- Email: [email protected]
Meta-analysis of procalcitonin for sepsis detection
Reflection and Reaction
Meta-analysis of procalcitonin for sepsis detection In a meta-analysis on the accuracy of an insensitive procalcitonin assay, Benjamin Tang and colleagues found that the assay failed to differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome (SIRS) in critically ill patients.1 Based on our experience,2–8 we believe this metaanalysis deserves several comments, clarifications, and corrections. First, circulating procalcitonin is a peptide of only 114 aminoacids, lacking the N-terminal dipeptide alanine-proline.3 Other functions of procalcitonin that are more important than participation in calcium homeostasis are pivotal roles in the metabolic and inflammatory host response to microbial infections. Administration of procalcitonin to septic hamsters with peritonitis doubled their death rate.9,10 Conversely, treatment with antiserum reactive against calcitonin precursors increased survival in monomicrobial and polymicrobial sepsis even when the animals were moribund. At the same time, circulating calcium levels remained within the normal range.3 Second, by including only 18 of 672 published studies (less than 3%), Tang and colleagues made a selection bias probable, which argues against a comprehensive review of the literature. Accordingly, several other metaanalyses in critically ill patients have drawn opposite conclusions.11,12 Third, any observational study and meta-analysis investigating the diagnostic accuracy of a given marker is biased by the choice of the gold standard. The aetiology of a presumed bacterial cause of fever cannot be detected in 50–80% of patients with suspected bloodstream infections.2 Thus, a gold standard to differentiate infectious from non-infectious causes in patients with SIRS does not exist, and therefore all observational studies are prone to a potential bias. This cannot be resolved by meta-analysing a limited selection of inherently flawed observational studies. Fourth, the authors state: “Investigators were contacted for further study details if needed”. Unfortunately, we were never contacted. Parameters of diagnostic accuracy depend on the cut-off levels applied. The likelihood of a bacterial infection increases gradually with increasing procalcitonin levels; obviously, the sensitivity and specificity of this blood marker depend 498
on the cut off applied. The reported levels of the cut-off to calculate diagnostic accuracies were very variable in the observational publications considered for this metaanalysis. Sepsis is merely a syndrome and optimum cutoff ranges for procalcitonin are likely to depend on the origin of infection. Cut-off ranges have to be calculated by multilevel likelihood ratios and adapted to different settings and types of infection. Fifth, we do agree that a biomarker must be part of, rather than in preference to, a clinical assessment. Tang and colleagues suggest that the additive value of procalcitonin to supplement a clinician’s bedside assessment should be evaluated. This analysis has been done repeatedly and procalcitonin improves the clinical diagnosis of sepsis in critically ill patients13 and patients with community-acquired pneumonia.8 Finally, the potential to change clinical decision making is, indeed, the most important performance measure for a biomarker. Therefore, randomised intervention studies have to be done in which the antimicrobial therapy is guided by a biomarker and in which clinical outcome is the primary measure of efficacy. If the patient recovers without antibiotics, there is no serious bacterial illness. For procalcitonin, and only for this marker, this observation has been shown in four intervention trials enrolling more than 1250 patients with respiratory tract infections, including comorbid, critically ill, and septic patients. Procalcitonin guidance reduced antibiotic use in 243 patients with lower respiratory tract infections by almost 50%.4 Procalcitonin-guided antibiotic duration was shortened by 55% (from 12·9 days to 5·8 days) in more than 300 patients who mostly had severe community-acquired pneumonia.6 Long-term safety was shown with a similar readmission rate between the procalcitonin-guided and control groups over 6 months in more than 200 acute exacerbations of chronic obstructive lung disease.7 In primary care, procalcitonin guidance safely reduced antibiotic exposure by 75%5 (Müller et al, unpublished data). Similar findings were also reported in meningitis, another critical illness.14 Therefore, all intervention studies successfully validated the superiority of procalcitonin guidance over a standard management without any excess of adverse outcome and fewer antibiotic-related side-effects. In http://infection.thelancet.com Vol 7 August 2007
Reflection and Reaction
this context, the findings and conclusion of the metaanalysis by Tang and colleagues seem dubious. Used appropriately, procalcitonin clearly improves clinical decision making in and outside the intensive care unit. The time has arrived to move beyond the observational reporting and meta-analysing of diagnostic accuracies for procalcitonin. Specific cut-off ranges should be proposed and more intervention studies done to really tackle the existing vicious cycle of diagnostic uncertainty, antibiotic overuse, and emerging multiresistance. *Beat Müller, Mirjam Christ-Crain, Philipp Schuetz
4
5
6
7
8
9
Department of Internal Medicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
10
[email protected] BM has served as a consultant and received payments from Brahms to attend meetings; he received research support and fulfilled speaking engagements. All other authors declare that they have no conflicts of interest. 1
2
3
Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and metaanalysis. Lancet Infect Dis 2007; 7: 210–17. MÜller B, Prat C. Markers of acute inflammation in assessing and managing lower respiratory tract infections: focus on procalcitonin. Clin Microbiol Infect 2006; 12 (suppl 9): 8–16. Becker KL, Nylen ES, White JC, Muller B, Snider RH Jr. 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: 1512–25.
