Interferon-Gamma Release Assays

Key points

Microbiology

The genus Mycobacterium consists of slow-growing organisms that are widely distributed throughout the world and range from organisms that cause no human disease to those like M tuberculosis and M leprae that cause enormous morbidity and mortality.⁶ TB is caused by members of the M tuberculosis complex that includes the clinically relevant species M tuberculosis, M bovis, and M africanum. All members of the M tuberculosis complex, except BCG substrains, contain a region of the genome referred to

Epidemiology

Understanding the epidemiology of TB is necessary to develop successful TB control interventions. As discussed previously, there were an estimated 8.6 million people who developed TB in 2012.¹ Twenty-two high-burden countries accounted for 81% of all estimated incident cases worldwide, with rates of approximately 150 to 300 cases per 100,000 population. In these high-burden countries, stopping transmission through TB case detection and treatment is the most important TB control intervention.

The

Clinical presentation

TB represents a spectrum of disease ranging from LTBI, in which patients are asymptomatic, to active TB, where patients are symptomatic and infectious. LTBI is defined solely by evidence of sensitization to mycobacterial proteins in the absence of symptoms or signs of active TB.¹⁹ In some instances, a chest radiograph may show the remnants of previous disease, such as calcified granulomas or apical pleural parenchymal fibrosis. By definition, however, there are no clinical symptoms or signs of

Pathogenesis

M tuberculosis is spread from person to person through the air by droplet nuclei—particles 1 to 5 μm in diameter that contain viable M tuberculosis.⁶ Droplet nuclei are expelled into the air when patients with infectious TB create an aerosol by talking, coughing, or singing. The likelihood of transmitting the bacilli depends on the number of bacilli expelled into the air, the concentration of organisms in the air, and the length of time the contact breathes the infected air. Whether or not an

Diagnosis

The TST had been the only test for diagnosing LTBI but has several well-described limitations. These include the need for 2 visits, subjective results, low sensitivity for active TB, and false-positive results due to prior BCG vaccination or NTM infection.²¹ The IGRAs were developed to overcome many of these limitations. They require a single blood draw and assess the cell-mediated immune response by measuring interferon gamma produced after incubation with TB-specific antigens.

Treatment

Treating patients with LTBI to prevent future active TB has been a recommended strategy for TB control in the United States since 1965.⁵⁰ As discussed previously, early placebo-controlled trials showed that isoniazid effectively decreased the risk of future TB in people with a positive TST.¹⁸ Because LTBI treatment has a proved benefit, similar controlled studies based on IGRA testing have not been conducted to date.

The recommended regimens for LTBI treatment are listed in Table 4. Isoniazid

Summary/Discussion

Compared with the TST, the IGRAs perform as well or better in most targeted populations. Ongoing challenges include a low sensitivity for active TB, limited ability to predict future progression to disease, and poor specificity in groups at lower risk for TB exposure. The IGRAs have overcome several limitations of the TST by requiring a single visit, providing objective results that are retrievable electronically, and being more specific in BCG-vaccinated people.⁵⁶ Because BCG vaccine is used