Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series

Abstract

Background: Invasive fungal infections are very severe infections associated with high mortality rates, despite the availability of new classes of antifungal agents. Based on pathophysiological mechanisms and limited pre-clinical and clinical data, adjunctive immune-stimulatory therapy with interferon-gamma (IFN-γ) may represent a promising candidate to improve outcome of invasive fungal infections by enhancing host defence mechanisms.

Methods: In this open-label, prospective case series, we describe eight patients with invasive Candida and/or Aspergillus infections who were treated with recombinant IFN-γ (rIFN-γ, 100 μg s.c., thrice a week) for 2 weeks in addition to standard antifungal therapy.

Results: Recombinant IFN-γ treatment in patients with invasive Candida and/or Aspergillus infections partially restored immune function, as characterized by an increased HLA-DR expression in those patients with a baseline expression below 50%, and an enhanced capacity of leukocytes from treated patients to produce proinflammatory cytokines involved in antifungal defence.

Conclusions: The present study provides evidence that adjunctive immunotherapy with IFN-γ can restore immune function in fungal sepsis patients, warranting future clinical studies to assess its potential clinical benefit.

Trial registration: ClinicalTrials.gov--NCT01270490.

Figures

Figure 1

Screening, randomization, and follow-up of the study patients. The principal investigator was immediately notified when Candida spp. were cultured in blood. With at least one systemic inflammatory response syndrome (SIRS) symptom present in the 24 hours prior to blood culture withdrawal, and administration of systemic antifungal therapy < 72 hours, patients were deemed eligible for the ‘IFN-γ as an adjunctive treatment for candidemia’ pilot-study. In addition, 5 patients not meeting inclusion criteria but who were also treated with rIFN-γ as a therapy of last resort, were included in analysis.

Figure 2

Effect of rIFN-γ on ex-vivo IL-1β and TNFα production. PBMCs of patients were isolated at baseline and day 1, 2, 7, 14 and 28 after rIFN-γ administration. Isolated PBMCs were stimulated for 24 hours with LPS, PHA, C. albicans blastoconidia, or C. albicans hyphae. IL-1β (A) and TNFα (B) concentrations were measured in culture supernatants. Baseline concentrations were used as control and set at 1; subsequent measurements are plotted as the mean relative fold change ± SEM. Significant change from baseline was determined by subjecting the data to Wilcoxons signed rank test. (* = p < 0.05; ** = p < 0.01).

Figure 3

Effect of rIFN-γ on ex-vivo IL-17 and IL-22 production. PBMCs of patients were isolated at baseline and day 1, 2, 7, 14 and 28 after rIFN-γ administration. Isolated PBMCs were stimulated for 7 days with PHA, C. albicans blastoconidia, or C. albicans hyphae. IL-17 (A) and IL-22 (B) concentrations were measured in culture supernatants. Baseline concentrations were used as control and set at 1; subsequent measurements are plotted as the mean relative fold change ± SEM. Significant change from baseline was determined by subjecting the data to Wilcoxons signed rank test. (* = p < 0.05).

Figure 4

Effect of rIFN-γ on ex-vivo IL-10 production. PBMCs of patients were isolated at baseline and day 1, 2, 7, 14 and 28 after rIFN-γ administration. Isolated PBMCs were stimulated for 48 hours with LPS, PHA, C. albicans blastoconidia, or C. albicans hyphae. IL-10 concentrations were measured in culture supernatants. Baseline concentrations were used as control and set at 1; subsequent measurements are plotted as the mean relative fold change ± SEM.

Figure 5

mHLA-DR expression in rIFN-γ treated patients, divided into immunoparalyzed patients with baseline HLA-DR expression below 50% (solid dots), and without HLA-DR defined immunoparalysis (open dots). Data are expressed as median [IQR].