Highlights
– The ImmunoSep randomized, double‑blind, double‑dummy trial used ferritin and monocyte HLA‑DR to triage patients with sepsis to targeted immunotherapy: IV anakinra for macrophage activation‑like syndrome (MALS) and subcutaneous interferon‑γ for sepsis‑induced immunoparalysis.
– The primary endpoint—reduction in mean SOFA score by ≥1.4 points by day 9—was met: 35.1% in precision immunotherapy vs 17.9% with placebo (difference 17.2%; 95% CI 6.8–27.2%; P = .002).
– There was no statistically significant difference in 28‑day mortality. Safety concerns included increased anemia with anakinra and bleeding events with interferon‑γ.
Background and clinical need
Sepsis is a leading cause of morbidity and mortality worldwide and remains biologically heterogeneous. Contemporary conceptual models emphasize that many patients traverse phases of hyperinflammation and immune paralysis, sometimes concurrently across organ systems and time points. Traditional ‘‘one‑size‑fits‑all’’ anti‑inflammatory or immune‑stimulating strategies have largely failed in unselected sepsis populations, underscoring the interest in precision immunotherapy guided by immune phenotyping rather than by infection site alone.
Two immunologic endotypes commonly described in sepsis are a macrophage activation–like syndrome (MALS), characterized by extreme hyperinflammation and markers such as very high ferritin, and sepsis‑induced immunoparalysis, identified by low monocytic HLA‑DR expression and functional defects in innate and adaptive immunity. These opposing phenotypes suggest opposite therapeutic approaches: targeted anti‑inflammation for MALS and immune stimulation for immunoparalysis. Prior translational and small clinical studies provided mechanistic rationale but insufficient evidence for routine practice. The ImmunoSep trial sought to test whether rapid, simple biomarker‑based selection could translate into clinically meaningful organ‑level benefit with tailored therapy.
Study design
ImmunoSep was an international randomized, double‑blind, double‑dummy, placebo‑controlled trial conducted across six countries. Adults meeting Sepsis‑3 criteria with community‑acquired or hospital‑acquired pneumonia, ventilator‑associated pneumonia, or bacteremia were screened. Enrollment was limited to patients whose immune phenotype fell into one of two predefined categories assessed at baseline:
- MALS: blood ferritin >4420 ng/mL.
- Sepsis‑induced immunoparalysis: ferritin ≤4420 ng/mL and <5000 HLA‑DR receptors on CD45/CD14 monocytes (low monocytic HLA‑DR by flow cytometry).
Eligible patients were randomized to precision immunotherapy plus standard care or to placebo plus standard care. In the active arm, patients with MALS received intravenous anakinra (an IL‑1 receptor antagonist) and subcutaneous placebo; those with immunoparalysis received subcutaneous recombinant human interferon‑γ and intravenous placebo. The comparator arm received both IV and subcutaneous placebo agents. Treatment continued up to 15 days. The primary endpoint was a decrease of at least 1.4 points in mean Sequential Organ Failure Assessment (SOFA) score from baseline by day 9. Key secondary outcomes included 28‑day mortality and safety/adverse events. The trial enrolled its first patient on August 5, 2021, and follow‑up concluded April 29, 2024 [NCT04990232].
Key results
Of 672 patients screened, 281 were randomized and 276 were included in the primary analysis (mean age 70 years, 33.7% female; median baseline SOFA 9 [IQR 7–11]). Baseline characteristics were balanced between groups.
Primary endpoint: 46 of 131 patients (35.1%) in the precision immunotherapy arm achieved the predefined SOFA improvement by day 9, compared with 26 of 145 patients (17.9%) in the placebo arm. The absolute difference was 17.2% (95% CI 6.8% to 27.2%; P = .002). This result indicates a clinically meaningful early improvement in organ dysfunction with biomarker‑guided therapy.
Secondary outcomes: 28‑day mortality did not differ significantly between groups. The trial was not primarily powered for mortality, so the absence of a mortality signal does not exclude a possible benefit in larger or more selected cohorts. Other secondary endpoints and subgroup analyses were reported in the primary manuscript; these should be interpreted with attention to multiplicity and sample size constraints.
Safety
A substantial number of treatment‑emergent serious adverse events were recorded (1069 events; 88.8% of patients had at least one), reflecting the high acuity of the enrolled population. Specific safety signals were noted: an increased incidence of anemia in patients receiving anakinra and an increased incidence of hemorrhagic events in those receiving recombinant interferon‑γ. Detailed adjudication, timing relative to therapy initiation, and baseline bleeding risk are important to assess causality. Overall, safety findings underscore that immunomodulation in sepsis carries nontrivial risks and requires careful monitoring.
