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Original article
Correlation of inflammatory and cardiovascular biomarkers with pneumonia severity scores
Correlación entre los niveles de biomarcadores inflamatorios y cardiovasculares con los índices de severidad de neumonía
Alicia Lacomaa,c, Albert Basa, Pere Tudelab, Montse Giméneza, Josep Maria Mòdolb, Miguel Péreza, Vicente Ausinaa,c, Jose Domingueza,c, Cristina Prat-Aymericha,c,
Corresponding author
cprat.germanstrias@gencat.cat

Corresponding author.
a Servei de Microbiologia, Hospital Universitari Germans Trias i Pujol, Institut d’Investigació Germans Trias i Pujol, Universitat Autonòma de Barcelona, Badalona, Spain
b Unitat de Curta Estada-Urgències, Hospital Universitari Germans Trias i Pujol, Institut d’Investigació Germans Trias i Pujol, Universitat Autonòma de Barcelona, Badalona, Spain
c CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Spain
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severity rules consider several clinical&#44; analytical and radiological findings that jointly reflect patient&#39;s general condition&#46; Although these rules can be useful for the management of patients with pneumonia&#44; they also present some disadvantages such as age overemphasis and complexity for its calculation&#46; In the last years&#44; two other severity scores have been defined&#58; severe CAP &#40;SCAP&#41; that was developed for identifying patients who are at risk for an adverse outcome and might need ICU admission&#44; being as accurate as current scoring systems<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5</span></a> and SMART-COP&#44; mainly designed for the prediction of patients that are likely to require intensive respiratory or vasopressor support &#40;IRVS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Main drawbacks for these last scores are the lack of consideration for the presence of comorbidities and the need of more testing and validation&#44; although results from a recent meta-analysis indicate their usefulness for the prediction of ICU admission or intensive treatment in patients with CAP&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In a study with patients aged &#60;50&#44; SMART-COP was superior to PSI and CURB-65 for the prediction of IRVS&#44; but incorrectly stratified 15&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In the last years&#44; it has also become more evident that it is also important to consider host inflammatory and cardiovascular response to an infection&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Procalcitonin &#40;PCT&#41;&#44; C-reactive protein &#40;CRP&#41; and neopterin are examples of biomarkers that can be useful for the management of patients with pneumonia&#44; as a correlation with the etiological origin and the severity has been demonstrated&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> Biomarkers reflecting cardiovascular impairment &#40;including endothelial dysfunction and volume homeostasis&#41; have also emerged as useful tools for pneumonia management&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a> Adrenomedullin &#40;ADM&#41; is a member of the CALC-gene family and has potent vasodilating&#44; immune modulating and metabolic properties&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Atrial natriuretic peptide &#40;ANP&#41; is synthesized by cardiac atrial myocytes in response to proinflammatory factors&#44; hypoxia and conditions of increased cardiac pressure and volume overload&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Biochemical assays aim specifically at the mid-region of the ADM and ANP precursors &#40;MR-proADM and MR-proANP&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a> Levels of both biomarkers have been evaluated as severity and prognostic markers in CAP and chronic obstructive pulmonary disease &#40;COPD&#41; exacerbations correlating with PSI&#44; CURB-65&#44; the simpler CRB-65 and prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#8211;23</span></a> Indeed these biomarkers have shown to improve usefulness of validated scores&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a> However&#44; little is known about how these biomarkers correlate with the severity indexes&#58; SCAP and SMART-COP&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Inflammatory and cardiovascular biomarkers have shown to correlate to some extent with etiology&#44; severity of CAP and to mortality risk scores&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;26</span></a> Therefore&#44; we hypothesized that biomarkers should also correlate to severity scores primary aimed to identify patients needing intensive care and even improve its usefulness&#46; Therefore&#44; the main objective of this study was to assess the correlation of PCT&#44; CRP&#44; neopterin&#44; MR-proANP and MR-proADM levels with mortality risk scores&#44; focusing on SCAP and SMART-COP&#46; The secondary objectives were to confirm the correlation of biomarkers with short term mortality and to evaluate its