According to recently published data, a biomarker‑guided immunotherapy strategy improved outcomes in patients with sepsis caused by pneumonia or bacteremia.1 The findings from the ImmunoSep trial suggest that tailoring therapy to a patient’s immune phenotype may represent a significant advance in sepsis care.
Despite decades of clinical trials, most immunotherapies for sepsis have failed to show benefit, a limitation widely attributed to the marked heterogeneity of immune responses seen in sepsis. The ImmunoSep investigators, led by Evangelos J. Giamarellos-Bourboulis, MD, PhD, sought to address this challenge by deploying precision immunotherapy based on objective biomarkers of immune dysregulation.
The ImmunoSep trial was an international, randomized, double‑blind, double‑dummy, placebo‑controlled phase 2b study conducted across 33 ICUs in six European countries. A total of 672 adults with presumed infectious sepsis were screened, of whom 281 were randomized and 276 were included in the primary analysis.
Eligible patients had sepsis defined by Sepsis‑3 criteria and a pulmonary or bloodstream source of infection. They were stratified into two immune phenotypes identified by rapid biomarker testing: macrophage activation-like syndrome and sepsis‑induced immunoparalysis. Dr. Giamarellos-Bourboulis, Professor of Internal Medicine and Infectious Diseases at the Medical School of the National and Kapodistrian University of Athens, said patients with neither immune pattern were excluded, highlighting both the rigor and the limitations of their approach.
Patients randomized to the precision immunotherapy group received standard care plus targeted treatment: intravenous anakinra for macrophage activation-like syndrome or subcutaneous recombinant human interferon gamma for sepsis‑induced immunoparalysis. Control patients received matching placebos in addition to standard care. Treatment was administered for up to 15 days.
The primary end point was a reduction of at least 1.4 points in the mean Sequential Organ Failure Assessment (SOFA) score by day 9, a threshold previously associated with improved survival in sepsis trials.
This end point was achieved by 35.1% of patients in the precision immunotherapy group compared with 17.9% in the placebo group, an absolute difference of 17.2 percentage points (P = .002). The unadjusted odds ratio for achieving the primary end point was 2.48 (95% CI, 1.42-4.32), and results remained significant after adjustment for baseline disease severity and comorbidities.
Importantly, Dr. Giamarellos-Bourboulis said the benefit was observed in both immune phenotypes. Among patients with macrophage activation-like syndrome, nearly half of those receiving anakinra achieved the prespecified SOFA reduction. Patients with sepsis‑induced immunoparalysis treated with interferon gamma also showed significantly greater improvement than placebo.
It is important to note that not all patients are hyperinflammatory, Dr. Giamarellos-Bourboulis said.
“The greatest teaching from ImmunoSep is that immunoparalysis and hyperinflammation can appear in different patients from the beginning of severe infection and that they may be separate entities,” he said. “The traditional concept that all patients start with hyperinflammation and then they progress to immunoparalysis is proven false by the ImmunoSep results. This may also explain the contradictory findings of the pneumonia trials with cortisone treatment.”
Despite improvements in organ dysfunction, 28‑day mortality did not differ significantly between groups (43.5% with precision immunotherapy vs 49.7% with placebo; P = .34) nor were differences observed at 90 days. However, Dr. Giamarellos-Bourboulis said the study was designed to detect organ dysfunction rather than mortality and cautioned against overinterpreting these findings.
Several prespecified secondary outcomes favored the precision approach. By day 15, patients receiving targeted immunotherapy were more likely to demonstrate continued SOFA improvement, reversal of sepsis‑induced immune dysfunction, and resolution of infection. Dr. Giamarellos-Bourboulis said these results are notable in a population dominated by severe pneumonia, where persistent organ failure and secondary infections are common clinical challenges.
Serious treatment‑emergent adverse events were common in both groups, reflecting the high baseline severity of illness. Only a small proportion were judged to be probably or possibly related to the study drugs. An increased incidence of anemia was observed in patients receiving anakinra, while hemorrhagic events were more frequent in those treated with interferon gamma, particularly among patients with thrombocytopenia. Overall, no new safety signals were identified.
The trial demonstrates the growing relevance of immune phenotyping in critical care. However, several practical barriers remain.
Ferritin tests are widely available, but standardized, rapid assessment of monocytic HLA‑DR expression may not yet be feasible in many hospitals. In addition, more than half of the screened patients were excluded because they did not meet the criteria for either immune phenotype, raising questions about the strategy’s broad applicability.
References
1. Giamarellos-Bourboulis EJ, Kotsaki A, Kotsamidi I, et al. precision immunotherapy to improve sepsis outcomes: the ImmunoSep randomized clinical trial. JAMA. 2026;335(9):775-786. doi:10.1001/jama.2025.24175
