To say procalcitonin (PCT)is useless is just not accurate; as a pulm-crit fellow I find it helpful. I see chronically ill, old, debilitated immunosuppressed people, and they may not manifest classical signs/symptoms of sepsis. "Clinical gestault" does not have to be at odds with our imaging or serum markers- we look at everything together, as a whole. Despite exhaustive microbiologic tests we fail to identify an organism 25% of the time and many times we identify commensal organisms or contaminants (Ranieri 2012). PCT is certainly not perfect. However a study by Su CP, Chen TH et al. 2011 looked at diagnostic accuracy of 32 clinical signs, symptoms and lab tests and PCT had the best diagnostic accuracy for predicting bacteremia. Tromp M, Lansdorp B et al, 2012 concluded that: "Of 342 included patients, PCT had the best predictive value for bacteremia with an area under the curve of 0.80, sensitivity 89%, specificity 58%. The predictive value of a combination of PCT plus a panel of other biomarkers, clinical signs, or analysis of serial PCT levels did not lead to a significant improvement of the predictive value of PCT alone." The Wacker meta-analysis that is mentioned (where PCT actually did not perform that bad) had enormous heterogeneity in the meta-analysis. The optimal diagnostic threshold was also unclear across studies. In fact a value <0.1ng/ml makes a serious bacterial infection highly unlikely. Gram negative infections give higher PCT values. Fungal infections can show normal or low PCT levels. PCT levels help predict GN bacteremia in hematologic pts with neutropenic fever (Koivula I, 2011). PCT levels help in scaling back or discontinuing antibiotics (Matthaiou DK 2012 and Kopterides P 2010)--contrary to what was said by Rory there is no statistically significant increase in mortality, or rate of persistent or recurrent infections. We do know pts in the PCT arm had less antibiotics, in the ICU pts that I see this is important in preventing resistant strains, C diff and other side effects of antibiotics.
I will grant you that there certainly is debate on the utility of procalcitonin for de-escalation of antibiotic therapy in the ICU. And while there are a few studies demonstrating an increase in the number of antibiotic free days with the use of procalcitonin (1,2), the largest trials to date all demonstrate no clinically important reduction in the use of antibiotics, nor an improvement in overall mortality (3,4,5).
While I do agree antibiotic stewardship is important, and maybe a procalcitonin guided strategy that safely and effectively de-escalates antibiotic use will be validated, as of now the data is inconsistent at best. On the other hand, there has certainly been recent data demonstrating it is possible to utilize shorter courses of antibiotics than what is traditionally utilized for specific infectious states in clinically improving patients (6,7,8). Maybe the answer lies in broadening such strategies.
Now I would never tell an Intensivist how best to manage his or her patients but from an Emergency Medicine standpoint I cannot envision a role for the procalcitonin assay. Its diagnostic test characteristics are nowhere near accurate enough to make important decisions regarding the necessity of antibiotics in a critical ill patient with a suspected infection. Even at the low level of 0.5 ng/ml the sensitivity is only approximately 77%(9). At the 1 ng/ml threshold you suggest it drops even lower. While individual Intensivists may find a procalcitonin assay helpful in the de-escalation of antibiotics, that is no reason to require it be ordered in the Emergency Department during a patient’s initial evaluation and resuscitation.
Thank you again for your thoughtful and provocative comments.
Sources: 1. Bouadma et al. Use of Procalcitonin to Reduce Patients’ Exposure to Antibiotics in Intensive Care Units: a Multicenter Randomized Controlled Trial. The Lancet Vol 375. Feb 6th 2010 2. De jong E, Van oers JA, Beishuizen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27. 3. Jensen et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011 Sep;39(9):2048-58 4. Bloos F, Trips E, Nierhaus A, et al. Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock: A Randomized Clinical Trial. JAMA Intern Med. 2016;176(9):1266-76. 5. Balk RA, Kadri SS, Cao Z, Robinson SB, Lipkin C, Bozzette SA. Effect of Procalcitonin Testing on Healthcare Utilization and Costs in Critically Ill Patients in the United States. Chest. 2016; 6. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588-98. 7. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372(21):1996-2005. 8. Uranga A, España PP, Bilbao A, et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA Intern Med. 2016; 9. Wacker et al. Procalcitonin As a Diagnostic Marker For Sepsis: a Systematic Review and Meta-Analysis. Lancet Infect Dis. 2013 May;13(5):426-35
I thought that PCT had been dying a slow death for many years. I guess it still takes an occasional terminal gasp. Rob Orman: you ought to take a detailed look at the Multiplex PCR's that are now coming on line. I'm working at a smallish rural hospital that for a mere $800 charge to someone else's money (Medicare pays about $560), I can quickly get a test for 20+ respiratory, or 20+ GI pathogens. Results back in about an hour or two. It's jarring to know that the guy on the vent is positive for rhinovirus only (thought that caused runny noses). The evidence base seems slim, and biased (100 percent sensitive for Yersinia Enterocolitica - but reading the entire literature base cited by that statement , only one confirmed case of Y Enterocolitica was identified in the multiple articles). I'm not sure if these are a great advance (deciding on which if any antibiotic is indicated), or are a waste of money (the guy's parakeet just died and the guy has pneumonia - I don't need an $800 test to give him so doxycycline), or are misleading (the test is positive for c dif, but we don't know if it is toxin positive or not). So, a good thorough review by an expert in the field might be useful in encouraging or discouraging the use of this incredibly useful, or perhaps perniciously misleading, or merely cool but expensive test.
Sorry for this long post: Yes I agree PCT has limitations. And it should never trump clinical judgement. Also I agree I don't find it as helpful in ruling in sepsis despite what some experts feel (Paul Marik for ie). But I don't use PCT in the hope to reduce mortality or anything like that. I use it because antibiotic overuse is a serious problem.
We are actually many a time HORRIBLE at distinguishing infectious vs non-infectious causes of SIRS, lets be honest. I see asthma, chronic bronchitis and COPD pts all day every day and these people get antibiotics every time they cough. Schuetz et al found in these pts with acute respiratory infections that a PCT guided strategy led to decreased antibiotic use with no difference in mortality or treatment failures [2].
In a well conducted study reported in Critical Care, Garnacho-Montero et al [1] investigated the role of biomarkers in distinguishing infectious from non-infectious SIRS. They demonstrated that PCT had excellent diagnostic accuracy (area under curve (AUC) 0.87; 95% confidence interval (CI) 0.81 to 0.94), while that for CRP was modest (AUC 0.69; 95% CI 0.59 to 0.79). Yes Wacker found that the Sn was .77 (95% CI 0.72 to 0.81) and Sp was .79 while the area under the ROC curve was .85 (95% CI 0.81 to 0.88) which is not bad. Lets keep in mind there was GI-normous heterogeneity in that meta-analysis. Additionally, several studies have shown that a RISE in procalcitonin can precede infection by 24 h, and that the change between procalcitonin measurements on day −1 and day 0 might be a better marker of sepsis than is one procalcitonin measurement on the day of fever [3]. This finding suggests the need to investigate an approach that uses procalcitonin kinetics (eg, two measurements within 8–12 h for newly admitted patients) and differential cutoffs to distinguish SIRS from sepsis. Stored blood samples from day 1 are frequently available for procalcitonin testing in inpatients and ICU patients with new onset fever. Once patients have started on antibiotics, intensivists are frequently reluctant to stop antibiotics unless cultures are negative at 48 h. Serial procalcitonin testing within 24 h could reduce unnecessary use of antibiotics and selective pressure for multiresistant pathogens.
All in all do I order PCT? Very rarely in fact I don't remember the last time I ordered it, because I feel comfortable observing pts off antibiotics-that's the elephant in the room-in this age where insurance companies are coming up with nonsensical bundles to force clinicians to treat pts with antibiotics as early as possible, they will not pay us to simply "observe people." Observing a pt -what a concept! Though that may sound like heresy that is what medicine used to be and we now live in an age where IV antibiotics run through the veins of every pt that walks in to our ED with a cough. And if PCT will help defend in any way my decision (so the suits don't go crazy), you can bet I'll use it.