usefulness for identifying bacterial etiology&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patients and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design and setting</span><p id="par0025" class="elsevierStylePara elsevierViewall">The study is observational&#44; descriptive and analytical and was approved by the ethical committee of the institution&#46; Population consists of patients attending a tertiary public university hospital with fever and symptoms of lower respiratory tract infection &#40;LRTI&#41; that consulted the medical area of the emergency department &#40;ED&#41; &#40;excluding surgical&#44; gynecological and pediatric areas&#41; and from whom blood cultures were obtained&#46; Patients were consecutively included during two months period&#46; Patients were followed up for 30 days after admission&#46; Pneumonia was defined by clinical &#40;presence of fever&#44; cough and dyspnea&#41; and radiographic signs &#40;pneumonic infiltrate in the chest radiograph&#41;&#44; as well as clinical evolution&#44; assessed by expert clinicians and radiologists&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Final diagnosis was set according to the clinical judgment mentioned in the emergency and hospital medical files&#44; or in the records of outpatient care&#46; For doubtful cases&#44; a consensus was achieved by three expert clinicians&#46; People conducting the chart abstraction&#44; and reviewing chest X-rays were blinded to the study hypothesis and blinded to biomarkers values&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Data collection and sample processing</span><p id="par0030" class="elsevierStylePara elsevierViewall">Epidemiological&#44; clinical&#44; microbiological&#44; analytical and radiological data were recorded from all cases&#46; Charlson index was also calculated for each patient&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Patients were stratified according to the PSI&#44; CURB-65&#44; SCAP and SMART-COP&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;5&#44;6</span></a> SMART-COP was calculated if all variables were available&#46; SMRT-CO was applied in cases when either one of the following variables was not recorded&#58; albumin&#44; arterial pH&#44; or Pa O<span class="elsevierStyleInf">2</span>&#46; Complications considered were&#58; respiratory failure &#40;Pa O<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>mmHg&#41;&#44; shock &#40;hypotension persisting despite fluid resuscitation and requiring vasopressor therapy&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> need of ICU admission&#44; and death&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">At the time of arrival to the ED&#44; samples were collected for microbiological diagnosis&#58; blood cultures&#44; respiratory specimens for culture and urine for antigen detection&#46; Pneumococcal pneumonia was diagnosed by isolation of <span class="elsevierStyleItalic">Streptococcus pneumoniae</span> from blood and&#47;or pleural effusion culture and&#47;or detection of C-polysaccharide antigen by inmunochromatography &#40;ICT&#41; &#40;Binax Now <span class="elsevierStyleItalic">S&#46; pneumoniae</span> urinary antigen test&#44; Binax&#46; Maine&#44; USA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In COPD patients&#44; because of the lack of specificity of ICT&#44;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> detection of polysaccharide capsular antigen was performed by counterimmunoelectrophoresis&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a><span class="elsevierStyleItalic">Legionella</span> pneumonia was diagnosed by urinary antigen detection of <span class="elsevierStyleItalic">Legionella pneumophila</span> serogroup 1 by enzyme immunoassay &#40;Bartels EIA <span class="elsevierStyleItalic">Legionella</span> urinary antigen&#44; Trinity Biotech Company&#44; Ireland&#41; or microorganism isolation in a respiratory sample&#46; Definite bacterial origin also included cases with isolation of a microorganism different from <span class="elsevierStyleItalic">S&#46; pneumoniae</span> from blood culture and&#47;or pleural effusion culture&#46; The isolation of a predominant microorganism in the sputum samples was considered as probable etiology and not as a definite diagnosis&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Plasma samples were collected at ED admission&#44; together with first routine hemogram&#46; All samples were stored at &#8722;20<span class="elsevierStyleHsp" style=""></span>&#176;C until biomarkers measurements&#46; CRP was measured by turbidimetric assay &#40;RCRP&#44; Siemens Dimension Rxl Max&#44; Siemens&#44; Germany&#41;&#46; PCT&#44; MR-proANP and MR-proADM were measured with an immunofluorescent assay &#40;KRYPTOR BRAHMS AG&#44; Germany&#41; and neopterin levels with a competitive immunoassay following the manufacturer&#39;s instructions &#40;Neopterin ELISA&#44; IBL&#44; Germany&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Categorical variables are expressed as counts &#40;percentages&#41; and