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

A Systems Immunology Approach to Characterize the Immune Response in Sepsis and Its Long-term Complications

Sepsis occurs when an infection, caused by bacteria, a virus, or a fungus, enters the body and throws the immune system out of balance. Instead of protecting the body, the immune response may become too strong and start damaging healthy organs, or it may become too weak and fail to control the infection. Both situations can be life-threatening. Even people who survive sepsis may experience long-term health problems, such as new infections, heart and blood vessel diseases, or early death.

This study aims to better understand how the immune system behaves during and after sepsis. We believe that there are different types of immune responses in sepsis, called immunotypes. We will identify these immunotypes by examining substances in the blood and changes in immune cells. We will then study which immunotypes help protect patients and which may cause short- or long-term harm.

Understanding these immunotypes may make it possible in the future to quickly determine what type of immune response a patient with sepsis has. This could help doctors choose the best treatment for each individual patient.

A total of 400 patients with sepsis from the intensive care unit will take part in this study. We will collect blood samples at several time points and gather information about their health. Participants will be followed from their intensive care admission until one year after they return home.

Study Overview

• Status: Recruiting
• Conditions: Sepsis
• Intervention / Treatment: Other: blood sampling

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

• Study Contact: Name: Tristan Couwenbergh; Phone Number: +31613456047; Email: tristan.couwenbergh@radboudumc.nl
• Study Contact Backup: Name: Wouter A. van der Heijden, dr.; Email: Wouter.vanderHeijden@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands
      • Recruiting
      • Radboud University Medical Center
      • Contact: Tristan Couwenbergh; Phone Number: +31613456047; Email: tristan.couwenbergh@radboudumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

ICU or medium care patients diagnosed with sepsis, as defined by the Sepsis-3 criteria, from the Radboudumc, Canisius Wilhelmina Ziekenhuis, Rijnstate Ziekenhuis, and Jeroen Bosch Ziekenhuis.

Description

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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Classification of hospitalized sepsis patients into distinct immunotypes.	Day 0 (within 48 hours of intensive care unit admission or start of sepsis)
Classification of hospitalized sepsis patients into distinct immunotypes.	Day 3 (defined as 3 days after day 0)
Classification of hospitalized sepsis patients into distinct immunotypes.	At hospital discharge.

Secondary Outcome Measures

Outcome Measure	Time Frame
Detection of persistent immunotypes at following hospital discharge.	Three months after hospital discharge.
Detection of persistent immunotypes at following hospital discharge.	Twelve months after hospital discharge.

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Dutch Research Council
• Investigators: Study Director: Mihai G. Netea, Prof. dr., Radboud University Medical Center; Principal Investigator: Wouter A. van der Heijden, dr., Radboud University Medical Center; Study Director: Peter Pickkers, Prof. dr., Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2025
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: November 14, 2025
• First Submitted That Met QC Criteria: November 27, 2025
• First Posted (Estimated): December 9, 2025

Study Record Updates

• Last Update Posted (Estimated): December 9, 2025
• Last Update Submitted That Met QC Criteria: November 27, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: cohort study; sepsis; observational; endotypes; immune endotypes; immunotypes; post-sepsis syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathological Conditions, Signs and Symptoms; Sepsis; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: NL010169

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The HEAL-SEPSIS project will share all pseudonymized IPD used in analyses and publications under restricted access, in accordance with participant consent and intellectual property protections. Privacy and confidentiality obligations prevent unrestricted sharing of full IPD datasets

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No