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.

Longitudinal Evaluation of the QuantiFERON-TB Gold Plus Assay in Hospitalized COVID-19 Patients with a First Indeterminate Result: Resolution of Inflammation and Restoration of T-Lymphocyte Counts and Interferon-Gamma Production

“…Ward et al reported that COVID-19 patients with both indeterminate and determinate QFT-P results were lymphopenic, although only subjects in the first group failed to produce an effective IFN-γ response after stimulation ( 1 ). Prior work performed by our group confirmed the results observed by Ward et al and provided evidence that T-lymphocyte reduction in the peripheral blood was correlated with the impairment of IFN-γ production upon phytohemagglutinin (mitogen) stimulation in the QFT-P assay and that this was leading to indeterminate results ( 6 ). Our longitudinal series shows that once the acute phase of COVID-19 is resolved, inflammatory markers and peripheral blood leukocyte counts tend to normalize, and effective interferon gamma production by T-lymphocytes is restored after both specific (mycobacterial peptide) and nonspecific (mitogen) stimulation.…”

“…In a previous study conducted by our group, we found an increased rate of indeterminate results at the QFT-P assay (22.1%) in COVID-19 hospitalized patients ( 6 ) compared to the rates observed in non-COVID-19 patients from the available literature (3.2%) ( 10 ) and from our previous experience in different settings (4.3% of results were indeterminate in hematopoietic stem cell transplant recipients from January 2015 to December 2019, unpublished data).…”

“…Several studies report an increased rate of indeterminate QuantiFERON-TB Gold Plus (QFT-P) results in patients hospitalized because of severe Coronavirus Disease (COVID)-19, and this is due to peripheral blood T-lymphocyte depletion and dysfunction ( 1 – 6 ), which are known to be associated with COVID-19 disease severity and mortality ( 7 – 9 ). So far, there are no reports concerning QFT-P responses and relations with lymphocyte counts or inflammation markers in subjects who survived COVID-19 and received a previous indeterminate result after the acute phase of the disease.…”

Prevalence of indeterminate tuberculosis interferon‐gamma release assays in COVID‐19 patients: Systematic review and meta‐analysis

“…11,12,[17][18][19][20]25 An indeterminate result was defined according to the manufacturers' definition in six studies, 11,12,17,18,22,25 and as (Nil [baseline] >8.0 IU/mL) or [nil ≤8.0 IU/mL and mitogen-nil <0.5 IU/ mL] in two studies. 19,20 The term "low response to the mitogen" was used in two other studies. 10,24 Palacios-Gutiérrez et al defined "a low IFN-ɣ response to PHA" as an IFN-ɣ concentration ≥0.5 IU/mL and less than 50% below the average values and "a very low IFN-ɣ response to PHA" for an IFN-ɣ concentration <0.5 IU/mL in the mitogen tube without mentioning the term "indeterminate."…”

Age-dependent blood signatures of rehabilitated patients with mild COVID-19

“…Major symptoms include fever, continuous cough, shortness of breath, diarrhea, and fatigue [4]. Abnormalities in the blood of COVID-19 patients include altered levels of the peripheral blood T, B-cell subsets, and serum in ammatory parameters [5]. These alterations may indicate different stages of COVID-19 infection and predict the prognosis of patients [6].…”