continuous variables as mean and standard deviation &#40;SD&#41; or as median and interquartile range &#40;IQR&#41;&#44; as appropriate&#46; Biomarkers levels are expressed as median and IQR&#46; Correlation analysis was performed using Spearman&#39;s correlation&#46; The <span class="elsevierStyleItalic">&#967;</span><span class="elsevierStyleSup">2</span>-test was used to compare categorical variables&#46; In case of quantitative variables&#44; Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span>-test and Kruskal&#8211;Wallis were used as appropriate&#46; To assess the accuracy of biomarkers for predicting the development of complications&#44; we performed receiver operating characteristic curves and determined the area under the curve &#40;AUC&#41;&#44; standard error &#40;SE&#41; and 95&#37; confidence interval &#40;95&#37; CI&#41;&#46; Associations were considered statistically significant if <span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46; The commercial statistical software package used was SPSS 15&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; IL&#44; USA&#41;&#46;</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">Samples from 162 patients were collected and after retrospective analysis&#44; 85 patients were considered to have presented with pneumonia&#46; Alternative diagnoses were COPD exacerbation &#40;25 patients&#41; and other bronchial infections without pneumonic infiltrate in chest X-ray &#40;52 patients&#41;&#46; In <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> biomarker levels in the three study groups are shown&#46; PCT &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; CRP &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;008&#41; and MR-proADM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41; showed significant differences when comparing levels in the three groups while no differences were found for MR-proANP and neopterin&#46; Specifically&#44; PCT showed significantly higher levels in pneumonia when comparing with COPD exacerbation &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; and bronchial infection &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#46; Levels of PCT were similar in COPD exacerbation and bronchial infection groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;446&#41;&#46; CRP only showed significantly higher levels when comparing pneumonia and bronchial infection groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#46; Finally&#44; MR-proADM showed statistical higher levels when comparing pneumonia group with COPD exacerbation &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#41; and bronchial infection &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41;&#46; Characteristics of patients with pneumonia are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; Regarding biomarkers levels&#44; no significant differences were found when comparing patients according to previous antibiotic and corticosteroid therapy&#46; Patients with congestive heart failure had higher levels of MR-proANP and MR-proADM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;056&#44; respectively&#41;&#46; Regarding renal disease&#44; levels of neopterin and MR-proANP were significantly higher &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;024&#41;&#46; Neopterin levels were nearly significantly higher in patients with COPD as comorbidity &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;058&#41;&#46; No significant differences were found when considering biomarkers levels and Charlson index classified as &#8804;1 and &#8805;2&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Severity pneumonia scores and prognosis</span><p id="par0055" class="elsevierStylePara elsevierViewall">Distribution of patients according to the severity pneumonia scores is shown in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; MR-proANP and MR-proADM showed significant differences across PSI groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; and higher levels were found in high risk &#40;IV&#8211;V&#41; in comparison to low risk &#40;I&#8211;III&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; MR-proANP and MR-proADM levels also increased statistically with CURB-65 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; No statistical differences were found for PCT&#44; CRP and neopterin&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">Regarding SCAP&#44; thirty patients had SCAP criteria and showed higher levels of MR-proANP &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41;&#44; MR-proADM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; neopterin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;011&#41; and PCT &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;069&#41; while for CRP levels no differences were found &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;549&#41;&#46; When considering all pneumonia patients&#44; regardless of SCAP criteria&#44; MR-proANP &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;015&#41; and