Markers of acute inflammation in assessing and managing lower respiratory tract infections: focus on procalcitonin

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1 REVIEW Markers of acute inflammation in assessing and managing lower respiratory tract infections: focus on procalcitonin B. Müller 1 and C. Prat 2 1 Department of Internal Medicine, University Hospital, Basel, Switzerland and 2 Microbiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain ABSTRACT This review describes the pathophysiological basis for using procalcitonin to help diagnose infections, and the strengths and weaknesses of implementing the test rationally in a routine clinical setting. Metaanalyses of observational studies and intervention studies both suggest that as a surrogate marker, procalcitonin allows an improved diagnostic assessment of a variety of infections, e.g., respiratory tract infections, meningitis, acute infectious endocarditis and pancreatitis. Measuring procalcitonin is not a substitute for careful clinical assessment and obtaining appropriate cultures in all patients. However, used appropriately, procalcitonin allows an earlier diagnosis of infection and can inform physicians about the course and prognosis of the disease better than more commonly used clinical and laboratory markers. With use of a sensitive assay, a procalcitonin-based therapeutic strategy can safely and markedly reduce antibiotic usage in those respiratory tract infections that are mostly viral, and in viral meningitis. More sensitive procalcitonin assays, with a functional sensitivity within the normal reference range of <0.03 lg L, should be available soon. There is a need for more intervention studies in other sites of infection to tackle the existing vicious cycle of antibiotic overuse and emerging multiresistance. Furthermore, as procalcitonin is a hormokine mediator, its immunoneutralisation might open new treatment options for sepsis. Keywords Antibiotics, procalcitonin, respiratory tract infection Clin Microbiol Infect 2006; 12 (suppl 9): 8 16 INTRODUCTION Despite important developments in diagnostic methods and broad-spectrum antibiotics, lower respiratory tract infections (LRTIs) remain a leading cause of death in hospitalised patients [1]. At the same time, both upper and lower respiratory tract infections remain the most common cause of unnecessary antibiotic treatments in the community [2 4]. The interpretation of clinical response in patients with bacterial infections, including LRTIs, lacks standardisation and validation, and is therefore prone to inter-observer variability. To improve routine clinical care, an ideal marker for bacterial infections should allow an early diagnosis and provide information about the course and prognosis of the disease. Traditional clinical signs Corresponding author and reprint requests: B. Müller, Department of Internal Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland happy.mueller@unibas.ch of infection (e.g., fever) and routine laboratory tests (e.g., white blood cell count) can be helpful in individual cases. However, these tests lack diagnostic accuracy and are sometimes even misleading. A positive microbial culture result has a relatively high specificity, but even this is not a reference standard, because it lacks sensitivity and is subject to a delay of 2 3 days. Although rapid tests exist for some pathogens, these can lack specificity in some clinical situations. For example, the immunochromatographic urine test for Streptococcus pneumoniae lacks specificity in patients with pneumococcal carriage, such as young children [5] and patients with chronic obstructive lung disease (COLD). While clinical risk scores for LRTIs, namely pneumonia, are available, most do not measure the severity of the disease but rather the risk of death, which is greatly influenced by age and the presence of comorbidities [6]. Indeed, LRTI diagnosis and monitoring is complicated in several patient groups, including infants and elderly patients, immunosuppressed patients, and patients with basal Ó 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases

2 Müller and Prat Procalcitonin and antibiotic stewardship 9 systemic inflammatory response syndrome (intensive care, post-operative or post-traumatic) or ventilator-associated pneumonia. Thus, there remains a need for a reliable marker for use in assessing the aetiology and severity of LRTIs, and hence in guiding antibiotic therapy. The inflammatory response to infection is a dynamic phenomenon involving multiple cellular activation processes and reflecting a highly complex process dependent on a series of interactions between a pathogen and the host. Factors depending on the microorganism include the genus, strain, virulence factors, immune-evasion mechanisms, size of the inoculum, and whether the microorganism is intracellular or extracellular. Factors depending on the host include age, immune status, site and extent of the infection, and previous antibiotic treatment. Even genetic polymorphisms in genes coding for proteins involved in the inflammatory response can influence the amount and function of protein produced in response to bacterial pathogens [7]. For example, there exists a tendency to septic shock and respiratory failure in patients with community-acquired pneumonia (CAP) and different tumour necrosis factor (TNF)-a polymorphism associations [8]. The measurement of most inflammatory cytokines is not useful in LRTI assessment, because of their short plasma half-life and rapid turn-over, the presence of blocking factors, and their compartmentalised production in the lung [9]. Acutephase proteins and the so-called hormokines [10] appear to be more reliable, because of their longer plasma half-lives, lesser variation in daily levels, and stability in vivo and ex vivo. Certain well-established laboratory tests now have a role in the follow-up assessment of pneumonia [11]. C-reactive protein (CRP) levels are elevated in bacterial infections more than in viral infections, and in systemic more than in localised infections [12], and have been shown to have value in establishing the diagnosis of CAP [13]. Neopterin is a marker of cell-mediated immunity infections [14]. Nevertheless, both parameters can be elevated during inflammation of non-infectious origin and hence show low specificity. Another disadvantage of CRP in routine care is the protracted increase, with peak levels 2 3 days after the infectious insult, and its suppression by steroid therapy, namely in patients with COLD. In contrast, procalcitonin appears to be a more specific marker of systemic bacterial infection. Levels of procalcitonin increase several-fold within hours of an infection and continue to increase until they reach several thousand times the normal level. This increase, and especially its time course, correlates with the severity and prognosis of the infection [15,16]. This review outlines the pathophysiology of procalcitonin and reviews its clinical use in the diagnosis and monitoring of infection, and in guiding antibiotic therapy. PROCALCITONIN PATHOPHYSIOLOGY Procalcitonin is a precursor peptide of the hormone calcitonin. It belongs to a family of functionally related peptides, including calcitonin gene-related peptides, adrenomedullin and amylin, and their respective precursor peptides [10]. These peptides emerged from duplications from a common ancestral calcitonin (CALC) gene. In the absence of infection, the extra-thyroidal transcription of the CALC-I gene is suppressed and is restricted to selective expression in neuro-endocrine cells found mainly in the thyroid, where the mature hormone is processed and stored in secretory granules [17]. Microbial infections and various forms of inflammation induce a ubiquitous increase in CALC-I gene expression and constitutive release of procalcitonin from all parenchymal tissues and differentiated cell types throughout the body, including the liver, kidney, adipocytes and muscle [18]. The greater procalcitonin release from parenchymal cells, in comparison with circulating blood cells, indicates a tissue-based rather than a leukocyte-based mechanism of host defence [19]. Thus, CALC gene products represent a prototype of hormokine mediators and can follow either a classical hormonal expression pathway in neuroendocrine cells or, alternatively, a cytokine-like ubiquitous expression pathway [18]. The release of hormokines can be induced either directly via microbial toxins (e.g., endotoxin) or indirectly via a humoral or cell-mediated host response (e.g., interleukin (IL)-1b, TNF-a and IL-6) [17]. The induction can be attenuated by cytokines that are also released during a viral infection (e.g., interferon-c). In sepsis, the predominance of procalcitonin as opposed to mature calcitonin is indicative of a constitutive pathway within cells lacking secretion granules and, hence, a bypassing of much of the enzymatic processing [17].

