Biomarkers in sepsis: towards precision medicine for the prevention of adverse outcomes

In 2016, an International Consensus has defined sepsis as a “life-threatening organ dysfunction caused by a dysregulated host response to infection” and septic shock as “a subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality compared to sepsis alone.” Globally, sepsis is an urgent public health issue and one of the leading causes of death in emergency departments, intensive care units (ICUs) and hospitals. The World Health Assembly resolution recommends the promotion of research to develop innovative means to prevent, diagnose, and treat sepsis, by including sepsis among the priorities in the research area for funding institutions4 in order to obtain the optimization of hospital resources and therapies. Current clinical biomarkers detected in urine or blood represent useful diagnostic and prognostic tools.5 The first, can be used to distinguish sepsis from non-infectious critical illness or to determine causative pathogens in order to promptly begin the best possible treatment. Prognostic biomarkers can help to identify patient’s risk profiles, predicting adverse clinical outcomes and allowing clinicians to better focus on preventing complications and death.5, 6 Furthermore, prognostic biomarkers permit the identification of pathophysiologic pathways targeting personalized therapies. Recently new attention is being focused on adrenomedullin and more specifically on its stable mid-regional fragment pro-adrenomedullin (MR-proADM)7 which has been demonstrated to be one of the most reliable biomarkers to predict the onset of pneumonia, other diseases and mortality. Adrenomedullin is a strong vasodilating, antimicrobial, immunomodulant peptide. It is synthetized by endocrine cells and then secreted systemically by various cell types, involved in the inflammatory reaction, in response to sepsis, hypoxia, or oxidative stress. Most of these factors are originated from the acute pathophysiological changes induced by sepsis and are not associated with comorbidities. Pro-adrenomedullin measured upon admission has been demonstrated to be a good predictor of severity and outcome for community-acquired pneumonia, improving prognostic accuracy. In this issue of Minerva Anestesiologica, Valenzuela-Sanchez et al. report the results of a prospective observational single-center study conducted on 120 consecutive ICU septic patients. This paper offers new important data to understand the importance of plasma levels of biomarkers in sepsis along the same line of recently published data. They found that the MRproADM clearance during five days of ICU stay was related to a good prognosis. In details, at hours following admission, the median MR-proADR plasma levels in surviving sepsis patients fell to 1.65 nmol/L but remained higher in the non-survivors. On day 5 the survivors showed greater MR-proADM. In accordance with other studies15 the Cox proportional hazards suggested by the authors showed that the MR-proADR plasma levels at 48 hours and at five day after ICU admission remained higher in patients not surviving sepsis compared to the survivors. Despite these indisputably interesting results, the paper leaves some open questions. Firstly, the reproducibility of the results should be replicated in a larger cohort. Indeed, it is not infrequent that findings from small, exploratory studies are not confirmed in larger trials. The work of Valenzuela-Sanchez et al.13 does not represent an exception. Secondly, it is to be investigated whether the detection of MR pro-ADM in plasma levels is useful to predict the pathology’s outcome. Indeed, its real usefulness to evaluate the organ dysfunction in septic patients is limited especially during the first 24 hours after ICU admission, and the correlation with the SOFA over time was not sufficiently studied, obstructing solid conclusion on organ failure predictivity. Thirdly,