MR-proADM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; showed statistical differences across the five SCAP risk categories&#46; SCAP score can also be classified according to low &#40;0&#8211;9 points&#41;&#44; intermediate &#40;10&#8211;19&#41; and high risk &#40;&#8805;20&#41;&#46; PCT &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;010&#41;&#44; neopterin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#44; MR-proANP &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;010&#41; and MR-proADM &#40;&#60;0&#46;0001&#41; showed higher levels in high risk group in comparison to low risk &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; MR-proANP &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;049&#41; and MR-proADM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;051&#41; also presented higher levels in intermediate risk in comparison to low risk&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The modified version SMRT-CO was available for all pneumonia patients&#46; MR-proADM was the only biomarker that showed significant differences across score groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;051&#41;&#46; Levels were statistically lower in patients with 0 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#41; and 1 point &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;041&#41; in comparison to patients with 3 points&#46; Patients with &#8805;2 points had significantly higher levels of PCT &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41; and MR-proADM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;022&#41;&#44; whereas for neopterin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;060&#41;&#44; CRP &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;147&#41; and MR-proANP &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;694&#41; no statistical differences were found &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; In contrast&#44; SMART-COP was only available for 28 patients&#46; Fourteen patients had 0&#8211;2 points&#44; 7 had 3&#8211;4 points&#44; 6 had 5&#8211;6 points&#44; and one patient had 8 points&#46; None of the biomarkers showed statistical differences between score groups&#46; However&#44; neopterin levels were significantly higher in patients with &#8805;3 points in comparison to patients with &#60;3 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;021&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">Nine patients developed complications related to the pneumonia and one patient died of a non-related cause which was cerebral lesion progression&#46; Levels of all biomarkers&#44; except CRP were higher in non-survivors &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; in comparison to survivors&#44; although without statistical differences &#40;data not shown&#41;&#46; Patients developing pneumonia related complications showed statistically higher levels of neopterin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;030&#41; and MR-proADM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;044&#41;&#46; Levels of PCT &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;053&#41;&#44; neopterin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; and MR-proADM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; were higher in patients admitted to ICU &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#41;&#46; The AUC &#40;SE&#44; 95&#37; CI&#41; to predict development of complications according to MR-proADM was 0&#46;706 &#40;0&#46;11&#44; 0&#46;491&#8211;0&#46;922&#41;&#46; A cut-off of 0&#46;95<span class="elsevierStyleHsp" style=""></span>nmol&#47;L had a sensitivity and specificity of 77&#46;8&#37; and 39&#46;5&#37;&#44; respectively&#46; A cut-off of 1&#46;50<span class="elsevierStyleHsp" style=""></span>nmol&#47;L had a sensitivity and specificity of 66&#46;7&#37; and 65&#46;8&#37;&#44; respectively&#46; In <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> is also shown the distribution of patients according to the risk scores and the development of complications&#46; It is of note that some patients were classified as low risk by all score indexes but still developed complications&#46; Among these patients classified as low risk by severity scores&#44; one of them was severely immunosuppressed with CD4<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>200 and died during the episode&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Microbiological and radiological findings</span><p id="par0075" class="elsevierStylePara elsevierViewall">Microbiological results for patients with pneumonia are shown in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46; PCT and MR-proADM showed significantly higher levels in cases of definite bacterial diagnosis in comparison to cases of probable bacterial origin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;044 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;028&#44; respectively&#41;&#46; If assembling cases of probable bacterial diagnosis and unknown origin&#44; MR-proADM was the only biomarker