European Journal of Internal Medicine 22 (2011) 460465

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European Journal of Internal Medicine

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m

Review article

Inammatory biomarkers for the diagnosis, monitoring and follow-up of community-acquired pneumonia: Clinical evidence and perspectives
Giuseppe Lippi a,, Tiziana Meschi b, Gianfranco Cervellin c
a b c

U.O. Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy Sezione di Medicina Interna e Lungodegenza Critica, Dipartimento di Scienze Cliniche, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy U.O. Pronto Soccorso e Medicina d'Urgenza, Dipartimento di Emergenza-Urgenza, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy

a r t i c l e

i n f o

a b s t r a c t
Community-acquired pneumonia (CAP) is dened as an infection of the alveolar or gas-exchanging portions of the lungs occurring outside the hospital, with clinical symptoms accompanied by the presence of an inltrate in the chest radiograph. Due to the high prevalence and the large demand of healthcare resources, an accurate clinical and therapeutic decision making is crucial in patients with CAP. As such, there is increasing interest on the use of traditional and innovative biomarkers such as procalcitonin (PCT) and C-reactive protein (CRP). At variance with other traditional inammatory and innovative biomarkers, PCT might help limiting unnecessary antibiotic use, reduce bacterial resistance and decrease medical costs and drug-related adverse events. PCT however carries some additional advantages over CRP, such as the greater specicity for infections and a more narrow range of normal concentrations. 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Article history: Received 29 December 2010 Received in revised form 13 February 2011 Accepted 25 February 2011 Available online 25 March 2011 Keywords: Community-acquired pneumonia Therapy Biomarkers Procalcitonin C-reactive protein

1. Introduction Community-acquired pneumonia (CAP) is typically dened as an infection of the alveolar or gas-exchanging portions of the lungs occurring outside the hospital, with clinical symptoms accompanied by the presence of an inltrate in the chest radiograph (Table 1) [1]. CAP not only is a frequent and potentially life-threatening disease that continues to challenge the mind of even expert physicians, but it is also the leading cause of death among infectious diseases in the western countries, being associated with a dramatic economic burden to the healthcare systems [2]. According to reliable estimations, the rate of CAP is 18.2 cases per 1000 person-years and 52.3 cases per 1000 person-years among subjects aged 6569 years and those older than 85 years, respectively (i.e., 1 of 20 persons older than 85 years would develop CAP yearly) [3,4]. Irrespective of advances in medical science, the mortality from CAP has changed modestly over the past decades. Basically, mortality and adverse outcomes both result from a complex interplay between the pathogen and the host [5]. The inpatient mortality for CAP ranges between 5.7% and 14%, while CAP also accounts for a signicant number of intensive care unit (ICU) admissions [6,7]. There is evidence that clinicians may both over- and underestimate the severity of CAP

Corresponding author. U.O. Diagnostica Ematochimica, Azienda OspedalieroUniversitaria di Parma, Via Gramsci, 14, 43100, Parma, Italy. Tel.: +39 0521 703050, +39 0521 703791. E-mail addresses: giuseppe.lippi@univr.it (G. Lippi), ulippi@tin.it (T. Meschi), glippi@ao.pr.it (G. Cervellin).

especially when relying on the clinical judgment only, so that they might often decide to inappropriately hospitalize or, vice versa, discharge patients requiring instead a different care pathway [8,9]. A variety of clinical as well as biochemical scoring systems have been proposed to help diagnosis, risk stratication, monitoring and follow-up of CAP. The most extensively studied scoring system, the Pneumonia Severity Index (PSI) was introduced in 1997 following a study (the Pneumonia Outcome Research Trial, PORT) of N50,000 patients with CAP. This twenty-point score classied patients into ve risk classes (IV) based on their 30- day percentage risk of death. Patients in the rst two classes, based on their low risk of death (0.1% to 07%), were recommended for outpatient treatment, whereas patients in the next three classes were recommended for inpatient treatment, with a strong recommendation for ICU-based treatment for those in class V [10]. The PSI, however, has some limitations. Probably overemphasizing the relative weight of the age in the calculation, it might occasionally underestimate the severity of pneumonia in younger patients. Moreover, the large number of variables makes it quite complex to be used in a crowded Emergency Department (ED). Facing with the aforementioned problems, the British Thoracic Society (BTS) subsequently derived its own, simpler prediction rule (Confusion, Urea, Respiratory-Rate, Blood-Pressure; CURB), which is also based on the 30-day risk of mortality and which has been further modied in 2003 by Lim and colleagues to CURB-65 [11]. This score, afterwards studied in N12,000 patients, is much easier to remember and use (e.g., as compared with the PSI), since it is composed of only ve variables with a single point awarded for each. CRB-65, a simplied algorithm not requiring the measurement of blood urea, has been then recommended for outpatients use [12]. Several clinical investigations

