Approximately 33% of the world's population has latent tuberculosis infection (LTBI). For this reason, screening for Mycobacterium tuberculosis infection is essential for public health. People with LBTI are at risk for developing active tuberculosis (TB) and becoming infectious. The greatest risk for progression occurs during the first two years of infection. The goal of testing for LTBI is to identify individuals who are at high risk of developing active TB. The decision to test should presuppose a decision to treat if the result is positive.
The tuberculin skin test (TST) and the interferon-gamma release assay (IGRA) are the current methods for screening and are based on the measurement of adaptive host immune response.
Tuberculin Skin Test (TST)
This test measures the immune response to the purified protein derivative (PPD) which is a solution of Mycobacterium tuberculosis complex antigens.
The administration should be performed by a skilled personnel: 5 tuberculin units (0.1 ml) are applied intradermally on the volar surface of the forearm to form a 6-10mm wheal (Mantoux method). After placement, a follow-up visit in 48 to 72 hours is needed so the results can be interpreted. The area of induration, not the erythema, is measured in millimeters.
Interferon Gamma Release Assay (IGRA)
Two assays are approved by the United States Food and Drug Administration, QuantiFERON-TB Gold In-Tube (QFT-GIT) test and the T-SPOT.TB (T-Spot) test. As previously mentioned, the CDC endorses the use of these methods for screening of LTBI in place of the TST, and United States TB screening guidelines indicate that they can be used in place of a PPD for latent infection screening.
Since the immune reaction is performed ex vivo in the laboratory, only one visit is needed for a single blood draw, and the results are available in 24-48 hours. Also, there is no chance of a cross-reaction with antigens of BCG with these tests.
IGRA methods are preferred for individuals who may not return for a TST reading. IGRA tests also may be more persuasive in a patient with prior BCG immunization because of the lack of cross-reactivity with antigens. 
Screening should be performed with the intent to treat if the result is positive.
Those at risk for new infection:
- Close contacts of patients with active TB.
- Casual contacts of patients with active TB (e.g., healthcare, homeless shelters, correctional facilities, refugee shelters, and nursing homes workers).
- Immigrants from TB-endemic regions.
Individuals with conditions or other factors associated with progression to active disease (reactivation):
- High risk: certain immunocompromising conditions, such as patients with HIV/AIDS, organ transplantation, tumor necrosis factor (TNF) inhibitor therapy or other biologics, chronic renal failure in hemodialysis, carcinoma of head and neck, malignancy, or silicosis. Also, recent tuberculosis infection within the past two years and radiographic evidence of prior healed TB, history of untreated, or inadequately treated tuberculosis.
- Moderate risk: chronic steroid use (greater than 15 mg/d of prednisone equivalent), diabetes mellitus, and young age (less than 5 years old) when infected.
- Increased risk: cigarette smoking, drug abuse, alcohol abuse, body mass index less than 20, or solitary granuloma on chest radiograph.
The CDC, IDSA, and the WHO guidelines endorse the use of either IGRA or TST for the screening of tuberculosis. In certain situations, one test is preferred over the other.
The TST is the test of choice for children younger than 5-years-old or when boosting of a waning immune response is needed. The TST may be somewhat preferred for a patient who needs repeat testing annually, such as healthcare workers, because IGRA test results may be less reproducible.
IGRAs are recommended for patients who may not return for the TST reading (history of drug abuse, homeless), those who were previously vaccinated with the BCG, or individuals older than 5 years who are likely to be infected with Mycobacterium tuberculosis, have low or intermediate risk of disease progression, and in whom it has been decided that testing for latent tuberculosis is warranted.
It is less clear if either TST is preferred over IGRA or vice-versa in individuals 5 years or older with a high risk of progression to disease. In cases in which the risk of progression is low, there is no need to screen; however, if this is necessary by law or credential bodies, IGRA is recommended over TST. It is important to mention that TST can be done in situations when IGRA is not available, too costly, or difficult to perform.
Simultaneous or sequential testing is not recommended, except in cases where the initial test is negative or indeterminate (borderline), but if the clinical suspicion is high, then repeat testing with TST or IGRA (depending on which test was done initially) can be done. The 2017 IDSA guidelines also recommend a second diagnostic test to confirm the diagnosis in cases of a positive test result in low-risk individuals.
Normal and Critical Findings
Interpreting the TST
As per the CDC, at least 5 mm of induration constitutes a positive test in high-risk persons:
HIV infection, close contact with an active TB patient, abnormal chest radiograph with fibrotic changes, organ transplant recipient, and another form of immunosuppression (taking the equivalent of > 15 mg/day of prednisone, TNF antagonists, other biologics)
Induration of 10 mm or greater indicates positivity in persons with above baseline risk of reactivation:
Chronic kidney disease on dialysis, silicosis, diabetes mellitus, malignancy, underweight status, jejunoileal bypass, gastrectomy, injection drug abuse, age less than 4-years old, foreign-born from countries with high incidence of TB who immigrated within the past 5 years, and residents or workers in prisons, jails, healthcare facilities, and homeless or refugee shelters.
Finally, induration of 15 mm or greater is deemed positive in low-risk patients:
If TST is positive:
- If there is a high risk of infection and progression, the test should not be repeated.
- A chest radiograph and clinical evaluation should follow.
- If there is no evidence of active disease is noted by history, physical or radiograph, the patient is deemed to have LTBI and should be treated.
- If the chest radiograph or clinical evaluation are suggestive of tuberculosis, then active infection needs to be excluded with further testing.
If TST is negative:
Repeat testing with another TST or an IGRA can be performed if the patient is at high risk of infection progression or active disease to rule out the possibility of a false negative test. (See below.) Not all of these cases would be amenable to repeat testing, however, and decisions to retest should be made on a case by case basis.
Drawing attention to two situations in which repeat testing may be most important:
TST can be negative in cases where testing occurs within the first 8 weeks of exposure when the immune response has not developed yet, or in cases with remote TB exposure where the tuberculin reaction might have waned. In the latter group, consisting primarily of the elderly where a response may have waned, a second TST (“booster”) applied a couple of weeks later often will be positive.
A repeat positive second test increases the sensitivity for detecting TB, although in immunocompromised patients a repeated negative test can be a result of lack of immune reaction rather than an exclusion of the tuberculosis diagnosis. High suspicion of the disease has to be used in this setting to decide whether or not to treat, always considering risk and benefits of therapy. Again, a case by case evaluation is key.
On the flip side, a false positive should be suspected in patients who are at a low risk for infection and progression.
In the case of foreign-born adults who have been vaccinated with BCG and have a positive PPD reaction, the positive reaction is more likely due to TB exposure than the remote vaccination, and the immunization history should be disregarded when interpreting test results and deciding upon treatment.
If concern persists about the induration being due to childhood immunization, an IGRA test may be considered, since these would never be positive due to a prior BCG vaccine.
In the case of healthcare workers, and occupational exposure risk, LTBI screening should be repeated yearly for the purposes infection prevention and healthcare epidemiology. More importantly, because those with LTBI infection are most likely to progress to active infection within the first 2 years of infection, such screening optimises the impact of LTBI treatment.
Results are reported as positive, negative and indeterminate. Indeterminate tests can occur in cases of anergic response, immunosuppression, high initial levels of interferon gamma, active infection, extremes of age, and improper handling of the samples.
Tuberculin Skin Test
False positive reactions:
- Can occur in patients with prior Bacille-Calmette-Guerin (BCG) vaccination or those with exposures to environmental mycobacteria, incorrect application, and/or interpretation.
False negative reactions:
Causes of false negative test include anergy secondary to immunosuppression (e.g., HIV infection or corticosteroids), natural waning of immunity, recent live virus vaccination (measles, mumps, polio, smallpox), recent viral infection, recent TB infection (within 8 to 10 weeks), advanced TB, age younger than 6-months, older adults, concomitant bacterial infections, and improper technique and/or reading.
Patient Safety and Education
Tuberculosis is an infection caused by Mycobacterium tuberculosis and spread through the air by coughed or sneezed contaminated droplets. It primarily affects the lungs but can affect other organs as well. Tuberculosis can be fatal which is why screening is so important. Treatment is available and effective.
People in close contact with someone diagnosed with tuberculosis, immunosuppressed, starting an immunosuppressive therapy, or if working in the healthcare field, jails, prisons, or homeless/ refugee centers should be screened for tuberculosis.
There are two tests to screen for tuberculosis: (1) a skin test called Tuberculin skin test, and (2) a blood test called the interferon gamma-release assay. A positive test does not necessarily mean that you have an active disease. However, further studies are needed to rule it out (e.g., chest x-ray, sputum cultures).
A positive test means a person was exposed to the mycobacteria, and the immune system reacted to it by:
Fighting and removing the bacteria.
Controlling the bacteria and keeping it dormant, also called latent tuberculosis because it does not show any symptoms or spread. For these cases, treatment and prevention are possible.
Not being able to control the disease which has symptoms is called active tuberculosis and requires immediate treatment.
A positive test also can be a false positive test. For this, the doctor will reassess the patient and the past medical history.
A negative test can mean that there is no infection, or that it is a false negative test. Depending on the patient's risk factors, the doctor will decide whether to retest.
Latent TB infection is prevalent, and treatment of patients with LTBI can reduce the burden of active tuberculosis, especially if screening is performed in populations at high risk for progression to active disease. Current United States guidelines endorse the use of either the TST or IGRA test for this purpose, although there are some minor differences in their performance in some populations. In general, both types of tests should not be used routinely in individual patients. A decision to test should presuppose intention to treat LTBI if detected.