that still showed a nearly significant difference when comparing to definite diagnosis group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;059&#41;&#46; A total of 6 blood cultures were positive&#58; 3 for <span class="elsevierStyleItalic">S&#46; pneumoniae</span>&#44; 1 for <span class="elsevierStyleItalic">Streptococcus mitis</span>&#44; 1 for <span class="elsevierStyleItalic">Klebsiella pneumoniae</span>&#44; and 1 for <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&#46; Levels of MR-proADM were nearly significantly higher in patients with documented bacteremia in comparison to those with negative blood culture results &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;053&#41;&#46; PCT &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;017&#41; and MR-proADM &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;004&#41; levels were also significantly higher when comparing patients with bacterial pneumonia with respect to other LRTI &#40;including ECOPD and bronchial infections without pneumonic infiltrate&#41; while no statistical differences were found for the other biomarkers&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">In 13 cases there was multilobar involvement and neopterin was the only biomarker that showed significantly higher levels &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;011&#41;&#46; Although there were no statistical differences&#44; all biomarkers were higher in patients with pleural effusion&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">The correct clinical management of patients with LRTI in the ED is still a challenge because of the difficulties in clinical decisions regarding antibiotic treatment and site of care&#46; Diagnostic mistakes in the ED are more frequent in patients presenting with fever and respiratory symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> In this setting&#44; biomarkers could act as a complementary tool&#44; together with clinical and microbiological criteria&#44; for the right identification of patients with bacterial pneumonia and patients at risk of developing complications&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;34</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">In one hand&#44; for severity assessment&#44; biomarkers measurement can predict disease severity in CAP patients&#44; aiming to complement the available risk scores&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In our study&#44; the correlation of MR-proANP and MR-proADM levels with validated risk scores&#58; PSI and CURB-65 has been confirmed&#46; In fact&#44; several studies have shown that the combination of score risks&#44; mainly PSI and CURB-65&#44; with a biomarker measurement can improve the prediction of outcome&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;24&#44;35&#44;36</span></a> In our previous experience&#44; we already demonstrated that MR-proANP correlates significantly with both rules and that this correlation is not affected by the presence of cardiac and renal comorbidities&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Regarding MR-proADM&#44; we confirm previous findings that demonstrate that MR-proADM admission levels correlate with a similar accuracy as these scores&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;23&#44;25&#44;36&#44;37</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">To our knowledge this is the first study that has explored the correlation of biomarkers with severity scores&#58; SCAP and SMART-COP&#46; MR-proANP and MR-proADM showed a strong correlation with SCAP&#44; since higher levels were found in patients in high and intermediate risk in comparison to patients classified as low risk&#46; Surprisingly&#44; two patients who developed respiratory failure&#47;shock and died did not have SCAP criteria&#46; One HIV patient had <span class="elsevierStyleItalic">P&#46; jirovecii</span> pneumonia and died 50 days later and MR-proADM levels were of 0&#46;59<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#46; The other one was a severely immunosuppressed patient with megaloblastic anemia who died because of respiratory failure after 12 days and whose MR-proADM levels were of 0&#46;95<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#46; There is another patient who did not have SCAP criteria but died of a cause not related to pneumonia&#44; whose MR-proADM and MR-proANP levels were 0&#46;96<span class="elsevierStyleHsp" style=""></span>nmol&#47;L and 208&#46;30<span class="elsevierStyleHsp" style=""></span>pmol&#47;L&#44; respectively&#46; Regarding SMART-COP&#44; only neopterin showed significantly higher levels in patients with &#8805;3 points&#46; However&#44; when considering its simplified version SMRT-CO&#44; that was available for all patients&#44; PCT and MR-proADM levels were higher in patients classified as moderate-high risk of needing IRVS in comparison to patients with very low&#47;low risk&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Given that severity scores were designed and validated in