Biological and mechanistic plausibility
The trial’s two‑arm, phenotype‑directed approach matches interventions to putative pathophysiology. MALS mirrors features of cytokine storm syndromes with very high ferritin and IL‑1–driven inflammation; anakinra blocks IL‑1 signaling and has biologic plausibility for rapidly dampening pathological hyperinflammation and protecting organs. Conversely, sepsis‑induced immunoparalysis is characterized by low monocyte HLA‑DR expression, defective antigen presentation, and susceptibility to secondary infections; interferon‑γ upregulates HLA‑DR expression and can restore monocyte function, offering mechanistic rationale for immune stimulation in this subgroup.
Expert commentary and interpretation
The ImmunoSep trial is a landmark in sepsis precision medicine because it operationalizes a feasible biomarker strategy to match opposing immune therapies to patients likely to benefit. The SOFA improvement by day 9 is clinically relevant: even modest reductions in organ dysfunction can shorten ICU length of stay, lower resource use, and reduce downstream morbidity.
However, several caveats must be considered. First, the trial’s primary endpoint is an organ dysfunction metric rather than mortality; while organ recovery is meaningful, mortality remains the most definitive patient‑centered outcome in sepsis trials. Second, the biomarker thresholds (ferritin >4420 ng/mL; HLA‑DR <5000 receptors) were prespecified but require external validation. Third, safety signals—particularly bleeding with interferon‑γ and anemia with anakinra—warrant cautious implementation and mechanistic study. Finally, practical implementation depends on rapid, reliable assays (flow cytometry for HLA‑DR) and logistics in real‑world settings; resource constraints could limit broad adoption.
Limitations
Key limitations include the moderate sample size and the trial’s focus on a subset of sepsis etiologies (pneumonia and bacteremia). The study population was older (mean age 70), which may influence generalizability. The trial was not powered for mortality, and subgroup estimates for individual interventions (anakinra vs interferon‑γ) are constrained by smaller numbers. Biomarker cutoffs were binary and do not capture immune dynamics over time; patients may transition between phenotypes. Finally, the double‑dummy design maintains blinding but increases complexity and cost for broader implementation.
Clinical implications and next steps
ImmunoSep suggests that rapid immune phenotyping to direct therapy can improve early organ recovery in sepsis. Pending confirmatory trials, clinicians should not change routine practice based on this single trial alone. However, the study supports several actions:
- Consider integrating immune phenotyping into research protocols and centers with capacity for rapid ferritin and HLA‑DR testing to confirm external validity.
- Design larger pragmatic trials powered for patient‑centered outcomes (mortality, long‑term functional status), potentially stratified by age, comorbidity, and infection type.
- Investigate safety mechanistically, especially bleeding risk with interferon‑γ and hematologic effects of anakinra, and establish monitoring protocols.
- Explore adaptive trial platforms where biomarker‑guided strategies can be tested efficiently across centers and populations.
Conclusion
The ImmunoSep randomized clinical trial demonstrates that a biomarker‑guided approach to sepsis—targeting anakinra to patients with macrophage activation‑like syndrome and interferon‑γ to those with sepsis‑induced immunoparalysis—can produce earlier and greater organ‑function recovery by day 9 compared with placebo. Mortality outcomes were unchanged in this trial and require further evaluation. The findings provide proof‑of‑concept that clinical immunophenotyping can transform sepsis therapy, but implementation will require confirmatory trials, attention to safety, and infrastructure for rapid immune diagnostics.
Funding and trial registration
The ImmunoSep trial was reported by Giamarellos‑Bourboulis and colleagues; funding sources and conflict of interest statements are reported in the primary manuscript. ClinicalTrials.gov Identifier: NCT04990232.
References
1. Giamarellos‑Bourboulis EJ, Kotsaki A, Kotsamidi I, et al; ImmunoSep Study Group. Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial. JAMA. 2025 Dec 8. doi:10.1001/jama.2025.24175. PMID: 41359996.
2. Hotchkiss RS, Monneret G, Payen D. Sepsis‑induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013 Dec;13(12):862‑874. doi:10.1038/nri3552.
3. Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med. 2021 Nov;47(11):1181‑1247. doi:10.1007/s00134-021-06506-y.