Procalcitonin in Clinical Practice: Should It Be in Your Diagnostic Toolkit?

Part of the procalcitonin series

During my training years, procalcitonin was rarely used, despite some of my teaching sessions presenting it as a tool for distinguishing viral from bacterial infections. Now, with more exposure, I still find myself lacking similar familiarity with procalcitonin that I have with other infectious markers like CRP or white blood cell count. In this series, I will review procalcitonin’s value in clinical practice, starting with the following questions:

1) What is the pathophysiological role of procalcitonin?

2) How good is procalcitonin in accurately guiding the initiation of antibiotics?

1) What is the pathophysiological role of procalcitonin?

Notwithstanding extensive literature on procalcitonin’s clinical use, its (patho)physiological role remains incompletely understood. In healthy individuals, procalcitonin is primarily found intracellularly in thyroid C-cells and in lung neuroendocrine cells (1,2). In these cells, procalcitonin is an intermediate, undergoing further cleavage to calcitonin by endopeptidases in the endoplasmic reticulum. Consequently, plasma levels of procalcitonin are extremely low in healthy individuals (5). All procalcitonin that would enter the circulation, are unaltered excreted by the kidneys (3).

Systemic infection or inflammation leads to an ubiquitous expression of the CALC-1 gene on chromosome 11 (6), resulting in a rise of plasma procalcitonin up to 100 000 times normal (5). This gene is activated by the subsequent mechanisms:

I. Directly by bacterial products such as lipopolysaccharide and lipoteichoic acid (6,7).

II. Indirectly by inflammatory mediators such as interleukin-1 and interleukin-6 and tumor necrosis factor-alpha(7), transforming their short-lived action into the long-lasting effect of procalcitonin (5). Importantly, viruses suppress some of these mediators via cytokines like interferon-gamma (4). This is the underlying mechanism how procalcitonin can differentiate between viral and bacterial infections.

III. Necrotic human cells (7).

Compared to CRP, procalcitonin rises even faster following a bacterial infection (7). For instance, endotoxin injection in healthy volunteers caused procalcitonin levels to rise within 3 hours, peaking 24 hours (8). However, the same study observed a very heterogeneous elimination of procalcitonin, with a half-life ranging from 26.9 to 45.7 hours. Unlike CRP, procalcitonin levels in all individuals did not normalize after one week (8). Besides interindividual variability, procalcitonin elimination is influenced by the following factors:

1) Appropriate antibiotic therapy or effective immune response, which is generally assumed to drop the procalcitonin levels by half every 24 hours (1).

2) Renal function. Since procalcitonin is excreted unchanged by the kidneys, elimination slows down with reduced renal clearance (9). Thus, therapeutic response should be assessed later in patients with impaired renal function (e.g., on day 5) (9).

Interestingly, despite its ubiquitous secretion and exponential rise during infection (5), procalcitonin’s function remains unclear. Some animal studies suggest procalcitonin may even be toxic (5). For example, intraperitoneal administration of procalcitonin in septic hamsters doubled mortality (6) whereas injecting of its antiserum improved survival (5). With regard to its function, several hypotheses have been postulated:

• Procalcitonin is often classified as a hormokine - a hormone with cytokine-like properties - that modulates the immune system. It may reduce neutrophil phagocytic activity and migration, while increasing pro-inflammatory cytokine production (5). Additionally, it may suppress appetite and increase body temperature (5).

• Procalcitonin may affect calcium metabolism, resulting in a decreased ionized calcium (8).

• Given its secretion from parenchymal cells, procalcitonin may serve as a tissue-based defense (4).

• Procalcitonin might help maintain vascular endothelial tone and metabolism during inflammation (6).

2) How good is procalcitonin in accurately guiding the initiation of antibiotics?

In clinical practice, procalcitonin is often used to guide antibiotic initiation by distinguishing between infectious and non-infectious causes, as well as between viral and bacterial etiologies (3). Before assessing its diagnostic accuracy for initiating antibiotics, it is important to consider potential false positives and false negatives.

False positives:

Infectious causes:

- Parasitic infections. Especially malaria-infections can lead to an increase in procalcitonin (4).

- Systemic fungal infections, such as candidiasis and aspergillosis (4).

- Severe viral infections, such as severe forms of Covid-19 (10).

Major tissue damage:

- Major trauma (3).

- Burns, with higher procalcitonin levels associated with poorer prognosis (2).

- Major surgery (11), with levels often peaking on the first postoperative day (2).

- Pancreatitis. While, in one randomized controlled trial, procalcitonin was successful in guiding antibiotic initiation in acute pancreatitis (22), it also serves as a marker for disease severity and the development of pancreatic necrosis (12).

- Circulatory shock. Due to gastrointestinal malperfusion, procalcitonin levels may rise in all types of shock, including cardiogenic shock (6).