immunocompetent population&#44; when applying them directly to immunosuppressed patients it is possible that some severity score might misclassify them&#46; In addition immunosuppressed patients are also likely to have a diminished inflammatory response&#44; and therefore influence the relationship between severity score and biomarkers levels&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Two different cut-offs for the prediction of mortality in pneumonia patients have been proposed for MR-proADM&#58; 1&#46;8<span class="elsevierStyleHsp" style=""></span>nmol&#47;L and 1&#46;3<span class="elsevierStyleHsp" style=""></span>nmol&#47;L&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;37</span></a> In our experience&#44; we chose a range of cut-off&#58; 0&#46;95<span class="elsevierStyleHsp" style=""></span>nmol&#47;L and 1&#46;50<span class="elsevierStyleHsp" style=""></span>nmol&#47;L that corresponded to higher sensitivity and specificity&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">On the other hand&#44; the identification of definite bacterial origin has direct implications in antibiotic treatment decisions&#46; Unfortunately&#44; microbiological diagnosis of pneumonia is only achieved in about 50&#37; of the cases&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Our results show that PCT and MR-proADM levels are significantly higher in cases of definite bacterial diagnosis in comparison to pneumonia of probable bacterial or unknown etiology&#46; This reinforces the fact that both biomarkers have a strong relationship with bacterial etiology&#46; In fact&#44; values were higher in patients with bacterial pneumonia with respect to other LRTI&#46; Recent clinical studies have shown that PCT<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">38&#44;39</span></a> and MR-proADM<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36&#44;40</span></a> help in the prediction of bacteremia&#46; This is of importance because the presence of bacteremia is associated with mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> In fact&#44; both biomarkers belong to the calcitonin gene family and are widely and extensively synthesized during severe infections&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> PCT has been broadly evaluated in different clinical settings&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;39&#44;43&#8211;45</span></a> ADM has pleiotropic effects and its role as antimicrobial agent might explain why its levels increase during sepsis<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> being also likely responsible for the hypotension characteristic of septic shock&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">This study has some limitations&#46; Firstly&#44; study inclusion was limited to patients likely to have a severe condition admitted to an ED of a tertiary hospital within a two month period&#44; so patients with milder symptoms were excluded&#46; Secondly&#44; although in our experience no significant differences were found&#44; it is not unlikely that some biomarkers might be influenced by previous antibiotic and corticosteroid treatment&#46; Thirdly&#44; ICU admission criteria can differ between hospitals&#46; And finally&#44; that the number of patients analyzed is small and so&#44; it is not possible to draw robust conclusions&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In summary&#44; in patients with final diagnosis of pneumonia&#44; MR-proADM and MR-proANP levels correlate significantly with validated PSI and CURB-65 index&#46; MR-proADM has also shown higher levels in high risk groups in comparison to low risk groups&#44; when assessing SCAP and modified SMART-COP&#46; MR-proANP and PCT have also shown a correlation with SCAP and SMRT-CO&#46; This is the first study evaluating the relationship between inflammatory and cardiovascular biomarkers and SCAP and SMART-COP indexes and although the number of patients is low it provides preliminary useful and important data that have to be confirmed in further studies&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflicts of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">No company had a role in the design or conducting of the study&#44; collection&#44; management&#44; or interpretation of the data&#44; preparation&#44; review&#44; or approval of this manuscript&#46; The authors have no conflict of interest&#44; including specific financial interests or relationships or affiliations to the subject matter or materials discussed in the manuscript&#46;</p></span></span>"
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          "titulo" => array:5 [
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        4 => array:2 [
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          "titulo" => "Introduction"
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        5 => array:3 [
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          "titulo" => "Patients and methods"
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              "titulo" => "Study design and setting"
