From the Guidelines
An immunocompromised person may have a false-negative Purified Protein Derivative (PPD) test because their weakened immune system cannot mount an adequate delayed-type hypersensitivity response to the tuberculin antigen. The PPD test relies on the body's cell-mediated immune response to recognize and react to tuberculin proteins if the person has been previously exposed to Mycobacterium tuberculosis. In immunocompromised individuals, such as those with HIV/AIDS, those on immunosuppressive medications like corticosteroids (prednisone), TNF-alpha inhibitors (infliximab, adalimumab), or transplant anti-rejection drugs (tacrolimus, cyclosporine), the immune system may be too suppressed to create the characteristic skin induration even when TB infection is present. This phenomenon, called anergy, can lead to false-negative results and missed TB diagnoses, as noted in the official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children 1.
Some key points to consider include:
- The sensitivity of the TST is high (95%–98%) in clinically well persons with previously treated tuberculosis, but false-negative reactions occur more frequently in immunocompromised individuals 1.
- A negative PPD test does not exclude the diagnosis of active tuberculosis, especially in immunocompromised patients, and alternative testing methods such as interferon-gamma release assays (IGRAs) like QuantiFERON-TB Gold or T-SPOT.TB tests may be preferred in these cases 1.
- In severely immunocompromised patients, a negative PPD should be interpreted with caution, and additional diagnostic approaches including chest imaging, symptom evaluation, and microbiological testing may be necessary, as suggested by the ATS, CDC, and IDSA update recommendations on the treatment of tuberculosis 1.
- Anergy testing is controversial and may not be useful in determining the risk of tuberculosis in immunocompromised patients, as noted in the preliminary guidelines for diagnosing and treating tuberculosis in patients with rheumatoid arthritis in immunosuppressive trials or being treated with biological agents 1.
Given the potential for false-negative results and the importance of early diagnosis and treatment of tuberculosis, alternative testing methods and a comprehensive diagnostic approach should be considered in immunocompromised patients with suspected TB infection.
From the Research
False-Negative PPD Test in Immunocompromised Individuals
- A false-negative PPD test in immunocompromised individuals can occur due to the weakened immune system's inability to mount an adequate response to the tuberculin skin test 2.
- The problem of anergy in immunocompromised patients, particularly those with HIV infection, can lead to false-negative results, making it challenging to diagnose tuberculosis infection 2.
- Immunocompromised individuals, such as those with HIV/AIDS, may not produce a sufficient immune response to the PPD test, resulting in a false-negative result, even if they are infected with Mycobacterium tuberculosis 3.
Factors Contributing to False-Negative Results
- Prior BCG vaccination can also increase the likelihood of a false-negative PPD test, although an induration of greater than 14 mm is unlikely to be due to prior BCG vaccination 4.
- The variability in the immune response to tuberculosis antigens can lead to false-negative results, highlighting the need for alternative testing methods, such as the interferon-gamma assay (QuantiFERON-TB Gold test) 5.
Alternative Testing Methods
- The QuantiFERON-TB Gold test has been proposed as an alternative to the PPD skin test, particularly for individuals who have received BCG vaccination, as it can provide a more accurate diagnosis of tuberculosis infection 4, 5.
- The use of in vitro whole-blood assays, such as the QuantiFERON-TB test, can help to overcome the limitations of the PPD skin test and provide a more sensitive and specific diagnosis of tuberculosis infection 5.