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Editorial |

Procalcitonin in Severe Community-Acquired Pneumonia: Some Precision Medicine Ready for Prime Time FREE TO VIEW

Daiana Stolz, MD, MPH, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: D. S. and/or her institution received research support, unrestricted grants, and/or speaker’s honoraria from the Swiss National Foundation (PP00-P3_128412/1), Gottfried und Julia Bangerter-Rhyner-Foundation, Lung Liga Switzerland, Thermo Scientific Biomarkers (formerly B∙R∙A∙H∙M∙S AG), Actelion AG, Bayer-Schering AG, Astra-Zeneca AG, Novartis AG, GSK AG, Roche AG, Pan Gas AG, and Weinmann AG.

Clinic of Respiratory Medicine and Pulmonary Cell Research, University Hospital Basel, Basel, Switzerland

CORRESPONDENCE TO: Daiana Stolz, MD, MPH, FCCP, Clinic of Respiratory Medicine and Pulmonary Cell Research, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(4):769-771. doi:10.1016/j.chest.2016.07.017
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Community-acquired pneumonia (CAP) is the third most common cause of death globally. The estimated costs for treating CAP exceeded $9 billion per year in the mid-1990s in the United States, more than half being attributed to inpatient care. Approximately 20% to 40% of patients with CAP are treated in the hospital, and 10% require admission to the ICU owing to the need for ventilator support or to septic shock. The mortality rate among patients treated in the ICU for severe CAP ranges from 19% to 50%. Survival depends on a combination of host factors (genetic, age, comorbidities, defenses), pathogens (virulence, serotypes), and therapy. A genome-wide association study of survivors of sepsis due to pneumonia demonstrated that common variants in the FER gene are strongly associated with survival, explaining why certain patients with low bacterial burden are still susceptible to fatal outcomes. It is widely accepted that clinical judgment is inadequate to assess disease severity. Accordingly, several severity scores have been developed and validated widely, with the aim of guiding the initial site of treatment and appropriate level of intervention. However, while clinical scores are recommended for clinical decision-making in the evaluation of patients with CAP, they are not exempt from weaknesses, in particular regarding positive predictive values. Accordingly, the PSI (pneumonia severity index) score and CURB-65 are clinical rules that identify a subset of individuals at low risk of death who could be treated on an ambulatory basis. All remaining patients are classified as “high risk,” for whom hospital admission is recommended despite the fact that a significant percentage of these patients can be safely treated at home. Most sensitive tests with a low false negative rate such as the PSI require that physicians gather data on 20 parameters including a detailed medical history, physical examination, and further investigations such as arterial blood gas measurements and chest radiograph, thus precluding their applicability in a busy ED setting. The CURB-65 score is easier to calculate. However, because it does not directly address comorbidities, it underestimates mortality risk in elderly patients with other underlying diseases. In contrast, SMART-COP (systolic blood pressure, multilobar chest radiography involvement, albumin level, respiratory rate, tachycardia, confusion, oxygenation, and arterial pH) performed better than both the CURB-65 and PSI but failed to identify younger patients (< 50 years of age) requiring mechanical ventilation and/or inotropic support due to CAP. In addition, the PSI and CURB-65 might have good discriminatory power for mortality, but their ability as predictors of ICU admission is no more than fair. Delayed ICU admission was identified as an important risk factor for short-term mortality, leading the Infectious Diseases Society of America and American Thoracic Society (ATS) to develop criteria to identify patients requiring direct ICU referral. It is clear that patients fulfilling major criteria (endotracheal intubation and mechanical ventilation; shock requiring vasopressors) should be considered for ICU admission; however, there is still controversy about the value of the minor criteria. ICU care is costly and a limited resource world-wide.

FOR RELATED ARTICLE SEE PAGE 819

Biomarkers are laboratory tests reflecting a disease process. Ideally, they are easily measured, objective, and dynamic. Biomarkers and clinical scoring systems are expected to capture and reflect different aspects of the host factors and response to therapy. Thus, there is increasing interest in biomarkers both as stand-alone tests and layered on top of clinical risk scores for enhanced risk assessment.

