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.
Highlights
The sepsis-induced immunodepression contributes to impaired clinical outcomes of various stress conditions
Effects on clinically relevant end-points can only be determined in randomized clinical trials, relevant data related to immunological properties, safety, and timing of treatment are needed to facilitate the design of such trials
The decision to administer interferon gamma (IFNγ) was made on the following criteria, which were not modified between 2004 and 2017: (1) an Intensive Care Unit (ICU) stay over 7 days; (2) a diagnosis of secondary infection/ colonization or an uncontrolled initial infection despite adequate antimicrobial therapy and/or interventional procedures; (3) a stable low level of mHLA-DR expression (
Summary
The 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. The molecular mechanisms are not fully elucidated yet, the reported immune dysfunction of the cells from septic patients during immunedepression concern both the innate and adaptive immunity [2]. This phenotype is observed in many other acute injuries suggesting a common pathophysiology after significant stress conditions as trauma [3], cardiopulmonary resuscitation [4], and major surgery [5]. Effects on clinically relevant end-points can only be determined in randomized clinical trials, relevant data related to immunological properties, safety, and timing of treatment are needed to facilitate the design of such trials
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