POINT/COUNTERPOINT Counterpoint Procalcitonin and Its Limitations: Why a Biomarker's Best Isn't Good Enough Ayesha Farooq1 and Jessica M. Colón-Franco1* Sepsis-related conditions remain the leading Intended uses now include supporting antibiotic Downloaded from https://academic.oup.com/jalm/article/3/4/716/5603063 by guest on 23 September 2021 causes of mortality, morbidity, and expenditures management decisions in respiratory infections worldwide despite efforts to standardize care and and sepsis. There is no reference method for PCT. expedite diagnosis and treatment, which are de- The BRAHMS Kryptor sensitive PCT assay (Thermo- terminants of outcome. As with most syndromes Fisher Scientific) and its predecessor were initially with complex pathophysiology, no gold standard available and used to derive PCT cutoffs. The diagnostic test exists. Diagnosis is complicated by BRAHMS assay can be run in automated immuno- nonspecific symptoms and lengthy blood cultures assay instruments from partner companies. Simi- with high false-negative rates. Empiric antibiotic larly, the Diazyme PCT immunotubidimetric assay treatment upon signs of sepsis is an increasing (Diazyme Laboratories) can be implemented in concern for antibiotic overuse and resistance. The common chemistry analyzers. This widespread need for biochemical biomarkers for sepsis diag- availability of PCT assays is facilitating clinical use nosis is well accepted. Several pro- and antiinflam- but analytical considerations come into play. The matory biomarkers have been investigated, but functional sensitivity of the Diazyme PCT assay is only few are incorporated in clinical practice (1). higher than the BRAHMS assay and above the Procalcitonin (PCT)2 is one such molecule that reference interval of healthy individuals (2, 3). Al- emerged as a biomarker for bacterial infection and though this may not compromise the interpreta- sepsis to guide antibiotic therapy. The clinical value tion at cutoffs 0.5 ng/mL and higher, caution is of PCT remains questionable and some hesitate to warranted at lower concentrations. incorporate PCT into routine standard of care. High PCT concentrations are detected in many Here we discuss factors limiting widespread use of clinical settings in the absence of infection, includ- PCT, particularly in the US. ing after major surgeries, transplant, trauma, and PCT is increased after severe inflammation and severe burns, prolonged or severe cardiogenic bacterial infections until resolution. Its use in the shock, severe organ perfusion anomalies, autoim- US was not as widespread as that in Europe and mune disorders, malignancies and metastasis, other countries until recently. PCT was initially in- noninfectious systemic inflammation, chronic kid- dicated to assess the risk of critically ill patients for ney disease (CKD), and physiologically in the neo- progression to severe sepsis and shock and the nate (4, 5). The diagnostic value of PCT in these cumulative 28-day risk of all-cause mortality. settings has been investigated and overall findings 1Department of Pathology, Medical College of Wisconsin, Milwaukee, WI. *Address correspondence to this author at: Medical College of Wisconsin, 9200 W Wisconsin Ave., Lab Bldg., L58, Milwaukee, WI 53226. Fax 414-805-8444; e-mail [email protected]. DOI: 10.1373/jalm.2017.025916 © 2018 American Association for Clinical Chemistry 2 Nonstandard abbreviations: PCT, procalcitonin; CKD, chronic kidney disease; SIRS, systemic inflammatory response syndrome. ......................................................................................................... 716 JALM | 716–719 | 03:04 | January 2019 Procalcitonin and Its Limitations POINT/COUNTERPOINT point at PCT being useful when interpreted within algorithms are safe to reduce antibiotic use in re- clinical context. Generally speaking, PCT cutoffs spiratory infections and critically ill patients, con- >0.5 to >2 ng/mL are used to rule in sepsis, severe tradictory findings have followed. Discrepancies sepsis, or septic shock, whereas PCT cutoffs <0.25 are attributed to study design, patient case mix, to <0.5 ng/mL have a high negative predictive value protocol adherence, and cutoff (12, 13). The reality (5). Diagnostic thresholds for different disease is that little is known about algorithm adherence in states have been investigated. For example, base- real life and correlation with outcomes. Protocol line PCT is higher in CKD relative to noninfected adherence is as low as 50% in controlled trials with individuals. Cutoffs by disease stage and therapy clinicians overruling the algorithm based on clin- Downloaded from https://academic.oup.com/jalm/article/3/4/716/5603063 by guest on 23 September 2021 modality may be needed (6). Higher cutoffs in- ical judgment (12). A multicenter quality obser- crease specificity for infection and the use of PCT vational survey monitored real-life adherence in 5 as a rule-out test may be contraindicated in CKD algorithm-experienced and 9 algorithm-naïve in- (6–8). Patients with solid metastatic tumors and stitutions. Compliance was remarkable at 82.5% burns may also benefit from using higher PCT cut- but algorithm-naïve institutions had lower compli- offs (9, 10). PCT concentrations peak 24 h after birth ance (14). The one participating US institution had in the term and preterm baby and decrease by day 3 the lowest compliance at 33.5%, more than half of to adult concentrations. Gestational and postnatal other algorithm-naïve institutions, suggesting edu- age-specific reference intervals for PCT may improve cational needs and unique antibiotic prescription diagnosis of early-onset neonatal sepsis but the su- practices in the US. The ProACT (Procalcitonin An- periority of this approach has not been validated clin- tibiotic Consensus) trial investigated PCT-guided ically and higher quality studies in neonates are protocols in patients with suspected respiratory urged (11). Using tailored vs universal cutoffs in dif- infection in 14 US institutions (15). It claimed to ferent disease settings is not well studied and guide- mimic real-life scenarios, like using clinical practice lines are lacking. guidelines, within the context of extensive educa- Neither PCT nor any biomarker to date can fully tion and interpretation guidance. The study did not account for the complex host response in sepsis and find antibiotic reduction in the PCT group, which patient heterogeneity (i.e., age, comorbidities, sur- was attributed in part to low adherence. However, gery, medications). Original focus was placed on the the study had high adherence to PCT ordering and systemic harms of a deregulated proinflammatory 64.8% adherence to PCT-based recommendations component, but it is now recognized that sepsis also (e.g., withholding antibiotics when PCT was low). involves an antiinflammatory response (1). Additional Other trials with adherence near 50% showed biomarkers that target several pathways may com- decreased antibiotic use and therefore the cor- plement PCT and overcome its sensitivity and speci- relation between adherence and outcomes re- ficity shortcomings across the sepsis spectrum. Over mains questionable (12). Additionally, the safety 100 molecules have been evaluated for sepsis diag- of PCT-guided protocols remains unclear in often- nosis and multimarker approaches have been inves- excluded (e.g., immunocompromised patients) or tigated although few are in clinical use. not well-studied populations (e.g., pediatric pa- PCT-guided algorithms for antibiotic steward- tients). The use of PCT in reducing antibiotic dura- ship may not be universally applicable across het- tion without adverse effect in neonates was erogeneous patient settings and in the “real world” recently studied in a multicenter clinical trial (16). outside the framework of clinical trials. The larger PCT was effective in reducing antibiotic duration randomized controlled trials to date are summa- but its safety could not be confirmed. This rized on (12). Although initial trials showed the study like many other trials was performed in ......................................................................................................... January 2019 | 03:04 | 716–719 | JALM 717 POINT/COUNTERPOINT Procalcitonin and Its Limitations Procalcitonin application Limitations Diagnosis of sepsis Lacks specificity Increased in several conditions and physiologically in neonates Tailored cutoffs may be needed Heterogeneous studies with lack of consensus Antibiotic stewardship Safety of de-escalation unconfirmed in neonates and understudied patient subgroups Universal applicability across infection types is not well understood Limited role in antibiotic initiation Applicability and adherence to algorithms needs evaluation in real world situations Downloaded from https://academic.oup.com/jalm/article/3/4/716/5603063 by guest on 23 September 2021 Side-by-side comparison of different algorithms is missing high-income countries. The lack of universally de- Until recently, sepsis was defined by the presence signed studies precludes the applicability of PCT- of systemic inflammatory response syndrome guided algorithms in low- and middle-income [SIRS; ≥2 signs: temperature >38 °C or <36 °C, countries with higher incidence of sepsis. The util- tachycardia, tachypnea, WBC (white blood cell) ity of PCT-guided algorithms remains unconfirmed >12000/mm3 or <4000/mm3 or >10% immature for antibiotic initiation, reducing the time to antibi- bands] and documented or suspected infection. otic initiation and reducing