Immune Profiling Enables Stratification of Patients With Active Tuberculosis Disease or <i>Mycobacteriu</i> <i>m tuberculosis</i> Infection
Darragh Duffy, Elisa Nemes, Alba Llibre, Vincent Rouilly, Munyaradzi Musvosvi, Nikaïa Smith, Elizabeth Filander, Hadn Africa, Simbarashe Mabwe, Lungisa Jaxa, Bruno Charbit, Humphrey Mulenga, Michèle Tameris, Gerhard Walzl, Stephanus T. Malherbe, Stéphanie Thomas, Mark Hatherill, Nicole Bilek, Thomas J. Scriba, Matthew L. Albert, Laurent Abel, Andrés Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James P. Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Odile Gelpi, Ivo Gomperts-Boneca, Milena Hasan, Serge Herçberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Étienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Éric Tartour, Antoine Toubert, Mathilde Touvier, Marie‐Noëlle Ungeheuer, Matthew L. Albert, Darragh Duffy, Lluís Quintana‐Murci
Abstract
BACKGROUND: Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. METHODS: We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb-specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. RESULTS: TruCulture showed discrimination of active TB cases from LTBI (P < .0001, AUC = .81) compared with QFT (P = .45, AUC = .56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC = .89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P < .0001, AUC = .91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. CONCLUSIONS: TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection.