Procalcitonin

Figure 1: Immature Calcitonin
Medical diagnostics
A 3D cartoon of procalcitonin's parent compound, calcitonin

Procalcitonin (PCT) is a peptide precursor of the hormone calcitonin, the latter being involved with calcium homeostasis. It arises once preprocalcitonin is cleaved by endopeptidase.[1] It was first identified by Leonard J. Deftos and Bernard A. Roos in the 1970s.[2] It is composed of 116 amino acids and is produced by parafollicular cells (C cells) of the thyroid and by the neuroendocrine cells of the lung and the intestine.

The level of procalcitonin in the blood stream of healthy individuals is below the limit of detection (0.01 µg/L) of clinical assays.[3] The level of procalcitonin rises in a response to a proinflammatory stimulus, especially of bacterial origin. It is therefore often classed as an acute phase reactant.[4]:542 In this case, it is produced mainly by the cells of the lung and the intestine. It does not rise significantly with viral or non-infectious inflammations. With the derangements that a severe infection with an associated systemic response brings, the blood levels of procalcitonin may rise to 100 µg/L. In serum, procalcitonin has a half-life of 25 to 30 hours. Remarkably the high procalcitonin levels produced during infections are not followed by a parallel increase in calcitonin or a decrease in serum calcium levels.

Biochemistry

Figure 2: Production pathway of PCT and CT in healthy and infected individuals via the induction of CALC-1 gene

PCT is a member of the calcitonin (CT) superfamily of peptides. It is peptide of 116 amino acid with an approximate molecular weight of 14.5 kDa, and its structure can be divided into three sections (see Figure 1):[5] amino terminus (represented by the ball and stick model in Figure 1), immature calcitonin (shown in Figure 1 from PDB as the crystal structure of procalcitonin is not yet available), and calcitonin carboxyl-terminus peptide 1.[5] Under normal physiological conditions, active CT is produced and secreted in the C-cells of the thyroid gland after proteolytic cleavage of PCT, meaning, in a healthy individual, that PCT levels in circulation are very low (<.05 ng/mL).[6] The pathway for production of PCT under normal and inflammatory conditions are shown in Figure 2.[7] During inflammation, LPS, microbial toxin, and inflammatory mediators, such as IL-6 or TNF-α, induce the CALC-1 gene in adipoctyes, but PCT never gets cleaved to produce CT.[7] In a healthy individual, PCT in endocrine cells is produced by CALC-1 by elevated calcium levels, glucocorticoids, CGRP, glucagon, or gastrin, and is cleaved to form CT, which is released to the blood.[7]

PCT is located on the CALC-1 gene on chromosome 11.[5] Bacterial infections induce a universal increase in the CALC-1 gene expression and a release of PCT (>1 μg/mL).[6] Expression of this hormone occurs in a site specific manner.[5] In healthy and non-infected individuals, transcription of PCT only occurs in neuroendocrine tissue, except for the C cells in the thyroid. The formed PCT then undergoes post-translational modifications, resulting in the production small peptides and mature CT by removal of the C-terminal glycine from the immature CT by peptidylglycine α-amidating monooxygenase (PAM).[8] In a microbial infected individual, non-neuroendocrine tissue also secretes PCT by expression of CALC-1. A microbial infection induces a substantial increase in the expression of CALC-1, leading to the production of PCT in all differentiated cell types.[9] The function of PCT synthesized in nonneuroendocrine tissue due to a microbial infection is currently unknown, but, it’s detection aids in the differentiation of inflammatory processes.[5]

Diagnostic Advantages

Due to PCT’s variance between microbial infections and healthy individuals, it has become a marker to improve bacterial infections identification and guide antibiotic therapy.[10] Table 1 is a summary from Schuetz, Albrich, and Mueller, summarizing the current data of selected, relevant studies investigating PCT in different types of infections, where ✓ represents moderate evidence in favor of PCT; ✓✓ is good evidence in favor of PCT; ✓✓✓ is strong evidence in favor of PCT; ~ is evidence in favor or against the use of PCT or still undefined.

