Sepsis is one of the main causes of hospital mortality worldwide and yet it remains one of the most unknown diseases in society. It is estimated that it causes as many deaths as acute myocardial infarction or some of the most common cancers, such as breast cancer. This ‘silent pandemic’ continues to be diagnosed late and treated without specific tools. Faced with this scenario, a group of professionals from Castilla y León has opted to develop a high-level biomedical research project that aims to change this reality, find an early diagnosis and open new avenues for treatment.
The initiative is led by professionals from the University Clinical Hospital and the University of Valladolid, within the Biocritic Group, which works to deepen the knowledge of sepsis, with doctors from other parts of Spain and also from European countries, in combination with laboratory people, biologists and engineers, as explained to Ical by the main researcher of this project, Eduardo Tamayo, professor of Anesthesiology and Critical Pathology at the University of Valladolid and Research Coordinator of the University Clinical Hospital of Valladolid.
The work, funded by the Carlos III Health Institute, applies a personalized precision medicine approach to improve the early diagnosis of sepsis and open new therapeutic avenues aimed at its biological mechanisms. It focuses on single-cell sequencing of circulating endothelial cells in post-surgical patients with sepsis due to intra-abdominal infection for the identification of early diagnostic biomarkers and new therapeutic targets.
Despite advances in intensive care, mortality associated with sepsis remains high, explains Tamayo, who specifies that the main reason is twofold. On the one hand, the absence of molecular tools that allow it to be diagnosed early and reliably; on the other hand, the lack of treatments specifically directed against the pathophysiological mechanisms responsible for organic damage.
In clinical practice, sepsis is diagnosed when the patient already has failure of one or more organs. “That is, when we are late.” Unlike other pathologies, such as myocardial infarction or kidney failure, there is no specific biomarker that allows sepsis to be clearly differentiated from other serious inflammatory responses, such as systemic inflammatory response syndrome (SIRS). This diagnostic delay has direct consequences: worse prognosis, higher mortality, longer hospital stays, more ICU admissions and a very significant increase in health spending, says the specialist, who is also the Hospital’s Quality, Research and Innovation coordinator.
The difficulty in accurately diagnosing sepsis also has an extremely important side effect, which is the indiscriminate use of antibiotics. Given clinical suspicion, many patients receive broad-spectrum antibiotic treatment even if they do not ultimately suffer from sepsis. This phenomenon contributes directly to the development of multi-resistant bacteria, already considered by the World Health Organization as one of the greatest threats to global health, warns Tamayo. In fact, forecasts suggest that, if no action is taken, “resistant infections could become the leading cause of global mortality in the coming decades.”
The endothelium, a key organ
In recent years, scientific research has identified the endothelium – the tissue that lines the inside of all blood vessels – as the central target organ of sepsis. Endothelial dysfunction precedes multiple organ failure and plays a decisive role in the progression to septic shock.
When the endothelium fails, the integrity of the vessels, tissue perfusion, coagulation mechanisms, and the inflammatory response are altered. The result is systemic damage that affects the entire organism. However, most of the current knowledge comes from animal models or cell cultures, due to the enormous difficulty of directly studying the endothelium in patients.
The project led from Valladolid proposes an innovative approach, which involves isolating circulating endothelial cells from peripheral blood samples of post-surgical patients with sepsis secondary to intra-abdominal infection.
During sepsis, some endothelial cells break away from blood vessels and enter the circulation. Analyzing them is equivalent, in practice, to performing “a liquid biopsy of the endothelium”, without invasive procedures.
These cells are studied using single-cell RNA sequencing (scRNA-seq), a cutting-edge technology that allows the gene expression of each cell to be analyzed individually. Thanks to this technique, researchers can identify cellular subpopulations, specific functional states and molecular alterations that are not detectable with conventional methods.
Jump to the clinic
The project has been designed as a prospective, multicenter and longitudinal study, structured in two phases: an identification cohort and a subsequent validation cohort. The objective is to compare the gene expression profiles of circulating endothelial cells in patients with sepsis and without sepsis, as well as to analyze their relationship with the severity, clinical evolution and development of septic shock.
The biomarkers and cell subpopulations identified by scRNA-seq will subsequently be validated by conventional flow cytometry, a technique already present in routine clinical practice. This step is key to facilitating that the results can be realistically transferred to the hospital.
The researchers hope that this work will allow progress towards an early and accurate diagnosis, capable of differentiating sepsis from other inflammatory responses, reducing the unnecessary use of antibiotics and substantially improving the prognosis of patients.
New targets
Furthermore, detailed knowledge of what is failing in the endothelium opens the door to the development of new therapeutic targets, specifically aimed at correcting endothelial dysfunction, an approach that is reminiscent of the progress experienced in oncology, where the identification of specific molecular alterations has made it possible to develop personalized treatments, says the person responsible for the project.
This project consolidates Castilla y León as a benchmark in biomedical research applied to critically ill patients, under the umbrella of the BioCritic Group, which has more than 20 years of experience, competitive national and international funding, high-impact scientific publications and patents, and maintains a stable line of research in precision medicine in sepsis.
