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Serum Procalcitonin Levels: Comment on “Effectiveness and Safety of Procalcitonin-Guided Antibiotic Therapy in Lower Respiratory Tract Infections in ‘Real Life’”

Serum Procalcitonin Levels: Comment on “Effectiveness and Safety of Procalcitonin-Guided... Albrich and colleagues1 successfully orchestrated an observational, multinational, multicenter, prospective study of the influence of serum procalcitonin (PCT) levels on the care of patients with lower respiratory tract infections (LRTIs). Specifically, does access to PCT levels plus the use of an interpretative advice algorithm influence the duration of antibiotic therapy? The comparison was between patients whose physicians were compliant with the algorithm vs patients whose physicians were noncompliant. Noncompliance was defined as failure to follow the algorithm by either initiation of antibiotic therapy or failure to discontinue therapy despite low PCT levels in the absence of predefined criteria that allowed the algorithm to be overruled. In short, the algorithm advice was overruled and managed based on clinical judgment. The primary end point was duration of antibiotic therapy. Of 1208 patients who received at least 1 dose of an antibiotic, the mean duration of therapy was 5.9 days when the algorithm was followed and 7.4 days (P < .001) when physicians did not comply with the algorithm. The shorter duration stood the test of multivariable analyses looking for confounders; of course, some important confounder may have been missed. Of interest, algorithm compliance was substantively better in those centers that had participated in earlier PCT studies. I suggest that algorithm compliance, or lack thereof, is a direct reflection of the confidence level of physicians in the interpretation of the meaning of serum PCT levels. The study by Albrich et al1 is the latest of several studies of patients with LRTIs and PCT treatment guidance. In most studies, compliance with the PCT algorithm shortened the duration of antibiotic therapy.2,3 Nonetheless, a healthy skepticism persists. Critics worry about the specificity of an increase in PCT levels for bacterial as opposed to viral infection. Physicians wonder what happens to serum PCT levels if there is dual infection, eg, pneumonia due to Streptococcus pneumoniae concomitant with influenza tracheobronchitis. Why does the serum PCT level increase in patients after aortocoronary bypass surgery or in patients with cardiogenic shock? In short, does the serum PCT level help the clinician beyond the usual markers of activation of an innate immune response, ie, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and white blood cell and differential counts? With the caveat that we need a lot more information, the emerging data suggest that PCT levels add value. Like ESR and CRP, PCT is part of the early phases of an innate immune response. A virtue of PCT levels is that they increase within 4 to 6 hours of initiation of bacterial infection or intravenous endotoxin, while increases in CRP level and ESR require 24 or more hours.4,5 Serum PCT levels do not increase substantively after uncomplicated viral respiratory tract infections (RTIs). The mechanism is believed to be viral-induced increases in γ-interferon, which in turn represses PCT gene transcription.6 Retrospective studies of children with RTIs indicate little to no increase in serum PCT levels in response to viral or mycoplasma infection.7 Note also that serum PCT levels increased in patients with bacterial meningitis but did not increase in patients with viral meningitis.8 Clearly, there is an urgent need to use the powerful modern tools of molecular diagnostics in patients of all ages with RTIs to establish a more definite microbial etiology (perhaps mixed pathogen etiology) of the RTI and correlate the results with serum PCT levels. Confidence in PCT levels would also be enhanced if the basic biology was better understood. In vitro, PCT synthesis is stimulated by bacterial lipopolysaccharide (endotoxin), tumor necrosis factor, and interleukin 1.4-6 Of interest, the magnitude of PCT production was greater in patients with bacteremia due to gram-negative bacteria as opposed to bacteremia with gram-positive bacteria.9 This observation is pertinent to clinical low intestinal perfusion states that are associated with elevations in serum PCT levels. Bacterial endotoxin is detectable in human serum during and after aortocoronary bypass surgery.10 Bacterial endotoxin is detectable in human serum in profound cardiogenic shock, some general surgery patients, patients with severe pancreatitis, and other patients with poor perfusion of the mucosa of the intestinal tract.4,10 The supposition is that the gut bacteria “translocate” into the submucosa and then to the bloodstream with concomitant elevation of PCT levels as a marker of activation of an innate immune response. Understanding the science will increase confidence. However, for serum PCT levels to influence patient care, the clinician needs the PCT result at point of care. Similar to white blood cell count, it is strongly suggested that, if offered, serum PCT levels should be available at all times with results within 1 hour of receipt of serum in the laboratory. The prompt report of a low PCT level, within the context of the rest of the clinical assessment, could influence the decision to start, continue, or discontinue antibiotic therapy. In the study by Albrich et al,1 compliance with the PCT algorithm in the participating US hospital was only 35%. Compliance would surely increase if physicians had more confidence in their understanding of the factors that drive an increase or decrease of serum PCT levels. Back to top Article Information Correspondence: Dr Gilbert, Department of Medical Education, Providence Portland Medical Center, 5050 Hoyt St NE, Ste 540, Portland, OR 97213 (david.gilbert@providence.org). Financial Disclosure: None reported. References 1. Albrich WC, Dusemund F, Bucher B, et al. Effectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in “real life”: an international, multicenter post-study survey (ProREAL). Arch Intern Med. 2012;172(9):ioi120010715-722Google Scholar 2. Li H, Luo Y-F, Blackwell TS, Xie C-M. Meta-analysis and systematic review of procalcitonin-guided therapy in respiratory tract infections. Antimicrob Agents Chemother. 2011;55(12):5900-590621947386PubMedGoogle ScholarCrossref 3. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med. 2011;171(15):1322-133121824946PubMedGoogle ScholarCrossref 4. Becker KL, Nylén ES, White JC, Müller B, Snider RH Jr. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab. 2004;89(4):1512-152515070906PubMedGoogle ScholarCrossref 5. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med. 2008;36(3):941-95218431284PubMedGoogle ScholarCrossref 6. Linscheid P, Seboek D, Nylen ES, et al. In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue. Endocrinology. 2003;144(12):5578-558412960010PubMedGoogle ScholarCrossref 7. Schützle H, Forster J, Superti-Furga A, Berner R. Is serum procalcitonin a reliable diagnostic marker in children with acute respiratory tract infections? a retrospective analysis. Eur J Pediatr. 2009;168(9):1117-112419107517PubMedGoogle ScholarCrossref 8. Schwarz S, Bertram M, Schwab S, Andrassy K, Hacke W. Serum procalcitonin levels in bacterial and abacterial meningitis. Crit Care Med. 2000;28(6):1828-183210890628PubMedGoogle ScholarCrossref 9. Charles PE, Ladoire S, Aho S, et al. Serum procalcitonin elevation in critically ill patients at the onset of bacteremia caused by either Gram negative or Gram positive bacteria. BMC Infect Dis. 2008;8:38-4618366777PubMedGoogle ScholarCrossref 10. Pathan N, Burmester M, Adamovic T, et al. Intestinal injury and endotoxemia in children undergoing surgery for congenital heart disease. Am J Respir Crit Care Med. 2011;184(11):1261-126921868501PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Serum Procalcitonin Levels: Comment on “Effectiveness and Safety of Procalcitonin-Guided Antibiotic Therapy in Lower Respiratory Tract Infections in ‘Real Life’”

Archives of Internal Medicine , Volume 172 (9) – May 14, 2012

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References (10)

Publisher
American Medical Association
Copyright
Copyright © 2012 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2012.1327
Publisher site
See Article on Publisher Site

Abstract

Albrich and colleagues1 successfully orchestrated an observational, multinational, multicenter, prospective study of the influence of serum procalcitonin (PCT) levels on the care of patients with lower respiratory tract infections (LRTIs). Specifically, does access to PCT levels plus the use of an interpretative advice algorithm influence the duration of antibiotic therapy? The comparison was between patients whose physicians were compliant with the algorithm vs patients whose physicians were noncompliant. Noncompliance was defined as failure to follow the algorithm by either initiation of antibiotic therapy or failure to discontinue therapy despite low PCT levels in the absence of predefined criteria that allowed the algorithm to be overruled. In short, the algorithm advice was overruled and managed based on clinical judgment. The primary end point was duration of antibiotic therapy. Of 1208 patients who received at least 1 dose of an antibiotic, the mean duration of therapy was 5.9 days when the algorithm was followed and 7.4 days (P < .001) when physicians did not comply with the algorithm. The shorter duration stood the test of multivariable analyses looking for confounders; of course, some important confounder may have been missed. Of interest, algorithm compliance was substantively better in those centers that had participated in earlier PCT studies. I suggest that algorithm compliance, or lack thereof, is a direct reflection of the confidence level of physicians in the interpretation of the meaning of serum PCT levels. The study by Albrich et al1 is the latest of several studies of patients with LRTIs and PCT treatment guidance. In most studies, compliance with the PCT algorithm shortened the duration of antibiotic therapy.2,3 Nonetheless, a healthy skepticism persists. Critics worry about the specificity of an increase in PCT levels for bacterial as opposed to viral infection. Physicians wonder what happens to serum PCT levels if there is dual infection, eg, pneumonia due to Streptococcus pneumoniae concomitant with influenza tracheobronchitis. Why does the serum PCT level increase in patients after aortocoronary bypass surgery or in patients with cardiogenic shock? In short, does the serum PCT level help the clinician beyond the usual markers of activation of an innate immune response, ie, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and white blood cell and differential counts? With the caveat that we need a lot more information, the emerging data suggest that PCT levels add value. Like ESR and CRP, PCT is part of the early phases of an innate immune response. A virtue of PCT levels is that they increase within 4 to 6 hours of initiation of bacterial infection or intravenous endotoxin, while increases in CRP level and ESR require 24 or more hours.4,5 Serum PCT levels do not increase substantively after uncomplicated viral respiratory tract infections (RTIs). The mechanism is believed to be viral-induced increases in γ-interferon, which in turn represses PCT gene transcription.6 Retrospective studies of children with RTIs indicate little to no increase in serum PCT levels in response to viral or mycoplasma infection.7 Note also that serum PCT levels increased in patients with bacterial meningitis but did not increase in patients with viral meningitis.8 Clearly, there is an urgent need to use the powerful modern tools of molecular diagnostics in patients of all ages with RTIs to establish a more definite microbial etiology (perhaps mixed pathogen etiology) of the RTI and correlate the results with serum PCT levels. Confidence in PCT levels would also be enhanced if the basic biology was better understood. In vitro, PCT synthesis is stimulated by bacterial lipopolysaccharide (endotoxin), tumor necrosis factor, and interleukin 1.4-6 Of interest, the magnitude of PCT production was greater in patients with bacteremia due to gram-negative bacteria as opposed to bacteremia with gram-positive bacteria.9 This observation is pertinent to clinical low intestinal perfusion states that are associated with elevations in serum PCT levels. Bacterial endotoxin is detectable in human serum during and after aortocoronary bypass surgery.10 Bacterial endotoxin is detectable in human serum in profound cardiogenic shock, some general surgery patients, patients with severe pancreatitis, and other patients with poor perfusion of the mucosa of the intestinal tract.4,10 The supposition is that the gut bacteria “translocate” into the submucosa and then to the bloodstream with concomitant elevation of PCT levels as a marker of activation of an innate immune response. Understanding the science will increase confidence. However, for serum PCT levels to influence patient care, the clinician needs the PCT result at point of care. Similar to white blood cell count, it is strongly suggested that, if offered, serum PCT levels should be available at all times with results within 1 hour of receipt of serum in the laboratory. The prompt report of a low PCT level, within the context of the rest of the clinical assessment, could influence the decision to start, continue, or discontinue antibiotic therapy. In the study by Albrich et al,1 compliance with the PCT algorithm in the participating US hospital was only 35%. Compliance would surely increase if physicians had more confidence in their understanding of the factors that drive an increase or decrease of serum PCT levels. Back to top Article Information Correspondence: Dr Gilbert, Department of Medical Education, Providence Portland Medical Center, 5050 Hoyt St NE, Ste 540, Portland, OR 97213 (david.gilbert@providence.org). Financial Disclosure: None reported. References 1. Albrich WC, Dusemund F, Bucher B, et al. Effectiveness and safety of procalcitonin-guided antibiotic therapy in lower respiratory tract infections in “real life”: an international, multicenter post-study survey (ProREAL). Arch Intern Med. 2012;172(9):ioi120010715-722Google Scholar 2. Li H, Luo Y-F, Blackwell TS, Xie C-M. Meta-analysis and systematic review of procalcitonin-guided therapy in respiratory tract infections. Antimicrob Agents Chemother. 2011;55(12):5900-590621947386PubMedGoogle ScholarCrossref 3. Schuetz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med. 2011;171(15):1322-133121824946PubMedGoogle ScholarCrossref 4. Becker KL, Nylén ES, White JC, Müller B, Snider RH Jr. Clinical review 167: Procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab. 2004;89(4):1512-152515070906PubMedGoogle ScholarCrossref 5. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med. 2008;36(3):941-95218431284PubMedGoogle ScholarCrossref 6. Linscheid P, Seboek D, Nylen ES, et al. In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue. Endocrinology. 2003;144(12):5578-558412960010PubMedGoogle ScholarCrossref 7. Schützle H, Forster J, Superti-Furga A, Berner R. Is serum procalcitonin a reliable diagnostic marker in children with acute respiratory tract infections? a retrospective analysis. Eur J Pediatr. 2009;168(9):1117-112419107517PubMedGoogle ScholarCrossref 8. Schwarz S, Bertram M, Schwab S, Andrassy K, Hacke W. Serum procalcitonin levels in bacterial and abacterial meningitis. Crit Care Med. 2000;28(6):1828-183210890628PubMedGoogle ScholarCrossref 9. Charles PE, Ladoire S, Aho S, et al. Serum procalcitonin elevation in critically ill patients at the onset of bacteremia caused by either Gram negative or Gram positive bacteria. BMC Infect Dis. 2008;8:38-4618366777PubMedGoogle ScholarCrossref 10. Pathan N, Burmester M, Adamovic T, et al. Intestinal injury and endotoxemia in children undergoing surgery for congenital heart disease. Am J Respir Crit Care Med. 2011;184(11):1261-126921868501PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: May 14, 2012

Keywords: lower respiratory tract infections,antibiotic therapy,procalcitonin

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