Towards personalized medicine: a scoping review of immunotherapy in sepsis

Abstract

Despite significant progress in our understanding of the pathophysiology of sepsis and extensive clinical research, there are few proven therapies addressing the underlying immune dysregulation of this life-threatening condition. The aim of this scoping review is to describe the literature evaluating immunotherapy in adult patients with sepsis, emphasizing on methods providing a "personalized immunotherapy" approach, which was defined as the classification of patients into a distinct subgroup or subphenotype, in which a patient's immune profile is used to guide treatment. Subgroups are subsets of sepsis patients, based on any cut-off in a variable. Subphenotypes are subgroups that can be reliably discriminated from other subgroup based on data-driven assessments. Included studies were randomized controlled trials and cohort studies investigating immunomodulatory therapies in adults with sepsis. Studies were identified by searching PubMed, Embase, Cochrane CENTRAL and ClinicalTrials.gov, from the first paper available until January 29th, 2024. The search resulted in 15,853 studies. Title and abstract screening resulted in 1409 studies (9%), assessed for eligibility; 771 studies were included, of which 282 (37%) were observational and 489 (63%) interventional. Treatment groups included were treatments targeting the innate immune response, the complement system, coagulation and endothelial dysfunction, non-pharmalogical treatment, pleiotropic drugs, immunonutrition, concomitant treatments, Traditional Chinese Medicine, immunostimulatory cytokines and growth factors, intravenous immunoglobulins, mesenchymal stem cells and immune-checkpoint inhibitors. A personalized approach was incorporated in 70 studies (9%). Enrichment was applied using cut-offs in temperature, laboratory, biomarker or genetic variables. Trials often showed conflicting results, possibly due to the lack of patient stratification or the potential influence of severity and timing on immunomodulatory therapy results. When a personalized approach was applied, trends of clinical benefit for several interventions emerged, which hold promise for future clinical trials using personalized immunotherapy.

Keywords: Enrichment; Immunomodulation; Immunotherapy; Personalized; Sepsis.

Fig. 1

Flow diagram for study selection. RCT, randomized controlled trial

Fig. 2

Overview of the included studies. Overview of the included studies in this review A divided per treatment strategy, study design and treatment group and B divided per year, study design and treatment group demonstrated from the earliest to the latest studies overtime. RCT, Randomized controlled trial

Fig. 3

Overview of all immunomodulatory treatments studies in adult patients with sepsis. Immunomodulatory treatments investigated in sepsis patients either modulate excessive inflammation (top op panel, in red) or aim at immune stimulation (bottom of panel, blue), furthermore there are combinations of these treatment strategies (bottom of panel, in grey) or treatments not fitting into these categories (bottom of panel, in green). All treatments displayed in this figure are included in this review; the treatments in bold are discussed in the text and in the supplement, treatment not in bold can be found in the supplement. Abbreviations: Ab, antibody; ACE, angiotensin-converting-enzyme; anti-PD-1, anti-programmed cell death protein 1; G(M)-CSF, granulocyte(-macrophage) colony-stimulating factor; Ig, immunoglobulin; IL, interleukin; L-NAME, L-NG-Nitro arginine methyl ester; NSAID, non-steroidal anti-inflammatory drugs; (r)a, (receptor) antagonist; TLR, toll-like receptor; TNF(r), tumor necrosis factor (receptor)