Low IFN-Gamma Response to Phytohemagglutinin in Mitogen Tubes of the QuantiFERON TB Gold Plus Assay During the COVID-19 Pandemic

Abstract

Background: The clinical implications of abnormal immune responses in COVID-19 for latent tuberculosis infection screening and potential reactivation are unclear. Since December of 2019, we have observed an unusual increase in the number of QuantiFERON TB Gold Plus (QTF-Plus) indeterminate results and low IFN-γ responses to phytohemagglutinin (PHA) in the mitogen tube. This fact coincides with the COVID-19 pandemic evolution. We hypothesized that these low IFN-γ responses to PHA were related to a biological effect of COVID-19 or its treatment.Methods: We reviewed QTF-Plus results (30,092 patients) from July 2016 until November 2020. We also studied a cohort of ninety hospitalized patients with suspected/confirmed COVID-19 pneumonia for two weeks in March 2020 (first pandemic wave), and a group of elderly hospitalized patients with COVID-19 who underwent serial QTF-Plus and immune profiling testing.Findings: The indeterminate QTF-Plus results rate went from 1·4% (from July 2016 to November 2019) to 3·9% during the COVID-19 pandemic (first and second waves). Forty-nine out of 90 patients (54·4%) had low/very low IFN-γ response to PHA; 22/90 (24·4%) had confirmed severe/critical COVID-19 pneumonia; none received immunosuppressants prior to testing. Abnormal radiological findings (P=0·01) but not COVID-19 severity were associated with low PHA response. The number of EMRA CD8+ T-cells showed a direct correlation with IFN-γ response to PHA (P=0·03).Interpretation: Low IFN-γ responses to PHA often occur in COVID-9 pneumonia. A low number of effector CD8+ T-cells subset but not disease severity or immunosuppressants were associated with this finding. The clinical implication is unclear.Funding: None.Declaration of Interests: P.E. and his institution have filed two patent applications related to immunodiagnostic laboratory methodologies for latent tuberculosis infection, which are not included in this manuscript. To date, there has been no income or royalties associated with those filed patent applications. P.E. participated in a short-term advisory scientific board for DiaSorin Molecular, and honorarium was paid to his institution. P.E. has no other conflicts to declare. The other authors have no conflicts of interest to declare.Ethics Approval Statement: Ethical clearance was approved by the Comité de Ética de la Investigación del Principado de Asturias, Spain