3 10 Clinical Microbiology and Infection, Volume 12 Supplement 9, 2006 Consequently, there is very little intracellular storage of procalcitonin in sepsis [18]. Procalcitonin is a potentially harmful mediator involved in the infection response. The administration of procalcitonin to septic hamsters with peritonitis doubled their death rate. Conversely, immunoneutralising elevated procalcitonin levels with a specific antiserum greatly increased the survival rate in septic hamsters [20] and pigs [21], even when the antiserum was administered after the animals were moribund [22]. Several characteristics of procalcitonin favour its use as a therapeutic target. In contrast to the transiently increased classical cytokines, for which immunoneutralisation trials in humans have been disappointing, the massive increase in circulating procalcitonin levels persists for several days. Furthermore, the procalcitonin level is frequently increased in overt sepsis, the onset of the increase is early (within 3 h), and the diagnostic accuracy of its measurement should greatly improve patient selection for any study of the therapeutic efficacy of procalcitonin immunoneutralisation and antibiotic therapy in humans. DIAGNOSTIC STUDIES OF PROCALCITONIN As no reference standard for the diagnosis of a bacterial infection exists, all observational studies are prone to bias, and premature results and conclusions can mislead physicians. Importantly, the diagnostic accuracy of procalcitonin is completely dependent on the use of a sensitive assay in a predefined clinical setting (Fig. 1) [23]. Virtually all published diagnostic studies of procalcitonin have been done using a manual assay with a functional sensitivity of approximately lg L [24], which is more than ten-fold above the normal reference values for healthy persons [23]. This sensitivity is not sufficient to detect moderately elevated procalcitonin levels, and thus limits the external validity of these studies to overt sepsis. Respiratory tract infection The most frequent source of sepsis is the lung [16]. In this context, LRTIs, including acute bronchitis, acute exacerbations of COLD and CAP, can be viewed as sepsis precursors. Consequently, as Fig. 1. Rational use of procalcitonin in routine clinical practice. These cut-off ranges are dependent on the clinical context and have to be adapted accordingly. For example, lower cut-off ranges are appropriate in patients with markedly impaired pulmonary reserve, and higher cut-off ranges are appropriate in patients with systemic inflammatory response syndrome on an intensive care unit. The course of procalcitonin yields important additional information, and follow-up measurements can be helpful to improve diagnostic accuracy and to support treatment decisions. The use of rapid and sensitive assays is needed for antibiotic stewardship. (Adapted and updated from Christ-Crain M, Müller B. Procalcitonin in bacterial infections hype, hope, more or less? SwissMedWkly 2005; 135: ) COLD, chronic obstructive lung disease; ICU, intensive care unit; PCT, procalcitonin; RTI, respiratory tract infection. many as 75% of all antibiotic doses are prescribed for acute respiratory tract infections, in spite of their predominantly viral aetiology. The randomised ProRESP intervention study recently assessed the capability of the procalcitonin measurement to identify bacterial LRTIs requiring antimicrobial treatment in the setting of an emergency department [25]. Procalcitonin was chosen as the test marker because of its advantages over CRP and other inflammatory markers, namely an earlier increase upon infection, a better negative predictive value, and the unattenuated increase in the presence of immunosuppressive medication (e.g., steroids in patients with COLD) [26]. Procalcitonin was measured using a rapid assay with a functional sensitivity of 0.06 lg L (Kryptor PCT; Brahms, Hennigsdorf, Germany). The assay time for procalcitonin measurements was less than 20 min, and results were routinely available within 1 h (24 h a day, 7 days per week). Investigating physicians used an algorithm developed at the University Hospital, Basel, Switzerland to classify the patients in the procalcitonin

