Indeterminate Result of Interferon-γ Release Assay—A Risk Factor of Mortality for COVID-19 and Non-COVID-19 Respiratory Infections

Abstract

Toward the end of 2022, the cessation of China's “dynamic zero-COVID policy” had led to a notable outbreak of SARS-CoV-2 infections and a substantial number of severe cases and deaths were reported, which raised serious concerns. Concurrently, our study identified a significant increase in the incidence of indeterminate results from the Interferon-γ Release Assay (IGRA) among hospitalized patients during this period. Peripheral T cells from these individuals were unable to produce measurable levels of IFN-γ upon stimulation with the PHA mitogen. This indeterminate IGRA results emerged as a potential risk factor for increased mortality among severely affected elderly COVID-19 patients, contributing to an understanding of the observed excess mortality. The deep serum proteomic analysis elucidated a dysfunctional immune response and defect in cardiac function of those patients. A predictive panel including IGRA results significantly enhanced the accuracy of predicting mortality outcomes in COVID-19 cases (AUC = 0.9762). We also extended the relevance of indeterminate IGRA outcomes as a risk factor for mortality to elderly non-COVID-19 respiratory infections, providing valuable prognostic insights into this type of disease and informing targeted and effective therapeutic interventions for similar outbreaks in the future.