IMPORTANCE: Sepsis is heterogeneous, and the optimal strategy for tailoring immunotherapy is uncertain.
OBJECTIVE: To investigate whether precision immunotherapy guided by the presence of macrophage activation-like syndrome or sepsis-induced immunoparalysis improves organ dysfunction by day 9.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted in 6 countries. Patients with sepsis, defined by Sepsis-3, were included if they had community-acquired or hospital-acquired pneumonia or ventilator-associated pneumonia or bacteremia and sepsis and had displayed either macrophage activation-like syndrome (blood ferritin >4420 ng/mL) or sepsis-induced immunoparalysis (blood ferritin =4420 ng/mL and <5000 human leukocyte antigen DR receptors on CD45/CD14 monocytes). The first patient was enrolled August 5, 2021, and the last follow-up, April 29, 2024.
INTERVENTIONS: Eligible patients were randomized to receive standard care and precision immunotherapy or standard care and placebo. Those in the precision immunotherapy group with macrophage activation-like syndrome received anakinra intravenously (IV) and placebo subcutaneously, and those with sepsis-induced immunoparalysis received subcutaneous recombinant human interferon gamma and IV placebo. Those in the placebo group received both IV and subcutaneous placebo. Treatment was administered for up to 15 days.
MAIN OUTCOMES AND MEASURES: The primary end point was a decrease of at least 1.4 points in the mean Sequential Organ Failure Assessment (SOFA) score from baseline by day 9. The SOFA score evaluates 6 organ systems, ranging from 0, no dysfunction, to 4, failure, and the total score ranges from 0, normal, to 24, most severe form of multiorgan failure. Key secondary outcomes included 28-day mortality.
RESULTS: Of 672 patients assessed for eligibility, 281 were randomized and 276 were included in the primary analysis population (mean [SD] age, 70 [13] years; 93 females [33.7%]; median baseline SOFA score, 9 [IQR, 7-11]). The SOFA decrease end point was attained by 46 of 131 patients (35.1%) in the precision immunotherapy group and by 26 of 145 patients (17.9%) in the placebo group (difference, 17.2% [95% CI, 6.8% to 27.2%]; P = .002). Mortality at 28 days was not statistically significantly different between groups. A total of 1069 serious treatment-emergent adverse events (88.8%) were reported; increased incidence of anemia was noted in the anakinra group; and hemorrhage in the recombinant human interferon gamma group.
CONCLUSIONS AND RELEVANCE: Among patients with sepsis, precision immunotherapy targeting macrophage activation-like syndrome and sepsis-induced immunoparalysis improved organ dysfunction by day 9 compared with placebo.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04990232.
| Specialty | Score |
|---|---|
| Intensivist/Critical Care | |
| Internal Medicine | |
| Infectious Disease | |
| Respirology/Pulmonology |
An admirably rigorous MC RCT suggesting that adjunctive immunotherapy of severe sepsis, guided by the immunopathogenic profile at the outset, improves outcome in terms of organ failure with a commensurate survival benefit limited by underpowering. Refinement of the immunopathogenic categories and their targeted therapies and study in a much larger patient population with sepsis deriving from all potential sources might show that this novel approach to treatment of severe sepsis can materially improve outcome, including survival.
Not necessarily practice-changing at this point, but it has patient-important outcomes and a novel design.
This study is very relevant to ICU practice and is useful because it addresses a very novel concept. It shows that not all sepsis patients have the same immune response, and treating them based on whether they’re inflamed or immunosuppressed can actually improve their organ function. We don’t see that often in sepsis trials. The idea makes sense clinically, but the main issue is that most hospitals don’t have fast HLA-DR testing, so it’s not something we can easily put into practice yet. Still, it’s an important step toward more personalized treatment instead of giving the same therapy to everyone.
Although the targeted interventions did reduce the SOfA score in patients, overall 28-day mortality was unchanged between the groups.
Sepsis continues to be a poorly understood disorder in which specific immune-directed therapies are getting traction. In this study, the authors enrolled a very sick population of patients with pneumonia and sepsis (88% were on the ventilator) and randomized them to immune suppression if they had macrophage activation (with the IL-1 inhibitor anakinra) or immune activation if they were hypo immune. I was surprised to see that the trial did not have much in the way of super infections or side effects. It did not improve survival in a very sick group but did make a surrogate of organ dysfunction look better faster. More than 2/3 of the population was dead at 90 days. I think the future of sepsis will likely be precision therapies, but we do not have the answer yet.
A complicated trial with 2 different immunotherapies for sepsis-related immune dysfunction. The trial was underpowered to detect patient-centered outcomes but showed a reduction in SOFA scores with personalized immunotherapies. Intriguing but difficult to generalize due to the enrollment criteria and primary outcome.
, McMaster University