4 Müller and Prat Procalcitonin and antibiotic stewardship 11 group into four subgroups according to the probability of bacterial infection (Fig. 2). The following procalcitonin cut-off ranges were derived by calculating multilevel likelihood ratios: A procalcitonin level of <0.1 lg L suggested the absence of bacterial infection, and the initiation or continuation of antibiotics was strongly discouraged. Antibiotic therapy could be considered in critically ill patients (Fig. 2). If antibiotics were given, an early discontinuation of antibiotic therapy after 1 3 days was endorsed if procalcitonin levels, checked daily, remained at <0.1 lg L. A procalcitonin level between 0.1 and 0.25 lg L indicated that bacterial infection was unlikely, and the initiation or continuation of antibiotics was discouraged. Antibiotic therapy can be considered in high-risk patients. Again, if antibiotics were given, early termination was endorsed if procalcitonin levels did not increase. A procalcitonin level between 0.25 and 0.5 lg L indicated a possible bacterial infection, and the initiation or continuation of antibiotic therapy was encouraged. A procalcitonin level of >0.5 lg L strongly suggested the presence of bacterial infection, and antibiotic treatment and continuation was strongly encouraged [25]. Fig. 2. Protocol for the classification, management and monitoring of patients according to the procalcitonin level and the associated probability of bacterial infection, as used in the ProRESP and the ProCAP study [25]. CAP, community-acquired pneumonia; COLD, chronic obstructive lung disease; CURB, confusion, urea nitrogen, respiratory rate, blood pressure; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICU, intensive care unit; PCT, procalcitonin; PSI, Pneumonia Severity Index; SaO 2, arterial blood oxygen saturation. *Involving Staphylococcus aureus, Klebsiella pneumoniae, anaerobic organisms, empyema or abscesses. The same cut-offs were used regardless of whether patients had been pretreated with antibiotics prior to admission to the emergency department. Re-evaluation of the clinical status and measurement of serum procalcitonin levels was recommended after 6 24 h in all persistently sick and hospitalised patients in whom antibiotics were withheld. The procalcitonin algorithm could be overruled in patients with immediately life-threatening disease (e.g., patients with the most severe co-morbidities, patients with emerging need for intensive care unit admission during the initial follow-up, patients with haemodynamic or respiratory instability, and very ill patients with a positive antigen test result for legionellosis). Physicians were advised that persistently elevated procalcitonin levels may indicate a complicated course (e.g., antibiotic resistance or abscess), while procalcitonin levels may remain relatively low in localised infections. Procalcitonin levels were reassessed on days 4, 6 and 8 in hospitalised patients receiving ongoing antibiotic therapy, and in patients showing a worsening or delayed recovery of signs and symptoms, and antibiotic was discontinued according to the procalcitonin cut-offs defined above. In patients with very high procalcitonin values upon admission (e.g., >10 lg L), discontinuation of antibiotic therapy was encouraged if levels decreased to below 80 90% of the initial value. In patients with an initial procalcitonin level >10 lg L and smaller reductions during follow-up, continuation of antibiotic treatment was encouraged. In the procalcitonin group of the ProRESP-study, the percentage of patients with LRTI who received antibiotic therapy was reduced by almost 50%, as compared with the standard group [25]. The clinical and laboratory outcomes were similar in both groups. Reduced antibiotic use was most striking in cases of acute bronchitis and acute exacerbations of COLD. COLD exacerbations present a particular challenge in terms of diagnosing an infectious cause. The majority of COLD patients have positive sputum culture results, although these do not necessarily imply an active infection. In the procalcitonin group, positive culture rates were similar in patients in whom antibiotics were given or withheld, as were outcomes, underlining the limited diagnostic usefulness of sputum cultures in COLD patients. Since patients with COLD have an impaired pulmonary reserve and the

5 12 Clinical Microbiology and Infection, Volume 12 Supplement 9, 2006 infection might be locally restricted, a procalcitonin cut-off level for withholding antibiotics of <0.1 lg L is advisable in patients with severe disease. This was validated in the ProCOLD study (ISRCTN ), which included more than 200 patients [27]. In the clinical context of CAP, the primary value of procalcitonin on admission lies not in the reduction of antibiotic prescriptions, but in facilitating and expediting the differential diagnosis of new or progressing infiltrates. Accordingly, procalcitonin guidance could markedly lower the number of antibiotic courses in patients with infiltrates on chest X-ray unrelated to pneumonia. Recently, the ProCAP study (ISRCTN ), involving over 300 patients with CAP requiring hospitalization, showed that procalcitonin guidance allowed a marked reduction in the duration of antibiotic treatment from a median of 12 days to 5 days [28]. Procalcitonin may also be useful as a prognostic parameter in patients with ventilator-associated pneumonia [29,30]. Whether procalcitonin guidance can reduce the high levels of unnecessary antibiotic use in upper and lower respiratory