Infectious disease/original researchRisk Prediction With Procalcitonin and Clinical Rules in Community-Acquired Pneumonia
Introduction
Community-acquired pneumonia accounts for 1.3 million hospitalizations in the United States each year1 at a cost of $8.4 billion.2 It is the most common cause of severe sepsis3 and infection-related death.4 Key to the safe and efficient management of community-acquired pneumonia is the ability to reliably predict who will fare well or poorly. The Pneumonia Severity Index5 and CURB-65 (Confusion, Uremia, Respiratory rate, low blood pressure, age 65 years or older)6 are clinical rules that identify a subset of individuals at low risk of death who are candidates for outpatient care.7, 8 However, all remaining patients are classified as high risk, usually prompting hospital admission and parenteral antibiotics, even though a large proportion may do well.9 Thus, there has been considerable interest in the development of rapidly available biomarkers that might confer additional prognostic information.10
Procalcitonin is a calcitonin precursor that is generally increased in bacterial infections but low in viral infections.11 Procalcitonin has good discrimination for bacterial infections and sepsis,12, 13, 14, 15 and 3 trials used low procalcitonin levels to withhold antibiotics in emergency department (ED) patients presenting with respiratory illnesses.16, 17, 18 However, 2 recent meta-analyses concluded that procalcitonin could not reliably differentiate sepsis from noninfectious inflammation in critically ill patients19 and had only moderate diagnostic performance for identifying bacteremia in ED patients.20 Furthermore, the prognostic value of procalcitonin measurement beyond existing prediction rules is unclear. Masia et al21 observed that patients with high Pneumonia Severity Index scores had higher procalcitonin levels and that higher concentrations were associated with mortality and complications,21 but Beovic et al23 found no association between procalcitonin and Pneumonia Severity Index score.22 These single center studies were limited by small sample sizes and used older procalcitonin assays with low sensitivity.23
Our goal was to determine the prognostic utility of a newer, high-sensitivity procalcitonin assay for 30-day mortality and assess its value beyond established clinical prediction rules. We tested this assay within a multicenter, prospective cohort of patients presenting to the ED with a clinical and radiographic diagnosis of community-acquired pneumonia. We hypothesized that an early singular procalcitonin measurement would aid risk assessment beyond that available from the Pneumonia Severity Index and CURB-65.
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Study Design and Setting
We conducted a multicenter, prospective, cohort study of patients presenting to the EDs of 28 teaching and nonteaching hospitals in southwestern Pennsylvania, Connecticut, southern Michigan, and western Tennessee between November 2001 and November 2003 (Genetic and Inflammatory Markers of Sepsis study). A specific aim of the Genetic and Inflammatory Markers of Sepsis study was to develop and validate risk prediction tools according to information available early in the course of disease. As
Characteristics of Study Subjects
Of the 2,320 subjects enrolled in the Genetic and Inflammatory Markers of Sepsis study, 1,651 (71.2%) had a day 1 procalcitonin test and formed the study cohort. Pneumonia Severity Index was measured in the ED in 1,384 (83.8%) of the 1,651 study cohort subjects (Figure 1). The study cohort was predominantly white, underlying disease was common, approximately half were identified as high risk by the Pneumonia Severity Index and CURB-65 clinical risk rules, and most were admitted to the hospital.
Limitations
We chose 30-day mortality as the primary outcome, following the methodology of the original Pneumonia Severity Index and CURB-65 studies. Other outcomes are important and not necessarily correlated with mortality. Nevertheless, subjects with a low procalcitonin level appeared to have lower rates of many other outcomes, including mortality measured at different points (Table E1, Table E2; available online at http://www.annemergmed.com). Second, although procalcitonin tier I was consistently
Discussion
More than a century ago, it was observed that “… the result of a laboratory test should have, in a given case, the same value as a cardinal symptom or an approved clinical sign … many … forget this, and fail to correlate the laboratory findings with the clinical findings.”39 We also observed that used alone, procalcitonin performed similarly to existing clinical prediction rules but that indiscriminately adding procalcitonin to all patients, regardless of clinical risk category, provided little
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Supervising editors: Gregory J. Moran, MD; Judd E. Hollander, MD
Dr. Moran and Dr. Hollander were the supervising editors on this article. Dr. Yealy did not participate in the editorial review or decision to publish this article.
Author contributions: DTH, LAW, JAK, DMY, and DCA conceived and designed the study, analyzed and interpreted the data, and provided important critical revisions of the article. DTH, DMY and DCA drafted the article. DTH, JAK, DMY, and DCA provided final approval. LAW and LK provided statistical expertise. LAW also contributed to drafting of the article, and LK contributed to analysis and interpretation of the data. JAK and DCA obtained funding for the study. JAK, MM, and DCA provided administrative, technical, and logistic support. MM also contributed to analysis and interpretation of the data and article revision. DTH takes responsibility for the paper as a whole.
Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article, that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Funding received from: NIGMS R01 GM061992. DTH, LAW, LK, DCA have provided consulting work to BRAHMS Diagnostica, the manufacturer of the procalcitonin assay used in this study. DTH has received one speaking honorarium and travel expenses for presentation at a satellite symposium of the September 2006 European Respiratory Society meeting in Munich, Germany. BRAHMS Diagnostica covered sample shipping and procalcitonin assay costs; no direct monetary grant support was provided.
Publication dates: Available online March 17, 2008.
Reprints not available from the authors.