Procalcitonin is a classic “hormokine,” which is secreted alongside the hormonal pathway in a cytokine-like manner. There is evidence suggesting that the development of severe sepsis and septic shock as a complication of pneumonia is associated with activation of the immune system. Procalcitonin is not accurate enough to enable the diagnosis of pneumonia as a stand-alone test. However, procalcitonin values vary according to the severity of pneumonia, and this association is stronger than that between disease severity and other clinical and laboratory variables. Besides being well known for its ability to decrease antibiotic prescription in CAP, ventilator-associated pneumonia, and COPD exacerbations without compromising clinical outcomes,,, procalcitonin also provides prognostic information in respiratory infections., There is a robust association between higher procalcitonin levels and adverse outcomes in patients with CAP. In this issue of CHEST, Self et al demonstrate that in a large cohort of adults hospitalized with CAP included in the EPIC (Etiology of Pneumonia in the Community) multicenter study conducted by the Centers for Disease Control and Prevention, procalcitonin is strongly associated with the risk of invasive respiratory or vasopressor support (IRVS) within 72 hours of admission. Undetectable procalcitonin (< 0.05 ng/mL) was associated with a 4% risk of IRVS, whereas concentrations of 10 ng/mL denoted a risk for IRVS of 22%. Procalcitonin was associated with pneumonia severity as assessed by the ATS minor criteria, PSI, and SMART-COP score. Most importantly, procalcitonin significantly improved risk stratification, applying the routinely used binary system (low-high risk) of each of the evaluated scores. For illustration, more than two-thirds of the patients requiring IRVS did not fulfill all three ATS minor criteria, considered to indicate the need for ICU admission. Interestingly, 50% of the included patients had procalcitonin levels below 0.15 ng/mL at admission despite “clinical and radiological evidence of CAP.” The number of patients with very low levels of procalcitonin in this study is surprisingly high and merits emphasis. Procalcitonin concentrations < 0.25 ng/mL are usually thought to indicate no need for antibiotic therapy. Accordingly, procalcitonin concentrations < 0.25 ng/mL have been used to withhold or discontinue antibiotics in most of the randomized studies evaluating procalcitonin guidance, which have included more than 4,000 patients in various clinical settings. The fact that CAP is a clinical diagnosis with inherent subjectivity raises the possibility that some of these patients with low procalcitonin levels might not actually have had pneumonia. In accordance with previous data, although the risk of IVRS increased linearly up to 10 ng/mL, a “dose response” was not observed for very high procalcitonin levels (> 10 ng/mL). This study further supports the notion that procalcitonin has limited prognostic accuracy as a stand-alone test. It also does not seem to outperform the risk estimation of a combination of clinical and laboratorial parameters. However, it also emphasizes its potential to capture nuances elusive to the clinical assessment, which do not seem to be consistently reflected even in elaborated severity scores recommended for clinical routine use.

Not all community-acquired pneumonia episodes are similar. Successful CAP management requires treatment strategies to take individual variability into account. To apply this concept we need methods to characterize patients, including fast, point-of-care approaches. Clinicians are looking forward to being able to identify specific immune profiles indicating protective rather than pathologic immune responses. Analyses of thousands of molecular signs by transcriptome will likely provide more diagnostic accuracy than the measurement of a single or a few biomarkers. Genomics and other new sciences might offer the opportunity to further improve diagnosis and prediction in the near future, but we should not allow too much information (or hope) to paralyze decision-making. While it is clear that no single biomarker can consistently predict prognosis, for now, procalcitonin may help to transfer the probability of risk derived from a population to an individual patient. A randomized study evaluating the outcome and cost-effectiveness of a procalcitonin-refined clinical score in severe CAP is needed. Then this new stratification paradigm has the potential to save money and lives.

References

Klein Klouwenberg P.M. .Ong D.S. .Bos L.D. .et al Interobserver agreement of Centers for Disease Control and Prevention criteria for classifying infections in critically ill patients. Crit Care Med. 2013;41:2373-2378 [PubMed]journal. [CrossRef] [PubMed]
 
Welte T. .Torres A. .Nathwani D. . Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax. 2012;67:71-79 [PubMed]journal. [CrossRef] [PubMed]
 
Woodhead M. .Welch C.A. .Harrison D.A. .Bellingan G. .Ayres J.G. . Community-acquired pneumonia on the intensive care unit: secondary analysis of 17,869 cases in the ICNARC Case Mix Programme Database. Crit Care. 2006;10:S1- [PubMed]journal
 
Rautanen A. .Mills T.C. .Gordon A.C. .et al Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med. 2015;3:53-60 [PubMed]journal. [CrossRef] [PubMed]
 
Marrie T.J. .Huang J.Q. . Admission is not always necessary for patients with community-acquired pneumonia in risk classes IV and V diagnosed in the emergency room. Can Respir J. 2007;14:212-216 [PubMed]journal. [CrossRef] [PubMed]
 
Loke Y.K. .Kwok C.S. .Niruban A. .Myint P.K. . Value of severity scales in predicting mortality from community-acquired pneumonia: systematic review and meta-analysis. Thorax. 2010;65:884-890 [PubMed]journal. [CrossRef] [PubMed]
 
Chalmers J.D. .Singanayagam A. .Hill A.T. . Predicting the need for mechanical ventilation and/or inotropic support for young adults admitted to the hospital with community-acquired pneumonia. Clin Infect Dis. 2008;47:1571-1574 [PubMed]journal. [CrossRef] [PubMed]
 
Schuetz P. .Muller B. .Christ-Crain M. .et al Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012;9:CD007498- [PubMed]journal. [PubMed]
 
Stolz D. .Smyrnios N. .Eggimann P. .et al Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J. 2009;34:1364-1375 [PubMed]journal. [CrossRef] [PubMed]
 
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 [PubMed]journal. [CrossRef] [PubMed]
 
Masia M. .Gutierrez F. .Shum C. .et al Usefulness of procalcitonin levels in community-acquired pneumonia according to the patients outcome research team pneumonia severity index. Chest. 2005;128:2223-2229 [PubMed]journal. [CrossRef] [PubMed]
 
Boeck L. .Eggimann P. .Smyrnios N. .et al Midregional pro-atrial natriuretic peptide and procalcitonin improve survival prediction in VAP. Eur Respir J. 2011;37:595-603 [PubMed]journal. [CrossRef] [PubMed]
 
Self W.H. .Grijalva C.G. .Williams D.J. .et al Procalcitonin as an early marker of the need for invasive respiratory or vasopressor support in adults with community-acquired pneumonia. Chest. 2016;150:819-828 [PubMed]journal
 

Figures

Tables

References

Klein Klouwenberg P.M. .Ong D.S. .Bos L.D. .et al Interobserver agreement of Centers for Disease Control and Prevention criteria for classifying infections in critically ill patients. Crit Care Med. 2013;41:2373-2378 [PubMed]journal. [CrossRef] [PubMed]
 
Welte T. .Torres A. .Nathwani D. . Clinical and economic burden of community-acquired pneumonia among adults in Europe. Thorax. 2012;67:71-79 [PubMed]journal. [CrossRef] [PubMed]
 
Woodhead M. .Welch C.A. .Harrison D.A. .Bellingan G. .Ayres J.G. . Community-acquired pneumonia on the intensive care unit: secondary analysis of 17,869 cases in the ICNARC Case Mix Programme Database. Crit Care. 2006;10:S1- [PubMed]journal
 
Rautanen A. .Mills T.C. .Gordon A.C. .et al Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med. 2015;3:53-60 [PubMed]journal. [CrossRef] [PubMed]
 
Marrie T.J. .Huang J.Q. . Admission is not always necessary for patients with community-acquired pneumonia in risk classes IV and V diagnosed in the emergency room. Can Respir J. 2007;14:212-216 [PubMed]journal. [CrossRef] [PubMed]
 
Loke Y.K. .Kwok C.S. .Niruban A. .Myint P.K. . Value of severity scales in predicting mortality from community-acquired pneumonia: systematic review and meta-analysis. Thorax. 2010;65:884-890 [PubMed]journal. [CrossRef] [PubMed]
 
Chalmers J.D. .Singanayagam A. .Hill A.T. . Predicting the need for mechanical ventilation and/or inotropic support for young adults admitted to the hospital with community-acquired pneumonia. Clin Infect Dis. 2008;47:1571-1574 [PubMed]journal. [CrossRef] [PubMed]
 
Schuetz P. .Muller B. .Christ-Crain M. .et al Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012;9:CD007498- [PubMed]journal. [PubMed]
 
Stolz D. .Smyrnios N. .Eggimann P. .et al Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J. 2009;34:1364-1375 [PubMed]journal. [CrossRef] [PubMed]
 
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 [PubMed]journal. [CrossRef] [PubMed]
 
Masia M. .Gutierrez F. .Shum C. .et al Usefulness of procalcitonin levels in community-acquired pneumonia according to the patients outcome research team pneumonia severity index. Chest. 2005;128:2223-2229 [PubMed]journal. [CrossRef] [PubMed]
 
Boeck L. .Eggimann P. .Smyrnios N. .et al Midregional pro-atrial natriuretic peptide and procalcitonin improve survival prediction in VAP. Eur Respir J. 2011;37:595-603 [PubMed]journal. [CrossRef] [PubMed]
 
Self W.H. .Grijalva C.G. .Williams D.J. .et al Procalcitonin as an early marker of the need for invasive respiratory or vasopressor support in adults with community-acquired pneumonia. Chest. 2016;150:819-828 [PubMed]journal
 
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