Reversal of trauma-induced monocyte paralysis by IFN-γ fails to prevent ventilator-associated pneumonia, implicating lymphoid deficits in infection risk
Abstract Ventilator-associated pneumonia (VAP) remains a frequent and severe complication in critically ill patients. Although interferon-gamma (IFN-γ) has been reported to restore trauma-associated immune defects, the PREV-HAP trial (ClinicalTrials.gov NCT04793568) did not show a benefit of IFN-γ on VAP prevention. To investigate the immunological basis of this therapeutic failure, we performed longitudinal high-dimensional immunoprofiling on 104 trial participants. IFN-γ improved phenotypic and metabolic features of monocyte immune suppression, most notably by increasing HLA-DR expression. Whereas HLA-DR on monocytes is a well-established biomarker for patient outcomes, its modulation via IFN-γ injection did not prevent lung pathology, possibly due to CCR7 induction. In contrast, we identified pre-existing deficits in T- and B-cell subsets in patients who subsequently developed VAP. Together, these findings suggest that monocytic HLA-DR expression reflects the immune status rather than directly influencing VAP susceptibility, and that lymphoid immune alterations may represent more relevant determinants of infection risk in ventilated patients.
Authors
- Tobias Wertheimer (ORCID: https://orcid.org/0000-0002-8480-7391)
- Juan Villar-Vesga (ORCID: https://orcid.org/0000-0002-1085-9922)
- Boris Novakovic (ORCID: https://orcid.org/0000-0002-5623-9008)
- Marijne Vermeer (ORCID: https://orcid.org/0000-0001-5869-0532)
- Anaísa V. Ferreira (ORCID: https://orcid.org/0000-0002-6274-0448)
- Mihai Gheorghe Netea (ORCID: https://orcid.org/0000-0003-2421-6052)
- Cécile Poulain (ORCID: https://orcid.org/0009-0000-6169-5713)
- Colin Sparano (ORCID: https://orcid.org/0000-0003-0776-6896)
- Stefanie Kreutmair (ORCID: https://orcid.org/0000-0001-8466-6675)
- Selma Tuzlak (ORCID: https://orcid.org/0000-0002-2406-1479)
- Antoine Roquilly (ORCID: https://orcid.org/0000-0002-1029-6242)
- Burkhard Becher (ORCID: https://orcid.org/0000-0002-1541-7867)
- Susanne Unger (ORCID: https://orcid.org/0000-0001-6916-7544)
- Can Ulutekin (ORCID: https://orcid.org/0000-0003-4406-5423)
- Julien Chabbey
- Laura Hurtado‐Navarro (ORCID: https://orcid.org/0000-0002-9544-6042)
- Jonas Schmid (ORCID: https://orcid.org/0000-0001-9105-9144)
- Mariolina Bruno (ORCID: https://orcid.org/0000-0002-5353-7691)
- Maud Mayoux (ORCID: https://orcid.org/0000-0002-3700-3120)
- Bruno François (ORCID: https://orcid.org/0000-0002-2531-1652)
- Athanasios Ziogas
- Stanislav Dergun (ORCID: https://orcid.org/0009-0000-7201-9032)
- Vanessa Dobernig (ORCID: https://orcid.org/0009-0003-2588-2302)
- Fernando P. Canale
- Minqi Lin
- Amir Elalfy
- Daehong Kim
- Philipp Häne
- Marijana Saric
Publication Details
- Journal
- Nature Communications
- Published
- 2026-10-31
- DOI
- https://doi.org/10.1038/s41467-026-78844-8
- Primary Topic
- Nosocomial Infections in ICU
- Type
- article
- Field-Weighted Citation Impact
- 0.00