Procalcitonin for the diagnosis, prognosis and monitoring of sepsis

Procalcitonin has been used in Europe for many years and was also approved for use in the United States by the US Food and Drug Administration (FDA) as a diagnostic aid for sepsis in 2005. It also gained an FDA indication in 2016 for serial use to assess sepsis progression and 28-day mortality risk. Several different procalcitonin assays exist, but all demonstrate good concordance at clinically relevant cutoffs.

Serum procalcitonin levels rise rapidly in response to systemic inflammatory insults, with peak levels that correlate with the intensity of the stimulus. Procalcitonin has a short half-life (25–30 hours), and levels decline rapidly with resolution of inflammation. These properties make it potentially useful in helping decide whether to start antibiotics and when to stop antibiotics in a clinically improving patient.

procalcitonin levels are significantly higher in culture-positive sepsis versus culture negative-sepsis, and thus diagnostic performance may be better in the former group of patients. Furthermore, in critically ill patients with microbiologically documented infection, procalcitonin levels differ by site of infection, with the highest levels in those with positive blood cultures and lowest with pulmonary cultures.

The use of procalcitionin in therapy decision making

Because of the lack of a reliable reference standard for identifying bacterial pneumonia and sepsis, particularly in culture-negative patients, the utility of procalcitonin cannot be determined through observational studies alone.

However, numerous randomized intervention studies have examined whether procalcitonin-based algorithms can help clinicians decide whether to start or stop antibiotic therapy, without adversely impacting patients through delayed antibiotic therapy or inadequate treatment courses.

These studies have primarily demonstrated efficacy in 2 clinical scenarios: adult patients with suspected respiratory infections, and critically ill adults with any type of suspected infection. Improving antibiotic use in these 2 clinical scenarios carries the potential for significant benefit given that respiratory infections are the most common indication for antibiotics in hospitalized patients and antibiotic use is most prevalent in ICUs.

Procalcitonin to guide antibiotic therapy for respiratory infections

The largest study to date examining procalcitonin for respiratory infections, the Procalcitonin Guided Antibiotic Therapy and Hospitalisation in Patients With Lower Respiratory Tract Infections (ProHOSP) concluded that procalcitonin levels can be safely used in patients with lower respiratory tract infections like pneumonia; to guide treatment decisions regarding initiation and discontinuation of therapy.

A subsequent Cochrane review concluded that procalcitonin guidance for respiratory patients in a variety of settings (including the emergency department, ICU, and primary care settings) resulted in a significant reduction in total antibiotic exposure (median 4 days vs 8 days), with no difference in mortality or rates of treatment failure.

How to interpret and use procalcitonin levels for guiding antibiotic therapy in stable and critically ill patients with infections?

Non-critically ill patients with suspected or proven respiratory infection

Procalcitonin can be safely used at a cutoff of <0.25 µg/L to withhold antibiotics in stable, low-risk patients with suspected respiratory infections. If antibiotics are given, procalcitonin can help inform early discontinuation of antibiotics based on serial measurements, even in those with documented bacterial infections.

Critically ill patients with suspected infection/sepsis

Clinicians are understandably reluctant to withhold antibiotics when sepsis is first suspected in unstable patients, regardless of procalcitonin levels, but serial procalcitonin measurements can be used at a cutoff of <0.5 µg/L or >80% decrease in peak level to help guide early antibiotic discontinuation once patients stabilize. Using procalcitonin in this fashion is safe, even in those with documented infections, and the largest trial to date (SAPS) suggests that it may even reduce mortality.

Precautions and Conclusions
  • Clinicians must remember that false positives and negatives can occur with procalcitonin testing and that sepsis is a complex and heterogeneous syndrome
  • In most of the procalcitonin trials, overruling of the algorithm was allowed and in fact common in the ICU-based studies, underscoring the fact that procalcitonin should not replace clinical judgment
  • Clinicians should also be aware of the patients typically excluded from trials, particularly severely immunocompromised patients. However, when used properly as a clinical decision aid, the evidence is robust that procalcitonin can be a powerful antibiotic stewardship tool