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

Abstract

Purpose: We aimed to determine whether interferon gamma-1b prevents hospital-acquired pneumonia in mechanically 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 subgroup of patients with decreased CCL17 response to interferon-gamma treatment.

Conclusions: Among mechanically ventilated patients with acute organ failure, treatment with interferon gamma-1b 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: Hospital-acquired pneumonia; Immunosuppression; Immunotherapy; Intensive care; Interferon-gamma.

Fig. 1

Hazard ratio of the primary outcome in prespecified subgroups. Odds ratio of the primary outcome in 6 prespecified subgroups. Square size representing the hazard ratio reflects the relative numbers in each subgroup, and horizontal bars represent 95% confidence intervals. Adjusted HR > 1 means a higher risk of mortality and/or HAP with the intervention. No statistical power analysis was performed and no adjustment were made for multiplicity in the analysis of subgroups. 95% CIs around estimates for subgroup analyses should not be used to infer definitive treatment effects. P values are for heterogeneity of the effect of the trial regimen on the primary outcome in each subgroup. HAP hospital-acquired pneumonia, SAPS-II Simplified Acute Physiological Score II

Fig. 2

Time course of inflammatory profiles. A, ) PLSDA representations of the 384- inflammatory protein distributions on day 7 in (A) all the patients and (B) in the interferon-gamma group. C Unsupervised heatmap of the filtered proteins on day 7 in patients treated with interferon gamma. D Correlation network of the protein from clusters interferon-1 and interferon-2. E Kaplan–Meier estimates of the ICU hospitalization rate among patients of clusters interferon-1 and interferon-2. F Relative expressions of CCL17 in patients with or without HAP, treated with placebo or interferon gamma-1b. Data are presented as mean with standard error of mean. P-values calculated by linear mixed-effects models are reported in eTable 5. Interaction (T-g): Interaction between the effects of time and of groups (treatment)