Organ failure:

- Liver: Procalcitonin is elevated in both acute (13) and acute-on-chronic liver failure (2).

- Neurologic: Procalcitonin has some predictive value for malignant cerebral edema when measured about 48 hours after the onset of massive cerebral infarction (14,15).

- Respiratory: Procalcitonin is frequently raised even in non-infectious COPD-exacerbation (2). Additionally, average procalcitonin levels are higher in smokers than in non-smokers (2).

- Renal: In patients with chronic kidney disease but no infection, baseline procalcitonin levels are often elevated (9,16). As a consequence, it remains unclear whether different reference ranges should be used for individuals with reduced renal clearance (9).

Other causes:

- Newborns: Intestinal bacterial colonization is thought to cause a significant increase in procalcitonin during the first two days of life (1,6).

- Cancer: While terminal cancer patients often have elevated procalcitonin levels, even without any infection, markedly high levels are typically associated with medullary thyroid carcinoma and small-cell lung cancer (2).

False negatives:

Besides elevated bilirubin and triglycerides, and high biotin consumption - which can interfere with the procalcitonin measurement (3), the literature often cites early and localized infections as cause of false negatives (4). Falsely low procalcitonin levels have been observed in infections such as cellulitis, appendicitis, empyema, abscess, and subacute bacterial endocarditis (3,4). However, procalcitonin can remain low in true bloodstream infections. For example, a single-center study of 332 patients with at least one positive blood culture found that procalcitonin was below 0.5 µg/L in one-third and below 0.25 µg/L in one-quarter of participants (17). The most common sources of infection in these patients were skin and bone, and Staphylococcus aureus was the most commonly isolated microorganism (17).

The diagnostic accuracy of procalcitonin:

Studies report widely varying diagnostic accuracies for procalcitonin in ruling out bacterial infections:

• In a meta-analysis of 3420 bloodstream infections, the sensitivity and specificity of procalcitonin, using a 0.5 µg/L cutoff, was respectively 76% and 69% (with an area under the ROC curve (AUC) of 0.79) (18).

• A retrospective study of 116 confirmed seasonal influenza cases found that procalcitonin, with a 0.25 µg/L cutoff, was 59% sensitive and 54% specific for ruling out bacterial co-infections (AUC 0.51) (19).

• A recent literature review reported a sensitivity of procalcitonin for sepsis of 75-85%, a specificity of 70-85% and an AUC of 0.75- 0.9 (20). For comparison, CRP had a sensitivity of 70-90% and a specificity of 50-70% (20).

Despite procalcitonin’s less-than-perfect diagnostic accuracy for guiding antibiotic initiation, a 2017 Cochrane review concluded that procalcitonin guidance significantly reduced start of antibiotic therapy without affecting mortality or treatment failure (21). Randomized trials such as PROCAP and ProHOSP confirmed this conclusion (22, 23). However, the multi-center, randomized controlled ProACT trial observed no significant difference in antibiotic initiation between usual care and procalcitonin-guided groups(24). This negative result is largely attributable to two factors:

1. An unusually low percentage of patients in the usual care group receiving antibiotics (25).

2. Non-adherence to the procalcitonin protocol by clinicians (24). Although procalcitonin levels at presentation indicated that 92.3% of patients did not need antibiotics, 57% still received antibiotic therapy in the following 30 days (26).

My view:

Clinicians too often prescribe antibiotics when they are not indicated. Although procalcitonin’s diagnostic accuracy is only slightly better than that of CRP, it may help reduce unnecessary antibiotic initiation. Adherence to a procalcitonin algorithm has never been associated with a marked increase in mortality. However, to ultimately solve antibiotic overconsumption, improved education and antibiotic stewardship programs are needed, perhaps even more than procalcitonin-based algorithms.

References:

1. Cleland DA, Eranki AP. Procalcitonin. [Updated 2023 Apr 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539794/

 2. Mućka S, Jakubiak GK, Pawlas N. Procalcitonin: Infection or Maybe Something More? Noninfectious Causes of Increased Serum Procalcitonin Concentration: Updated Knowledge. Life (Basel). 2025 Mar 12;15(3):446.

 3. Paudel R, Dogra P, Montgomery-Yates AA, Coz Yataco A. Procalcitonin: A promising tool or just another overhyped test? Int J Med Sci. 2020 Jan 18;17(3):332-337.

 4. Christ-Crain M, Müller B. Procalcitonin in bacterial infections--hype, hope, more or less? Swiss Med Wkly. 2005 Aug 6;135(31-32):451-60.

5. Becker KL, Snider R, Nylen ES. Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target. Br J Pharmacol. 2010 Jan 1;159(2):253-64.

 6. Schuetz P, Mueller B. Procalcitonin-guided antibiotic stewardship from newborns to centennials. Lancet. 2017 Aug 26;390(10097):826-829.

