Use of Presepsin as a Marker for Immunotherapy Administration in Pneumonia

Sepsis is a potentially lethal syndrome, which is characterized by the dysregulated response of the host to an infection. Due to its severity, sepsis should always be considered in patients with confirmed or suspected infection as it can rapidly progress to organ failure with poor prognosis. Conversely, patients with new-onset organ failure should be suspected for occult infection. Current epidemiology is suggesting an increase in the incidence of new cases. Sepsis has considerable economic burden on the community as septic patients merit higher-level of healthcare and prolonged hospital stay. Subsequently, prompt recognition and treatment are of essence in order to mitigate the overall toll.

In the past years, numerous efforts have been made to identify a biomarker that portends the presence of sepsis, but none has managed to consistently predict which patients will eventually develop this syndrome. This is largely attributed to still-unknown host and pathogen mechanisms by which the sepsis cascade is initiated. Therefore, further understanding of the pathophysiology is of paramount importance.

The pathogenesis of sepsis is multifaceted and includes immune, cardiovascular, coagulation and metabolic perturbations. Immune dysregulation is a well-established component that leads to tissue injury. Activation of the innate immunity is a crucial step in the sequence of the upcoming events. As such, if we manage to early recognize the activation of one specific immune pathway during the initial stages of sepsis in the human host and promptly commence immunotherapy directed against this specific pathway, we may prevent the cascade of events leading the patient to life-threatening organ dysfunction. This paradigm of timely intervention on the immune system upon early recognition of a specific pathway activation is the SAVE-MORE trial in COVID-19. Preemptive initiation of anakinra treatment guided by the early increase of the biomarker suPAR (soluble urokinase plasminogen activator receptor) well before clinical signs of deterioration develop led to a 64% overall improvement and a 55% relative decrease in mortality. This early personalized treatment was registered in December 2021 by the European Medicines Agency.

One similar cascade of events is happening in sepsis. Bacterial lipopolysaccharide (LPS) of the cell membrane of Gram-negative bacteria and danger-associated molecular patterns (DAMPs) like high-mobility group box-1 (HMGB1) and mitochondrial DNA (mtDNA) are recognized by toll-like receptors (TLRs). Cluster of Differentiation 14 (CD14) is the naturally occurring receptor of LPS on the surface of monocytes/macrophages and the regulator of TLR-4 signal transduction. In 2004, a novel form of CD14, named soluble CD14 subtype (sCD14-ST) or presepsin was found significantly increased in patients with sepsis. Numerous studies have validated its use as an early indicator of sepsis, but a definite cut-off value has not been established due to the heterogeneity in the study design, selection of patients and clinical context. Once LPS binds and activates TLR-4, production of interleukin (IL)-1 ensues. As a consequence, early detection of increased presepsin coupled with anakinra, one short half-life inhibitor of the activity of IL-1α and IL-1β, may be a promising personalized treatment strategy for sepsis.

In recent years, studies conducted by the Hellenic Sepsis Study Group have shown that presepsin levels over 350 pg/ml have satisfactory diagnostic and prognostic value for sepsis. In particular, results from the INTELLIGENCE-1 study showed that in patients with at least one of the qSOFA criteria, presepsin more than 350 pg/ml has a sensitivity for diagnosing sepsis and 28-day mortality of 80.2% and 91.5%, respectively. Similar results were reproduced by 2 more independent studies; INTELLIGENCE-2, which also included patients with qSOFA ≥ 1 and SAVE trial, which investigated patients with COVID-19.

On the other hand, presepsin's role in determining the appropriateness of treatment remains unclear. In a controlled clinical trial conducted by Hongli Xiao et al, presepsin was used at predefined cut-offs in order to modulate the duration of antimicrobial therapy in septic patients. The primary endpoints were the number of days free of antibiotics in a 28-day period and mortality on days 28 and 90. The results revealed significantly fewer days of antibiotic exposure to the presepsin group (14.54 days vs. 11.01 days; P < 0.001).