Despite millennia of evolving definitions—from Hippocrates’ first description to Schottmuller’s 1914 focus on bacteremia to the current Sepsis-3 criteria—sepsis remains a syndrome defined by its heterogeneity.1–3 Immunomodulatory trials have repeatedly failed when applied uniformly to all patients. Early work in pediatric sepsis demonstrated that specific gene expression profiles were associated with increased mortality when corticosteroids were used, yet translating transcriptomic findings to the bedside has remained elusive.4 We are now entering an era of precision immunotherapy that targets specific pathways of the immune response based on measurable biomarkers.
The PROVIDE and ImmunoSep trials established a two-biomarker system to classify sepsis patients into distinct immune endotypes using serum ferritin and HLA-DR expression on CD14 monocytes.5,6 Two actionable endotypes were defined: macrophage activation-like syndrome (MALS), characterized by ferritin >4,420 ng/mL, and sepsis-induced immunoparalysis, defined by ferritin ≤4,420 ng/mL with <5,000 HLA-DR receptors per monocyte. Patients with MALS received anakinra (an interleukin [IL]-1 receptor antagonist), while those with immunoparalysis received recombinant interferon-gamma (IFN-γ).
The PROVIDE pilot RCT enrolled 240 patients with sepsis due to pneumonia, acute cholangitis, or bacteremia across Greek medical centers. Of these, only 36 were classified into the MALS or immunoparalysis endotypes and randomized to immunotherapy or placebo; the remaining 204 were classified as intermediate.5 Among randomized patients, 42.9% receiving immunotherapy were alive at day 7 with a concurrent decrease in SOFA score, compared with 10.0% in the placebo group (P = .042).5 However, 28-day mortality (the primary end point) did not reach statistical significance, making this finding hypothesis-generating.5,7
The ImmunoSep trial expanded this framework internationally, randomizing 281 patients (276 analyzed) with bacteremia or pneumonia-associated sepsis across six European countries.6 Treatment was administered for up to 15 days. The primary end point was a ≥1.4-point decrease of mean SOFA score by day 9 and was met in 35.1% of the precision immunotherapy group vs 17.9% of the placebo group (OR 2.48; P = .002).6
Three limitations temper immediate translation to bedside. First, ImmunoSep improved organ dysfunction but did not demonstrate a mortality benefit (28-day mortality: 43.5% vs 49.7%; P = .34).6 Phase 3 confirmation is essential. Second, the majority of patients who were screened did not meet criteria for either endotype. They comprised a heterogeneous group that included moderate immunoparalysis, T-cell exhaustion, and the IFN-γ/CXCL9-driven endotype, which accounts for approximately 20% of patients with sepsis with roughly 40% mortality.7 Third, mHLA-DR flow cytometry is unavailable in most ICUs, and the time from sepsis onset to study drug administration underscores the need for rapid phenotyping platforms.6
What clinicians can do now: check ferritin in patients with sepsis who are failing to improve. A ferritin >4,420 ng/mL identifies the approximately 3% to 4% of patients with MALS who may benefit from IL-1 blockade, which was a signal first identified in the Shakoory post hoc reanalysis of a prior phase 3 anakinra trial (HR 0.28; P = .007).8
The call to action extends beyond novel immunotherapies. Post hoc analyses consistently suggest phenotype-dependent corticosteroid effects. The VANISH reanalysis found hydrocortisone associated with increased mortality in immunocompetent patients with a specific transcriptomic profile (OR 7.9; interaction P = .02).9 Corroborating this, hydrocortisone was independently associated with a 3.7-fold longer duration of multiple organ dysfunction in immunoparalyzed children (P = .0006).10 Seymour and colleagues demonstrated that varying phenotype frequencies within a randomized controlled trial changed simulated treatment results from benefit to harm.11 Yet no major corticosteroid trial has been reanalyzed by immune phenotype.
Prospective trials must be stratified by immune endotype using clinically available biomarkers. The development of rapid, multidimensional immune phenotyping tools is essential to translate precision sepsis care from concept to bedside.
References
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8. Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275-281. doi:10.1097/CCM.0000000000001402
9. Antcliffe DB, Burnham KL, Al-Beidh F, et al. Transcriptomic signatures in sepsis and a differential response to steroids: from the VANISH randomized trial. Am J Respir Crit Care Med. 2019;199(8):980-986. doi:10.1164/rccm.201807-1419OC
10. Bline KE, Moore-Clingenpeel M, Hensley J, et al. Hydrocortisone treatment is associated with a longer duration of MODS in pediatric patients with severe sepsis and immunoparalysis. Crit Care. 2020;24(1):545. doi:10.1186/s13054-020-03266-x
11. Seymour CW, Kennedy JN, Wang S, et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019;321(20):2003-2017. doi:10.1001/jama.2019.5791