1. Garnacho-Montero J, Huici-Moreno MJ, Gutierrez-Pizarraya A, Lopez I, Marquez-Vacaro JA, Macher HC, Guerrero JM, Puppo-Moreno A. Prognostic and diagnostic value of eosinopenia, C-reactive protein, procalcitonin, and circulating cell-free DNA in critically ill patients admitted with suspicion of sepsis. Crit Care. 2014;18:R116. 2. Schuetz, P, Briel, M, Christ-Crain, M et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis. 2012; 55: 651–662. 3. Charles, PE, Kus, E, Aho, S, Prin, S, Doise, JM, Olsson, NO et al. Serum procalcitonin for the early recognition of nosocomial infection in the critically ill patients: a preliminary report. BMC Infect Dis. 2009; 9: 49.
Rory or Rob, do you get a sense that many hospitals are using procalcitonin driven protocols to stop or deescalate antibiotics. I am the director of sepsis for my hospital and have chosen not to have it in our ER protocol. The docs can order it selectively based on the clinical scenario. The hospital however has had some push through antibiotic stewardship to use a similar protocol to PRORATA for the inpatients. I have also not been a fan of this change but the pharmacist are telling me "all the hospitals are doing this" I will have a chance to plead my case in the coming weeks before they decide to add such a protocol. My opinion is that it is more background noise/useless information if used this way. I'm going to put up a little fight but I really would be interested to know how many centers are doing this.
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Mohammed A. - October 2, 2016 12:54 PM
To say procalcitonin (PCT)is useless is just not accurate; as a pulm-crit fellow I find it helpful.
I see chronically ill, old, debilitated immunosuppressed people, and they may not manifest classical signs/symptoms of sepsis. "Clinical gestault" does not have to be at odds with our imaging or serum markers- we look at everything together, as a whole.
Despite exhaustive microbiologic tests we fail to identify an organism 25% of the time and many times we identify commensal organisms or contaminants (Ranieri 2012).
PCT is certainly not perfect. However a study by Su CP, Chen TH et al. 2011 looked at diagnostic accuracy of 32 clinical signs, symptoms and lab tests and PCT had the best diagnostic accuracy for predicting bacteremia. Tromp M, Lansdorp B et al, 2012 concluded that:
"Of 342 included patients, PCT had the best predictive value for bacteremia with an area under the curve of 0.80, sensitivity 89%, specificity 58%. The predictive value of a combination of PCT plus a panel of other biomarkers, clinical signs, or analysis of serial PCT levels did not lead to a significant improvement of the predictive value of PCT alone."
The Wacker meta-analysis that is mentioned (where PCT actually did not perform that bad) had enormous heterogeneity in the meta-analysis. The optimal diagnostic threshold was also unclear across studies. In fact a value <0.1ng/ml makes a serious bacterial infection highly unlikely. Gram negative infections give higher PCT values. Fungal infections can show normal or low PCT levels.
PCT levels help predict GN bacteremia in hematologic pts with neutropenic fever (Koivula I, 2011).
PCT levels help in scaling back or discontinuing antibiotics (Matthaiou DK 2012 and Kopterides P 2010)--contrary to what was said by Rory there is no statistically significant increase in mortality, or rate of persistent or recurrent infections. We do know pts in the PCT arm had less antibiotics, in the ICU pts that I see this is important in preventing resistant strains, C diff and other side effects of antibiotics.
Rory S. - October 3, 2016 7:33 PM
Thank you Mohammed for your comments.
I will grant you that there certainly is debate on the utility of procalcitonin for de-escalation of antibiotic therapy in the ICU. And while there are a few studies demonstrating an increase in the number of antibiotic free days with the use of procalcitonin (1,2), the largest trials to date all demonstrate no clinically important reduction in the use of antibiotics, nor an improvement in overall mortality (3,4,5).
