Procalcitonin Testing in Suspected Infection: Review
Procalcitonin Test: Overview
Procalcitonin (PCT) is the precursor of the hormone calcitonin and is mainly produced by the thyroid. Procalcitonin is a so-called acute phase reactant, rising in response to tissue inflammation and injury. Outside the thyroid, PCT is secreted by the lungs, intestines and other tissues in increasing amounts in response to bacterial endotoxin in the bloodstream. This makes PCT a more specific biomarker for infection than acute phase reactants like erythrocyte sedimentation rate or C-reactive protein, or negative acute phase reactants like prealbumin. Procalcitonin tests are immunoassays, often with short turnaround times (minutes to hours). PCT can be detected in blood within 2 to 4 hours of infection. Procalcitonin levels peak within 6 and 24 hours and may be detected for up to 7 days. PCT's half-life is approximately 24 hours. A PCT normal level is zero; any PCT elevation may be considered abnormal. A PCT test costs about $25. Millions of patients annually are evaluated in emergency departments or other health care settings with signs and symptoms consistent with infection, but these evaluations are often inconclusive. The PCT test might help guide initial testing and treatment for patients with suspected infections. A PCT assay has been approved by the U.S. FDA for:
"use in conjunction with other laboratory findings and clinical assessments to aid in the risk assessment of critically ill patients on their first day of ICU admission for progression to severe sepsis and septic shock";
"to help health care providers determine if antibiotic treatment should be started or stopped in patients with lower respiratory tract infections, such as community-acquired pneumonia, and stopped in patients with sepsis."
The PCT test lacks sufficient precision as a stand-alone method to diagnose or rule out infection, and must always be considered in context with individualized clinical decision-making. [tabby title="Limitations"]
Limitations of Procalcitonin Testing
The PCT test's performance characteristics (sensitivity, specificity, etc.) are unknown, and cannot be known given the limitations of medical practice today. This is because there is no reference test (gold standard) for the diagnosis of infection. Pathogens are isolated in fewer than 10% of patients with a clinical diagnosis of pneumonia, and in fewer than 30% of patients with a sepsis diagnosis. Without a reference standard to define "truth", the PCT test's accuracy cannot be calculated. The vast majority of patients are therefore treated empirically for suspected infections that are never verified nor ruled out objectively. Procalcitonin does not solve this problem, but does add an additional data point that may help physicians and health care providers estimate the probability of infection. PCT can thus theoretically improve decision-making regarding the initiation and cessation of antibiotic therapy. There are no clinically validated, reproducible cutoff values for PCT to accurately diagnose or rule out infection. Experts do not agree on the optimal or appropriate use of procalcitonin in clinical settings. [tabby title="Pneumonia"]
Procalcitonin in Pneumonia
In multiple randomized trials (mostly in Europe), using procalcitonin to guide antibiotic duration in community-acquired pneumonia resulted in shorter antibiotic courses, with equivalent or improved outcomes overall. Patients whose treatment courses were guided by PCT usually had shorter hospital stays without an increase in overall adverse events or mortality. However, the studies were small and used varying cutoff values for PCT as discriminators. A review of 14 U.S.-based randomized trials enrolling 4,467 patients of varying acuity (primary care, EDs, ICUs), mostly with pneumonias, also found that PCT use reduced antibiotic use, without an increase in mortality. Often-used PCT cutoff values to guide initial antibiotic use in these studies were:
<0.1 ng/mL (µg/L) : antibiotics withheld
>0.25 : antibiotics provided
PCT falling below a threshold level (e.g.,< 0.25 µg/L) along with clinical improvement during antibiotic treatment was frequently used as a discriminator to discontinue antibiotics. PCT elevations may be smaller in atypical pneumonia (such as those due to Mycoplasma), compared to typical pneumonias (e.g., Streptococcus pneumoniae). PCT has not been thoroughly tested or validated in the diagnosis of ventilator-associated pneumonia (VAP) or health care associated-pneumonia (HAP or HCAP) There is no known procalcitonin elevation that is consistently reliable for use in guiding antibiotic treatment decisions for community-acquired pneumonia. Experts do not advise using PCT to the exclusion of other clinical data to guide antibiotic treatment decisions. The Procalcitonin Antibiotic Consensus Trial (ProACT) tested the use of PCT in 1,664 patients with suspected pneumonia at emergency departments at 13 U.S hospitals. Cutoff values used in ProACT were:
< 0.1 ng/mL (µg/L): antibiotics strongly discouraged
0.1 - 0.25: antibiotics discouraged
0.25 - 0.5: antibiotics recommended
0.5: antibiotics strongly recommended.