11
12
13
14
Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitoninguided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004; 363: 600–07. Briel M, Christ-Crain M, Young J, et al. Procalcitonin-guided antibiotic use versus a standard approach for acute respiratory tract infections in primary care: study protocol for a randomised controlled trial and baseline characteristics of participating general practitioners [ISRCTN73182671]. BMC Fam Pract 2005; 6: 34. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006; 174: 84–93. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007; 131: 9–19. MÜller B, Harbarth S, Stolz D, et al. Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia. BMC Infect Dis 2007; 7: 10. Nylen ES, Whang KT, Snider RH Jr, Steinwald PM, White JC, Becker KL. Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis. Crit Care Med 1998; 26: 1001–06. Wagner KE, Martinez JM, Vath SD, et al. Early immunoneutralization of calcitonin precursors attenuates the adverse physiologic response to sepsis in pigs. Crit Care Med 2002; 30: 2313–21. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 2006; 34: 1996–2003. Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2004; 39: 206–17. Harbarth S, Holeckova K, Froidevaux C, et al. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med 2001; 164: 396–402. Marc E, Menager C, Moulin F, et al. Procalcitonin and viral meningitis: reduction of unnecessary antibiotics by measurement during an outbreak. Arch Pediatr 2002; 9: 358–64 (in French).
Meta-analysis of procalcitonin for sepsis detection We read with great interest Benjamin Tang and colleagues’ meta-analysis regarding the accuracy of biomarker procalcitonin for sepsis diagnosis.1 Tang and colleagues argued that they did not include investigations that estimated the accuracy of procalcitonin towards the clinical condition septic shock “since these conditions were usually recognised by simple clinical criteria”. This statement is correct, but ironically it also applies to the condition Tang and colleagues mainly investigate in the meta-analysis—namely sepsis. Although not always of great clinical use regarding treatment of the causative agent, sepsis criteria (in the most used form as systemic inflammatory response syndrome [SIRS] plus evidence of localised infection) are very easy to apply, and it does not appear relevant to focus on identifying additional expensive biomarkers for sepsis diagnosis alone. Conversely, if the biomarker could offer some more specific information on aetiology and/or proposed http://infection.thelancet.com Vol 7 August 2007
treatment and monitoring of treatment effect, it would be attractive. Procalcitonin may offer some of this information regarding infections caused by a wide spectrum of bacteria, and to a lesser degree on Candida spp infections and malaria, but only if measurements are made according to the best documented method, that is daily consecutive measurements.2,3 Since clinical investigations have mainly focused on accuracy of a single measurement of procalcitonin to assess sepsis, less focus has been placed on its usefulness to identify and monitor the course of bacterial infections.2,4 Procalcitonin plasma levels do not increase in viral infection,2 and only to a lesser degree in severe fungal infection.5 Conversely, procalcitonin levels increase rapidly while systemic bacterial infection is progressing, either because of lack of source control, lack of antimicrobial spectrum, or both. Other conditions that might cause transient increases in procalcitonin levels include clinical 499
Meta-analysis of procalcitonin for sepsis detection In a meta-analysis on the accuracy of an insensitive procalcitonin assay, Benjamin Tang and colleagues found that the assay failed to differentiate sepsis from other non-infectious causes of systemic inflammatory response syndrome (SIRS) in critically ill patients.1 Based on our experience,2–8 we believe this metaanalysis deserves several comments, clarifications, and corrections. First, circulating procalcitonin is a peptide of only 114 aminoacids, lacking the N-terminal dipeptide alanine-proline.3 Other functions of procalcitonin that are more important than participation in calcium homeostasis are pivotal roles in the metabolic and inflammatory host response to microbial infections. Administration of procalcitonin to septic hamsters with peritonitis doubled their death rate.9,10 Conversely, treatment with antiserum reactive against calcitonin precursors increased survival in monomicrobial and polymicrobial sepsis even when the animals were moribund. At the same time, circulating calcium levels remained within the normal range.3 Second, by including only 18 of 672 published studies (less than 3%), Tang and colleagues made a selection bias probable, which argues against a comprehensive review of the