While I do agree antibiotic stewardship is important, and maybe a procalcitonin guided strategy that safely and effectively de-escalates antibiotic use will be validated, as of now the data is inconsistent at best. On the other hand, there has certainly been recent data demonstrating it is possible to utilize shorter courses of antibiotics than what is traditionally utilized for specific infectious states in clinically improving patients (6,7,8). Maybe the answer lies in broadening such strategies.
Now I would never tell an Intensivist how best to manage his or her patients but from an Emergency Medicine standpoint I cannot envision a role for the procalcitonin assay. Its diagnostic test characteristics are nowhere near accurate enough to make important decisions regarding the necessity of antibiotics in a critical ill patient with a suspected infection. Even at the low level of 0.5 ng/ml the sensitivity is only approximately 77%(9). At the 1 ng/ml threshold you suggest it drops even lower. While individual Intensivists may find a procalcitonin assay helpful in the de-escalation of antibiotics, that is no reason to require it be ordered in the Emergency Department during a patient’s initial evaluation and resuscitation.
Thank you again for your thoughtful and provocative comments.
Sources:
1. Bouadma et al. Use of Procalcitonin to Reduce Patients’ Exposure to Antibiotics in Intensive Care Units: a Multicenter Randomized Controlled Trial. The Lancet Vol 375. Feb 6th 2010
2. De jong E, Van oers JA, Beishuizen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16(7):819-27.
3. Jensen et al. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011 Sep;39(9):2048-58
4. Bloos F, Trips E, Nierhaus A, et al. Effect of Sodium Selenite Administration and Procalcitonin-Guided Therapy on Mortality in Patients With Severe Sepsis or Septic Shock: A Randomized Clinical Trial. JAMA Intern Med. 2016;176(9):1266-76.
5. Balk RA, Kadri SS, Cao Z, Robinson SB, Lipkin C, Bozzette SA. Effect of Procalcitonin Testing on Healthcare Utilization and Costs in Critically Ill Patients in the United States. Chest. 2016;
6. Chastre J, Wolff M, Fagon JY, et al. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290(19):2588-98.
7. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372(21):1996-2005.
8. Uranga A, España PP, Bilbao A, et al. Duration of Antibiotic Treatment in Community-Acquired Pneumonia: A Multicenter Randomized Clinical Trial. JAMA Intern Med. 2016;
9. Wacker et al. Procalcitonin As a Diagnostic Marker For Sepsis: a Systematic Review and Meta-Analysis. Lancet Infect Dis. 2013 May;13(5):426-35
Rabbott - October 5, 2016 8:32 PM
I thought that PCT had been dying a slow death for many years. I guess it still takes an occasional terminal gasp. Rob Orman: you ought to take a detailed look at the Multiplex PCR's that are now coming on line. I'm working at a smallish rural hospital that for a mere $800 charge to someone else's money (Medicare pays about $560), I can quickly get a test for 20+ respiratory, or 20+ GI pathogens. Results back in about an hour or two. It's jarring to know that the guy on the vent is positive for rhinovirus only (thought that caused runny noses). The evidence base seems slim, and biased (100 percent sensitive for Yersinia Enterocolitica - but reading the entire literature base cited by that statement , only one confirmed case of Y Enterocolitica was identified in the multiple articles). I'm not sure if these are a great advance (deciding on which if any antibiotic is indicated), or are a waste of money (the guy's parakeet just died and the guy has pneumonia - I don't need an $800 test to give him so doxycycline), or are misleading (the test is positive for c dif, but we don't know if it is toxin positive or not). So, a good thorough review by an expert in the field might be useful in encouraging or discouraging the use of this incredibly useful, or perhaps perniciously misleading, or merely cool but expensive test.
Mohammed A. - October 22, 2016 5:23 AM
Sorry for this long post: Yes I agree PCT has limitations. And it should never trump clinical judgement. Also I agree I don't find it as helpful in ruling in sepsis despite what some experts feel (Paul Marik for ie). But I don't use PCT in the hope to reduce mortality or anything like that. I use it because antibiotic overuse is a serious problem.