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              "titulo" => "Data collection and sample processing"
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              "identificador" => "sec0025"
              "titulo" => "Statistical analysis"
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        6 => array:3 [
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          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Severity pneumonia scores and prognosis"
            ]
            1 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Microbiological and radiological findings"
            ]
          ]
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        7 => array:2 [
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          "titulo" => "Discussion"
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        8 => array:2 [
          "identificador" => "sec0050"
          "titulo" => "Conflicts of interest"
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        9 => array:2 [
          "identificador" => "xack75076"
          "titulo" => "Acknowledgements"
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        10 => array:1 [
          "titulo" => "References"
        ]
      ]
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-04-19"
    "fechaAceptado" => "2013-07-10"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec297951"
          "palabras" => array:4 [
            0 => "Biomarkers"
            1 => "Pneumonia"
            2 => "Prognosis"
            3 => "Severity scores"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec297952"
          "palabras" => array:4 [
            0 => "Biomarcadores"
            1 => "Neumon&#237;a"
            2 => "Pron&#243;stico"
            3 => "&#205;ndices de severidad"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Purpose</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To assess the correlation of procalcitonin &#40;PCT&#41;&#44; C-reactive protein &#40;CRP&#41;&#44; neopterin&#44; mid-regional pro-atrial natriuretic peptide &#40;MR-proANP&#41;&#44; and mid-regional pro-adrenomedullin &#40;MR-proADM&#41; with severity risk scores&#58; severe CAP &#40;SCAP&#41; and SMART-COP in patients with community-acquired pneumonia &#40;CAP&#41;&#44; as well as short term prognosis and to determine the correlation with mortality risk scores&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Eighty-five patients with a final diagnosis of pneumonia were consecutively included during a two month period&#46; Epidemiological&#44; clinical&#44; microbiological&#44; and radiological data were recorded&#46; Patients were stratified according to the PSI&#44; CURB-65&#44; SCAP and SMART-COP&#46; Complications were defined as respiratory failure&#47;shock&#44; need of ICU&#44; and death&#46; Plasma samples were collected at admission&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">MR-proANP and MR-proADM showed significantly higher levels in high risk SCAP group in comparison to low risk&#46; When considering SMART-COP none of the biomarkers showed statistical differences&#46; MR-proADM levels were high in patients with high risk of needing intensive respiratory or vasopressor support according to SMRT-CO&#46; Neopterin and MR-proADM were significantly higher in patients that developed complications&#46; PCT and MR-proADM showed significantly higher levels in cases of a definite bacterial diagnosis in comparison to probable bacterial&#44; and unknown origin&#46; MR-proANP and MR-proADM levels increased statistically according to PSI and CURB-65&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Biomarker levels are higher in pneumonia patients with a poorer prognosis according to SCAP and SMART-COP indexes&#44; and to the development of complications&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Establecer la correlaci&#243;n entre los niveles de procalcitonina &#40;PCT&#41;&#44; prote&#237;na C reactiva&#44; neopterina&#44; pro-p&#233;ptido natriur&#233;tico auricular &#40;MR-proANP&#41; y pro-adrenomedulina &#40;MR-proADM&#41; y los &#237;ndices de severidad&#58; severe CAP &#40;SCAP&#41; y SMART-COP en pacientes con neumon&#237;a adquirida en la comunidad &#40;NAC&#41;&#44; as&#237; como el pron&#243;stico a corto plazo&#44; y confirmar su correlaci&#243;n con los &#237;ndices de severidad PSI y CURB-65&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Ochenta y cinco pacientes con diagn&#243;stico final de NAC fueron incluidos de forma consecutiva durante 2 meses&#46; Se recogieron los datos epidemiol&#243;gicos&#44; cl&#237;nicos&#44; microbiol&#243;gicos y radiol&#243;gicos&#46; Los pacientes se clasificaron en funci&#243;n del PSI&#44; CURB-65&#44; SCAP y SMART-COP&#46; Las complicaciones se definieron como insuficiencia respiratoria&#47;shock&#44; ingreso en la UCI o muerte&#46; Las muestras de plasma se recogieron en el momento del ingreso hospitalario&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los niveles de MR-proANP y MR-proADM fueron significativamente superiores en aquellos pacientes clasificados como alto riesgo seg&#250;n SCAP en comparaci&#243;n con los de bajo riesgo&#46; Al considerar SMART-COP ninguno de los biomarcadores mostr&#243; significaci&#243;n estad&#237;stica&#46; Los niveles de MR-proADM fueron superiores en los pacientes con alto riesgo de necesitar soporte intensivo&#47;vasopresor seg&#250;n SMRT-CO&#46; Los valores de neopterina y MR-proADM fueron significativamente superiores en pacientes que desarrollaron alguna complicaci&#243;n&#46; En los casos con diagn&#243;stico bacteriano de seguridad&#44; se observaron niveles significativamente m&#225;s elevados de PCT y MR-proADM&#44; respecto de los casos de probable origen bacteriano o origen desconocido&#46; Los niveles de MR-proANP y MR-proADM se incrementaron en funci&#243;n del PSI y de CURB-65&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los niveles de biomarcadores son superiores en pacientes con peor pron&#243;stico&#44; seg&#250;n los &#237;ndices de severidad evaluados&#44; as&#237; como con el desarrollo de complicaciones&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Biomarker&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Pneumonia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">PCT &#40;ng&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;25 &#40;0&#46;09&#8211;2&#46;04&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;09 &#40;0&#46;05&#8211;0&#46;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;10 &#40;0&#46;06&#8211;0&#46;25&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">Neopterin &#40;ng&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">CRP &#40;mg&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">116 &#40;50&#8211;184&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">87 &#40;20&#8211;154&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">MR-proANP &#40;pmol&#47;L&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t">9&#46;6 &#40;10&#46;27&#41;</td></tr><tr title="table-row"><td class="td" title="\n
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        "texto" => "<p id="par0130" class="elsevierStylePara elsevierViewall">The company BRAHMS Thermo Fisher has supplied the necessary kits of PCT and MR-proADM&#46; This study was supported by a grant of <span class="elsevierStyleGrantSponsor" id="gs0005">Fundaci&#243; Catalana de Pneumologia &#40;FUCAP&#41;</span>&#46; We thank Microbiology and Hematology Laboratory technicians of the Hospital Universitari Germans Trias i Pujol for the help in sample collection and Oriol Martos for technical assistance&#46; J&#46; Dom&#237;nguez is a researcher of the &#8220;Miguel Servet&#8221; programme of the Instituto de Salud Carlos III &#40;Spain&#41;&#46;</p>"
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Article information
ISSN: 0213005X
Original language: English
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2022 July 17 15 32
2022 June 25 8 33
2022 May 24 6 30
2022 April 23 9 32
2022 March 16 10 26
2022 February 15 7 22
2022 January 18 16 34
2021 December 14 12 26
2021 November 20 11 31
2021 October 27 8 35
2021 September 13 9 22
2021 August 16 10 26
2021 July 23 6 29
2021 June 23 8 31
2021 May 29 5 34
2021 April 44 23 67
2021 March 27 8 35
2021 February 23 8 31
2021 January 17 14 31
2020 December 16 3 19
2020 November 18 5 23
2020 October 10 5 15
2020 September 21 9 30
2020 August 19 7 26
2020 July 20 3 23
2020 June 25 7 32
2020 May 23 16 39
2020 April 20 4 24
2020 March 49 5 54
2020 February 43 7 50
2020 January 46 8 54
2019 December 56 16 72
2019 November 42 7 49
2019 October 28 12 40
2019 September 22 7 29
2019 August 15 4 19
2019 July 21 11 32
2019 June 28 18 46
2019 May 133 23 156
2019 April 64 23 87
2019 March 12 8 20
2019 February 16 13 29
2019 January 9 7 16
2018 December 10 14 24
2018 November 15 14 29
2018 October 21 9 30
2018 September 11 1 12
2018 August 20 5 25
2018 July 21 3 24
2018 June 24 2 26
2018 May 23 9 32
2018 April 27 0 27
2018 March 8 2 10
2018 February 12 0 12
2018 January 7 2 9
2017 December 8 1 9
2017 November 24 3 27
2017 October 14 1 15
2017 September 12 12 24
2017 August 13 4 17
2017 July 20 5 25
2017 June 17 22 39
2017 May 15 11 26
2017 April 44 22 66
2017 March 46 23 69
2017 February 25 4 29
2017 January 26 3 29
2016 December 24 3 27
2016 November 20 4 24
2016 October 69 5 74
2016 September 34 5 39
2016 August 34 5 39
2016 July 33 3 36
2016 June 23 6 29
2016 May 13 1 14
2016 April 16 17 33
2016 March 20 12 32
2016 February 20 18 38
2016 January 33 18 51
2015 December 29 8 37
2015 November 20 7 27
2015 October 31 5 36
2015 September 24 10 34
2015 August 23 10 33
2015 July 22 7 29
2015 June 15 3 18
2015 May 14 5 19
2015 April 18 2 20
2015 March 20 4 24
2015 February 36 7 43
2015 January 17 3 20
2014 December 26 6 32
2014 November 15 12 27
2014 October 35 14 49
2014 September 23 14 37
2014 August 26 12 38
2014 July 36 23 59
2014 June 26 16 42
2014 May 17 14 31
2014 April 46 48 94
2014 March 141 213 354
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos