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Tuberculin Skin Testing: Methods and Indications


The tuberculin skin test is the most frequently used method for detecting asymptomatic latent tuberculosis infection. There is growing interest in other diagnostic tests for latent infection that might be simpler to administer, but the tuberculin skin test remains the preferred modality because of its ease of use and low cost. The decision to perform an annual test or a single test depends on the population each specific patient represents. Interpretation of the reaction to the test should be done by trained health care professionals, keeping in mind that factors such as immunization can cause false-negative or false-positive results.

Obi Okoye, MD
Fellow
Section of Infectious Diseases
Tulane University
New Orleans, La
Keyvan Ravakhah, MD, FACP
Program Director
Department of Medicine
Huron Hospital, Cleveland Clinic Health System
Assistant Clinical Professor
Case Western Reserve University
Cleveland, Ohio

PRACTICE POINTS

  • The Mantoux tuberculin skin test is safe and reliable and remains the most often used method for identifying latent TB infection.
  • Certain high-risk or high-prevalence populations, such as those with HIV infection or those with increased susceptibility to active TB, require annual testing.
  • The reaction to the test should be read by a trained professional at 48 to 72 hours after inoculation.
  • The criteria for a positive test depends on the amount of induration and varies by the individual's risk status.

Tuberculin is a solution of a protein derivative of Mycobacterium tuberculosis that was first prepared by Robert Koch in 1890 from heatkilled live cultures of M tuberculosis. Tuberculin skin testing has occasional benefit in the diagnosis of active tuberculosis (TB), but its primary use is in the diagnosis of latent infection.1 The test is safe and reliable, with high specificity, particularly in areas with a high prevalence of TB. It remains the most widely used test for diagnosis of latent TB infection and can be used in pregnancy.1 The Mantoux tuberculin test is performed by placing an intradermal injection of 0.1 mL of tuberculin into the skin. In the Sterneedle tuberculin test, a drop of tuberculin is put on the forearm, and a spring-loaded device with a circle of sharp prongs is used to force the tuberculin through punctures in the skin.

Currently available types of tuberculins include old tuberculin, which is often used in veterinary medicine, and purified protein derivative (PPD), the only material available for the standard intradermal Mantoux test. PPD is prepared by precipitation with trichloroacetic acid, which removes some of the large carbohydrate antigens. An investigational recombinant PPD (called DPPD, based on the first 4 amino acids of its N-terminus sequence), is based on the gene for a protein found only in tuberculous complex mycobacteria that has been sequenced and can be expressed as a recombinant protein.2 Preliminary data suggest that DPPD elicits cutaneous reactions similar to those of PPD in persons with latent infection but may offer increased specificity because of fewer false-positive reactions secondary to non-TB mycobacterial infection.

In the United States, tuberculin testing is mainly used to identify persons at high risk for TB infection who will benefit from treatment for latent TB infection.3 Physicians should administer the PPD skin test to high-risk persons as part of their routine evaluation. Institutional testing is recommended for the staff of health care facilities and the staff and residents of long-term care institutions where TB cases are found. It is important that all testing activities be accompanied by a plan for follow-up care of persons who are diagnosed with latent or active TB.4

The Immune Response to Tuberculin

The tuberculin skin test measures the delayed-type hypersensitivity response to the PPD. Cellular infiltration by T lymphocytes and other recruited inflammatory cells results in maximal induration (palpable raised, hardened skin) at 48 to 72 hours after inoculation with intradermal antigen.

A period of 4 to 7 weeks after primary infection is generally required for skin test conversion.5 The ability to mount such a response is usually maintained for many years, although reactivity may wane among individuals and, more often, in the elderly.

Administering the Test

High-risk asymptomatic groups require annual testing (Table 1), and a single test is appropriate in certain asymptomatic patients (Table 2).6

The Mantoux tuberculin skin test is performed by placing an intradermal injection of 0.1 mL of PPD containing 5 tuberculin units into the inner surface of the forearm, preferably in an area free of lesions and away from veins. Adisposable tuberculin syringe should be used to inject the PPD just beneath the surface of the skin, with the needle bevel facing upward. It is worth emphasizing that the PPD should be injected intradermally, not subcutaneously. This should produce a discrete, pale elevation of the skin (wheal) from 6 to 10 mm in diameter.6

Reading the Test

The reaction to the Mantoux skin test should be read by trained health care workers at 48 to 72 hours after injection. Patients should never be allowed to interpret their own test. However, if a patient fails to show up for a scheduled reading, a positive reaction may still be measurable up to 1 week after testing. If a patient who has not returned within 72 hours of testing has a negative result, repeat the test.6

The area of induration around the site of injection represents the reaction to tuberculin. The diameter of the induration should be measured across the forearm perpendicular to the long axis. The region of erythema should not be included in the measurement. All reactions should be recorded in millimeters, even those classified as negative. If no induration is found, it should be recorded as 0 mm.

