Interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients: a phase 2, placebo-controlled randomized clinical trial

Intensive Care Med https://doi.org/10.1007/s00134-023-07065-0 ORIGINAL Interferon gamma‑1b for the prevention of hospital‑acquired pneumonia in critically ill patients: a phase 2, placebo‑controlled randomized clinical trial Antoine Roquilly1,2* , Bruno Francois3, Olivier Huet4, Yoann Launey5, Sigismond Lasocki6, Emmanuel Weiss7, Melanie Petrier2, Yannick Hourmant1, Marwan Bouras1,2, Karim Lakhal1, Cecilia Le Bel1, Delphine Flattres Duchaussoy1, Laia Fernández‑Barat8,9, Adrian Ceccato9, Laurent Flet10, Alexandra Jobert11,13, Jeremie Poschmann2, Veronique Sebille12,13, Fanny Feuillet12,13, Despoina Koulenti14,15 and Antoni Torres8 on behalf of the Atlanrea study group and the Société Française d’Anesthésie Réanimation (SFAR) Research Network © 2023 The Author(s) Abstract Purpose: We aimed to determine whether interferon gamma-1b prevents hospital-acquired pneumonia in mechani‑ cally ventilated patients. Methods: In a multicenter, placebo-controlled, randomized trial conducted in 11 European hospitals, we randomly assigned critically ill adults, with one or more acute organ failures, under mechanical ventilation to receive interferon gamma-1b (100 µg every 48 h from day 1 to 9) or placebo (following the same regimen). The primary outcome was a composite of hospital-acquired pneumonia or all-cause mortality on day 28. The planned sample size was 200 with interim safety analyses after enrolling 50 and 100 patients. Results: The study was discontinued after the second safety analysis for potential harm with interferon gamma-1b, and the follow-up was completed in June 2022. Among 109 randomized patients (median age, 57 (41–66) years; 37 (33.9%) women; all included in France), 108 (99%) completed the trial. Twenty-eight days after inclusion, 26 of 55 participants (47.3%) in the interferon-gamma group and 16 of 53 (30.2%) in the placebo group had hospital-acquired pneumonia or died (adjusted hazard ratio (HR) 1.76, 95% confidence interval (CI) 0.94–3.29; P = 0.08). Serious adverse events were reported in 24 of 55 participants (43.6%) in the interferon-gamma group and 17 of 54 (31.5%) in the placebo group (P = 0.19). In an exploratory analysis, we found that hospital-acquired pneumonia developed in a sub‑ group of patients with decreased CCL17 response to interferon-gamma treatment. Conclusions: Among mechanically ventilated patients with acute organ failure, treatment with interferon gamma1b compared with placebo did not significantly reduce the incidence of hospital-acquired pneumonia or death on day 28. Furthermore, the trial was discontinued early due to safety concerns about interferon gamma-1b treatment. Keywords: Intensive care, Hospital-acquired pneumonia, Interferon-gamma, Immunotherapy, Immunosuppression *Correspondence: 1 Nantes Université, CHU Nantes, INSERM, Anesthesie Réanimation, CIC 1413, 44000 Nantes, France Full author information is available at the end of the article The members of the Atlanrea study group are listed in the Acknowledgements Introduction Hospital-acquired pneumonia (HAP) is a health concern worldwide and a public health priority in Europe. In 2017, the European Centre for Disease Prevention and Control estimated more than 500,000 cases/year in Europe, accounting for a significant proportion of disability, since infected patients lose an average of 7.7 quality-adjusted life years [1]. HAP has significant medical consequences, notably prolonged hospitalization equivalent to 7 extra days on average in the intensive care unit (ICU) and attributable mortality of 10% [2, 3]. With an average cost for each episode of HAP of 40,000 euros, annual expenses for HAP treatment are estimated to reach 8 billion $ in the United States of America [3]. In this context, American, European, and French intensive care societies have published guidelines for preventing and treating HAP [4–6]. However, even after implementing these guidelines, the rates of HAP still routinely reach 30% of critically ill patients hospitalized for more than three days in ICUs [7], which suggests that new approaches are urgently needed. The involvement of critical illness-related immunosuppression as a risk factor for hospital-acquired infections is well described in ICU patients [8–10]. An emerging trend is that immune restoration could help prevent infection and improve outcomes for this population [11, 12]. While patients with an inherited deficiency in interferon gamma (IFN-γ) are susceptible to respiratory infections [13, 14], it has been shown in experimental models and human samples that the IFN- γ production by immune cells was decreased before and during HAP [15–17]. Following the demonstration that in vitro IFN-γ treatment restores the metabolic activity and the functions of monocytes from critically ill patients [18, 19], several observational cases of rescue therapies with interferon gamma-1b have shown promising effects in patients with protracted infections or difficult-to-treat pathogens [20–22]. The human recombinant interferon gamma-1b for the prevention of hospital-acquired pneumonia in critically ill patients (PREV-HAP) trial was conducted to test the hypothesis that interferon gamma-1b could restore immunity and prevent HAP in critically ill patients under invasive mechanical ventilation. Methods Design We conducted an investigator-initiated multicenter, parallel-group, double-blind, randomized clinical trial to investigate the effects of interferon gamma-1b in critically ill patients at risk of HAP. The study protocol is available in the electronic supplementary material (ESM) 1. Take‑home message In this randomized clinical trial that included 109 adult critically ill patients requiring invasive mechanical ventilation that was discon‑ tinued early for safety concerns, early treatment with interferon gamma-1b vs placebo resulted in an adjusted hazard ratio for hos‑ pital-acquired pneumonia or death of 1.76 (95% confidence inter‑ val 0.94–3.29; P = 0.08) on day 28. Further studies are necessary to identify patients in which interferon-gamma treatment could be well tolerated. Ethics The Ethics Committee of Ouest II Angers (France) approved the study protocol in March 2021. This trial complied with the Declaration of Helsinki and was registered in March 2021 (number ClinicalTrial.gov NCT04793568). The patient’s legal surrogate provided written informed consent for participation. In agreement with the local laws, patients could be enrolled before the provision of legal surrogate consent if the next of kin could not be informed within the maximum delay for inclusion. When able to provide it, patient’s follow-up consent was requested up to 90 days after inclusion. Trial sites and study population The study was conducted at eleven ICUs in France, Spain, and Greece. Patients aged between 18 and 85 years, admitted to the participating sites within the last 48 h, receiving invasive mechanical ventilation, were eligible if presenting with one or more acute organ f (...truncated)