 7. Vijayan AL, Vanimaya, Ravindran S, et al. Procalcitonin: a promising diagnostic marker for sepsis and antibiotic therapy. J Intensive Care. 2017 Aug 3;5:51.

 8. Preas HL 2nd, Nylen ES, Snider RH, et al. Effects of anti-inflammatory agents on serum levels of calcitonin precursors during human experimental endotoxemia. J Infect Dis. 2001 Aug 1;184(3):373-6.

 9. Özger HS, Çorbacıoğlu ŞK, Boyacı-Dündar N, et al. Changes of Procalcitonin Kinetics According to Renal Clearance in Critically Ill Patients with Primary Gram-Negative Bloodstream Infections. Infect Dis Clin Microbiol. 2024 Sep 26;6(3):206-215.10. Gupta S, Klompas M, Rhee C. Reassessing Procalcitonin-Guided Antibiotic Therapy in Critically Ill Patients with Sepsis: Lessons from the ADAPT-Sepsis Trial. Clin Infect Dis. 2025 Jun 20:ciaf336.11. Rhee C. Using Procalcitonin to Guide Antibiotic Therapy. Open Forum Infect Dis. 2016 Dec 7;4(1):ofw249.

 10. Gupta S, Klompas M, Rhee C. Reassessing Procalcitonin-Guided Antibiotic Therapy in Critically Ill Patients with Sepsis: Lessons from the ADAPT-Sepsis Trial. Clin Infect Dis. 2025 Jun 20:ciaf336.

11. Rhee C. Using Procalcitonin to Guide Antibiotic Therapy. Open Forum Infect Dis. 2016 Dec 7;4(1):ofw249.

12. Siriwardena AK. A Practical Guide to the Roles of Procalcitonin Measurement in Patients with Acute Pancreatitis. J Clin Med. 2026 Feb 2;15(3):1153.

 13. Sugihara T, Koda M, Okamoto T, et al. Serum Procalcitonin in Patients with Acute Liver Failure. Yonago Acta Med. 2017 Mar 9;60(1):40-46.

 14. Zhang Y, Liu G, Wang Y, Su Y, Leak RK, Cao G. Procalcitonin as a Biomarker for Malignant Cerebral Edema in Massive Cerebral Infarction. Sci Rep. 2018 Jan 17;8(1):993.

 15. Gürsoy C, Gürsoy G, Demirbilek SG. C-reactive protein-albumin ratio and procalcitonin in predicting intensive care unit mortality in traumatic brain injury. Acute Crit Care. 2022 Aug;37(3):462-467.

16. Wu SC, Liang CX, Zhang YL, et al. Elevated serum procalcitonin level in patients with chronic kidney disease without infection: A case-control study. J Clin Lab Anal. 2020 Feb;34(2):e23065.

 17. Goodlet KJ, Cameron EA, Nailor MD. Low Sensitivity of Procalcitonin for Bacteremia at an Academic Medical Center: A Cautionary Tale for Antimicrobial Stewardship. Open Forum Infect Dis. 2020 Mar 16;7(4):ofaa096.

 18. Hoeboer SH, van der Geest PJ, Nieboer D, et al. The diagnostic accuracy of procalcitonin for bacteraemia: a systematic review and meta-analysis. Clin Microbiol Infect. 2015 May;21(5):474-81.

 19. Christensen I, Berild D, Bjørnholt JV, et al. The Role of Procalcitonin as an Antimicrobial Stewardship Tool in Patients Hospitalized with Seasonal Influenza. Antibiotics (Basel). 2023 Mar 14;12(3):573.

 20. Chen L, Zhang X, Shi P. Recent advances in biomarkers for detection and diagnosis of sepsis and organ dysfunction: a comprehensive review. Eur J Med Res. 2025 Nov 7;30(1):1081.

21. Schuetz P, Wirz Y, Sager R, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2017 Oct 12;10(10):CD007498.

 22. Siriwardena AK, Jegatheeswaran S, Mason JM, et al. PROCalcitonin-based algorithm for antibiotic use in Acute Pancreatitis (PROCAP): study protocol for a randomised controlled trial. Trials. 2019 Jul 29;20(1):463.

 23. Schuetz P, Christ-Crain M, Albrich W, et al. Guidance of antibiotic therapy with procalcitonin in lower respiratory tract infections: insights into the ProHOSP study. Virulence. 2010 Mar-Apr;1(2):88-92.

 24. Huang DT, Yealy DM, Filbin MR, et al. Procalcitonin-Guided Use of Antibiotics for Lower Respiratory Tract Infection. N Engl J Med. 2018 Jul 19;379(3):236-249.

 25. Spellberg B, Gaffin N. Procalcitonin-Guided Antibiotic Use. N Engl J Med. 2018 Nov 15;379(20):1972-3.

 26. Bremmer DN, Shively NR, Walsh TL. Procalcitonin-Guided Antibiotic Use. N Engl J Med. 2018 Nov 15;379(20):1972.