© 2005 American Thoracic Society doi: 10.1164/rccm.2410002
Procalcitonin and Ventilator-associated PneumoniaYet Another Breath of Fresh AirDepartment of Internal Medicine, University Hospital Basel, Switzerland Rarely has a marker for a disease stirred controversy like procalcitonin (ProCT) for the diagnosis of bacterial infection. The article by Luyt and coworkers in this issue of the Journal (pp. 48–53) brings a fresh breeze into an ongoing discussion regarding ventilator-associated pneumonia (VAP) (1). Patients with microbiologically defined VAP who failed treatment (defined by death, recurrent VAP, or extrapulmonary infection) had higher levels of ProCT throughout their intensive care unit (ICU) stay as compared with patients with favorable outcomes. In a multivariate analysis, ProCT and the PaO2:FIO2 ratio proved to be predictive of adverse outcome in this observational study. The authors conclude that ProCT could be useful in risk stratifying patients with VAP and may provide an early indication of treatment failure. Specifically, two findings of this article merit attention. First, although VAP was clinically suspected in 172 patients, it was microbiologically confirmed in only 69 (40%), which exemplifies the dilemma that there is no diagnostic gold standard. Second, among the 63 patients enrolled in the study, 38 (60%) had unfavorable outcomes, which adds human drama to the medical dilemma. This reinforces the perception that antibiotics should be prescribed early and frequently in patients at risk for VAP, perpetuating the vicious cycle of antibiotic overuse and multi-resistance in ICUs. Several laboratory markers have proven especially valuable in diseases where clinical symptoms are ambiguous. Among these are natriuretic peptides, troponins, and D-dimers for the diagnosis of congestive heart failure, myocardial infarction, and venous thromboembolism, respectively, when interpreted in the proper clinical context. For infections, the ideal marker should allow an early diagnosis, help to differentiate bacterial from nonbacterial causes of systemic inflammation, and should inform about clinical course and prognosis. Studies have shown that ProCT encompasses many of these features: its use significantly improves the sensitivity and specificity of a diagnosis of bacterial sepsis (2); it is more helpful than C-reactive protein (3, 4) and proinflammatory cytokines in discriminating between viral and bacterial infections and noninfectious causes of inflammation (including in the acute respiratory distress syndrome), and it is predictive of outcome (5). Clinically apparent infections are a sequel of complex and variable interactions between host immune response, microbes, and their toxins. Obviously, the resulting clinical syndrome is far too complex to be reduced to elevated levels of any specific surrogate marker. Accordingly, it cannot be overemphasized that the diagnostic accuracy of ProCT and its optimum cutoffs are completely dependent on use of a sensitive assay in an appropriate clinical setting. ProCT is not a substitute for a careful history and physical examination. Yet, as a surrogate marker, it provides important additional information and calls into question currently used "gold standards" for the clinical diagnosis of bacterial infections, including VAP. Ideally, an ultrasensitive ProCT assay should reliably measure the normal circulating concentrations of this molecule in healthy individuals (6). A rapid assay assures that results can be incorporated into clinical decision making. However, as is the case for all diagnostic tests, a serum ProCT concentration must always be evaluated with appropriate respect for the clinical context. Circulating ProCT can be enhanced in noninfectious disorders, and may remain relatively low even in sepsis induced by bacterial infection (7). As the clinical usefulness of ProCT is becoming more evident, it is encouraging that our understanding of the complexity of its regulation and biological role is growing as well (8). In the past, the "classic" paradigm limited the expression of calcitonin (CALC) genes to neuroendocrine cells. In thyroidal C-cells, mature calcitonin (CT) is initially biosynthesized as a precursor protein (i.e., ProCT) that is subsequently processed into smaller peptides and finally released as amidated mature calcitonin hormone. However, after a severe bacterial infection, circulating ProCT concentrations are increased in thyroidectomized patients, whereas the levels of mature CT are not increased. This suggests the presence of a nonthyroidal source of inflammation and sepsis-mediated CALC gene expression and ProCT secretion (9, 10). Indeed, there is a trimodal expression pattern of the CALC gene and a closely regulated biphasic behavior of infection-related ProCT secretion (11). CALC-gene products, including ProCT, are thereby prototypes of hormokine mediators, which can follow either a classical hormonal expression or, alternatively, a cytokine-like expression pathway (11, 12).
In this context, what happens after the invasion of bacteria into the host organism? Both inflammatory and infectious stimuli result in leukocyte recruitment to the site of infection, where these cells orchestrate the inflammatory reaction. However, among these blood derived cells, including monocytes and macrophages, ProCT release is transient, is limited in amount, and occurs exclusively during a short period following attachment of cells to the endothelium while transmigrating to the site of infection. Thus, white blood cells are not a major source of the increased ProCT concentrations found in human sepsis. Conversely, combined stimulation by microbial products (e.g., endotoxin [LPS]) and by pro-inflammatory mediators of the host response (e.g., tumor necrosis factor-
It was recently demonstrated that ProCT-guided antimicrobial treatment reduces the use of antibiotics, without jeopardizing clinical outcome in patients with mostly viral respiratory tract infections (13). Interferons, including interferon- It is now known that ProCT is not only a marker, but acts as a modulator of the inflammatory/immunologic host reaction (14). Thus, administration of human ProCT worsened outcome, whereas neutralization of endogenous ProCT improved survival in septic hamsters suffering from Escherichia coli peritonitis (15). In septic pigs, the administration of antibodies to ProCT reduced mortality and improved physiologic and metabolic parameters during a polymicrobial infection, even when administered after the animals were moribund (16). Some welcome air as a refreshing breeze, whereas others dislike it as disturbing gust. Clearly, ProCT is considerably more than "just another marker" for infections. Importantly, any observational study investigating the diagnostic accuracy of a given marker is biased by the choice of the "gold standard." In infections this gold standard does not exist, and thus all studies are prone to a potential bias, which explains the ongoing controversy. Conversely, interventional studies, in which antimicrobial therapy is guided by a marker and in which the primary measure of efficacy is outcome, have the potential to resolve the dilemma and provide important data. For ProCT, initial attempts in lower respiratory tract infections and meningitis to guide antibiotic therapy have shown promising results (13, 17). The time has arrived to conduct an adequately powered international multicenter intervention study using sensitive ProCT assays in critically ill patients with VAP to tackle the vicious cycle of antibiotic overuse and widespread multi-resistance in ICUs. FOOTNOTES Conflict of Interest Statement: B.M. has received payments from Brahms for Advisory Board (2003: $5,000), expert witness (2004: $10,000), lecture fees (2002: $7,500, 2003: $16,000, 2004: $12,500), and partial support for investigator initiated projects (2003: $45,000). REFERENCES
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and interleukin [IL]-1 ß) results in a generalized, tissue-wide induction of CT mRNA and a consequent massive secretion of several CT precursors, including ProCT, into the circulation. LPS treatment alone also strongly induces ProCT synthesis. Parenchymal cells (including adipocytes, liver, lung, brain, and muscle cells) constitute the major source of sepsis-related ProCT secretion, which may reach more than 100,000-fold levels above normal (
(IFN-