infections in community practice is also being investigated (PARTI ProDOC-study, ISRCTN ) [31]. Several studies have demonstrated the complementary utility of procalcitonin and other markers in LRTIs. In children, CRP and procalcitonin showed a significant association with the bacterial aetiology of LRTIs [32]. In the differentiation of pneumococcal and atypical infections (i.e., Mycoplasma and Chlamydia spp.) from viral infections, CRP yielded better sensitivity, but procalcitonin was more specific. Procalcitonin was also more specific in differentiating pneumococcal infections from all other aetiologies combined, while the two tests showed similar sensitivity in this regard. Thus, procalcitonin and CRP measurement may have an additive value in rationalising antibiotic therapy before microbiological results are obtained. Another study examined the usefulness of procalcitonin and neopterin in distinguishing different aetiologies, and assessing infection severity, in adults with CAP [33]. Pneumococcal pneumonia was the only aetiology that presented with elevated levels of both procalcitonin and neopterin, which were especially high in bacteraemic pneumonia. In the case of Legionella pneumonia, neopterin levels were greatly increased while procalcitonin levels were only moderately elevated. Finally, infections with Mycobacterium tuberculosis and with Pneumocystis jiroveci were associated with elevated neopterin levels and low or undetectable procalcitonin levels. Thus, neopterin was more elevated in infections with cellmediated immunity. Patients with both pneumococcal and Legionella pneumonia were stratified using the Pneumonia Severity Index, and patients in high-risk classes (IV and V) had significantly more elevated procalcitonin levels. Both procalcitonin and neopterin levels were significantly more elevated when patients presented with multilobar radiographic infiltrates. Other infections Procalcitonin can also be helpful in the diagnosis of bacterial infections at extra-pulmonary sites [34]. A recent meta-analysis showed that procalcitonin is a more accurate marker for systemic bacterial infections than is CRP, independent of the infection source. The superiority of procalcitonin was apparent both when differentiating bacterial infections from non-infective causes of inflammation and when differentiating bacterial infections from viral infections [24]. On pooled analysis, procalcitonin showed a sensitivity of 88% (95% CI 80 93) and a specificity of 81% (95% CI 67 90). Procalcitonin was the only independent predictor of acute infectious endocarditis upon admission in a multivariate analysis. Its diagnostic accuracy was comparable to that of B-type natriuretic peptide for the emergency diagnosis of heart failure [35]. However, procalcitonin levels may remain very low in some patients with sub-acute endocarditis. Patients with oedematous or toxic pancreatitis have low concentrations of procalcitonin, whereas patients with infectious pancreatitis have very high procalcitonin concentrations. Increased procalcitonin levels may reflect the derangement in gut barrier function and may hence predict those patients in whom the translocation of bacteria into dead pancreas, with consequent infected necrosis, is more likely. Data on the clinical use of procalcitonin in diverticulitis or other gastrointestinal infections are lacking [34]. Procalcitonin may be useful in the diagnosis of urinary tract infections, for which there are no well-identified severity markers. In children, procalcitonin was correlated with the severity of

6 Müller and Prat Procalcitonin and antibiotic stewardship 13 renal scars caused by urinary infection (as assessed by scintigraphy), while TNF-a, IL-6, IL-8 and CRP showed no such correlation [36,37]. Procalcitonin is also helpful in differentiating between viral and bacterial meningitis [15] and can facilitate antibiotic stewardship during an epidemic of viral meningitis [38]. As expected, localised infections yield lower procalcitonin levels than generalised infections, and positive blood cultures. In a closed focus of infection, procalcitonin concentrations are only moderately high, as in some cases of infectious arthritis in adults. Other than bacterial infections, malaria is the main condition in which procalcitonin concentrations are high. These elevated procalcitonin levels are probably due to elevated TNF-a levels, as large quantities of procalcitonin are produced after perfusion of TNF-a in humans. LIMITATIONS OF PROCALCITONIN AS A MARKER The potential limitations and weaknesses of procalcitonin as a marker are listed in Table 1 [34]. In cases of falsely high procalcitonin levels in the absence of an infection, typically seen after severe trauma or surgery, procalcitonin levels are usually moderately elevated, between 1 and 10 lg L, but decline rapidly to values below 1 lg L within 48 