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IPF is inevitably associated with a poor prognosis&#44; with a median survival of 2&#8211;3 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;13</span></a> No proven effective pharmacological therapy has yet been found&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Some prognostic factors have already been described&#44; which may have implications for potential therapy&#44; particularly when to refer for lung transplant&#44; which up until now has been the only therapy with demonstrated survival benefit&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a> Recently&#44; Pirfenidone&#44; an oral antifibrotic and anti-inflammatory drug&#44; has been approved by EMEA &#40;European Medicines Agency&#41; for the treatment of IPF&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Our aim was to describe the clinical presentation and the course of IPF patients who have been evaluated in recent years in our Interstitial Lung Diseases &#40;ILD&#41; outpatient clinic and analyze factors associated with survival and the clinical course&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">Patients diagnosed with IPF&#44; who attended an ILD outpatient clinic in Hospital de S&#227;o Jo&#227;o&#44; a tertiary reference center in Oporto&#44; Portugal&#44; were identified&#46; IPF diagnosis was obtained through an UIP compatible histology by surgical lung biopsy in 25 patients &#40;30&#46;9&#37;&#41;&#46; In 56 patients &#40;69&#46;1&#37;&#41;&#44; IPF diagnosis was based on ATS&#47;ERS criteria &#40;according to 2002 consensus&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Whenever atypical signs were found on HRCT or other atypical characteristics that could raise diagnostic issues&#44; patients were sent for surgical lung biopsy&#46; Patients whose UIP pattern could be explained by other diseases &#40;connective tissue diseases&#44; hypersensitivity pneumonitis&#44; drug lung toxicity and other ILDs whose final stage is fibrosis&#41;&#44; were excluded&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Medical records were retrospectively analyzed&#46; Patients were characterized clinically&#44; physiologically and by radiological findings&#44; at the time of diagnosis&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Rest and exercise physiological assessments &#40;spirometry&#44; lung diffusing capacity for carbon monoxide &#8211; DLCO&#44; Total Lung Capacity &#8211; TLC&#44; six-minute walk test &#8211; 6MWT and cardiopulmonary exercise test&#41; were measured according to ERS and ATS recommendations<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#8211;20</span></a> and results were expressed as percentages of the normal predicted values&#46; Physiological parameters obtained after any medication that could probably modify the course of the disease were excluded&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Some patients were not able to perform the exercise capacity evaluation due to a high degree of disability at diagnosis&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">All patients performed HRCT scan at diagnosis&#46; As this was a retrospective study&#44; some of the HRCT images were not available for analysis&#44; although all the reports were accessible&#46; For imaging characterization&#44; chest HRCT images were analyzed by two radiologists and the extent of the disease was calculated as a fibrotic score&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> the same used to validate the Composite Physiologic Index &#40;CPI&#41;&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Bronchoalveolar lavage &#40;BAL&#41; was performed on an outpatient basis&#46; At the time of BAL&#44; no symptoms or signs suggestive of respiratory infection or exacerbation of the disease were observed&#46; The performance and processing of BAL was carried out according to guidelines of the ERS Task Group on BAL&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Total and differential cell count was classified according to the values proposed by ERS Task Group on BAL &#40;lymphocytosis<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>15&#37;&#44; neutrophilia<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>3&#37;&#44; eosinophilia<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Open lung biopsy was performed under general anesthesia and the most common approach used was a limited anterolateral thoracotomy via a 4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>cm submammary incision&#44; which allowed access to segments of different lobes in order to obtain multiple biopsy specimens&#46; Open lung biopsy was always performed through thoracotomy&#46; The site of the biopsy was decided on the basis of the HRCT scan&#46; Biopsy samples were observed and evaluated independently by two pathologists&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">To evaluate the occurrence of pulmonary hypertension&#44; all patients performed echocardiography&#46; Only the patients referred for lung transplantation underwent right heart catheterization&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Clinical course was classified as slow progression&#44; rapid progression and acute exacerbation &#40;AE-IPF&#41;&#46; Rapid progression was differentiated from slow progression by a shorter duration of symptoms at diagnosis &#40;&#60;6 months&#41; and a more rapid clinical deterioration&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> AE-IPF was defined as a sudden worsening of respiratory symptoms with hypoxemia and appearance of new radiological infiltrates without an identifiable cause&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Patients included had IPF diagnoses established between 2000 and 2010&#46; They were followed during the course of the disease&#44; until death or lung transplant&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical analysis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Kolmogorov&#8211;Smirnov test was used to check for normality of the distributions in all continuous variables&#46; Medians for covariates and percentages of factors were computed and baseline differences in patients with slow versus rapid progression were assessed through <span class="elsevierStyleItalic">U</span> Mann&#8211;Whitney&#44; Chi square or Fischer exact test&#44; as appropriate&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Median survival was estimated using Kaplan&#8211;Meier survival curves&#46; Patients were censored at the time of death or lung transplant&#46; Follow-up was stopped after 48 months&#44; to increase statistical power of the study&#46; To identify the strength of prognostic factors&#44; Hazard Ratios &#40;and their respective 95&#37; confidence intervals&#41; were computed using univariate Cox regression models&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">All analyses were performed using SPSS<span class="elsevierStyleSup">&#174;</span> software v&#46; 18&#46; A <span class="elsevierStyleItalic">p</span>-value<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered significant&#46;</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Patients&#8217; characterization at diagnosis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Eighty-one patients were included&#44; 56 &#40;69&#46;1&#37;&#41; men and 25 &#40;30&#46;9&#37;&#41; women&#46; Mean age at diagnosis was 