Bacterial pneumonia

Study objectives: To evaluate the usefulness of procalcitonin serum levels as a predictor of etiology and prognosis in adult patients with community-acquired pneumonia (CAP) when they are stratified according to severity.

Design: One-year, population-based, prospective study.

Setting: University teaching hospital.

Patients: All adult patients who received a diagnosis of CAP throughout the study period.

Interventions and measurements: An extensive nouinvasive microbiological workup was performed. In patients who gave informed consent, a blood sample was collected at the time the diagnosis of CAP was established to measure biological markers. Procalcitonin levels were measured by a commercially available monoclonal immunoluminometric assay (limit of detection, 0.1 [micro]g/L). Patients were classified according to microbial diagnosis, Patients Outcome Research Team pneumonia severity index (PSI), and outcome measures, and procalcitonin levels were compared among groups.

Results: Of 240 patients who received a diagnosis of CAP during the study period, procalcitonin concentrations were measured in 185 patients (77.1%). Levels were higher in patients with high-severity risk classes (PSI classes III-V) [p = 0.01] and in those with complications (p = 0.03) or death (p < 0.0001). Among patients classified into PSI low-severity risk classes (classes I-II), levels tended to be higher in those with bacterial etiology (p = 0.08); in this group, a serum procalcitonin level [greater than or equal to] 0.15 [micro]g/L was more frequently found in patients with bacterial pneumonia than in those with nonbacterial pneumonia (p = 0.03). In patients with higher-severity risk classes, no significant differences were observed in procalcitonin levels among etiologic groups, but higher concentrations were associated with development of complications (p = 0.01) and death (p < 0.0001).

Conclusions: Procalcitonin contribution to the evaluation of CAP varies according to severity. While procalcitonin may have a role to predict the microbial etiology in patients with a low PSI score, in patients classified within high PSI risk classes, it is a prognostic marker rather than a predictor of etiology.

Key words: biological markers; biomarkers; community-acquired pneumonia; etiology; outcome; pneumonia severity index; predictive scoring system; procalcitonin; prognosis

Abbreviations: CAP = community-acquired pneumonia; PORT = Patients Outcome Research Team; PSI = pneumonia severity index

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The utility of serum markers of systemic infection such as C-reactive protein, lipopolysaccharide-binding protein, or procalcitonin for the differential diagnosis of various infectious conditions has become a matter of interest in the last few years. Of all, procalcitonin stands out as one of the most accurate sepsis markers. (1,2) It has shown a superior diagnostic utility in sepsis when compared with C-reactive protein, interleukin-6, and lactate, and has been largely evaluated in multiple polymorbid situations, including lower respiratory tract infections, to discriminate bacterial infection from other causal mechanisms. (2)

Identifying clinically the etiology of community-acquired pneumonia (CAP) is difficult because single clinical, radiologic, or laboratory parameters have limited value to predict the infectious organism, (3) and no rapid test has been standardized for the diagnosis of "atypical" or viral pathogens. As a result, broadspectrum initial antibiotic therapy is usually empirically chosen. (4,5) Procalcitonin serum levels or other biological markers of bacterial infection might help clinicians to choose targeted antibiotic therapy in patients with CAP by differentiating between classic bacterial and atypical or viral etiology.

At present, there are few data addressing the usefulness of procalcitonin to predict etiology in patients with CAP, (6) and most clinical studies have been performed in children. Investigation in adult patients has mainly focused on lower respiratory tract infections. (7,8) While some studies (6,7,9) have found higher levels of procalcitonin in bacterial infections, there is no general agreement about the value of procalcitonin as a predictor of etiology. Recently, Christ-Crain et al (7) found that a procalcitonin-based therapeutic strategy was useful to reduce antibiotic use in lower respiratory tract infections, based on the ability of procalcitonin to discriminate between patients with or without clinically relevant bacterial infection. Similarly, procalcitonin serum levels were found to be higher in bacterial vs viral or atypical etiologies in two studies (6,9) of CAP, one of them performed in children. In contrast, in other studies, (8,10,11) no differences were found in procalcitonin levels between bacterial and nonbacterial etiologies.

Procalcitonin has been mainly associated with severe systemic infection. (12,13) A correlation between increased serum concentration and the severity of infection, clinical course, and mortality has been previously reported. (12-14) Most studies (6,8,15) of lower respiratory tract infections have also disclosed an association between procalcitonin levels and prognosis. The usefulness of procalcitonin to predict etiology of CAP when patients are stratified by severity according to the Patients Outcome Research Team (PORT) pneumonia severity index (PSI) has not been previously assessed. Since CAP caused by "classic" bacteria usually implicates a higher severity of disease, (16) high levels of procalcitonin in this setting might also indicate a worse prognosis rather than any specific microbial etiology. In addition, it is not known if procalcitonin maintains its prognostic value when patients are classified by severity risk classes. To determine the usefulness of procalcitonin as a predictor of etiology and prognosis in adult patients with CAP when they are stratified according to PSI score, we analyzed data from a population-based study in which patients were prospectively evaluated and an extensive microbiological investigation was carried out.

MATERIALS AND METHODS

Setting and Population Studied

A prospective, population-based investigation of CAP was conducted over a 24-month period (October 1.5, 1999, through October 14, 200i) at Hospital Universitario de Elche, a 430-bed teaching hospital covering a population of 239,335 people living in three municipalities of the "Health Authority of Bajo Vinalopo," on the Mediterranean coast of Spain. All adult patients ([greater than or equal to] 15 years old) from this health authority with signs and symptoms compatible with pneumonia over the 24-month study period were eligible for inclusion in the study. The study was approved by the local ethical committee. Attending clinicians were asked to consider pneumonia in any patient with an acute illness and symptoms suggesting lower respiratory tract infection, including new cough with high fever or chills, pleuritie chest pain, dyspnea, or prolonged fever. Patients were evaluated clinically and roentgenographically, and those with a provisional diagnosis of CAP were seen by a study investigator to confirm the diagnosis. CAP was defined as an acute illness associated with at least one of the following signs or symptoms: fever, new cough with or without sputum production, pleuritic chest pain, dyspnea, or altered breath sound on auscultation, plus a chest radiograph showing an opacity compatible with the presence of acute pneumonia. Patients with a prior hospitalization within 2 weeks of a current diagnosis of pneumonia were excluded. Demographic and clinical data were collected by a study investigator using a written standardized questionnaire.

To calculate the severity of pneumonia we used the PORT predictive PSI scoring system, (17) which classifies patients according to outcome in five risk classes (class I includes patients with the most favorable prognosis, and class V includes those with the poorest prognosis). The score of classes I and II is [less than or equal to] 70 points; class III, 71 to 90 points; class IV, 91 to 130 points, and class V, > 130 points. All patients were followed up for at least 4 weeks or until death. A repeat chest radiograph and blood sample were obtained from 2 to 4 weeks after the initial diagnosis of CAP.

During the first 12-month study period from October 15, 1999, to October 14, 2000, patients enrolled in the investigation who gave their informed consent had a blood sample collected within the first 24 h after fulfilling the pneumonia criteria, for measuring biological markers. Subjects recruited through that time period comprised the cohort included in this study.

Microbiological Investigations

The laboratory workup for a patient with CAP has been previously described in detail. (18) Briefly, it included sputum samples for Gram stain and culture, two blood samples for culture, urine sample for detection of Legionella pneumophila and Streptococcus pneumoniae antigens, and serum samples for serologic testing drama during the acute stage of the illness and at least 2 weeks later.

Criteria for Etiologic Diagnosis

The following criteria were used to classify a pneumonia as being of known etiology: (1) for Mycoplasma pneumoniae, Chlamydia psittaci, Coxiella burnetii, influenza viruses A and B, parainfluenza virus, respiratory syncytial virus, and adenovirus: a fourfold or greater antibody rise by complement fixation test; (2) for Chlamydia pneumoniae: a fourfold rise in microimmunofluorescence antibody titters to [greater than or equal to] 1/128, or the presence of IgM antibodies ([greater than or equal to] 1/20); (3) for L pneumophila: isolation of organism from respiratory samples or Legionella antigen detected in urine, or fourfold or greater rise in immunofluorescence antibody titer; (4) for S pneumoniae: isolation from blood or from pleural fluid or the predominant organism isolated from a qualified sputum, or antigen detected in urine; (5) for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and other bacteria, including Gram-negative enterobacteria: isolation from blood or from pleural fluid or the predominant organism isolated from a qualified sputum. Organisms included in the definition of "bacterial" pneumonia and pneumonia caused by atypical pathogens are shown in Table 1. Cases that fulfilled the etiologic diagnostic criteria described above for more than one pathogen were considered mixed pneumonia. Mixed pneumonia included the following combinations of two or more pathogens: classic bacteria plus atypical organisms, atypical organisms plus viruses, two or more classic bacteria, two or more atypical organisms, and two or mores viruses. Cases that did not fulfil the etiologic diagnostic criteria described above were considered "pneumonia of unknown etiology."

Detection of Procalcitonin

Samples were centrifuged, decanted, aliquoted, and frozen at -80[degrees]C until analyzed in May 2003. Procalcitonin levels were measured by monoclonal immunoluminometric assay (Liaison Brahms PCT; Brahms Diagnostica GMBH; Berlin, Germany; limit of detection, 0.1 [micro]g/L). (19) Biochemical testing was performed in a blinded fashion, without knowing the results of other microbiological investigations.

Data Analysis

Patients were classified according to microbial diagnosis and outcomes measures. Procalcitonin levels in etiologic groups were compared in the whole sample of patients, in patients with PSI-defined low-risk classes (I-II), and in patients with PSI-defined high-risk classes (III-V). A cutoff point of procalcitonin was established to separate bacterial from nonbacterial CAP after obtaining the results of the analysis. Using receiver operating characteristic curves, a cutoff point of 0.15 [micro]g/L showed the best discriminatory power. Serum levels of procalcitonin were also compared between patients with PSI-risk classes I-II and III-V, those who had or did not have complications, and those who died or survived. Since a cutoff point of 0.5 [micro]g/L has also been found to have discriminatory power in previous studies, (8,13,15) a comparison of patients according to this value was also made. Statistical analysis was performed using software (SPSS Version 11; SPSS; Chicago, IL). Descriptive statistics were computed by standard methods. To detect differences between specified groups, we used the Mann-Whitney U test for continuous variables, as they were not normally distributed according to the Kolmogorov-Smirnov test. For categorical variables, we used the [chi square] test or Fisher Exact Test where appropriate. A two-tailed p value of 0.05 was considered significant.

RESULTS

Of 251 patients evaluated from October 15, 1999, to October 14, 2000, 11 patients were subsequently found not to have CAP, leaving 240 patients in the study cohort. The mean age was 59 years (range, 15 to 93 years), and 62.5% were male. In 115 patients (48%), there was one or more underlying disease, mostly diabetes mellitus (n = 55) and COPD (n = 51). Sixty patients (25%) had previously been treated with antibiotics.

The causative pathogen was found in 131 of the 240 patients (54.6%) [56 classic bacterial pathogens, 43 atypical pathogens, 16 viral pathogens, and 16 mixed]. In 154 patients (64.2%), the pneumonia resolved without complications, and the following complications developed in 49 patients (20.4%): septic shock, 6 patients (2.25%); mechanical ventilation requirement, 4 patients (1.7%); and empyema, 2 patients (0.8%). Seventeen of the 240 patients (7.1%) died.

Procalcitonin serum levels were measured in 185 patients (77.1%). In the remaining patients, the test was not performed because a serum sample obtained within the first 24 h of diagnosis of pneumonia was not available or was insufficient. There were no differences in age, sex, comorbidity, or PORT PSI scores between patients in whom procalcitonin was measured and those in whom it was not (data not shown). The etiologic distribution of the 185 eases is shown in Table 1. There were no significant differences in procalcitonin levels between major etiologic groups (Fig 1), although patients with bacterial pneumonia showed a wider interquartile range compared with the rest of the patients.

[FIGURE 1 OMITTED]

The severity of pneumonia was assessed using the PORT PSI. Overall, the median PSI score was 70.0 (range, 9 to 172) in the 185 patients. The median PSI score was lower in patients with pneumonia due to atypical organisms: 51.0 (range, 9 to 150) vs 77.0 (range, 15 to 172) in the rest of the pneumonias (p = 0.002). No significant differences were observed in median PSI scores among the other etiologic groups: 82.0 (range, 20 to 159) in bacterial pneumonia, 82.0 (range, 15 to 138) in viral pneumonias, 77.5 (range, 21 to 132) in mixed pneumonia, and 75 (range, 20 to 172) in pneumonias of unknown etiology. Mean procalcitonin levels were calculated according to PSI risk class. Mean procalcitonin value was 0.33 [micro]g/L (range, 0.10 to 8.95 [micro]g/L) in class I; 0.27 [micro]g/L (range, 0.10 to 3.45 [micro]g/L) in class II; 0.44 [micro]g/L (range, 0.10 to 10.57 [micro]g/L) in class III; .77 [micro]g/L (range, 0.10 to 6.80 [micro]g/L) in class IV; and 1.15 [micro]g/L (range, 0.10 to 5.47 [micro]g/L) in class V. Patients included in risk classes III-V (PORT PSI > 70) had a mean procalcitonin value of 0.67 [micro]g/L (range, 0.10 to 10.57 [micro]g/L), compared to 0.31 [micro]g/L (range, 0.10 to 8.95 [micro]g/L) in those included in classes I-II (p = 0.01). Likewise, patients with complications (including empyema, mechanical ventilation requirement, or septic shock) or who died had a higher procalcitonin level than those who did not (p = 0.03 and p < 0.0001, respectively) [Table 2].

Patients were stratified according to PSI-defined risk classes in those with a low risk (classes I-II) and with a higher risk (classes III-V). When procalcitonin serum levels were again evaluated according to the etiology, among patients classified into classes I-II, those with CAP caused by classic bacteria tended to have higher procalcitonin levels than patients with CAP of any other etiology, although differences did not reach statistical significance (p = 0.08) [Fig 2]. A cutoff point of procalcitonin of [greater than or equal to] 0.15 [micro]g/L captured 37.5% of the patients with bacterial etiology and 13.3% of the patients with other etiologies (p = 0.03). No differences in procalcitonin levels were found between etiologic groups in patients included in classes III-V (Fig 2). Development of complications and death were significantly associated with higher procalcitonin levels in patients of PSI-defined risk classes III-V (p = 0.01 and p < 0.0001, respectively). No differences in procalcitonin levels in connection to development of complications or death were found in patients of PSI-defined risk classes I-II.

In 21 patients, procalcitonin serum levels were [greater than or equal to] 0.5 [micro]g/L. The clinical characteristics of these 21 patients were compared with those of the 164 patients with procalcitonin serum levels < 0.5 [micro]g/L (Table 3). There were no differences in age, previous antibiotic therapy, body temperature, pulse rate, systolic BP, platelet count, or etiology. Patients with procalcitonin levels [greater than or equal to] 0.5 [micro]g /L, however, had a higher PORT PSI score (p < 0.0001), higher respiratory rate (p = 0.001), higher WBC and neutrophil counts (p = 0.01), and lower diastolic BP (p = 0.02) compared to those with procalcitonin levels < 0.5 [micro]g/L. Mortality was also higher in patients with procalcitonin levels [greater than or equal to] 0.5 [micro]g/L (p = 0.001). When the same procalcitonin cutoff point was considered, and patients with PSI-risk classes I-II were evaluated, only respiratory rate was significantly higher in patients with procalcitonin levels [greater than or equal to] 0.5 [micro]g/L (p = 0.005). In patients with PSI-risk classes III-V, those with procalcitonin levels [greater than or equal to] 0.5 [micro]g/L also had lower systolic BP (p = 0.04); lower diastolic BP (p = 0.02); higher rate of complications including empyema, mechanical ventilation requirement, or septic shock (p = 0.02); and higher frequency of death (p = 0.003).

DISCUSSION

The results of this study suggest that procalcitonin contribution to the evaluation of patients with CAP varies according to severity of pneumonia. While procalcitonin may have a role to predict the microbial etiology in patients with a low PSI score, in patients classified within high PSI risk classes it is a prognostic marker rather than a predictor of etiology.

To our knowledge, this is the largest study to date performed in adults with CAP in which procalcitonin serum levels have been evaluated as a predictor of etiology. Herein, strict criteria were used for the microbial diagnosis, and a final etiologic diagnosis was achieved in a relatively high number of patients, compared to other studies (6) in which procalcitonin levels were measured. In addition, biochemical testing for detection of procalcitonin was performed in a blinded fashion to avoid any classification bias. In the present study, no differences in procalcitonin levels were found between major etiologic groups when the whole sample of patients with CAP was considered. However, when patients were stratified according to PSI, the highest procalcitonin levels predicted bacterial etiology in patients with a low PSI score (risk classes I and II). No differences in procalcitonin levels were found between major etiologic groups in patients with higher PSI scores (risk classes III-V).

The results of this study corroborate that procalcitonin is a good predictor of severity of pneumonia, as previously described. (6,8,15) Patients with a higher PSI score or with complications or death had significantly higher procalcitonin levels than those with an uncomplicated clinical course. Additionally, patients with higher procalcitonin levels also had other markers of a more severe disease, such as higher WBC or neutrophil counts and respiratory rate.

CAP syndrome comprises a wide spectrum of severity of disease, even when only bacterial pneumonia is considered. (20) In our study, classic bacteria pneumonia was the most frequent etiology in the subset of patients with higher procalcitonin concentrations, but also atypical organisms and viruses were found in this group. Besides bacteria, severe cases of pneumonia due to atypical organisms and viruses have been reported, (21) and distribution of pathogens in severe and nonsevere disease forms has been found to be comparable in a previous study (20) of severe CAP. Our study showed that in CAP patients with a high PSI score, procalcitonin levels were elevated independently of the microorganism implicated, and there were no significant differences in procalcitonin values between main etiologic groups. Procalcitonin levels are raised in severe systemic inflammatory syndrome and sepsis and also in noninfectious marked systemic inflammation, such as inhalation burn injury (22) or chemical pneumonitis, (23) Therefore, high procalcitonin levels are not only a predictor of bacterial etiology. By contrast, in patients included in the lowest PSI risk classes (I and II), in which overall procalcitonin levels are also low, higher values of procalcitonin may be useful to predict bacterial etiology. This information can be used by clinicians to select targeted antimicrobial therapy in a proportion of patients with CAP. The discrepancies between the diverse studies of lower respiratory tract infections in which procalcitonin has been evaluated as a predictor of etiology might be explained by the spectrum of severity of disease of the population included in each study.

Overall, we found lower procalcitonin serum concentrations than those described in patients with lower respiratory tract infections or CAP in other studies. (6,7,10) However, in those studies, only patients admitted to the hospital were included and mean age was higher, (6,7) both factors usually associated with a higher severity of infection and subsequently potentially higher values of procalcitonin. Our study was population based, with a wide spectrum of severity of disease and age range. When patients with CAP not admitted to the hospital have also been included, lower serum procalcitonin levels have been found. (11,15)

The present study has some limitations and potential biases that should be acknowledged. Unfortunately, as in most pneumonia studies, despite the extensive microbiological investigation carried out, the etiology remained unidentified in a considerable proportion of cases because of the low sensitivity of conventional microbiological tests. As a result, the sample size in some of the etiologic groups was small, and the lack of statistical power may have precluded us to detect significant differences among groups. An additional challenge facing all new laboratory techniques used for the etiologic diagnosis of CAP relates to the lack of a satisfactory reference standard for the microbial diagnosis. Although the chosen criteria in this study were very strict, some microbiological tests may not have sufficient diagnosis accuracy to rule out etiologic misclassification, including the possibility of mixed infections in some cases (eg, bacterial superinfection in cases of viral pneumonia). Finally, a subset of patients had been previously treated with antibiotics, and this factor may have influenced the level of procalcitonin.

The limitation of procalcitonin as a diagnostic marker in patients with CAP may be related to the low sensitivity of the commercially available assay. This assay may be useful to detect markedly elevated procalcitonin in patients with severe systemic bacterial infection or sepsis, but it may not be sensitive enough to detect mildly or moderately elevated procalcitonin levels, which limits its diagnostic use in conditions other than overt sepsis. (24) Christ-Crain et al, (7) who employed a lower limit of detection (0.06 [micro]g/L instead of 0.1 [micro]g/L) in their study, supported that diagnostic accuracy of procalcitonin depends on the sensitivity of the assay for its determination. A lower limit of detection should have helped to characterize better the differences between the major etiologic agents implicated in the patients with low PSI scores, in which many values were under the limit of detection. Further studies should evaluate whether more sensitive procalcitonin assays have a superior accuracy as diagnostic markers in patients with CAP.

In conclusion, the role of serum procalcitonin in adult patients with CAP differs among the PORT PSI score groups. Procalcitonin is mainly a marker of poorer outcome in patients with CAP classified into PSI high-severity risk classes, whereas in low-severity risk classes it may help clinicians to predict classic bacteria and subsequently to select empiric antimicrobial therapy.

This work was performed at Hospital General Universitario de Elche, Alicante, Spain.

Manuscript received March 20, 2005; revision accepted April 7, 2005.

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Mar Masia, MD; Felix Gutierrez, MD; Conrado Shum, MD; Sergio Padilla, MD; Juan Carlos Navarro, MD; Emilio Flores, MD; and Ildefonso Herndndez, MD

* From the Infectious Diseases Unit, Internal Medicine Department (Drs. Masia, Gutierrez, and Padilla), Pneumology Section (Dr. Shum), and Biochemistry Section (Drs. Navarro and Flores), Hospital General Universitario de Elche Alicante; and Public Health Department (Dr. Hernandez), Miguel Hernandez University, Alicante, Spain.

Correspondence to: Mar Masia, MD; Unidad de Enfermedades Infecciosas, Hospital General Universitario de Elche, Cami de la Almazara S/N; 03203 ELCHE, Alicante, Spain; e-mail: marmasia@ya.com

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