0953-6205/$ see front matter 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.02.023

G. Lippi et al. / European Journal of Internal Medicine 22 (2011) 460465 Table 1 Leading microorganisms causing community-acquired pneumonia. Agent Outpatients Non-intensive care unit inpatients X X X X X Intensive care unit inpatients X

461

Streptococcus pneumoniae Chlamydophila pneumoniae Mycoplasma pneumoniae Haemophilus inuenzae Respiratory viruses (inuenza A and B, adenovirus, respiratory syncytial virus, and parainuenza) Legionella species Staphylococcus aureus Gram-negative bacilli

X X X X X

X X

X X X

included in a recent meta-analysis have shown that the two scoring systems exhibit similar performances in predicting mortality and in identifying the low-risk categories of patients [12], so that both the PSI and CURB-65 have been internationally adopted, and are now recommended along with the clinical judgment by a large number of national and international Guidelines. The use of these two scoring systems allows to stratify the mortality risk and to identify the optimal treatment setting although rather obviously they are unable to limit ICU transfers or lower the overall mortality. To overcome this limitation, increasing interest is being placed on the potential usefulness of novel biomarkers, such as procalcitonin (PCT) and C reactive Protein (CRP) [5; Table 2]. 2. Traditional diagnostic approach to community-acquired pneumonia According to a historical perspective, there are three breakthroughs in the past three centuries that have contributed to clarify the clinical features of CAP. First, in 1761 the great Italian anatomist GB Morgagni published his fundamental work The seats and Causes of Diseases Investigated by Anatomy, correlating clinical ndings with post-mortem pathology. In his work he rstly described the consolidation changes occurring within the lung affected by pneumonia [13]. The second hallmark was the invention of the stethoscope, in 1816, by RTH Lannec. Lannec himself is credited with creating the terms rales, bronchophony, and egophony [14]. The third breakthrough has been undeniably the discovery of the clinical usefulness of X-rays (i.e., radiographs), by Rntgen, in 1885. The application of radiographs in the clinical assessment of the patients suspected of having pneumonia has lead to the denition of the disease as we now know, conrmed by the presence of an inltrate on the chest radiograph [15]. The clinical denition of CAP that has been used in community studies has varied widely, but has generally included a complex of symptoms and signs both from the respiratory tract and regarding the general health status of the patient. The terms lobar and typical/atypical pneumonia have outgrown their historical usefulness and are not yet recommended. The diagnosis of CAP is typically suspected in the presence of select clinical features (e.g., cough, fever, sputum production, and pleuritic chest pain) and is conrmed by imaging of the lung, usually by chest radiograph. Unfortunately, most patients do not have all the classic symptoms. Elderly patients with CAP more frequently present with nonspecic symptoms (i.e., decreased mentation and/or confusion, nonspe-

