Clinical and Epidemiological Correlates of Low IFN-Gamma Responses in Mitogen Tube of QuantiFERON Assay in Tuberculosis Infection Screening During the COVID-19 Pandemic: A Population-Based Marker of COVID-19 Mortality?

Abstract

Background: The clinical and epidemiological implications of abnormal immune responses in COVID-19 for latent tuberculosis infection (LTBI) screening are unclear.

Methods: We reviewed QuantiFERON TB Gold Plus (QFT-Plus) results (36,709 patients) from July 2016 until October 2021 in Asturias (Spain). We also studied a cohort of ninety hospitalized patients with suspected/confirmed COVID-19 pneumonia and a group of elderly hospitalized patients with COVID-19 who underwent serial QFT-Plus and immune profiling testing.

Results: The indeterminate QFT-Plus results rate went from 1.4% (July 2016 to November 2019) to 4.2% during the COVID-19 pandemic. The evolution of the number of cases with low/very low interferon-gamma (IFN-gamma) response in the mitogen tube paralleled the disease activity and number of deaths during the pandemic waves in our region (from March 2020 to October 2021). The percentages of positive QFT-plus patients did not significantly change before and during the pandemic (13.9% vs. 12.2%). Forty-nine patients from the suspected/confirmed COVID-19 pneumonia cohort (54.4%) had low/very low IFN-gamma response to mitogen, 22 of them (24.4%) had severe and critical pneumonia. None received immunosuppressants prior to testing. Abnormal radiological findings (P = 0.01) but not COVID-19 severity was associated with low mitogen response. Immune profiling showed a reduction of CD8 + T cells and a direct correlation between the number of EMRA CD8 + T-cells and IFN-gamma response to mitogen (P = 0.03).

Conclusion: Low IFN-gamma responses in mitogen tube of QFT-Plus often occur in COVID-19 pneumonia, which is associated with a low number of an effector CD8 + T-cell subset and does not seem to affect LTBI screening; however, this abnormality seems to parallel the dynamics of COVID-19 at the population level and its mortality.

Keywords: COVID-19 pneumonia; IGRA; Latent Tuberculosis Infection; Phytohemagglutinin; SARS-CoV-2.

Graphical abstract

Figure 1

Low IFN-γ Response to Phytohemagglutinin (PHA) in QuantiFERON TB Gold Plus (QFT) Assays and COVID-19 Pandemic Evolution in the Principado de Asturias (Spain) from Spring of 2020 to Autumn of 2021 (Source: ASTURSALUD (www.astursalud.es), Principado de Asturias). A) Figure shows IFN-γ response to PHA measured in the mitogen tube of QFT assay in patients from January 2018 to October 2021 (27,480 patient-samples). Blue line: Patients with very low IFN-γ response to PHA (IFN-γ concentration (minus nil) in mitogen tube < 0.5 IU/mL; QFT indeterminate result). Red line: Patients with low IFN-γ response to PHA (IFN-γ concentration (minus nil) ≥ 0.5 IU/mL in mitogen tube and less than 50% below the average values). Red and blue arrows indicate the historically maximal rate (%) of low and very low response to PHA (%) in relationship with the onset of the COVID-19 pandemic. Green line indicates % of patients with QFT-positive results. B) Figure shows distribution of the 27,480 QuantiFERON assays performed per month from January 2018 to October 2021 (monthly average = 604.2; range: 398-842).

Figure 2

Evolution Over time of COVID-19 Deaths and of Patients with Low IFN-gamma Response to Phytohemagglutinin (PHA) in Mitogen Tube of QuantiFERON TB Gold Plus (QFT).

Figure 3

Immunophenotyping of Lymphocytes and T Cell Subsets and IFN-γ Level Responses to Phytohemagglutinin (PHA). A) Pearson correlations between lymphocyte subsets counts and IFN-γ level responses to PHA in whole blood of patients with COVID-19 pneumonia, including statistical significant correlations in CD8 T-cell counts and IFN-γ level responses to PHA (lower right-side quadrant; P < 0.05). B) Statistical significant positive correlations in EMRA CD8 T-cell counts and IFN-γ level responses to PHA (lower right-side quadrant; P < 0.05). C) EMRA CD8 + T-cell Counts (solid line with triangles) and IFN-γ Response Levels (IU/mL) to PHA (dashed line with squares) at Days 1 and 7 After Hospital Admittance of Ten QFT-monitored Patients (named A to J). Their Clinical Evolution is Also Included. Left, 5 patients with initial normal response to PHA at day 1 (four of them had low/very low response to PHA at day 7); Right, 5 patients with initial low/very low response to PHA at day 1 (three of them had normal response to PHA at day 7).