literature. Accordingly, several other metaanalyses in critically ill patients have drawn opposite conclusions.11,12 Third, any observational study and meta-analysis investigating the diagnostic accuracy of a given marker is biased by the choice of the gold standard. The aetiology of a presumed bacterial cause of fever cannot be detected in 50–80% of patients with suspected bloodstream infections.2 Thus, a gold standard to differentiate infectious from non-infectious causes in patients with SIRS does not exist, and therefore all observational studies are prone to a potential bias. This cannot be resolved by meta-analysing a limited selection of inherently flawed observational studies. Fourth, the authors state: “Investigators were contacted for further study details if needed”. Unfortunately, we were never contacted. Parameters of diagnostic accuracy depend on the cut-off levels applied. The likelihood of a bacterial infection increases gradually with increasing procalcitonin levels; obviously, the sensitivity and specificity of this blood marker depend 498
on the cut off applied. The reported levels of the cut-off to calculate diagnostic accuracies were very variable in the observational publications considered for this metaanalysis. Sepsis is merely a syndrome and optimum cutoff ranges for procalcitonin are likely to depend on the origin of infection. Cut-off ranges have to be calculated by multilevel likelihood ratios and adapted to different settings and types of infection. Fifth, we do agree that a biomarker must be part of, rather than in preference to, a clinical assessment. Tang and colleagues suggest that the additive value of procalcitonin to supplement a clinician’s bedside assessment should be evaluated. This analysis has been done repeatedly and procalcitonin improves the clinical diagnosis of sepsis in critically ill patients13 and patients with community-acquired pneumonia.8 Finally, the potential to change clinical decision making is, indeed, the most important performance measure for a biomarker. Therefore, randomised intervention studies have to be done in which the antimicrobial therapy is guided by a biomarker and in which clinical outcome is the primary measure of efficacy. If the patient recovers without antibiotics, there is no serious bacterial illness. For procalcitonin, and only for this marker, this observation has been shown in four intervention trials enrolling more than 1250 patients with respiratory tract infections, including comorbid, critically ill, and septic patients. Procalcitonin guidance reduced antibiotic use in 243 patients with lower respiratory tract infections by almost 50%.4 Procalcitonin-guided antibiotic duration was shortened by 55% (from 12·9 days to 5·8 days) in more than 300 patients who mostly had severe community-acquired pneumonia.6 Long-term safety was shown with a similar readmission rate between the procalcitonin-guided and control groups over 6 months in more than 200 acute exacerbations of chronic obstructive lung disease.7 In primary care, procalcitonin guidance safely reduced antibiotic exposure by 75%5 (Müller et al, unpublished data). Similar findings were also reported in meningitis, another critical illness.14 Therefore, all intervention studies successfully validated the superiority of procalcitonin guidance over a standard management without any excess of adverse outcome and fewer antibiotic-related side-effects. In http://infection.thelancet.com Vol 7 August 2007
Reflection and Reaction
this context, the findings and conclusion of the metaanalysis by Tang and colleagues seem dubious. Used appropriately, procalcitonin clearly improves clinical decision making in and outside the intensive care unit. The time has arrived to move beyond the observational reporting and meta-analysing of diagnostic accuracies for procalcitonin. Specific cut-off ranges should be proposed and more intervention studies done to really tackle the existing vicious cycle of diagnostic uncertainty, antibiotic overuse, and emerging multiresistance. *Beat Müller, Mirjam Christ-Crain, Philipp Schuetz
4
5
6
7
8
9
Department of Internal Medicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland
10
[email protected] BM has served as a consultant and received payments from Brahms to attend meetings; he received research support and fulfilled speaking engagements. All other authors declare that they have no conflicts of interest. 1
2
3
Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systematic review and metaanalysis. Lancet Infect Dis 2007; 7: 210–17. MÜller B, Prat C. Markers of acute inflammation in assessing and managing lower respiratory tract infections: focus on procalcitonin. Clin Microbiol Infect 2006; 12 (suppl 9): 8–16. Becker KL, Nylen ES, White JC, Muller B, Snider RH Jr. 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: 1512–25.