cic aches or pains), have comorbid disease, a higher mortality, and are less likely to have fever than younger patients. [6]. Several studies, including an ED evidenced-based review, have shown that there is no one historical nding or physical examination nding or combination of ndings capable to rule in or rule out the diagnosis of pneumonia [16]. Although chest radiograph is still the cornerstone in diagnosing CAP, it has also several limitations and does not have 100% sensitivity or specicity, since it can miss up to 31% of cases of suspected pneumonia [17]. CT scanning of the chest is therefore becoming increasingly popular, but has no routine role in the investigation of CAP at present [6]. Microbiological studies may support the diagnosis due to an infectious agent, but routine tests are frequently falsely negative and often nonspecic [1]. As many as 30% of patients presenting to an ED may have been already treated with antimicrobial agents by personal physician, previous ED visit, or even self-prescription [18]. Recommendations for diagnostic testing remain thereby controversial. The Infectious Diseases Society of America/American Thoracic Society Consensus Guidelines on the Management of CAP in Adults recently released a list of clinical indications for more extensive diagnostics, which have been developed on the basis of two main criteria that are when the result is likely to change individual antibiotic management and when the test is likely to have the highest yield [1]. On this basis, it was suggested that (i) routine diagnostic tests to identify an etiologic diagnosis are optional for outpatients with CAP (moderate recommendation, level III evidence), (ii) pretreatment blood samples for culture and an expectorated sputum sample for stain and culture should be obtained from hospitalized patients (moderate recommendation; level I evidence), (iii) pretreatment Gram stain and culture of expectorated sputum should be performed only if a goodquality specimen can be obtained and quality performance measures for collection, transport, and processing of samples can be met (moderate recommendation; level II evidence) and (iv) patients with severe CAP should at least have blood samples drawn for culture, urinary antigen tests for Legionella pneumophila and Streptococcus pneumoniae performed, and expectorated sputum samples collected for culture (moderate recommendation; level II evidence) [1]. Similarly, the British Thoracic Society guidelines for the management of CAP in Adults suggest the following investigations: oxygenation saturations (arterial blood gases when necessary), chest radiograph, urea and electrolytes, CRP (to distinguish CAP from other acute respiratory illnesses and as a baseline measure), full blood count, liver function tests and microbiological tests on all patients with moderate and high severity CAP [6]. 3. Biology and structure of procalcitonin PCT is a 116 amino acid protein, precursor of calcitonin, which is physiologically produced by the C-cells of the thyroid after intracellular processing of the prohormone [19]. The half-life of PCT is around 2024 h and the plasma concentration in healthy individuals is typically b0.1 g/L. PCT is probably catabolyzed by proteolytic degradation, whereas the kidney seems to play a minor role in its metabolism [19]. PCT is a relatively innovative and highly specic marker for the diagnosis of clinically relevant bacterial infections and sepsis, so that it is increasingly recognized as an important diagnostic tool in clinical practice (Table 3). Although high PCT levels are typically observed
Table 3 Leading applications of procalcitonin measurement [19].

Table 2 Scoring systems for diagnosis, risk stratication, monitoring and follow-up of CAP. Pneumonia Severity Index (PSI). CURB (Confusion, Urea, Respiratory-Rate, Blood-Pressure) CURB-65 (Confusion, Urea, Respiratory-Rate, Blood-Pressure, age 65 years) CRB-65 (Confusion, Respiratory-Rate, Blood-Pressure, age 65 years)

Diagnosis of infection with systemic inammation Differential diagnosis of inammatory diseases and fever of unknown origin Monitoring therapy and the course of bacterial infections Management of inammatory diseases of unknown origin Prognostic information and clinical management in sepsis, septic shock and multiple organ dysfunction syndrome

