified falsely as new tuberculin converters.
Smith DT. Diagnostic and prognostic significance of the quantitative tuberculin tests. The influence of subclinical infections with atypical mycobacteria. Ann Intern Med 1967;67:919.
Review. Lack of a reaction to second-strength PPD-S (250 TU) is strong evidence against tuberculosis; a reaction of 2 to 9 mm to PPD-S (5 TU) suggests an atypical infection.
Sokal JE. Measurement of delayed skin-test responses. N Engl J Med 1975;293:501.
A discussion of how to identify a positive reaction.
Stead WW, To T. The significance of the tuberculin skin test in elderly persons. Ann Intern Med 1987;107:837.
An increase of at least 12 mm in the size of a tuberculin skin test reaction is evidence of a new M. tuberculosis infection.
Steele RW, et al. Screening for cell-mediated immunity in children. Am J Dis Child 1976;130:1218.
Three fourths of children ages 6 weeks to 12 years reacted to Candida or tetanus toxoid skin test antigen.
Stimpson PG, et al. Delayed-hypersensitivity skin testing for assessing anergy in the mid-South. South Med J 1976;69:424.
When a battery of six antigens was used (mumps, PPD, histoplasmin, Candida, streptokinase-streptodornase, and Trichophyton), 95% of controls reacted.
Webster CT, et al. Two-stage tuberculin skin testing in individuals with human immunodeficiency virus infection. Am J Respir Crit Care Med 1995;151:805–808.
Use of two-stage tuberculin skin testing (booster technique) is of limited value in HIV-infected patients.
Woeltje KF, et al. Tuberculosis infection and anergy in hemodialysis patients. Am J Kidney Dis 1998;31:848–852.
Of hemodialysis patients, 16% had a positive tuberculin skin test result or history of tuberculosis and 32% were anergic.



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