Biomarkers stories: procalcitonin (PCT) PDF

Biomarkers stories: procalcitonin (PCT) Jean BRETON, PharmD, PhD UFR de Pharmacie UMR CEA / Université Grenoble Alpes / CNRS Service Systèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé...

Biomarkers stories: procalcitonin (PCT) Jean BRETON, PharmD, PhD UFR de Pharmacie UMR CEA / Université Grenoble Alpes / CNRS Service Systèmes Moléculaires et nanoMatériaux pour l’Energie et la Santé 2024-2025  Biomarkers stories: procalcitonin Outline 1. Biology and biochemistry of PCT 2. PCT as a biomarker: from cancer and Gulf War to sepsis 3. Clinical applications of PCT 4. PCT assays 5. PCT as a therapeutic target? 6. Conclusion  Biomarkers stories: procalcitonin 1. Biochemistry and biology of PCT 116 amino acids 13 kDa PCT = precursor of the hormone calcitonin McGee and Baumann Clinical Laboratory News 2009  Biomarkers stories: procalcitonin 1. Biochemistry and biology of PCT After its synthesis, PCT is stored in secretory granules of all cells Under the action of endoproteases, PCT is cleaved into its constituent peptides (including calcitonin - CT) only in a few cell types o Thyroid C cells o Pulmonary endocrine cells Physiological role of CT: calcium homeostasis CT is reducing calcemia by: o Inhibiting osteoclasts o Decreasing calcium intestinal absorption o Increasing calcium renal excretion  Biomarkers stories: procalcitonin 1. Biochemistry and biology of PCT  Biomarkers stories: procalcitonin Outline 1. Biology and biochemistry of PCT 2. PCT as a biomarker: from cancer and Gulf War to sepsis 3. Clinical applications of PCT 4. PCT assays 5. PCT as a therapeutic target? 6. Conclusion  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis Calcitonin = already known as a marker for medullary thyroid cancer  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis In order to optimise CT (radio)immunoassays, researchers obtained a wide panel of Mabs recognizing CT but also PCT and its constituent peptides Using antibodies against PCT, research teams tried to study if this molecule could constitute a biomarker for malignant and non-malignant diseases  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis Oat cell carcinoma = small cell carcinoma  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis Problem: larger studies trying to reproduce these results in cancerous diseases were not conclusive Some years later (1990-1991) … Gulf War  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis French army physicians and medical biologists tried to study if PCT (among other markers) could constitute a biomarker in lung injuries caused by toxic gases Among patients included in this study, some of them presented very high levels of PCT After consultation of their medical files → common characteristic = sepsis  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis Sepsis = « attack upon the host by pro-inflammatory cytokines that has been precipitated by an infection » (Becker et al., 2010) Symptoms: fever / hypothermia / tachypnea / tachycardia / leukocytosis / leukopenia Complications: hypotension / cardiac failure / coma / renal failure / intravascular coagulation … death (France: 60,000 deaths/year, source: Institut Pasteur, 2021) Launch of new studies dedicated to sepsis and PCT  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis 1359 (2021)  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis Exemple of mechanism explaining how bacterial infection can induce PCT hypersecretion (Becker et al., 2010)  Biomarkers stories: procalcitonin 2. PCT as a biomarker: from cancer and Gulf War to sepsis PCT analysis recorded in the french « Nomenclature des actes de biologie médicale » in July 1997.  Biomarkers stories: procalcitonin Outline 1. Biology and biochemistry of PCT 2. PCT as a biomarker: from cancer and Gulf War to sepsis 3. Clinical applications of PCT 4. PCT assays 5. PCT as a therapeutic target? 6. Conclusion  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions b. PCT as a prognostic factor of sepsis c. PCT for diagnosis of bacterial infections?  