THE ROLE OF PANCREATIC STONE PROTEIN (PSP) AND PSP-GUIDED EARLY MEROPENEM TREATMENT TO MITIGATE SEPSIS RISK AT THE EMERGENCY DEPARTMENT: THE PROMISE DOUBLE BLIND, PHASE III, RANDOMIZED CONTROLLED CLINICAL TRIAL

Sepsis is among the leading causes of death worldwide. It is well-perceived that early start of antibiotics is the mainstay of management. According to the Surviving Sepsis Campaign guidelines, early resuscitation with antibiotics should start in all patients with suspected infection and clinical features suggestive of sepsis. Current clinical assessment tools, including the quick Sequential Organ Failure Assessment (qSOFA) and the National Early Warning Score 2 (NEWS2), are useful for identifying patients at increased risk of adverse outcomes. However, patients who do not meet criteria for overt sepsis or have only limited clinical abnormalities may still be at substantial risk of unfavorable outcome. Biomarkers may provide additional information for the early identification of such patients and may allow targeted intervention before the development of clinically overt organ dysfunction.

Patients with only one qSOFA sign, and even some patients with nil criteria of qSOFA, may still be at risk of unfavorable outcomes. Previous analyses from the Hellenic Sepsis Study Group showed that patients with one qSOFA sign and elevated soluble urokinase plasminogen activator receptor (suPAR) blood levels had a risk of 28-day mortality similar to that of patients with qSOFA of 2 or more. In the randomized controlled SUPERIOR trial, patients identified by one qSOFA sign and elevated suPAR were randomized to receive a single dose of meropenem or placebo. Early meropenem treatment resulted in a 74% relative reduction in early worsening of the clinical state, defined as at least a 1-point increase in the total SOFA score from baseline. These findings support the concept of using biomarkers together with clinical assessment to identify patients with suspected infection who may benefit from early antimicrobial intervention.

Pancreatic Stone Protein (PSP), also known as Regenerating Protein 1A (Reg1A), is a 16-kDa C-type lectin-like glycoprotein predominantly secreted by pancreatic acinar cells and, also, expressed in other tissues, including gastric and intestinal epithelium. PSP is involved in tissue regeneration and in systemic stress and immune responses. Through its ability to bind and aggregate bacteria and activate neutrophils, PSP has been proposed as a biomarker of systemic inflammation and infection. Previous clinical studies have demonstrated increased PSP concentrations in patients with sepsis compared with patients with organ dysfunction unrelated to infection. PSP may increase earlier than conventional inflammatory biomarkers, including C-reactive protein and procalcitonin, and may therefore have a role in the early identification of patients at risk of sepsis and clinical deterioration.

The PROMPT study, which took place at the Emergency Departments (ED) of six hospitals in Greece, evaluated PSP in patients admitted with suspected infection, defined by the presence of fever, hypothermia, or tachycardia. PSP concentrations were retrospectively measured in stored blood samples using the IVD CAPSULE PSP assay on the abioSCOPE device. This post-hoc analysis showed that the combination of PSP ≥300 ng/mL with one sign of qSOFA and/or a NEWS2 score of 5 or 6 had a sensitivity of more than 30% and a specificity of more than 90% for the detection of sepsis. The diagnostic performance of this combination was similar to that of qSOFA ≥2. These findings support the use of PSP in combination with clinical assessment to identify patients with suspected infection who may be at increased risk of sepsis, including patients who do not have sufficient clinical abnormalities to meet higher-risk qSOFA criteria.

Early antimicrobial treatment is a cornerstone of the management of patients with suspected bacterial infection and sepsis. Meropenem is a broad-spectrum antibacterial agent with activity against a wide range of clinically relevant pathogens and is an established treatment option for severe bacterial infections. The selection of meropenem for the PROMISE trial is supported by promising results of the SUPERIOR trial in which patients with suspected infection at risk of death. The dose selected for PROMISE remains within the scope of the approved dosing recommendations for hospitalized patients who may require continued antibiotic treatment. Administration of a single study dose therefore does not impose any restriction on subsequent antimicrobial management.