What is the purpose and interpretation of an anergy (lack of immune response) test?

Anergy Testing: Purpose and Interpretation

Anergy testing is not recommended for routine use in identifying tuberculosis infection in individuals, including those who are HIV infected, due to its questionable validity, lack of standardization, and unpredictable variations over time. 1

What is Anergy Testing?

Anergy testing assesses a person's response to skin test antigens to which a cell-mediated delayed-type hypersensitivity (DTH) response is expected. It is performed by:

• Using the Mantoux method of intradermal injection
• Traditionally considering a positive result as ≥5 mm induration at the injection site within 48-72 hours
• Using antigens such as mumps and Candida (FDA-approved for DTH testing) 1

Individuals who mount a response to any antigen are considered to have relatively intact cellular immunity, whereas those who cannot mount any responses are considered "anergic." 1

Historical Context and Original Purpose

Anergy testing was historically used for two main purposes:

1. To interpret negative PPD-tuberculin skin test results: A positive DTH response to anergy testing with a negative PPD was interpreted as evidence that the negative PPD was a true negative. Conversely, lack of DTH response with a negative PPD was interpreted as potential inability to respond to PPD even if infected with M. tuberculosis. 1

2. As an indication for TB preventive therapy: In 1991, CDC guidelines recommended anergy testing alongside PPD-tuberculin skin testing for HIV-infected persons, suggesting that demonstration of anergy in an HIV-infected, PPD-negative person at high risk for M. tuberculosis infection was an indication for isoniazid preventive therapy. 1

Problems with Anergy Testing

Several factors limit the usefulness of anergy testing:

1. Standardization and Reproducibility Issues

• Lack of standardized protocols for antigen selection and number needed 2
• No uniform criteria for defining cutaneous reactivity 2
• Variable skin test administration methods and reading techniques 1
• Multiple antigens may be necessary to maximize detection of responders 1

2. Unpredictable Variations

• Serial anergy testing among HIV-infected persons has shown unpredictable differences over time 1, 3
• In one study, 30% of persons initially classified as anergic had reactions to mumps or Candida antigens when retested 12 months later 3
• Variation may result from changes in host immune competence or from test characteristics 1

3. Selective Nonreactivity

• Selective nonreactivity to PPD is a recognized phenomenon 1
• Mumps reactivity may remain after loss of PPD reactivity 1
• PPD boosting can occur in people with an initial positive reaction to control antigens 1

4. Poor Predictive Value

• A positive DTH response to antigens other than PPD is not proof that a negative PPD indicates absence of TB infection 1
• Failure to respond to anergy tests does not mean an individual will not respond to PPD 1
• The results of anergy testing do not predict the risk for progression to active disease in either HIV-negative or HIV-positive patients 2

Current Recommendations

Based on the most recent and highest quality evidence:

1. Anergy testing is not recommended for routine use in identifying tuberculosis infection in individuals, including those who are HIV infected 1

2. CDC revised recommendations (1997) state that "anergy testing is no longer recommended as a routine component of TB screening among HIV-infected persons" 1

3. For HIV-infected persons, a TST reaction size of ≥5 mm of induration is considered positive (indicative of M. tuberculosis infection) 1

4. In HIV-negative patients with active tuberculosis, 10% to 20% have negative tuberculin test results, and 5% to 10% have a negative tuberculin result but have a positive reaction to another antigen 2

Clinical Implications

• A negative tuberculin skin test result does not exclude either latent infection or active disease, even in the presence of a reaction to other antigens 2
• Neither anergy testing nor tuberculin testing obviates the need for microbiologic evaluation when there is suspicion for active tuberculosis infection 2
• In settings with high TB prevalence, tuberculin and anergy skin testing have a low predictive value in detecting M. tuberculosis infection in HIV-infected persons 4

Special Populations

• HIV-infected persons: Anergy is directly related to decreasing CD4+ T cell counts; as HIV infection causes decreasing CD4+ counts, the incidence of anergy increases 1
• Children: The applicability of skin-testing methods to pediatric populations is uncertain. Children with HIV infection have had DTH responses, and lack of response has been associated with the stage of HIV-related disease 1
• Primary immunodeficiency diseases: Skin testing for DTH reactions remains an important tool in diagnosing a variety of primary (non-HIV-related) immunodeficiency diseases 1

In conclusion, while anergy testing may provide some information about a person's cell-mediated immunity status, its utility in guiding tuberculosis preventive therapy decisions is limited, and it should not be used for routine TB screening.