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions Context: need for the reduction of antibiotic overuse Advantages of PCT: o Released mostly in response to bacterial infections and not to viral agents (exceptions) o Correlation with the extent and severity of the infection o Interesting kinetic profile Plasmatic half-life ≈ 20-24 hours Rapid increase and decrease of plasmatic levels  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions PCT plasma concentrations (ng/ml) in a 76 year old woman, following an infusion solution accidentally contaminated with Acinetobacter baumanii. (Brunkhorst F.M. et al., Intens Care Med 1998, 24: 888-892). Source: Brahms - Thermofisher  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions A case of catheter related sepsis (Maki et al., 2006 ; Becker et al., 2010)  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions ADML, 2023  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions Usefulness of PCT: o Should we start an antibiotherapy for this patient? o Should we stop the treatment for this patient? o Validated only for some medical situations  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions Evidence regarding procalcitonin (PCT) for diagnosis and antibiotic stewardship in organ- related infections (Sager et al., 2017)  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions (Bréchot et al., 2015)  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions Procalcitonin (PCT) algorithm in patients with respiratory tract infections in the emergency department (Sanger et al., 2017)  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions Procalcitonin (PCT) algorithm in patients with sepsis in the intensive care unit (ICU) (Sanger et al., 2017)  Biomarkers stories: procalcitonin 3. Clinical applications of PCT a. PCT as a guide for antibiotic decisions  Biomarkers stories: procalcitonin 3. Clinical applications of PCT b. PCT as a prognostic factor for sepsis PCT levels are increasing with the severity of sepsis and organ dysfunction (Kibe et al., 2011)  Biomarkers stories: procalcitonin 3. Clinical applications of PCT c. PCT for diagnosis of bacterial infection? Advantages in comparison with microbiological methods: o Shorter delays (when compared with culture) o Sensitivity (when compared with blood culture) Advantages in comparison with markers of inflammation (C Reactive Protein, white blood cells) o More specific for bacterial infections  Biomarkers stories: procalcitonin 3. Clinical applications of PCT c. PCT for diagnosis of bacterial infection? But … Possibilities of false positive results (lack of specificity) o Babies during a few days after birth o Plasmodium falciparum infections o Polytraumatic patients o… Possibilities of false negative results (lack of sensitivity) o Subacute bacterial endocarditis o…  Biomarkers stories: procalcitonin Outline 1. Biology and biochemistry of PCT 2. PCT as a biomarker: from cancer and Gulf War to sepsis 3. Clinical applications of PCT 4. PCT assays 5. PCT as a therapeutic target? 6. Conclusion  Biomarkers stories: procalcitonin 4. PCT assays (Becker et al., 2010)  Biomarkers stories: procalcitonin 4. PCT assays (Becker et al., 2010)  Biomarkers stories: procalcitonin 4. PCT assays PCT is a patented marker of BRAHMS The first commercialised assay was immunoluminometric (ILMA) Then, adaptation to the TRACE technology (Cezanne company) KRYPTOR (Brahms)  Biomarkers stories: procalcitonin 4. PCT assays Time Resolved Cryptate Emission KRYPTOR (Brahms)  Biomarkers stories: procalcitonin 4. PCT assays Time Resolved Cryptate Emission KRYPTOR (Brahms)  Biomarkers stories: procalcitonin 4. PCT assays Licensing agreements signed between BRAHMS (now Thermo Fisher Scientific group) and other companies: o bioMérieux (VIDAS BRAHMS PCT) Technique: ELFA  Biomarkers stories: procalcitonin 4. PCT assays  Biomarkers stories: procalcitonin 4. PCT assays  Biomarkers stories: procalcitonin 4. PCT assays Licensing agreements signed between BRAHMS (now Thermo Fisher Scientific group) and other companies: o Roche Diagnostics (ELECSYS BRAHMS PCT) o Siemens Healthcare (ADVIA Centaur BRAHMS PCT) o Diasorin (LIAISON BRAHMS PCT) o…  Biomarkers stories: procalcitonin 4. PCT assays The number of machines offering the PCT assay has now expanded o Kryptor BRAHMS PCT sensitive o Abbott Architect BRAHMS PCT o Beckman Coulter Access PCT (on Access and DXI) o BioMérieux Vidas BRAHMS PCT o Diasorin Liaison BRAHMS PCT o Fujirebio Lumipulse G BRAHMS PCT o Roche BRAHMS PCT (on Cobas E801) o Diazyme PCT (on Roche Cobas C702) o SNIBE Maglumi PCT o Siemens Atellica BRAHMS o…  Biomarkers stories: procalcitonin 4. PCT assays www.procalcitonin.com  Biomarkers stories: procalcitonin 4. PCT assays 2019 A mistake was made by the authors in this table. Could you detect it? Abbott Architect i2000  Biomarkers stories: procalcitonin 4. PCT assays Exercise  Biomarkers stories: procalcitonin 4. PCT assays Exercise - Questions 1. Can you use sodium citrate as an anticoagulant? 2. One single QC with a well characterized concentration has to be run at least once every 24h. Is this sentence correct or not? 3. What is the usefulness of the automated dilution function? 4. A patient with a suspicion of sepsis shows a PCT level of 1.3 ng/mL. What should the biologist recommend? 5. For which criteria have spiking experiments been performed?  Biomarkers stories: procalcitonin 4. PCT assays Exercise - Questions 1. Can you use sodium citrate as an anticoagulant?  Biomarkers stories: procalcitonin 4. PCT assays Exercise - Questions 2. One single QC with a well characterized concentration has to be run at least once every 24h. Is this sentence correct or not?  Biomarkers stories: procalcitonin 4. PCT assays Exercise 3. What is the usefulness of the automated dilution function? Avoid hook effect  Biomarkers stories: procalcitonin 4. PCT assays Exercise 4. A patient with a suspicion of sepsis shows a PCT level of 1.3 ng/mL. What should the biologist recommend?  Biomarkers stories: procalcitonin 4. PCT assays Exercise 5. For which criteria have spiking experiments been performed?  Biomarkers stories: procalcitonin 4. PCT assays POCT  Biomarkers stories: procalcitonin 4. PCT assays POCT  Biomarkers stories: procalcitonin 4. PCT assays POCT  Biomarkers stories: procalcitonin Outline 1. Biology and biochemistry of PCT 2. PCT as a biomarker: from cancer and Gulf War to sepsis 3. Clinical applications of PCT 4. PCT assays 5. PCT as a therapeutic target? 6. Conclusion  Biomarkers stories: procalcitonin 5. PCT as a therapeutic target? Already demonstrated: o Administration of procalcitonin to sceptic animals increases mortality o Injection of antibodies neutralizing procalcitonin reduced symptoms and mortality of animals suffering from a severe sepsis  Biomarkers stories: procalcitonin 5. PCT as a therapeutic target? (Tavares et al., 2014)  Biomarkers stories: procalcitonin 5. PCT as a therapeutic target? (Becker et al., 2010)  Biomarkers stories: procalcitonin Outline 1. Biology and biochemistry of PCT 2. PCT as a biomarker: from cancer and Gulf War to sepsis 3. Clinical applications of PCT 4. PCT assays 5. PCT as a therapeutic target? 6. Conclusion  Biomarkers stories: procalcitonin 6. Conclusion  Biomarkers stories: procalcitonin 6. Conclusion Will financial restrictions affecting healthcare have an impact on procalcitonin prescription? Factors inhibiting widespread use of PCT (ADLM, 2023): Lack of specificity for sepsis/infection Overall lack of consensus on the utility of PCT across various clinical settings and patient populations Variability in its interpretation (i.e., cutoffs, when to measure) Potential competitor biomarkers?  Biomarkers stories: procalcitonin 6. Conclusion 2024  Biomarkers stories: procalcitonin 6. Conclusion  Biomarkers stories: procalcitonin 6. Conclusion  Biomarkers stories: procalcitonin 6. Conclusion  Biomarkers stories: procalcitonin 6. Conclusion  Biomarkers stories: procalcitonin 6. Conclusion  Biomarkers stories: procalcitonin 6. Conclusion Molecular biology to identify organisms responsible for sepsis Biomarkers stories: procalcitonin