Effects of acute critical illnesses on the performance of interferon-gamma release assay

One-third of the individuals worldwide are infected with Mycobacterium tuberculosis (MTB)1. Among them, immunocompetent subjects have a 5–10% lifetime risk of progressing to active tuberculosis (TB). Thus, latent TB infection (LTBI) serves as a significant reservoir of future epidemics. Identification and treatment of LTBI is a key element in post-2015 strategy for global TB control2. The tuberculin skin test (TST) and interferon-gamma (IFN-γ) release assays (IGRAs) are currently available methods for diagnosis of LTBI. The TST has been the most widespread used test for detecting LTBI since a century ago3. Until recently, IGRAs arise as a promising alternative to the TST because of their equivalent sensitivity and improved specificity4,5. IGRAs are functional assays measuring T cell response to MTB-specific antigens in either whole blood or peripheral blood-derived mononuclear cells5. IGRAs also have advantages of an objective readout, no need for revisit and no boost effect compared to the TST4. In light of this, IGRAs have been incorporated into international guidelines for LTBI screening and diagnosis in several countries, either as a confirmatory test for a positive TST or as a substitute for the TST6. Despite these logistical advantages, many issues regarding IGRAs, such as suboptimal reproducibility, unknown prognostic value and limited interpretive criteria, need to be settled7. The causes of considerable IGRA variability are far from fully understood. It has been shown that assay, preanalytical and analytical factors all have an impact on reproducibility of IGRA results8,9,10. Even a small change in blood volume or the extent of tube shaking may significantly influence IGRA performance11. These emphasize the importance of assay standardization and appropriate quality control. Additionally, IGRA performance may be altered because of host biological and immunological variations; certain chronic illnesses or conditions like age, malnutrition, lymphocytopaenia, human immunodeficiency virus (HIV) infection, malignancy and renal dysfunction are recognized ones12,13,14. Acute febrile illnesses or dysfunction of organs are associated with altered immune reactions15,16,17, and they may theoretically have effects on the performance and reproducibility of IGRAs. However, little is known about how acute insults affect IGRA results. Clinically, such data are essential because diagnosis and treatment decisions could be impacted by testing results. In this way, physicians would better realize the limitations in applying IGRAs. In the present study, we aimed to investigate IGRA performance among patients suffering from acute critical illnesses. In addition, we explored patient factors, which may influence the IGRA results.