h. Persistently high procalcitonin levels in these patients indicate that a complicating bacterial infection is likely to be present. Conversely, initially falsely low procalcitonin levels, typically seen during the early course or localised state of an infection, often show a gradual increase during follow-up measurements after 6 24 h and thereby point to an underlying bacterial disease. This further underlines the importance of follow-up measurements. Procalcitonin had no clear usefulness in the diagnosis of fungal infections, even when severe (e.g., invasive aspergillosis) [39,40]. Also, the severity of some viral infections (e.g., cytomegalovirus) cannot be assessed using procalcitonin. To establish the promising findings from the ProRESP, ProCAP, ProCOLD and ProDOC PARTI studies as an international standard of care, residual limitations have to be resolved. Three of the four studies were performed at a single university hospital, which raises questions concerning their external validity. Standard care was used in the control group, and the use of very recent guidelines was not strictly enforced. Only the Pro- DOC PARTI study, a non-inferiority study enrolling 50 family physicians, had adequate power to assess clinical outcome. However, the low rate of adverse events in the outpatient setting of primary care is arguably not representative for hospitalised patients and their higher complication rates. Finally, despite a marked reduction in duration of antibiotic therapy in the procalcitonin group within the ProCAP study, the overall length of hospital stay was not the target of intervention and was therefore similar between the treatment groups. Some experts argue that once a patient is clinically stable and intravenous antibiotics are discontinued, then discharge from the hospital should be safe unless there are extenuating circumstances. Cost-effectiveness is relevant in a public health perspective. Further research is also required to elucidate the role of biomarkers during infection in order to assess immunomodulating therapies. Procalcitonin has a role in several steps of the inflammatory response, such as calcium homeostasis [41], nitric oxide synthesis [42] and chemotaxis [43,44], and immunoneutralisation of procalcitonin has been shown to be useful as a therapy for sepsis in animal models [22]. CONCLUSION As is the case for all diagnostic tests, serum procalcitonin levels must always be evaluated and re-evaluated during follow-up, and interpreted with regard to a careful clinical and microbiological assessment. The diagnosis of all serious infections will continue to require a high level of suspicion, a careful history and a thorough physical examination and blood cultures in all patients. Clinicians should withstand the temptation to rely solely on the result of laboratory tests rather than a demanding clinical assessment. Moreover, clinicians must bear in mind the limitations of every biomarker, the causes of false-positive and falsenegative results, and the time kinetics of the test. Also, one must consider the diagnostic accuracy of the test in each group of patients, and in every infection aetiology. Clinically apparent infections are a sequel of variable interactions between host immune response, microbes and their toxins, and are far too complex to be reduced to a single cut-off value of any specific surrogate marker. Optimal test cut-offs also depend on the clinical setting, the

7 14 Clinical Microbiology and Infection, Volume 12 Supplement 9, 2006 Table 1. Potential limitations of procalcitonin as a marker (adapted and updated from Christ-Crain M, Müller B. Procalcitonin in bacterial infections hype, hope, more or less? SwissMedWkly 2005; 135: ) The optimal cut-off ranges of procalcitonin are variable and dependent on: the clinical setting (e.g., primary care, emergency room, intensive care unit, post-operative or trauma care units) the site and extent of the infection (e.g., RTI, endocarditis, meningitis) co-morbidities (e.g., impaired pulmonary reserve, immunosuppression) the clinical implications (e.g., diagnosis, prognosis, antibiotic stewardship) For many infections, the optimal cut-off ranges remain to be determined in observational studies using sensitive assays and validated in intervention studies Common causes of false-negative and false-positive results: False-positive (i.e. falsely high levels in the absence of a bacterial infection): physiological status of newborns (first days of life) acute respiratory distress syndrome acute attacks of Plasmodium falciparum malaria systemic fungal infections (e.g., candidiasis, aspergillosis) severe mechanical trauma post surgical trauma administration of monoclonal or polyclonal anti-thymocyte globulin in the treatment of acute rejection after transplantation chemical pneumonitis severe burns and heat strokes medullary thyroid cancer, small