Table 1: Diagnostic Summary of Studies Investigating the Therapeutic Advantages of PCT[10]

Infection Type/Setting Study Design PCT Cut-Off (ug/L) PCT Benefit Conclusion References
Abdominal Infections observational 0.25 ~ PCT may help exclude ischemia and necrosis in bowel blockage ,[11][12][13][14]
Arthritis observational 0.1-0.25 ✓ PCT differentiates non-infectious (gout) arthritis from true infection ,[15][16][17]
Bacteremic infections observational 0.25 ✓✓ Low PCT levels help rule out microbial infections ,[18][19][20]
Blood stream infection (primary) observational 0.1 ✓✓ PCT differentiates contamination from true infection [21]
Bronchitis RCT 0.1-0. 5 ✓✓✓ PCT reduces antibiotic exposure without adverse outcomes in the ED ,[22][23]
COPD exacerbation RCT 0.1-0. 5 ✓✓✓ PCT reduces antibiotic exposure without adverse outcomes in the ED and hospital ,[22][23][24]
Endocarditis observational 2.3 ✓ PCT is an independent predictor with high diagnostic accuracy for acute endocarditis ,[25][26]
Meningitis before-after 0.5 ✓ PCT reduces antibiotic exposure during outbreak of viral meningitis ,[27][28][29]
Neutropenia observational 0.1-0.5 ✓ PCT is helpful at identifying neutropenic patients with systemic bacterial infection ,[30][31][32]
Pancreatitis observational 0.25-0.5 ~ PCT correlates with severity and extent of infected pancreatitis ,[33][34]
Pneumonia RCT 0.1-0. 5; 80-90% ↓ ✓✓✓ PCT reduces antibiotic without adverse outcomes exposure in the hospital ,[22][23][35][36][37][38]
Postoperative fever observational 0.1-0.5 ✓ PCT differentiates non-infectious fever from post-operative infections [39]
Postoperative infections RCT 0.5-1.0; 75-85% ↓ ✓✓ PCT reduces antibiotic exposure without adverse outcomes in the surgical ICU ,[40][41]
Severe sepsis/Shock RCT 0.25-0.5; 80-90% ↓ ✓✓✓ PCT reduces antibiotic exposure without adverse outcomes in the ICU ,[42][43]
Upper respiratory tract infections RCT 0.1-0.25 ✓✓ PCT reduces antibiotic exposure without adverse outcomes in primary care [44]
Urinary tract infections observational 0.25 ✓ PCT correlates with severity of urinary tract infections ,[19][45]
Ventilator-associated pneumonia RCT 0.1-0.25 ✓✓ PCT reduces antibiotic exposure without adverse outcomes ,[43][46]

Medical uses

Sepsis

Measurement of procalcitonin can be used as a marker of severe sepsis caused by bacteria and generally grades well with the degree of sepsis,[47] although levels of procalcitonin in the blood are very low. PCT has the greatest sensitivity (85%) and specificity (91%) for differentiating patients with systemic inflammatory response syndrome (SIRS) from those with sepsis, when compared with IL-2, IL-6, IL-8, CRP and TNF-alpha.[48] Evidence is emerging that procalcitonin levels can reduce unnecessary antibiotic prescribing to people with lower respiratory tract infections.[49] Currently, procalcitonin assays are widely used in the clinical environment.[50]

A meta-analysis reported a sensitivity of 76% and specificity of 70% for bacteremia.[51]

Pneumonia

Given procalcitonin is a blood marker for bacterial infections, evidence shows that it is a useful tool in guiding the initiation and duration of antibiotics in patients with bacterial pneumonia and other acute respiratory infections.[52] The use of procalcitonin guided antibiotic therapy leads to lower mortality, less antibiotic usage, decreased side effects due to antibiotics and promotes good antibiotic stewardship.[52]

Kidney disease

Patients with chronic kidney disease and end-stage renal disease are at higher risk for infections, and procalcitonin has been studied in these populations, who often have higher levels. Procalcitonin can be dialyzed, and so levels are dependent upon when patients receive hemodialysis. While there is no formally accepted cutoff value for patients undergoing HD, using a value of greater or equal to 0.5 ng/mL yielded a sensitivity of 97-98% and a specificity of 70-96%.[53]