For outpatients in ProACT, antibiotic duration was also advised based on PCT level:
0.25-0.5 ng/mL (ug/L): 3 days antibiotics
0.5-1.0 : 5 days antibiotics
>1.0 : 7 days antibiotics
The results of ProACT have not yet been reported at this writing. [tabby title="Sepsis"]
Procalcitonin in Sepsis
Evidence regarding the utility of procalcitonin in the diagnosis or management of sepsis is limited. In its package insert, the manufacturer of the most widely-used commercially available PCT assay advises cutoff values for PCT to help make a sepsis diagnosis:
≤ 0.5 ng/mL (µg/L) : sepsis is unlikely
> 0.5 and ≤ 2 ng/mL: sepsis is possible
> 2 and < 10 ng/mL: sepsis or another cause of severe inflammation is likely
≥ 10.0 ng/mL : sepsis is very likely
But the manufacturer also warns "the optimal cut-off values ranges of PCT are variable and dependent" on numerous poorly-defined factors. In general, PCT levels increase with severity of organ failure and therefore may help predict mortality from sepsis. However, the severity of organ failure in such patients is usually clinically evident, and PCT's marginal utility is uncertain. A strategy used in studies for PCT-guided antibiotic therapy in critically ill patients with suspected infection was:
PCT > 0.50 ng/mL: antibiotics encouraged
PCT > 1.0 ng/mL: antibiotics strongly encouraged
Measure procalcitonin serially; stop antibiotics when levels fell 80-90% or to 0.25-0.50 ng/mL.
A randomized open-label Dutch trial reported a 5% absolute reduction (20% vs 25%) in mortality in critically ill patients with sepsis whose antibiotic courses were shortened when PCT levels became normal. A Cochrane review of 10 randomized trials described "very low to moderate quality evidence" with low-powered studies that "do not clearly support the use of procalcitonin-guided antimicrobial therapy" to improve outcomes in sepsis. Most trials did report reduction by ~1 day in antibiotic courses. A 2013 Lancet ID review concluded procalcitonin was "a helpful biomarker for early diagnosis of sepsis in critically ill patients," but only as a component of overall decision-making. Heterogeneity of studies precluded any specific recommendations for use of PCT in sepsis. In 2017, a leading U.S. expert in critical care described the use of procalcitonin in the diagnosis or management of sepsis as "controversial and poorly supported by evidence." Another leading expert wrote, also in 2017: "We routinely measure PCT in all our patients [in the emergency department] suspected of having sepsis." Patients with PCT > 2 ng/mL and signs of sepsis receive specialized sepsis treatment at that center, with procalcitonin levels followed during sepsis treatment to determine whether source control has been achieved. [tabby title="False Positives"]
Causes of Procalcitonin Elevation
Severe systemic inflammation of any cause can potentially increase secretion of procalcitonin, an acute phase reactant. Conditions other than bacterial infection known to sometimes increase serum PCT (causing false positives) include:
Non-septic shock (e.g. cardiogenic shock)
Cardiothoracic or abdominal surgery
Fungal infections (e.g., invasive candidiasis)
Anti-T cell or other monoclonal antibody treatments
[tabby title="Take Home"]
Procalcitonin: Take Home Points
Procalcitonin (PCT) is an acute phase reactant that is more specific for infection than C-reactive protein or erythrocyte sedimentation rate.
PCT tests are FDA-approved to assist in decisions to start or stop antibiotics in patients with pneumonia, and whether to stop antibiotics in patients with sepsis.
Evidence mostly from outside the U.S. suggests use of PCT can reduce antibiotic use without negative outcomes. Evidence is stronger for use of PCT in diagnosis and treatment of pneumonia than for PCT in sepsis.
Results from a multicenter trial (ProACT) will provide data on the use of PCT testing for patients with pneumonia in the U.S. health care system.
Experts disagree on the utility and optimal use of PCT in clinical settings.
Systemic inflammation can produce false positive PCT elevations in the absence of infection.
Schuetz P et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012.
Wacker C et al. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. Lancet Infect Dis 13, No. 5, 426–435, May 2013.
Schuetz P et al. Role of procalcitonin in managing adult patients with respiratory tract infections. Chest. 2012 Apr;141(4):1063-1073. Schuetz P et al. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med. 2011 Aug 8;171(15):1322-31 de Jong E et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016 Jul;16(7):819-827. Andriolo BN et al. Effectiveness and safety of procalcitonin evaluation for reducing mortality in adults with sepsis, severe sepsis or septic shock. Cochrane Database Syst Rev. 2017 Jan 18;1:CD010959.
FDA Advisory Committee presentation on procalcitonin testing. November 10, 2016.
Ramon Sager et al. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Medicine 2017;15:15. https://doi.org/10.1186/s12916-017-0795-7