cell cancer of the lung, some carcinoid tumours, tumours with paraneoplastic hormone production inflammation associated with cytokine storms, e.g., IL-1b in familial Mediterranean fever, therapeutic infusions of TNF-a (e.g., for melanoma) False-negative (i.e., falsely low levels in the presence of a bacterial infection): very early course of infections localised and sub-acute infections (e.g., endocarditis) Procalcitonin is not an immediate marker of infection. Follow-up and re-evaluation of procalcitonin upon clinical suspicion of infection and during the course of the disease is pivotal A single procalcitonin value upon admission is not a very good prognostic marker Although it is higher in patients who survive than in non-survivors, procalcitonin is a diagnostic rather than a prognostic marker. In contrast, the course of procalcitonin has strong prognostic implications Costs Procalcitonin is more expensive than other, less reliable, biomarkers (e.g. CRP), for which, however, no intervention studies exist Different assays available with very different test performances The diagnostic accuracy of procalcitonin is completely dependent on the use of a sensitive assay in an appropriate, defined clinical setting Ultrasensitive assays to determine subtle elevations of procalcitonin are not yet widely available CRP, C-reactive protein; IL, interleukin; RTI, respiratory tract infection; TNF-a, tumour necrosis factor a. age of the patient, the extent of the infection, and the presence of co-morbidities. Despite these caveats, the likelihood and prognosis of bacterial infection strongly correlate with procalcitonin levels. Cut-off ranges for the diagnosis of bacterial infections and for antibiotic stewardship have been developed and validated in several intervention trials in respiratory tract infections (ProRESP, ProCAP, ProCOLD, Pro- DOC PARTI), which enrolled over 1000 patients. In addition, a French study was successful in safely controlling antibiotic use during a meningitis outbreak in children. Thus, procalcitonin assays might expedite the diagnostic assessment of infections and the installation of adequate therapeutic measures, and help to improve resource utilisation, e.g., of diagnostic imaging. In the future, additional emerging biomarkers are likely to complement the diagnostic and prognostic power of procalcitonin. Thus, the optimal use of such tests may involve serial measurement, in carefully selected patients, of a combination of biomarkers. There is a need for more intervention studies of procalcitonin in other sites of infection to tackle the existing vicious cycle of antibiotic overuse and emerging multiresistance. Furthermore, as procalcitonin is a hormokine mediator, its immunoneutralisation might provide new treatment options for sepsis.

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9 16 Clinical Microbiology and Infection, Volume 12 Supplement 9, Prat C, Dominguez J, Andreo F et al. Procalcitonin and neopterin correlation with aetiology and severity of pneumonia. J Infect 2006; 52: Christ-Crain M, Müller B. Procalcitonin in bacterial infections hype, hope, more or less? Swissmedwkly 2005; 135: Mueller C, Huber R, Laifer G, Mueller B, Buerkle G, Perruchoud AP. Procalcitonin and the early diagnosis of infective endocarditis. Circulation 2004; 109: Tullus K, Fituri O, Linne T et al. Urine interleukin-6 and interleukin-8 in children with acute pyelonephritis, in relation to DMSA scintigraphy in the acute phase and at 1-year follow-up. Pediatr Radiol 1994; 24: Benador N, Siegrist CA, Gendrel D et al. Procalcitonin is a marker of severity of renal lesions in pyelonephritis. Pediatrics 1998; 102: 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: Dornbusch HJ, Strenger V, Kerbl R et al. Procalcitonin and C-reactive protein do not discriminate between febrile reaction to anti-t-lymphocyte antibodies and Gram-negative sepsis. Bone Marrow Transplant 2003; 32: Petrikkos GL, Christofilopoulou SA, Tentolouris NK, Charvalos EA, Kosmidis CJ, Daikos GL. Value of measuring serum procalcitonin, C-reactive protein, and mannan antigens to distinguish fungal from bacterial infections. Eur J Clin Microbiol Infect Dis 2005; 24: Müller B, Becker KL, Kranzlin M et al. Disordered calcium homeostasis of sepsis: association with calcitonin precursors. Eur J Clin Invest 2000; 30: Hoffmann G, Czechowski M, Schloesser M, Schobersberger W. Procalcitonin amplifies inducible nitric oxide synthase gene expression and nitric oxide production in vascular smooth muscle cells. Crit Care Med 2002; 30: Wiedermann FJ, Kaneider N, Egger P et al. Migration of human monocytes in response to procalcitonin. Crit Care Med 2002; 30: Monneret G, Arpin M, Venet F et al. Calcitonin gene related peptide and N-procalcitonin modulate CD11b upregulation in lipopolysaccharide activated monocytes and neutrophils. Intensive Care Med 2003; 29: