Reversal of trauma-induced monocyte paralysis by IFN-γ fails to prevent ventilator-associated pneumonia, implicating lymphoid deficits in infection risk

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.