Classification of the Tuberculin Reaction

The American Thoracic Society and the Centers for Disease Control and Prevention (CDC) have outlined the following criteria for the determination of a positive reaction, based on the probability or likelihood of true infection with M tuberculosis.1

A tuberculin reaction of more than 5 mm of induration is classified as positive in the following populations:

  • HIV-infected individuals
  • Recent contacts of TB cases
  • Persons with fibrotic changes on chest x-ray consistent with old, healed TB
  • Organ transplant recipients and those taking immunosuppressive medications.

A tuberculin reaction of more than 10 mm of induration is classified as positive in the following populations:

  • Injection drug users
  • Residents and employees of high-risk congregate settings, such as prisons and jails, nursing homes, hospitals and other health care facilities, or homeless shelters
  • Recent immigrants (within 5 years) from countries with a high prevalence of TB
  • Children younger than 4 years
  • Medically underserved and low-income populations
  • Tuberculin skin test converters (increase of >10 mm induration within a 2-year period).

Induration measuring more than 15 mm is classified as positive in all other persons.

Factors Affecting the Tuberculin Skin Test

Several factors can affect the test reaction. Infection with mycobacteria other than M tuberculosis can lead to false-positive results. Bacille Calmette-Gu?rin (BCG) immunization may influence the tuberculin reaction, depending on the age at vaccination and the time interval before skin testing. BCG immunization at birth or later can cause reactivity to tuberculin that may persist for up to 25 years.7 Regardless, tuberculin skin testing is not contraindicated in BCG-vaccinated persons. Tuberculin reactivity caused by BCG immunization usually wanes over time and is unlikely to persist for more than 10 years after vaccination in the absence of M tuberculosis infection.8 If BCG immunization was not recently administered, a diagnosis of latent TB infection should be considered in any BCG-vaccinated person who has more than 10 mm of induration in any of the following circumstances8,9:

  • Recent contact with another person with infectious TB
  • Having been born in or resided in a country with a high TB prevalence
  • Continual exposure to populations with a high prevalence of TB.

Vaccination with live viruses may cause false-negative reactions. The Advisory Committee on Immunization Practices recommends a tuberculin skin test on either the same day as vaccination with live-measles virus or 4 to 6 weeks later.10

Anergy, the absence of a reaction to the skin test, can occur in certain patients (Table 3). Anergy testing is used to help determine the competence of the cellular immune system.11 The physician administers 2 Mantoux-type tests (mumps and Candida); cut-off diameters are 5 mm of induration, but the interpretation of the results depends on the individual's risk for TB.11 The CDC no longer recommends routine anergy testing as a component of TB testing in HIV-infected patients.

Tuberculin cannot sensitize an uninfected person; however, it can restimulate remote hypersensitivity that has deteriorated. This booster effect?a positive tuberculin test after a negative one?develops within several days after the first injection and may be persistent.12 This boosted response may be misinterpreted as a new reaction. Frequency increases with age, and it is more common in the elderly. The booster effect may also occur in persons infected with non-TB mycobacteria and in those who had previously received the BCG vaccination.13,14

A 2-step testing protocol is used to separate a latent old infection from a recent one. If the reaction to the first test is negative, a second test should be performed within 1 to 3 weeks. If this is positive, it is most likely a boosted reaction, and the patient should be classified as previously infected. Individuals with the boosted response are at a low risk for the development of active TB and may be managed as nonreactors.12 If the second test is negative, the individual should be classified as uninfected. Any subsequent positive test result is regarded as skin-test conversion. This 2-step process is usually used in adults who need periodic retesting.15

There is growing interest in pursuing alternative methods for diagnosing latent TB infection. In 2001, the QuntiFERON-TB (QFT) whole-blood test was approved by the US Food and Drug Administration to detect latent TB infection. The test is available in the United States, and guidelines for its use have been published.16 This in-vitro diagnostic test measures a cell-mediated immune reactivity to M tuberculosis; it is based on the quantification of interferon-? released from sensitized lymphocytes in whole blood incubated overnight with PPD from M tuberculosis and control antigens.

Conclusion

Used appropriately, the tuberculin skin test is a valuable test that is reliable and safe, even during pregnancy. Although the QFT whole-blood test was approved for latent TB, until more data on its accuracy are available, the skin test remains the only widely used modality for detecting asymptomatic M tuberculosis infection.


SELF-ASSESSMENT TEST

1. All these statements about the tuberculin skin test are true, except:

  1. It is primarily used to identify persons at high risk for TB infection
  2. Skin-test conversion occurs 2 to 3 weeks after primary infection
  3. Maximal induration occurs at 48 to 72 hours after inoculation
  4. Reactivity to the test may wane in the elderly

2. Which of these reactions to the skin test would- NOT be considered positive?

  1. 6 mm of induration in an HIV-infected woman
  2. 11 mm of induration in a man with fibrotic changes on chest x-ray consistent with old, healed TB
  3. 8 mm of induration in an injection drug user
  4. 12 mm of induration in a 3-year-old child

3. All these are indications for annual testing, except:

  1. HIV infection
  2. Nursing home residence
  3. Diabetes mellitus
  4. Immigration from a country with a high prevalence of TB

4. All the following conditions can interfere with the tuberculin skin test reaction, except:

  1. Infection with Mycobacterium avium complex
  2. Infection with Streptococcus pneumoniae
  3. BCG immunization
  4. Vaccination with live-measles virus

5. Which of these is not a potential cause of anergy?

  1. Injection-drug use
  2. Sarcoidosis
  3. Live-virus vaccination
  4. Protein malnutrition

(Answers at end of reference list)

1. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med. 2000; 161:1376-1395.

2. Coler RN, Skeiky YA, Ovendale PJ, et al. Cloning of a Mycobacterium tuberculosis gene encoding a purified protein derivative that elicits strong tuberculosis-specific delayed-type hypersensitivity. J Infect Dis. 2000;182:224-233.

3. The American Thoracic Society and the Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221-S247.

4. Centers for Disease Control and Prevention. Essential components of a tuberculosis prevention and control program. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Recomm Rep. 1995;44(RR-11):1-16.

5. Menzies D. Interpretation of repeated tuberculin tests. Boosting, conversion, and reversion. Am J Respir Crit Care Med. 1999;159:15-21.

6. Centers for Disease Control and Prevention. Screening for tuberculosis and tuberculosis infection in high-risk populations. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Recomm Rep. 1995;44(RR-11):19-34.

7. Miret-Cuadras P, Pina-Gutierrez JM, Juncosa S. Tuberculin reactivity in Bacillus Calmette-Gu?rin vaccinated subjects. Tuber Lung Dis. 1996;77:52-58.

8. Centers for Disease Control and Prevention. The role of BCG vaccine in the prevention and control of tuberculosis in the United States. A joint statement by the Advisory Council for the Elimination of Tuberculosis and the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 1996;45(RR-4):1-18.

9. Bugiani M, Borraccino A, Migliore E, et al. Tuberculin reactivity in adult BCG-vaccinated subjects: a cross-sectional study. Int J Tuberc Lung Dis. 2003;7:320-326.

10. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1994;43(RR-1):1-38.

11. Centers for Disease Control and Prevention. Anergy skin testing and preventive therapy for HIV-infected persons: revised recommendations. MMWR Recomm Rep. 1997;46(RR-15):1-10.

12. Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 5th ed. New York, NY: Churchill Livingstone; 2000:2582-2584.

13. Moreno S, Blazquez R, Novoa A, et al. The effect of BCG vaccination on tuberculin reactivity and the booster effect among hospital employees. Arch Intern Med. 2001;161:1760-1765.

14. Menzies D. What does tuberculin reactivity after Bacille Calmette-Gu?rin vaccination tell us? Clin Infec Dis. 2000;31(suppl 3):S71-S74.

15. Rosenberg T, Manfreda J, Hershfield ES. Two-step tuberculin testing in staff and residents of a nursing home. Am Rev Respir Dis. 1993;148:1537-1540.

16. Centers for Disease Control and Prevention. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. MMWR Recomm Rep. 2003;52(RR-2):15-18.

Answers: 1. B; 2. C; 3. D; 4. B; 5. A

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