Establishing a new global standard for precision medicine in sepsis and critical care

A University of Malta researcher, Dr Brendon Scicluna of the Department of Applied Biomedical Science, Faculty of Health Sciences, designed and spearheaded one of the studies and made significant contributions to the second, placing the University at the forefront of the global effort to bring precision medicine to the sickest patients in our hospitals.

For decades, developing new treatments for critical illnesses like sepsis, acute respiratory distress syndrome (ARDS), and trauma has been hampered by a major challenge, that is, although treated as single conditions, every patient's body responds differently. This biological diversity, known as heterogeneity, has been a primary barrier to progress.  The two new studies tackle this problem head-on, providing a robust, unified way to classify patients into distinct cellular biological subtypes.

The first study, "A consensus blood transcriptomic framework for sepsis," led by Dr Scicluna, aggregated data from over 1,800 sepsis patients. Using a technique called blood transcriptomics, which measures the activity of thousands of genes to create a real-time snapshot of a patient's immune response, the team created a single, harmonized classification system. It identifies three "Consensus Transcriptomic Subtypes" (CTSs) of sepsis, each with a unique molecular signature:

• CTS1: A classic, strong inflammatory response driven by an aggressive but immature neutrophil attack.
• CTS2: Characterised by disturbances in blood clotting and the processing of heme, a key component of red blood cells.
• CTS3: Associated with a unique immune state involving antiviral interferon signals and features typically seen in organ transplant rejection.

"Our goal was to create a standardised model for sepsis research," explains Dr Scicluna, a Principal Investigator and resident academic at UM. "We've unified years of research into one robust molecular framework that everyone can use. This provides the common language we desperately needed to make real progress in the field."

Crucially, the study delivered a stark warning. A reanalysis of a major randomized controlled trial revealed that patients assigned to the CTS2 subtype were actually harmed by corticosteroids, a common anti-inflammatory treatment for sepsis and other immune-related disorders. This finding underscores the urgent need to move beyond a one-size-fits-all approach.

The second study, "A consensus immune dysregulation framework for sepsis and critical illnesses," from the international SUBSPACE consortium to which Dr Scicluna contributed, complements this work perfectly. Analysing over 7,000 patient samples from 37 cohorts, this study identified two core patterns of immune dysregulation, one in myeloid cells (the immune system's first responders) and one in lymphoid cells (responsible for targeted immunity). Remarkably, the study found this same fundamental dysregulation was present not only in sepsis but also in patients with ARDS, trauma, and burns, suggesting shared biological mechanisms across multiple forms of critical illness.

"Seeing these two studies published side-by-side is a landmark moment," states Dr Scicluna. "They are a synergy. Together, they provide undeniable evidence that this multidisciplinary data-driven approach is the future of critical care."

The complementary findings from these two extensive studies offer a powerful new framework for understanding critical illness and, for the first time, provide a clear path forward for designing clinical trials that can finally deliver on the promise of precision medicine for the most vulnerable patients in the Intensive Therapy Unit (ITU).

“These studies are a powerful example of what happens when you combine clinical expertise with immunobiology and molecular profiling" concludes Dr Scicluna. 

Dr Brendon Scicluna is a Principal Investigator leading the Translational Immunology and Infection lab at the University of Malta.

The research described in these publications was supported by funding from the European Society for Intensive Care Medicine, a University of Malta Research Excellence Award, and multiple grants from the Xjenza Malta Research Excellence Program. The work also received foundational support from the Center for Translational Molecular Medicine in the Netherlands.

Papers cited in this article:

A consensus blood transcriptomic framework for sepsis | Nature Medicine

A consensus immune dysregulation framework for sepsis and critical illnesses | Nature Medicine

"The work doesn't stop here. Our lab at the University of Malta is already pushing forward alongside our colleagues at Mater Dei Hospital's ITU and Saint Vincent de Paul long-term care facility. We are now focused on the next crucial step, that is, deciphering the specific mechanisms of these disease subtypes to identify new treatment targets and improve patient outcomes. I'm proud to be surrounded by such an enthusiastic team.”