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after major surgery, trauma injuries as well as in other pathological situations and infections characterized by the onset of organ dysfunction such as sepsis or septic shock (i.e., PCT serum levels N0.5 g/L usually reect acute infections accompanied by a systemic inammatory reaction), there are emerging evidence that PCT measurement might also be helpful in other clinically relevant conditions warranting various intensive therapeutic interventions, such as CAP. Localized bacterial or organ-related infections and capsulated abscesses might only trigger a modest PCT increase, whereas viral infections, autoimmune disorders and malignancies do not signicantly modify the plasma concentration of the protein [19]. The origin of inammatory-triggered PCT has not been fully elucidated as yet. There are however emerging evidences that the sources of PCT in inammation might be extrathyroidal, involving principally the macrophage and monocyte systems as well as the liver parenchyma, neurocrine cells of the lung and the intestine rather than the thyroid gland per se. This hypothesis is conrmed by the observation that bacterial endotoxins along with some pro-inammatory cytokines (e.g., TNF-alpha and IL-6) are powerful inducer of PCT synthesis [19]. The clinical usefulness of PCT is double. Whereas a single basal measurement is helpful for establishing a diagnosis of bacterial infections and a differential diagnosis with non-bacterial disorders (e.g., acute pancreatitis, viral meningitis, non-infectious acute respiratory distress syndrome, non-bacterial fever in immunosuppressed patients, acute organ rejection), serial measurement of PCT can be used for the follow-up of disease and to monitor the effectiveness a given therapeutic regimen in severe bacterial infection, since increasing values reect continuing disease activity while a decrease mirrors the potential resolution of the infection [19]. 4. Diagnostic and prognostic usefulness of inammatory biomarkers in CAP The release of PCT is generally modest in patients with isolated pneumonia due to the relative organ-circumscribed nature of the infection. Nevertheless, emerging evidence attests that the measurement of this marker might be useful in CAP because the most frequently used markers (body temperature, leukocytosis, CRP) display suboptimal sensitivity and specicity [20]. While Ruiz-Gonzlez et al. recently concluded that changes in CRP levels might be useful to monitor the treatment of CAP and thereby help the clinical decision making [21], several other clinical investigations have proven that alternative testing strategies might be at least as useful. Lee et al. assessed the serum levels of PCT and CRP as well as the ESR and the leukocytosis in hospitalized patients with CAP and healthy controls, concluding that serum PCT level had comparable diagnostic performances than CRP in Receiver Operating Characteristic (ROC) curves analysis (area under the curve [AUC]: 0.83 versus 0.77), both markers displaying a greater AUC than ESR (AUC: 0.73). A PCT value N1 g/L had a sensitivity of 90% and a specicity of 83%, whereas a CRP N6 mg/L displayed sensitivity and specicity of 90% and 38%, respectively [22]. Mller et al. also carried out a prospective cohort study including 925 patients with CAP who underwent blood culture sampling on hospital admission. PCT was conrmed as a signicantly better predictor for blood culture positivity than White Blood Cells (WBC) count, CRP and other clinical parameters. Antibiotic pretreatment and PCT serum levels (adjusted odds ratio: 3.72; p b 0.001) were the only independent predictors in multivariate regression analysis. Specically, it was demonstrated that a 0.1 g/L PCT cutoff would reduce the total number of blood cultures by 12.6%, still retaining a diagnostic sensitivity of 99% as compared with blood cultures [23]. In a further investigation, the ProHOSP Study Group assessed the performance of PCT to predict all-cause mortality and adverse events within 30 days follow-up in the identical cluster of CAP patients. PCT titers were stratied into four groups (b0.1; 0.1

