In Patients with Severe COVID-19, the Profound Decrease in the Peripheral Blood T-Cell Subsets Is Correlated with an Increase of QuantiFERON-TB Gold Plus Indeterminate Rates and Reflecting a Reduced Interferon-Gamma Production

Abstract

Increased rates of indeterminate QuantiFERON-TB Gold Plus Assay (QFT-Plus) were demonstrated in patients hospitalized with Coronavirus Disease (COVID)-19. We aimed to define the prevalence and characteristics of hospitalized COVID-19 patients with indeterminate QFT-Plus. A retrospective study was performed including hospitalized COVID-19 patients, stratified in survivors and non-survivors, non-severe and severe according to the maximal oxygen supply required. Statistical analysis was performed using JASP ver0.14.1 and GraphPad Prism ver8.2.1. A total of 420 patients were included, median age: 65 years, males: 66.4%. The QFT-Plus was indeterminate in 22.1% of patients. Increased rate of indeterminate QFT-Plus was found in non-survivors (p = 0.013) and in severe COVID-19 patients (p < 0.001). Considering the Mitogen-Nil condition of the QFT-Plus, an impaired production of interferon-gamma (IFN-γ) was found in non-survivors (p < 0.001) and in severe COVID-19 patients (p < 0.001). A positive correlation between IFN-γ levels in the Mitogen-Nil condition and the absolute counts of CD3+ (p < 0.001), CD4+ (p < 0.001), and CD8+ (p < 0.001) T-lymphocytes was found. At the multivariable analysis, CD3+ T-cell absolute counts and CD4/CD8 ratio were confirmed as independent predictors of indeterminate results at the QFT-Plus. Our study confirmed the increased rate of indeterminate QFT-Plus in COVID-19 patients, mainly depending on the peripheral blood T-lymphocyte depletion found in the most severe cases.

Keywords: CD3; IFN; IGRA; QuantiFERON-TB Gold; SARS-CoV-2; lymphopenia.

Figure 1

QFT-Plus indeterminate results and IFN-γ production in COVID-19 patients stratified according to the maximal oxygen supply needed during hospitalization. (a) Rates of determinate and indeterminate results at the QFT-Plus assay in COVID-19 patients stratified according to the maximal oxygen support needed during the entire hospitalization are represented. (b) The levels of IFN-γ in the Mitogen-Nil condition of the QFT-Plus assay in COVID-19 patients stratified according to the maximal oxygen support received during the entire hospitalization are represented. (c) As in (b), after removing COVID-19 patients with an indeterminate result of the QFT-Plus Assay. The histogram height represents the median value. Whiskers represent the interquartile range. QFT-Plus: QuantiFERON-TB Gold Plus; IFN-γ: interferon-γ; AA: ambient air; VMK: Venturi oxygen mask; NRM: Non-Rebreather Mask; NIV: non-invasive ventilation; OTI: orotracheal intubation for mechanical ventilation.

Figure 2

Correlation between IFN-γ levels in the Mitogen-Nil condition of the QFT-Plus assay and laboratory parameters in COVID-19 patients. The statistical significance is represented for each couple of parameters by asterisks. The color intensity in each square box represents the value of the Spearman rho coefficient, ranging from −1 (red), through 0 (white) to 1 (blue). QFT-Plus: QuantiFERON-TB Gold Plus; IFN-γ: interferon-γ; #: absolute counts; Neut: neutrophils; Lympho: lymphocyte; N/L ratio: neutrophils-to-lymphocytes ratio; CRP: C-reactive protein; IL-6: interleukine-6; TNF-α: tumor necrosis factor-α. 0.01 < * < 0.05; 0.001 < ** < 0.01; 0.0001 < *** < 0.001; **** < 0.0001.