Multicentric experience with interferon gamma therapy in sepsis induced immunosuppression. A case series

Abstract

BackgroundThe sepsis-induced immunodepression contributes to impaired clinical outcomes of various stress conditions. This syndrome is well documented and characterized by attenuated function of innate and adaptive immune cells. Several pharmacological interventions aimed to restore the immune response are emerging of which interferon-gamma (IFNγ) is one. It is of paramount relevance to obtain clinical information on optimal timing of the IFNγ-treatment, −tolerance, −effectiveness and outcome before performing a RCT. We describe the effects of IFNγ in a cohort of 18 adult and 2 pediatric sepsis patients.MethodsIn this open-label prospective multi-center case-series, IFNγ treatment was initiated in patients selected on clinical and immunological criteria early (< 4 days) or late (> 7 days) following the onset of sepsis. The data collected in 18 adults and 2 liver transplanted pediatric patients were: clinical scores, monocyte expression of HLA-DR (flow cytometry), lymphocyte immune-phenotyping (flow cytometry), IL-6 and IL-10 plasma levels (ELISA), bacterial cultures, disease severity, and mortality.ResultsIn 15 out of 18 patients IFNγ treatment was associated with an increase of median HLA-DR expression from 2666 [IQ 1547; 4991] to 12,451 [IQ 4166; 19,707], while the absolute number of lymphocyte subpopulations were not affected, except for the decrease number of NK cells 94.5 [23; 136] to 32.5 [13; 90.8] (0.0625)]. Plasma levels of IL-6 464 [201–770] to 108 (89–140) ng/mL (p = 0.04) and IL-10 from IL-10 from 29 [12–59] to 9 [1–15] pg/mL decreased significantly. Three patients who received IFNγ early after ICU admission (<4 days) died. The other patients had a rapid clinical improvement assessed by the SOFA score and bacterial cultures that were repeatedly positive became negative. The 2 pediatric cases improved rapidly, but 1 died for hemorrhagic complication.ConclusionGuided by clinical and immunological monitoring, adjunctive immunotherapy with IFNγ appears well-tolerated in our cases and improves immune host defense in sepsis induced immuno suppression. Randomized clinical studies to assess its potential clinical benefit are warranted.

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“…Our observation with the IFN-g level in CLP mice is not in line with previous studies [29], and it is likely due to the differences in the time of measurement after CLP. However, our results are similar to the clinical ndings that support adjuvant IFN-g immunotherapy concept to improve the host immune response against infection [30,31].…”

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“…These very encouraging results need now to be confirmed in a larger study. There are some 50 reported cases of sepsis that received rIFN-g, and the treatment appears to have been well tolerated (91,92). In a recent prospective case series, IFN-g was associated with an increase in monocytic HLA-DR as well as a decrease in IL-6 and IL-10 plasma levels (92).…”

“…There are some 50 reported cases of sepsis that received rIFN-g, and the treatment appears to have been well tolerated (91,92). In a recent prospective case series, IFN-g was associated with an increase in monocytic HLA-DR as well as a decrease in IL-6 and IL-10 plasma levels (92). Nevertheless, RCTs are needed to ascertain the putative benefit of IFN-g on sepsis survival: one phase II trial is ongoing (NCT03332225), and one phase III study was completed with results not yet published (NCT01649921).…”

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“…In critically ill adults, clinical trial data demonstrates that IFN-γ is associated with clearance of persistent bacteremia and improved cytokine profiles in the setting of sepsis-induced immunosuppression. Further investigation in clinical trials in sepsis is ongoing (70). It has also been shown to correct HLA-DR expression on monocytes in patients with sepsis which provides a useful marker of response (56).…”