byUniversity of Malta

Identification of the CTSs of sepsis. Credit:Nature Medicine(2025). DOI: 10.1038/s41591-025-03964-5

In an advance for critical care medicine, two international studies published in parallel in the journalNature Medicinehave established a new unified framework for understanding the biological chaos of sepsis and other life-threatening illnesses. 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 a single condition, 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.

Thefirst 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'simmune response, the team created a single, harmonized classification system. It identifies three "Consensus Transcriptomic Subtypes" (CTSs) of sepsis, each with a unique molecular signature:

"Our goal was to create a standardized 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.

Thesecond 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. Analyzing 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 insepsisbut 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 designingclinical trialsthat 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.

More information: Brendon P. Scicluna et al, A consensus blood transcriptomic framework for sepsis, Nature Medicine (2025). DOI: 10.1038/s41591-025-03964-5 Andrew R. Moore et al, A consensus immune dysregulation framework for sepsis and critical illnesses, Nature Medicine (2025). DOI: 10.1038/s41591-025-03956-5 Journal information: Nature Medicine

Provided by University of Malta