0.25; 0.250.5 and N0.5 g/L) and compared with both PSI and CURB65 score. Although the initial PCT levels performed only moderately for predicting mortality in ROC curves (AUC: 0.60) and did not substantially improve the clinical risk scores, the follow-up measurements on the following days showed much better diagnostic performances (AUCs of 0.61, 0.68 and 0.73 at days three, ve and seven, respectively). The calculated AUC was 0.66 for prediction of adverse events and PCT also improved signicantly the PSI (AUC from 0.67 to 0.71) and the CURB65 (AUC from 0.64 to 0.70). Finally, PCT tiers signicantly separated patients within PSI and CURB65 risk classes for adverse events prediction [24]. The ProHOSP Study Group also assessed clinical parameters and ve biomarkers, the precursor levels of proadrenomedullin (ProADM), endothelin-1 (ET1), atrial natriuretic peptide (ANP), copeptin and PCT in patients with lower respiratory tract infections and CAP as compared with PSI and CURB65 score to predict serious complications (i.e., death, ICU admission and disease-specic complications). The AUCs for predicting serious complications in CAP patients were 0.72 for ProADM and ET1, 0.70 for copeptin, 0.66 for PCT and 0.65 for ProANP. The combination of proADM alone (or all ve biomarkers jointly) with PSI and CURB65 scores signicantly increased the AUC from 0.69 to 0.75 for PSI and from 0.66 to 0.73 for CURB65 [25]. In a multicenter prospective cohort study in 28 community and teaching EDs, Huang et al. described the pattern of PCT in CAP patients and assessed whether this marker might provide useful prognostic information beyond the PSI and CURB65. When used alone, PCT was shown to have modest diagnostic performances (35% specicity and 92% sensitivity; 1.41 positive likelihood ratio and 0.22 negative likelihood ratio). The combination of PCT with the PSI minimally improved the overall diagnostic efciency, although subjects with PCT levels b0.1 g/L had a lower 30- day mortality regardless of clinical risk. Moreover, only 25% of the high-risk patients (PSI classes IV/V) had PCT levels b0.1 g/L, displaying a negative likelihood ratio of 0.09 (similar results were observed after CURB-65 stratication). PCT b0.1 g/L was also associated with lower burden of other adverse outcomes. As such, it was concluded that a selective use of PCT in combination with existing rules may offer additional prognostic information in high-risk patients [26]. In the CAPNETZ study, 991 CAP patients were enrolled and followed-up for 28 days for survival. PCT, CRP and WBC were assessed to investigate the inuence of antimicrobial pre-treatment on these inammatory markers. Patients without antimicrobial pre-treatment were characterized by signicantly higher values of PCT and WBC, but not of CRP as compared with those with antimicrobial pre-treatment. Although the values of PCT, WBC and CRP were not signicantly different in survivors and non-survivors in the subset of patients with antimicrobial pre-treatment, survivors had lower values of PCT, WBC and CRP compared to non-survivors in those without antimicrobial pre-treatment. PCT, CRP and WBC were predictive for 28 day mortality in patients without antimicrobial pre-treatment but not in those with antimicrobial pre-treatment [27]. In a further CAPNETZ investigation innovative and traditional markers (i.e., midregional proadrenomedullin [MR-proADM], midregional proatrial natriuretic peptide [MR-proANP], copeptin, proendothelin-1 [CT-proET-1], PCT, CRP, WBC, clinical confusion, respiratory rate, blood pressure, and age over 65 years) were compared for prediction of short- and long-term all-cause mortality in CAP. In patients who died of any cause within 28 and 180 days, MR-proADM, MR-proANP, copeptin, CT-proET-1, PCT and CRB-65 were signicantly higher as compared with survivors. MR-proADM had the best performance for both 28 (hazard ratio: 3.67) and 180 days (hazard ratio: 2.84) survival. Time-dependent AUCs for survival outcome after 28 days were 0.85 for MR-proADM, 0.79 for MR-proANP, 0.77 for copeptin, 0.76 for CT-proET-1, 0.65 for PCT, 0.63 for WBC and 0.59 for CRP. Time-dependent AUCs for prediction of 180 days mortality were instead 0.79 for MR-proADM, 0.76 for CT-proET-1, 0.73 for MR-proANP, 0.72 for copeptin, 0.60 for