Hepatitis

PCT, possibly together with CRP, is used to corroborate the MELD score.[54][55]

Research

Excessive overdose on amphetamine or its analogs can induce systemic inflammation; in a case of amphetamine overdose, sans bacterial infection, significant elevations in procalcitonin were observed.[56]

References

  1. ↑ "Procalcitonin: Reference Range, Interpretation, Collection and Panels". 2017-03-09.
  2. ↑ Deftos, L J; Roos, B A; Parthemore, J G (1975-12-01). "Calcium and skeletal metabolism.…". Western Journal of Medicine. 123 (6): 447–458. ISSN 0093-0415. PMC 1130411. PMID 1105981.
  3. ↑ Dandona P, Nix D, Wilson MF, et al. (December 1994). "Procalcitonin Increase after Endotoxin Injection in Normal Subjects". Journal of Clinical Endocrinology and Metabolism. 79 (6): 1605–1608. doi:10.1210/jc.79.6.1605. PMID 7989463.
  4. ↑ Long, Sarah S.; Pickering, Larry K.; Prober, Charles G., eds. (2012), "Bacterial infections in the neonate", Principles and Practice of Pediatric Infectious Diseases (4th ed.), Elsevier, ISBN 978-1437727029.
  5. 1 2 3 4 5 Ming, Jin,; I., Khan, Adil (2010-03-01). "Procalcitonin: Uses in the Clinical Laboratory for the Diagnosis of Sepsis". Laboratory Medicine. 41 (3): 173–177. doi:10.1309/LMQ2GRR4QLFKHCH9. ISSN 0007-5027.
  6. 1 2 Hendrickson, W. A.; Ward, K. B. (1975-10-27). "Atomic models for the polypeptide backbones of myohemerythrin and hemerythrin". Biochemical and Biophysical Research Communications. 66 (4): 1349–1356. ISSN 1090-2104. PMID 5.
  7. 1 2 3 Vijayan, Ashitha L.; Vanimaya; Ravindran, Shilpa; Saikant, R.; Lakshmi, S.; Kartik, R.; G, Manoj. (2017-08-03). "Procalcitonin: a promising diagnostic marker for sepsis and antibiotic therapy". Journal of Intensive Care. 5: 51. doi:10.1186/s40560-017-0246-8. ISSN 2052-0492. PMC 5543591. PMID 28794881.
  8. ↑ Snider, R. H.; Nylen, E. S.; Becker, K. L. (December 1997). "Procalcitonin and its component peptides in systemic inflammation: immunochemical characterization". Journal of Investigative Medicine. 45 (9): 552–560. ISSN 1081-5589. PMID 9444882.
  9. ↑ Linscheid, Philippe; Seboek, Dalma; Nylen, Eric S.; Langer, Igor; Schlatter, Mirjam; Becker, Kenneth L.; Keller, Ulrich; Müller, Beat (December 2003). "In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue". Endocrinology. 144 (12): 5578–5584. doi:10.1210/en.2003-0854. ISSN 0013-7227. PMID 12960010.
  10. 1 2 Schuetz, Philipp; Albrich, Werner; Mueller, Beat (2011-09-22). "Procalcitonin for diagnosis of infection and guide to antibiotic decisions: past, present and future". BMC Medicine. 9: 107. doi:10.1186/1741-7015-9-107. ISSN 1741-7015. PMC 3186747. PMID 21936959.
  11. ↑ Kafetzis, D. A.; Velissariou, I. M.; Nikolaides, P.; Sklavos, M.; Maktabi, M.; Spyridis, G.; Kafetzis, D. D.; Androulakakis, E. (2005-07-01). "Procalcitonin as a predictor of severe appendicitis in children". European Journal of Clinical Microbiology and Infectious Diseases. 24 (7): 484–487. doi:10.1007/s10096-005-1360-4. ISSN 0934-9723. PMID 15995845.
  12. ↑ Sand, M.; Trullen, X.V.; Bechara, F.G.; Pala, X.F.; Sand, D.; Landgrafe, G.; Mann, B. (2009). "A Prospective Bicenter Study Investigating the Diagnostic Value of Procalcitonin in Patients with Acute Appendicitis". European Surgical Research. 43 (3): 291–297. doi:10.1159/000232939. ISSN 0014-312X. PMC 2790741. PMID 19672084.
  13. ↑ Anielski, Ryszard; Kuśnierz-Cabala, Beata; Szafraniec, Krystyna (2010-11-01). "An evaluation of the utility of additional tests in the preoperative diagnostics of acute appendicitis". Langenbeck's Archives of Surgery. 395 (8): 1061–1068. doi:10.1007/s00423-009-0565-x. ISSN 1435-2443. PMID 19924436.
  14. ↑ Markogiannakis, Haridimos; Memos, Nikolaos; Messaris, Evangelos; Dardamanis, Dimitrios; Larentzakis, Andreas; Papanikolaou, Dimitrios; Zografos, George C.; Manouras, Andreas (March 2011). "Predictive value of procalcitonin for bowel ischemia and necrosis in bowel obstruction". Surgery. 149 (3): 394–403. doi:10.1016/j.surg.2010.08.007. ISSN 1532-7361. PMID 20869092.
  15. ↑ Hügle, T.; Schuetz, P.; Mueller, B.; Laifer, G.; Tyndall, A.; Regenass, S.; Daikeler, T. (May 2008). "Serum procalcitonin for discrimination between septic and non-septic arthritis". Clinical and Experimental Rheumatology. 26 (3): 453–456. ISSN 0392-856X. PMID 18578968.
  16. ↑ Butbul-Aviel, Yonatan; Koren, Ariel; Halevy, Raphael; Sakran, Waheeb (2005-12-01). "Procalcitonin as a Diagnostic Aid in Osteomyelitis and Septic Arthritis". Pediatric Emergency Care. 21 (12): 828–832. doi:10.1097/01.pec.0000190226.12610.24. ISSN 0749-5161.
  17. ↑ Martinot, M.; Sordet, C.; Soubrier, M.; Puéchal, X.; Saraux, A.; Lioté, F.; Guggenbuhl, P.; Lègre, V.; Jaulhac, B. (May 2005). "Diagnostic value of serum and synovial procalcitonin in acute arthritis: a prospective study of 42 patients". Clinical and Experimental Rheumatology. 23 (3): 303–310. ISSN 0392-856X. PMID 15971417.
  18. ↑ Seif, Fadi; Khayyata, Said; Hejal, Rana (2010). "Lipoid Pneumonia Presenting as Solitary Pulmonary Nodule". Chest. 138 (4): 121A. doi:10.1378/chest.10954.
  19. 1 2 van Nieuwkoop, Cees; Bonten, Tobias N.; van't Wout, Jan W.; Kuijper, Ed J.; Groeneveld, Geert H.; Becker, Martin J.; Koster, Ted; Wattel-Louis, G. Hanke; Delfos, Nathalie M. (2010-11-17). "Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome: a prospective observational study". Critical Care. 14 (6): R206. doi:10.1186/cc9328. ISSN 1364-8535. PMC 3220019. PMID 21083886.
  20. ↑ Riedel, Stefan; Melendez, Johan H.; An, Amanda T.; Rosenbaum, Janet E.; Zenilman, Jonathan M. (2011-02-01). "Procalcitonin as a Marker for the Detection of Bacteremia and Sepsis in the Emergency Department". American Journal of Clinical Pathology. 135 (2): 182–189. doi:10.1309/ajcp1mfyinqlecv2. ISSN 0002-9173. PMID 21228358.
  21. ↑ Schuetz, P.; Mueller, B.; Trampuz, A. (2007-10-01). "Serum Procalcitonin for Discrimination of Blood Contamination from Bloodstream Infection due to Coagulase-Negative Staphylococci". Infection. 35 (5): 352–5. doi:10.1007/s15010-007-7065-0. ISSN 0300-8126. PMID 17882355.
  22. 1 2 3 Christ-Crain, Mirjam; Jaccard-Stolz, Daiana; Bingisser, Roland; Gencay, Mikael M; Huber, Peter R; Tamm, Michael; Müller, Beat (2004). "Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial". The Lancet. 363 (9409): 600–607. doi:10.1016/s0140-6736(04)15591-8. PMID 14987884.
  23. 1 2 3 Schuetz, Philipp; Christ-Crain, Mirjam; Thomann, Robert; Falconnier, Claudine; Wolbers, Marcel; Widmer, Isabelle; Neidert, Stefanie; Fricker, Thomas; Blum, Claudine (2009-09-09). "Effect of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections". JAMA. 302 (10): 1059–66. doi:10.1001/jama.2009.1297. ISSN 0098-7484. PMID 19738090.
  24. ↑ Stolz, Daiana; Christ-Crain, Mirjam; Bingisser, Roland; Leuppi, Jörg; Miedinger, David; Müller, Christian; Huber, Peter; Müller, Beat; Tamm, Michael (2007). "Antibiotic Treatment of Exacerbations of COPD". Chest. 131 (1): 9–19. doi:10.1378/chest.06-1500. PMID 17218551.
  25. ↑ Knudsen, Jane B.; Fuursted, Kurt; Petersen, Eskild; Wierup, Per; Mølgaard, Henning; Poulsen, Steen H.; Egeblad, Henrik (2010). "Procalcitonin in 759 Patients Clinically Suspected of Infective Endocarditis". The American Journal of Medicine. 123 (12): 1121–1127. doi:10.1016/j.amjmed.2010.07.018. PMID 20870199.
  26. ↑ Mueller, Christian; Huber, Peter; Laifer, Gerd; Mueller, Beat; Perruchoud, André P. (2004-04-13). "Procalcitonin and the Early Diagnosis of Infective Endocarditis". Circulation. 109 (14): 1707–1710. doi:10.1161/01.cir.0000126281.52345.52. ISSN 0009-7322. PMID 15066945.
  27. ↑ Gendrel, Dominique; Raymond, Josette; Assicot, Marcel; Moulin, Florence; Iniguez, Jean-Luc; Lebon, Pierre; Bohuon, Claude (1997-06-01). "Measurement of Procalcitonin Levels in Children with Bacterial or Viral Meningitis". Clinical Infectious Diseases. 24 (6): 1240–1242. doi:10.1086/513633. ISSN 1058-4838.
  28. ↑ Marc, E; Ménager, C; Moulin, F; Stos, B; Chalumeau, M; Guérin, S; Lebon, P; Brunet, F; Raymond, J (2002). "Procalcitonine et méningites virales : réduction des traitements antibiotiques inutiles par le dosage en routine au cours d'une épidémie". Archives de Pédiatrie. 9 (4): 358–364. doi:10.1016/s0929-693x(01)00793-x.
  29. ↑ Mary, R; Veinberg, F; Couderc, R (2003). "[Acute meningitidis, acute phase proteins and procalcitonin]". Annales de Biologie Clinique. 61 (2). ISSN 0003-3898.
  30. ↑ Stryjewski, Glenn R.; Nylen, Eric S.; Bell, Michael J.; Snider, Richard H.; Becker, Kenneth L.; Wu, Amy; Lawlor, Christopher; Dalton, Heidi (2005-03-01). "Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children". Pediatric Critical Care Medicine. 6 (2): 129–135. doi:10.1097/01.pcc.0000149317.15274.48. ISSN 1529-7535. PMID 15730597.
  31. ↑ Sakr, Y.; Sponholz, C.; Tuche, F.; Brunkhorst, F.; Reinhart, K. (2008-10-01). "The Role of Procalcitonin in Febrile Neutropenic Patients: Review of the Literature". Infection. 36 (5): 396–407. doi:10.1007/s15010-008-7374-y. ISSN 0300-8126. PMID 18759057.
  32. ↑ Koivula, Irma; Hamailainen, Sari; Jantunen, Esa; Pulkki, Kari; Kuittinen, Taru; Nousiainen, Tapio; Juutilainen, Auni (10 Dec 2010). "Elevated procalcitonin predicts Gram-negative sepsis in haematological patients with febrile neutropenia". Scandinavian Journal of Infectious Disease. 43 (6–7): 471–478. doi:10.3109/00365548.2011.554855. PMID 21299364.
  33. ↑ Gurda-Duda, Anna; Kuśnierz-Cabala, Beata; Nowak, Wojciech; Naskalski, Jerzy W.; Kulig, Jan (2008-11-01). "Assessment of the Prognostic Value of Certain Acute-Phase Proteins and Procalcitonin in the Prognosis of Acute Pancreatitis". Pancreas. 37 (4): 449–453. doi:10.1097/mpa.0b013e3181706d67. ISSN 0885-3177. PMID 18953261.
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  35. ↑ Christ-Crain, Mirjam; Stolz, Daiana; Bingisser, Roland; Müller, Christian; Miedinger, David; Huber, Peter R.; Zimmerli, Werner; Harbarth, Stephan; Tamm, Michael (2012-12-20). "Procalcitonin Guidance of Antibiotic Therapy in Community-acquired Pneumonia". American Journal of Respiratory and Critical Care Medicine. 174 (1): 84–93. doi:10.1164/rccm.200512-1922oc. PMID 16603606.
  36. ↑ Kristoffersen, K.B.; Søgaard, O.S.; Wejse, C.; Black, F.T.; Greve, T.; Tarp, B.; Storgaard, M.; Sodemann, M. (2009). "Antibiotic treatment interruption of suspected lower respiratory tract infections based on a single procalcitonin measurement at hospital admission—a randomized trial". Clinical Microbiology and Infection. 15 (5): 481–487. doi:10.1111/j.1469-0691.2009.02709.x. PMID 19416298.
  37. ↑ Long, Wei; Deng, Xing-Qi; Tang, Jian-Guo; Xie, Juan; Zhang, Yi-Cui; Zhang, Yu; Gao, Yu-Yao; Lu, Gang (March 2009). "[The value of serum procalcitonin in treatment of community acquired pneumonia in outpatient]". Zhonghua Nei Ke Za Zhi. 48 (3): 216–219. ISSN 0578-1426. PMID 19576090.
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  39. ↑ Hunziker, Sabina; Hügle, Thomas; Schuchardt, Katrin; Groeschl, Isabelle; Schuetz, Philipp; Mueller, Beat; Dick, Walter; Eriksson, Urs; Trampuz, Andrej (2010-01-01). "The Value of Serum Procalcitonin Level for Differentiation of Infectious from Noninfectious Causes of Fever After Orthopaedic Surgery". The Journal of Bone and Joint Surgery. American Volume. 92 (1): 138–148. doi:10.2106/jbjs.h.01600. ISSN 0021-9355. PMID 20048106.
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  43. 1 2 Bouadma, Lila; Luyt, Charles-Edouard; Tubach, Florence; Cracco, Christophe; Alvarez, Antonio; Schwebel, Carole; Schortgen, Frédérique; Lasocki, Sigismond; Veber, Benoît (2010). "Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial". The Lancet. 375 (9713): 463–474. doi:10.1016/s0140-6736(09)61879-1. PMID 20097417.
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  55. ↑ Sakkarin Chirapongsathorn; Worawan Bunraksa; Dollapas Punpanich; Amnart Chaiprasert; Patrick S. Kamath (Nov 17, 2015). "Adding C-reactive Protein and Procalcitonin to the MELD Score Improves Mortality Prediction in Patients Admitted with Complications of Cirrhosis".
  56. ↑ Lovas A, Agoston Z, Késmárky K, Hankovszky P, Molnár Z (2014). "Extreme Procalcitonin Elevation without Proven Bacterial Infection Related to Amphetamine Abuse". Case Reports in Critical Care. 2014: 1–3. doi:10.1155/2014/179313. PMC 4006559. PMID 24826347.
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