11
12
13
14
Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitoninguided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004; 363: 600–07. Briel M, Christ-Crain M, Young J, et al. Procalcitonin-guided antibiotic use versus a standard approach for acute respiratory tract infections in primary care: study protocol for a randomised controlled trial and baseline characteristics of participating general practitioners [ISRCTN73182671]. BMC Fam Pract 2005; 6: 34. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial. Am J Respir Crit Care Med 2006; 174: 84–93. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007; 131: 9–19. MÜller B, Harbarth S, Stolz D, et al. Diagnostic and prognostic accuracy of clinical and laboratory parameters in community-acquired pneumonia. BMC Infect Dis 2007; 7: 10. Nylen ES, Whang KT, Snider RH Jr, Steinwald PM, White JC, Becker KL. Mortality is increased by procalcitonin and decreased by an antiserum reactive to procalcitonin in experimental sepsis. Crit Care Med 1998; 26: 1001–06. Wagner KE, Martinez JM, Vath SD, et al. Early immunoneutralization of calcitonin precursors attenuates the adverse physiologic response to sepsis in pigs. Crit Care Med 2002; 30: 2313–21. Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med 2006; 34: 1996–2003. Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 2004; 39: 206–17. Harbarth S, Holeckova K, Froidevaux C, et al. Diagnostic value of procalcitonin, interleukin-6, and interleukin-8 in critically ill patients admitted with suspected sepsis. Am J Respir Crit Care Med 2001; 164: 396–402. Marc E, Menager C, Moulin F, et al. Procalcitonin and viral meningitis: reduction of unnecessary antibiotics by measurement during an outbreak. Arch Pediatr 2002; 9: 358–64 (in French).
Meta-analysis of procalcitonin for sepsis detection We read with great interest Benjamin Tang and colleagues’ meta-analysis regarding the accuracy of biomarker procalcitonin for sepsis diagnosis.1 Tang and colleagues argued that they did not include investigations that estimated the accuracy of procalcitonin towards the clinical condition septic shock “since these conditions were usually recognised by simple clinical criteria”. This statement is correct, but ironically it also applies to the condition Tang and colleagues mainly investigate in the meta-analysis—namely sepsis. Although not always of great clinical use regarding treatment of the causative agent, sepsis criteria (in the most used form as systemic inflammatory response syndrome [SIRS] plus evidence of localised infection) are very easy to apply, and it does not appear relevant to focus on identifying additional expensive biomarkers for sepsis diagnosis alone. Conversely, if the biomarker could offer some more specific information on aetiology and/or proposed http://infection.thelancet.com Vol 7 August 2007
treatment and monitoring of treatment effect, it would be attractive. Procalcitonin may offer some of this information regarding infections caused by a wide spectrum of bacteria, and to a lesser degree on Candida spp infections and malaria, but only if measurements are made according to the best documented method, that is daily consecutive measurements.2,3 Since clinical investigations have mainly focused on accuracy of a single measurement of procalcitonin to assess sepsis, less focus has been placed on its usefulness to identify and monitor the course of bacterial infections.2,4 Procalcitonin plasma levels do not increase in viral infection,2 and only to a lesser degree in severe fungal infection.5 Conversely, procalcitonin levels increase rapidly while systemic bacterial infection is progressing, either because of lack of source control, lack of antimicrobial spectrum, or both. Other conditions that might cause transient increases in procalcitonin levels include clinical 499