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WBC, 0.58 for both PCT and CRP [28]. The clinical usefulness of PCT assessment might not be limited to the diagnosis of CAP, but might also be integrated to establish disease severity and predict the prognosis. Okimoto et al. investigated 162 CAP patients with different degree of disease severity, and reported that PCT was positive in 12.8% of the patients with mild disease, 27.1% of those with moderate disease, 59.5% of the patients with severe disease, and 80.0% of those with super severe disease. The mortality was also signicantly different between PCT-positive and PCT-negative patients (37.7% versus 12.8%) [29]. Finally, Claessens et al. assessed the effectiveness of CRP, PCT, and ANP measures in assisting emergency physicians deciding hospital admission for CAP with low risk of complications [30]. Admission requirements were signicantly predicted by ANP (AUC: 0.76), PCT (AUC: 0.65) and CRP (AUC: 0.59). 5. Inammatory biomarkers-based algorithms for guiding CAP therapy As regards the therapeutic guidance, several small trials conrmed that the use of PCT-based clinical algorithms might lead to signicant reduction in antibiotic use with comparable rates of disease-related complications [3136]. In 2009, Schuetz et al. carried out a multicenter, noninferiority, randomized controlled trial in the EDs of 6 tertiary care hospitals in Switzerland, with an open intervention of 1359 patients with mostly severe lower respiratory tract infections [37]. The intervention was based on administration of antibiotics based on a PCT algorithm with predened thresholds for initiating or stopping antibiotics (PCT group), or according to standard guidelines (control group). Overall, the rate of overall adverse outcomes was similar in the PCT and control groups, but the mean duration of antibiotics exposure in the PCT group was lower in all patients (5.7 versus 8.7 days; relative change, 35%) as well as in those with CAP (7.2 versus 10.7 days; 32%), when compared with the control group. Antibiotic-associated adverse effects were expectedly less frequent in the PCT group (19.8% versus 28.1%; difference, 8.2%), and this difference was even more signicant in the subgroup of patients with CAP (difference, 10%). These data seem to attest that a strategy of PCT guidance might be effective to reduce both antibiotic exposure and antibiotic-associated adverse effects in patients with CAP. In the same year, Tang et al. performed a systematic review of the scientic literature to assess the effect of PCT-guided treatment in patients with different infections [38]. The seven studies with over 1400 patients included in the meta-analysis conrmed that PCT-guided therapy is associated with a signicant reduction in antibiotic prescription at inclusion (pooled odds ratio: 0.506), duration of antibiotic therapy (weighted mean difference: 2.785 days), total antibiotic exposure days/1000 days (pooled relative risk: 1.664) and length of stay in the intensive care unit (pooled weighted mean difference: 3.49 days), although no difference was observed in both length of stay in the hospital (pooled weighted mean difference: 1.003 days; p = 0.17) and mortality (pooled odds ratio: 0.838, p = 0.365). Identical results were obtained in a further metaanalysis carried out by Kopterides et al. in 2010 [39], who observed decreased duration of antibiotic therapy for the rst episode of infection (weighted mean difference: 2.36 days) and total duration of antibiotic treatment (weighted mean difference: 4.19 days). Moreover, the use of PCT-guided therapy was not associated with any apparent adverse clinical outcome including 28-day mortality (odds ratio: 0.93), intensive care unit length of stay (pooled weighted mean difference: 0.49 days), and relapsed/persistent infection rate (odds ratio: 0.97). Menndez et al. also investigated the usefulness of CRP and PCT to assess stability after 72 h of treatment and the absence of subsequent severe complications in 394 hospitalised patients with CAP [40]. The patients who achieved clinical stability at 72 h had signicantly lower levels of both CRP (4.2 versus 7 mg/dl) and PCT (0.33 versus 0.48 g/L). The AUC to predict the absence of severe complications after 72 h calculated by association of clinical stability with one of the two

