The Efficacy of Procalcitonin as a Biomarker in the Management of Sepsis: Slaying Dragons or Tilting at Windmills?

Background: Sepsis is defined as systemic inflammatory response syndrome (SIRS) in the context of an underlying infectious process, and is associated with high rates of morbidity and mortality, particularly when initial therapy is delayed. Numerous biomarkers, including but not limited to cytokines (interleukins-2 and -6 [IL-2, IL-6] and tumor necrosis factor- [TNF-]), leukotrienes, acute-phase proteins (C-reactive protein [CRP]), and adhesion molecules, have been evaluated and rejected as unsuitable for the diagnosis of sepsis, predicting its severity, and guiding its treatment. Most recently, procalcitonin (PCT) has been suggested as a novel biomarker that may be useful in guiding therapeutic decision making in the management of sepsis. This article assesses critically the published literature on the clinical utility of PCT concentrations for guiding the treatment of sepsis in adult patients. Methods: A comprehensive search of all published studies of the use of serum concentrations of PCT to guide the treatment of sepsis in adult patients (1996 to 2011) was conducted with PubMed and Google Scholar. The search focused on the value of PCT concentrations to guide the diagnosis, prognosis, monitoring, and escalation and de-escalation of antbiotic therapy in these patients. Keywords searched included procalcitonin, sepsis, sepsis biomarker, sepsis diagnosis, sepsis prognosis, sepsis mortality, antibiotic escalation, antibiotic de-escalation, antibiotic duration, and antimicrobial stewardship. Results: Forty-six trials evaluating the efficacy of PCT concentrations in diagnosing sepsis have been published, with 39 of these trials yielding positive results and 7 yielding negative results. Wanner et al. published the largest study (n=405) demonstrating that peak PCT concentrations occur early after injury in both patients with sepsis and those with multiple organ dysfunction syndrome (MODS). Among 17 trials assessing the prognostic value of PCT concentrations with regard to clinical outcome and morbidity, 12 trials yielded positive results and five showed negative or equivocal results. Reith et al. published the largest study of the prognostic use of PCT concentrations (n=246), demonstrating that median PCT values on post-operative days (POD) one, four, and 10 were predictive of mortality in patients with abdominal sepsis (p<0.01). Among 14 trials of the utility of PCT concentrations for establishing an infectious cause of sepsis, 13 yielded positive results and only one yielded negative results. The largest study of this use of PCT concentrations, conducted by Baykut et al. (n=400), evaluated these concentrations in post-operative patients with infection, and demonstrated that concentrations of PCT remained elevated until POD 4, with a second increase observed between POD 4 and POD 6. In uninfected patients, PCT concentrations began to decrease on POD 2. Only a single study has assessed the utility of PCT concentrations in guiding the escalation of antibiotic therapy, and its results were negative. Specifically, Jensen et al. (n=1,200) compared a PCT-guided antibiotic escalation strategy with the standard of care for sepsis and found no difference in outcomes. They also found that the PCT group had a longer average stay in the intensive care unit (ICU), greater rates of mechanical ventilation, and a decreased estimated glomerular filtration rate (eGFR). Among four trials focusing on PCT concentrations and antibiotic de-escalation, all showed positive results with the measurement of PCT concentrations. The largest such study, by Bouadma et al. (n=621), demonstrated a four-day decrease in antibiotic duration when PCT concentrations were used to guide therapy relative to the study arm given the standard of care, with no increase in mortality (p=0.003). Conclusions: The diagnostic value of serum PCT concentrations for discriminating among SIRS, sepsis, severe sepsis, and septic shock remains to be established. Although higher PCT concentrations suggest a systemic bacterial infection as opposed to a viral, fungal, or inflammatory etiology of sepsis, serum PCT concentrations do not correlate with the severity of sepsis or with mortality. At present, PCT concentrations are solely investigational with regard to determining the timing and appropriateness of escalation of antimicrobial therapy in sepsis. Nevertheless, serum PCT concentrations have established utility in monitoring the clinical response to medical and surgical therapy for sepsis, and in surveillance for the development of sepsis in burn and ICU patients, and may have a role in guiding the de-escalation of antibiotic therapy.