ISSUE 2 - JANUARY 2026

IMMUNO-SEPSIS
DIGEST

REVIEWED BY THE SCIENTIFIC COMMITTEE OF THE PLATINIUM STUDY
Pr. RS HOTCHKISS, WashU Medicine, St Louis (US)
Pr. G MONNERET, Hospices Civils de Lyon (France)
Pr. JM TADIE, CHU de Rennes (France)

20 YEARS OF mHLA-DR FOLLOW UP :

UNDERSTANDING CLUSTERS TO CHANGE PATIENTS’ TRAJECTORIES

By Dr. A HERNANDEZ on behalf of the PLATINIUM trial Scientific Committee

The recent analysis of a 20-year cohort of over 1000 septic shock patients with repeated mHLA-DR measurements embedded in routine practice (Monneret et al, ICM 2025) demonstrated that in critically ill patients mHLA-DR levels are way below the 8000 Ab/c threashold already used in immune-stimulation trials.

Aluvial plots and cluster data identified three types of patients: Immunosuppressed, non-improvers, composed by most than half of patients showing a persistently very low mHLA-DR, and the highest mortality and secondary infection rates. In contrast, immunosuppressed improvers, and immunocompetent subjects had higher trajectories, and clearly better outcomes.

An isolated early value below 8000 Ab/c on day 1 is not predictive on its own, as it may reflect physiological early downregulation.  Instead, delayed and persistent downregulation signals pathological immunosuppression and relates to worst clinical prognosis.

In patients admitted for CAP at the ED (Lafon et al, Cytometry B Clin Cytom 2025), the assessment at admission of PaO2/FiO2 ratio, CRP and procalcitonin levels, together with low mHLA-DR and immature granulocytes, associated to clinical deterioration at D7, defined as ARDS, ICU admission, shock, worsening organ dysfunction or in-hospital mortality.

The ImmunoSep trial (Giamarellos-Bourboulis et al, JAMA 2025) included over 500 patients with pneumonia or bacteriemia meeting sepsis 3 criteria, and targeted those with macrophage activation-like syndrome defined by elevated blood ferritin, or sepsis-induced immune-paralysis defined by a low mHLA-DR with decreased ferritin, to propose anakinra or interferon gamma, respectively.

This intervention improved organ dysfunction by day 9 compared to placebo, but had no impact in 28-day mortality.

A smaller, earlier trial (Meisel et al, Am J Respir Crit Care Med 2009), evaluated showed that GM-CSF treatment in immunosuppressed septic shock patients (< 8000 Ab/cell) associated to a significant increase in mHLA-DR, increased total granulocyte and monocyte counts, improved APACHE II score, and shorter time in mechanical ventilation.

These results support PLATINIUM design (Hernandez-Padilla et al, BMJ Open 2026) as:

  1. They show the interest of targeting patients with diminished mHLA-DR later after ICU admission, when the 8000 Ab/c threshold does differentiate between the three clusters, and
  2. Immune-boosting strategies have shown a positive impact in biological and clinical outcomes in these patients.