We are actually many a time HORRIBLE at distinguishing infectious vs non-infectious causes of SIRS, lets be honest. I see asthma, chronic bronchitis and COPD pts all day every day and these people get antibiotics every time they cough.
Schuetz et al found in these pts with acute respiratory infections that a PCT guided strategy led to decreased antibiotic use with no difference in mortality or treatment failures [2].
In a well conducted study reported in Critical Care, Garnacho-Montero et al [1] investigated the role of biomarkers in distinguishing infectious from non-infectious SIRS. They demonstrated that PCT had excellent diagnostic accuracy (area under curve (AUC) 0.87; 95% confidence interval (CI) 0.81 to 0.94), while that for CRP was modest (AUC 0.69; 95% CI 0.59 to 0.79).
Yes Wacker found that the Sn was .77 (95% CI 0.72 to 0.81) and Sp was .79 while the area under the ROC curve was .85 (95% CI 0.81 to 0.88) which is not bad. Lets keep in mind there was GI-normous heterogeneity in that meta-analysis.
Additionally, several studies have shown that a RISE in procalcitonin can precede infection by 24 h, and that the change between procalcitonin measurements on day −1 and day 0 might be a better marker of sepsis than is one procalcitonin measurement on the day of fever [3]. This finding suggests the need to investigate an approach that uses procalcitonin kinetics (eg, two measurements within 8–12 h for newly admitted patients) and differential cutoffs to distinguish SIRS from sepsis. Stored blood samples from day 1 are frequently available for procalcitonin testing in inpatients and ICU patients with new onset fever. Once patients have started on antibiotics, intensivists are frequently reluctant to stop antibiotics unless cultures are negative at 48 h. Serial procalcitonin testing within 24 h could reduce unnecessary use of antibiotics and selective pressure for multiresistant pathogens.
All in all do I order PCT? Very rarely in fact I don't remember the last time I ordered it, because I feel comfortable observing pts off antibiotics-that's the elephant in the room-in this age where insurance companies are coming up with nonsensical bundles to force clinicians to treat pts with antibiotics as early as possible, they will not pay us to simply "observe people." Observing a pt -what a concept! Though that may sound like heresy that is what medicine used to be and we now live in an age where IV antibiotics run through the veins of every pt that walks in to our ED with a cough. And if PCT will help defend in any way my decision (so the suits don't go crazy), you can bet I'll use it.
1. Garnacho-Montero J, Huici-Moreno MJ, Gutierrez-Pizarraya A, Lopez I, Marquez-Vacaro JA, Macher HC, Guerrero JM, Puppo-Moreno A. Prognostic and diagnostic value of eosinopenia, C-reactive protein, procalcitonin, and circulating cell-free DNA in critically ill patients admitted with suspicion of sepsis. Crit Care. 2014;18:R116.
2. Schuetz, P, Briel, M, Christ-Crain, M et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis. 2012; 55: 651–662.
3. Charles, PE, Kus, E, Aho, S, Prin, S, Doise, JM, Olsson, NO et al. Serum procalcitonin for the early recognition of nosocomial infection in the critically ill patients: a preliminary report. BMC Infect Dis. 2009; 9: 49.
Anthony H. - November 12, 2017 12:25 PM
Rory or Rob, do you get a sense that many hospitals are using procalcitonin driven protocols to stop or deescalate antibiotics. I am the director of sepsis for my hospital and have chosen not to have it in our ER protocol. The docs can order it selectively based on the clinical scenario. The hospital however has had some push through antibiotic stewardship to use a similar protocol to PRORATA for the inpatients. I have also not been a fan of this change but the pharmacist are telling me "all the hospitals are doing this"
I will have a chance to plead my case in the coming weeks before they decide to add such a protocol. My opinion is that it is more background noise/useless information if used this way. I'm going to put up a little fight but I really would be interested to know how many centers are doing this.