A Study on How the Immune System Responds to Sepsis and Its Long-term Effects

Sepsis is a life-threatening organ failure syndrome caused by a dysregulated host response to infection. Despite advances in antimicrobial therapy and intensive care, mortality remains high due to our inability to rebalance the host immune response. Current immunotherapy strategies fail to account for the highly heterogeneous immunopathological mechanisms underlying sepsis. Some patients experience hyperinflammation, others immune paralysis, with these states often coexisting or shifting over time. Moreover, different immunological mechanisms may drive each of these broad patterns of immune dysregulation. Defining patient immunotypes and identifying associated biomarkers is therefore essential for developing targeted immunotherapies. Additionally, the long-term morbidity and mortality following sepsis, potentially driven by lasting epigenetic changes, are poorly understood. A deeper understanding of immunotypes and their impact on both acute and long-term outcomes is essential to improve patient stratification and guide future precision medicine approaches in sepsis.

This study aims to characterize sepsis immunotypes linked to short- and long-term outcomes and identify novel biomarkers and therapeutic targets. This is a multicenter, prospective, observational cohort study. We aim to recruit a cohort of 400 intensive care or medium care patients diagnosed with sepsis, as defined by the Sepsis-3 criteria. No randomization will be performed. Blood samples and clinical data will be collected on the following timepoints: day 0 (within 48 hours of ICU/MC admission), day 3 (±1 day, defined as 3 days after day 0), at hospital discharge (±2 days), and at 3 and 12 months post-discharge (each ±2 weeks). Patients will be retrospectively classified into subgroups according to infection site, as defined by the International Sepsis Forum Consensus Conference definitions. This study involves no interventions beyond scheduled blood collection. The amount of blood drawn at each timepoint will not exceed 40 ml. To minimize additional venipunctures during admission, blood collection will be incorporated into routine clinical care whenever possible. Clinical data at 3 and 12 months post-discharge will be gathered through questionnaires or phone interviews. The only additional travel required for the study is for post-discharge blood collection, which participants can choose to complete at an external Radboudumc-affiliated blood collection site closest to their home. Therefore, for all patients-including those who may be incapacitated during the acute phase of sepsis-the risks and burden associated with participation are considered minimal. Patients will not receive any direct benefit from participating in this study. However, the knowledge gained is expected to guide future sepsis diagnoses, treatment and prediction of health outcomes.

Inclusion criteria

• Adults (≥18years).
• Sepsis 3 criteria: defined as having a suspected or documented infection accompanied by organ dysfunction, represented by a total Sequential Organ Failure Assessment (SOFA-2) score 2 or more for new admissions or as 2 or more point-increase of the total SOFA-2 score for hospitalized patients.

Exclusion criteria

• Known chemotherapy-induced or long-term neutropenia.
• Known CD4 counts <400 cells/µL.
• History of primary immunodeficiency
• Chronic intake of corticosteroids (defined as total daily dose equal or greater than 0.4 mg/kg of equivalent prednisone for more than the last 15 days).
• Current use of biologics.
• Solid organ transplant recipients.
• Recipients of allogeneic bone marrow transplants.