biomarkers was slightly improved when using CRP (from 0.77 to 0.84), but not with PCT (0.77). The marker levels also fell below the cut-off points (0.25 g/L for PCT and 3 mg/dL for CRP) when clinical stability was achieved within 72 h, but no severe complications occurred. Recent data also support the role of PCT measurement for discriminating between severe lower respiratory tract infections of bacterial and pandemic H1N1 u origin [41], as well as for identifying bacterial co-infection in patients affected by H1N1 inuenza [42]. More recently, Bafadhel et al. compared the usefulness of both PCT and CRP in patients with a diagnosis of CAP and exacerbations of asthma or chronic obstructive pulmonary disease (COPD) [43]. Beside the signicant correlation between PCT and CRP, increased levels of both biomarkers were observed in patients with CAP. The AUC for discriminating patients with pneumonia (antibiotics required) from those with exacerbations of asthma (antibiotics not required) was 0.93 for PCT and 0.96 for CRP, values much greater than those calculated for other traditional parameters such as peripheral neutrophil counts (0.77), temperature on admission (0.65) and modied early warning score (0.54). Overall, the product of PCT and CRP yielded an AUC value of 0.98. For identifying patients with CAP, a CRP value N48 mg/L had optimal diagnostic performances (sensitivity 91% and specicity of 93%), whereas a 0.08 g/L PCT threshold value was characterized by a sensitivity of 89% and a specicity of 78%. As such, the use of a PCT threshold value of N0.25 g/L would have reduced antibiotic use by 93% in patients with exacerbation of asthma, by 91% in patients with exacerbation of COPD and 27% in those with pneumonia. Contextually, a CRP threshold value N48 mg/L would have reduced antibiotics by 88% in patients with asthma, 76% in patients with exacerbation of COPD, and 9% in patients with pneumonia. In both cases, withholding antibiotics from patients with low levels of biomarkers was not associated with adverse outcomes. The effectiveness of a PCT-based algorithm to guide antibiotic therapy was conrmed in a observational quality control survey outside of trial conditions, where it was reported that antibiotics were administered according to a prespecied PCT algorithm in 72.5% of patients, with non signicant increase of adverse medical outcome [44]. Finally, Almirall et al. also showed that serum CRP measurement might be useful for establishing the diagnosis of CAP in adult patients with lower respiratory tract infections (e.g., high CRP values are especially observed in patients with pneumonias caused by S. pneumoniae or L. pneumophila), and that high CRP values are also suggestive of severity, and thereby help deciding the appropriateness of inpatient care [45]. 6. Conclusions Due to the high prevalence and the large demand of healthcare resources, an accurate clinical and therapeutic decision making is crucial in patients with CAP. Although antibiotic policies are usually based on interpretation of national guidelines, in most cases they should be administered as soon as possible to inuence the prognosis [46]. Whether an algorithm combining inammatory (e.g., PCT, CRP and interleukin-6) or innovative biomarkers (e.g., MR-proANP, copeptin, CTproET-1, and MR-proADM) with a simple clinical score (e.g., the CRB65) might be really useful for guiding the clinical decision making in patients with CAP still merits further investigation. Nevertheless, emerging evidence form randomized controlled trials including over 3500 patients attests that at variance with other traditional inammatory and innovative biomarkers, PCT (and/or CRP) in conjunction with a thorough clinical assessment might help limiting unnecessary antibiotic use in primary care, ED, as well as in hospitalized and more severely ill patients with CAP [47] (Fig. 1), though most studies focused on lower respiratory tract infections. This is a valuable aspect for reducing bacterial resistance and decreasing medical costs and drug-related adverse events. While some evidences attest that CRP might display a similar accuracy for detection of CAP, PCT carries some advantages over other inammatory biomarkers. PCT is in fact a specic marker of infection rather than acute phase inammation, displays narrower

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Fig. 1. Clinical usefulness of procalcitonin (PCT) and C-reactive protein (CRP) in patients with community-acquired pneumonia.

plasma levels, is easy to measure on conventional laboratory instrumentation [48]. It is also noteworthy that point-of-care testing for PCT is becoming widely available (although not highly sensitive), thereby enabling a larger use of this strategy in smaller facilities and even outpatient physician ofces, providing timely information beyond that of readily available clinical examination. Nevertheless, the correct interpretation of PCT test results within the specic clinical setting (e.g.,. the cut-off for discontinuing antibiotics might differ among hospitalized, ICU and dialysis patients), the generalizability of the results of the published studies, as well as the accurate knowledge about the analytical (e.g., traditional versus highly-sensitive PCT assays), and clinical (e.g., the use of different cut-offs) characteristics of the different commercial assays are essential requisites for a meaningful use of this novel and attractive biomarker [47]. Learning points Due to the high prevalence and the large demand of healthcare resources, an accurate clinical and therapeutic decision making is crucial in patients with community-acquired pneumonia. Clinical signs, imaging techniques and scoring systems do not permit to guide clinicians in the choice of optimal therapeutic approach, limit intensive care unit transfers or lower the overall mortality. Emerging clinical evidence attests that procalcitonin and/or Creactive protein might help limiting unnecessary antibiotic use in primary care, emergency department, as well as in hospitalized and more severely ill patients with community-acquired pneumonia. Inammatory biomarkers-based algorithms for guiding communityacquired pneumonia therapy (especially those procalcitonin-based) might be effective to reduce bacterial resistance and decrease medical costs as well as drug-related adverse events.

Conict of interest All authors have no actual or potential conict of interest including any nancial, personal or other relationships with other people or organizations within three years of beginning the submitted work that could inappropriately inuence, or be perceived to inuence, their work. References
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