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- Interferon-gamma Release Assay (IGRA) for Mycobacterium tuberculosis
The QuantiFERON®-TB Gold test is an in vitro assay to aid in the diagnosis of both latent and active infection with Mycobacterium tuberculosis.
Spontaneous interferon-γ production (independent of TB stimulation) or lack of a response to mitogen (such as that due to anergy or immune suppression) may render the results indeterminate. A negative result should not be used alone to exclude M tuberculosis infection in persons with symptoms or signs suggestive of TB disease. Those who have a negative result, but who are likely to have latent TB infection (LTBI) and who are at greater risk for severe illness or poor outcome in case of TB disease, might require treatment or closer monitoring for disease.1
In healthy persons who have a low likelihood both of M tuberculosis infection and of progression to active tuberculosis if infected, a single positive interferon-γ release assay (IGRA) or tuberculin skin test (TST) result should not be taken as reliable evidence of M tuberculosis infection. Because of the low probability of infection, a false-positive result is more likely. In such situations, the likelihood of M tuberculosis infection and of disease progression should be reassessed, and the initial test results should be confirmed. Repeat testing (using a newly collected specimen), with either the initial test or a different test, may be considered on a case-by-case basis. For such persons, an alternative is to assume, without additional testing, that the initial result is a false positive.2
The QuantiFERON® TB test has been shown to be accurate in HIV-positive individuals with moderately advanced disease, but in the severely immunocompromised the test may be impaired by T-cell anergy.3,4
Active TB disease may result in a negative test as reduction of in vitro IFN-γ release has been described and may be due to suppressive cytokines associated with TB disease.5 Patients with mycobacterial infections, other than tuberculosis, might also be responsive to ESAT-6, CFP-10, and TB7.7, as the genes encoding these proteins are present in M kansasii, M szulgai, and M marinum.6
Mycobacterium tuberculosis antigen-stimulated interferon-γ production with detection by enzyme-linked immunosorbent assay (ELISA). Test includes PHA (positive) and nil (negative) controls. This is also known as an interferon-γ release assay (IGRA). QuantiFERON® and QFT® are trademarks of the QIAGEN® Group.
Tuberculosis (TB) is a highly contagious respiratory disease caused by bacteria of the Mycobacterium tuberculosis complex (M tuberculosis, M bovis, and M africanum). In the US, tuberculosis is relatively uncommon, due to public health efforts; however, latent TB infection, which is a noncommunicable, asymptomatic condition, is more common. Latent tuberculosis infection (LTBI) results when a person becomes exposed to M tuberculosis and their body controls, but does not eradicate, the infection. It is estimated that 11 million people in the US have LTBI7 and anticipated that approximately 10% of these will progress to active TB during the course of their lifetime.8 Immunosuppression, as occurs in HIV infection or with certain therapies (eg, TNF-α inhibitors), can result in reactivation of the LTBI and development of infectious tuberculous disease. Diagnosis of LTBI is an important step in preventing reactivation of tuberculosis, particularly in at-risk populations.9-11 Treatment of LTBI can markedly reduce the risk of progression to active disease.12,13
The QuantiFERON®-TB Gold assay has been approved by the FDA as an in vitro test to aid in the diagnosis of M tuberculosis infection. The test uses three recombinant peptides from M tuberculosis (ESAT-6, CFP-10, and TB7.7) to stimulate T-cell interferon-γ production in individuals with M tuberculosis infection. These peptide antigens do not usually stimulate lymphocytes from uninfected, BCG-vaccinated persons without disease or risk for LTBI.3,6,14-40 The test also includes a positive "mitogen" control that demonstrates an individual is capable of mounting an immune response to the Tb-antigens and a negative "nil" control. The interpretation of the test is based on a combination of the Tb minus nil control values as well as appropriate nil and mitogen values.
In the past, the tuberculin skin test (TST or Mantoux reaction) was the only method for assessing TB infection. Although widely used, the TST had a number of limitations that have been addressed in the QuantiFERON®-TB Gold assay. For this laboratory assay, the stimulation of lymphocytes with M tuberculosis antigens occurs in the phlebotomy tube, rather than in the patient's arm. As a result, there is no booster effect from repeated testing (as is the case with the TST). Results of the QuantiFERON®-TB Gold test are available following a single patient visit without the need for a second visit to evaluate the skin test. The in vitro assay is not associated with adverse hypersensitivity reactions. The recombinant antigens chosen as stimulants in this assay are not present in the BCG vaccine; therefore, the assay is more specific and prior BCG vaccination will not cause false positives in this test, as it does in the TST.23,26 In addition, the interpretation of the lab test is more objective than the TST result.
Numerous clinical studies have demonstrated that the interferon-γ release assays are a sensitive and specific method for the assessment of tuberculosis infection (both latent and active disease). The CDC has recommended this test for use in all settings in which skin testing is applicable, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control (eg, those for health care workers).1 Additional utility may be found in the setting of iatrogenic immunosuppression (eg, anti-TNF therapy for arthritis, Crohn's disease and other conditions thought to be immune-mediated) where the identification of LTBI prior to anti-TNF therapy may allow patients to be treated prophylactically to prevent subsequent active TB disease.11,41,42
A positive result indicates that TB infection is likely and should prompt the same public health and medical interventions as a positive TST result. No reason exists to follow a positive QuantiFERON®-TB Gold result with a TST; alternatively, because of the higher specificity, the QuantiFERON®-TB Gold may have value in excluding a diagnosis of TB infection among individuals with positive TST results caused by nontuberculous mycobacteria, thereby reducing overdiagnosis of TB and guiding clinical management.43 Persons who have a positive QuantiFERON®-TB, regardless of symptoms or signs, should be evaluated for TB disease before LTBI is diagnosed.
There has been some controversy regarding individuals with relatively low positive values. A conference was held in June 2012 to discuss the meaning of these without consensus being reached. Some laboratorians believe the cutoff should be modified--or repeat testing offered--while others believe all patients with positive values should be evaluated without repeat testing.44 (For general guidance: http://www.cdc.gov/tb/)
The majority of healthy adults who have negative QuantiFERON®-TB Gold results are unlikely to have M tuberculosis infection and do not require further evaluation; however, for individuals with recent contact with persons who have infectious TB, negative QuantiFERON®-TB Gold results should be confirmed with a repeat test performed weeks after the end of exposure, as is recommended for a negative TST result.23,26
1 mL x three tubes (see Container)
0.8 mL x three tubes
Refer to collection instructions included with draw kit. Special specimen collection kit contains three gel-barrier tubes as noted above. All three tubes are required for a single test result. Each tube is designed to draw only 1 mL and fill time may be longer than other blood collection tubes. Because of the limited vacuum in these tubes, use a needle and holder (not a butterfly) to collect QuantiFERON® specimens. If a butterfly is required, first collect other required tubes or use another Vacutainer® tube to purge the butterfly line of air and then proceed with drawing the QuantiFERON tubes. Fill tubes to the black fill line on the tube. If a tube is underfilled or overfilled (see kit insert), immediately collect a replacement tube.
Following proper fill, label the tubes appropriately and shake tubes 10 times firmly enough to ensure the entire surface of the tube is coated with blood cells to solubilize the antigen on the tube walls. After shaking, the volume may fall below the fill line. Do not centrifuge or refrigerate specimens.
Return each of the three properly filled, labeled, and shaken tubes to the box labeled "QFT® kit." Seal the top by removing tape from the adhesive. Tubes should be incubated (in an incubator, not a water bath or heat block) upright for 16 to 24 hours at 37°C ± 1°C in the box/kit within 16 hours of collection.
Please indicate date and time of venipuncture on the test request form. If the specimen has been incubated for 16 to 24 hours at 37°C ± 1°C, please mark the top of the specimen box where indicated to denote incubation.
Incubation: If blood is not incubated immediately after collection, remix the tubes by inverting 10 times immediately prior to incubation and within 16 hours of collection. Within 16 hours of collection, incubate the tubes upright in an incubator at 37°C ± 1°C for 16 to 24 hours. The incubator does not require CO2 or humidification. Water baths or heat blocks are not suitable alternatives for a laboratory incubator. Following incubation, forward the tubes to the laboratory at 17°C to 27°C.
After incubation, maintain specimen at room temperature (17°C to 27°C). Do not centrifuge, refrigerate, or ship tubes on ice.
Causes for Rejection
Specimen frozen; specimen more than 94 hours old on receipt by lab; unlabeled specimens not in QuantiFERON® kit box; blood collection in four tube QuantiFERON® TB Gold Plus configuration
This test is time-sensitive and specimens must be received in the laboratory within 70 hours after incubation by the client (no more than 94 hours from the time of collection). Specimen collection times will vary depending on logistics from the incubating location to a LabCorp lab. This test requires a special collection kit that may not be available at all PSCs.
To submit QuantiFERON specimens that are not client incubated prior to submission, order QuantiFERON®-TB Gold .
|Order Code||Order Code Name||Order Loinc||Result Code||Result Code Name||UofM||Result LOINC|
|183244||QuantiFERON Client Incubated||71775-1||182878||QuantiFERON TB Gold||71773-6|
|183244||QuantiFERON Client Incubated||71775-1||183761||QuantiFERON Criteria||8251-1|
|183244||QuantiFERON Client Incubated||71775-1||183462||QuantiFERON TB Ag Value||IU/mL||46217-6|
|183244||QuantiFERON Client Incubated||71775-1||183461||QuantiFERON Nil Value||IU/mL||71776-9|
|183244||QuantiFERON Client Incubated||71775-1||183465||QuantiFERON Mitogen Value||IU/mL||71772-8|
|183244||QuantiFERON Client Incubated||71775-1||183463||QFT TB Ag minus Nil Value||IU/mL||64084-7|
|183244||QuantiFERON Client Incubated||71775-1||182876||Interpretation:||48767-8|