63&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;2 years old&#46; Two patients &#40;2&#46;5&#37;&#41; had familial IPF&#46; A smoking history was found in 51&#46;9&#37; &#40;27&#46;5&#37; current and 72&#46;5&#37; former smokers&#41; accounting for a mean of 37&#46;5 pack-years&#46; The main symptom at presentation was dyspnea &#40;96&#46;3&#37;&#41;&#44; followed by cough &#40;77&#46;9&#37;&#41;&#46; Median time between beginning of symptoms and time of diagnosis was 12 months&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Restrictive physiology and reduced lung diffusion capacity were the main functional abnormalities &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; as well as exercise capacity impairment&#46; 6MWT was taken into consideration for 40 patients&#44; with a mean &#40;Standard deviation &#8211; SD&#41; distance of 369&#46;6 &#40;149&#46;4&#41; meters and a mean &#40;SD&#41; lowest oxygen saturation of 81&#46;5 &#40;8&#46;1&#41; &#37;&#46; Cardiopulmonary Exercise Test was looked at for only 15 patients with a mean &#40;SD&#41; peak oxygen consumption of 66&#46;6 &#40;18&#46;4&#41;&#37;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">HRCT scan fibrotic score was measured in 42 patients&#46; Mean &#40;SD&#41; fibrotic score was 10&#46;8 &#40;2&#46;3&#41;&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">The prevalence of emphysema in this IPF cohort was 26&#46;4&#37; &#40;14&#47;53 HRCT available for reevaluation&#41;&#46; Patients with emphysema were younger &#8211; 61&#46;8 vs&#46; 69&#46;9 years &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;042&#41;&#44; had a higher smoking load &#8211; 28&#46;3 vs&#46; 10&#46;7 pack-years &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#44; lower FEV1&#47;FVC &#8211; 79 vs&#46; 86&#46;9&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and more severely compromised diffusion capacity &#40;DLCO&#41; &#8211; 36&#46;8 vs&#46; 49&#46;9&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;016&#41;&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">BAL was performed in 56 patients at the time of diagnosis&#44; with neutrophilia &#40;mean<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#46;8&#44; SD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;3&#41; in 52 &#40;92&#46;9&#37;&#41; patients&#44; eosinophilia &#40;mean<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;1&#44; SD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>5&#46;0&#41; in 48 &#40;85&#46;7&#37;&#41; patients and mild lymphocytosis being detected in 14 &#40;25&#37;&#41; patients &#40;mean<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>12&#44; SD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;8&#41;&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Clinical course</span><p id="par0120" class="elsevierStylePara elsevierViewall">Regarding therapeutic approach&#44; ATS&#47;ERS statement was followed and&#44; if there were no contraindications&#44; low doses of corticosteroids &#40;86&#46;4&#37;&#41; and immunosuppressive drugs &#40;65&#46;4&#37;&#41;&#44; preferably azatioprine or alternatively&#44; cyclophosphamide were used&#46; After the publication of IFIGENIA trial<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> in 2005&#44; N-acetylcysteine &#40;1800<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; was added to this regimen &#40;51&#46;9&#37;&#41;&#46; Up until now&#44; Pirfenidone has not been available in Portugal&#46; Moreover&#44; when the included IPF patients were diagnosed&#44; Pirfenidone was still not approved by EMEA and there was no Portuguese center participating in any clinical trial using this drug&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Since a protocol was established in 2007 with Hospital Juan Canalejo &#40;Coru&#241;a&#41; and Hospital Santa Marta &#40;Lisbon&#41;&#44; patients under 65 years have been considered to lung transplantation&#46; As this series includes patients diagnosed since 2000&#44; there is still only a small percentage of transplanted patients&#46; To be precise&#44; 9 patients &#40;7&#46;4&#37;&#41; were selected for lung transplantation and single lung transplant was performed in 6 &#40;2 patients were excluded because of infection by <span class="elsevierStyleItalic">Aspergillus fumigatus</span>&#41;&#46; Another patient is on waiting list&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Clinical course &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>76&#41; was mainly slowly progressive &#40;72&#46;3&#37;&#41;&#46; In 10 patients &#40;13&#46;2&#37;&#41;&#44; IPF had a rapid progression and 11 &#40;14&#46;5&#37;&#41; patients had an AE-IPF during the course of their disease&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">IPF&#39;s rapid progression &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; was found to be associated to a higher functional impairment at diagnosis&#44; namely with FVC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41; and TLC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;032&#41;&#46; A smoking history was associated with a slowly progressive clinical course &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;020&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">Most IPF patients &#40;69&#46;6&#37;&#41; died of causes directly related to the disease &#8211; respiratory failure&#44; while in 13 patients &#40;23&#46;2&#37;&#41;&#44; the cause of death was due to other causes&#46; Four patients &#40;7&#46;1&#37;&#41; died of post-lung transplant complications&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">AE-IPF occurred in 11 patients&#46; Among them&#44; 6 &#40;54&#46;5&#37;&#41; died during the episode and 2 were submitted to lung transplantation&#44; dying due to post-transplant complications&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Survival</span><p id="par0150" class="elsevierStylePara elsevierViewall">Median survival was 36 months &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Twenty-five patients were still alive at the time of evaluation&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">Factors found to be associated with poorer survival&#44; in univariate analysis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#44; were lower levels of FVC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#41;&#44; TLC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; 6MWT distance &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#41; and rest PaO<span class="elsevierStyleInf">2</span> &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;008&#41;&#44; as well as higher BAL neutrophil count &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;039&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0160" class="elsevierStylePara elsevierViewall">It was not possible to identify cut-points for each prognostic factor because of the lack of statistical power &#40;small sample size&#41;&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Testing cut-points of the baseline prognostic factors described in the last consensus document<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> &#40;DLCO<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#37; of predicted&#59; desaturation<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>88&#37; during 6MWT&#59; presence of pulmonary hypertension&#41;&#44; had no significant associations in this sample&#44; although estimates follow the expected direction&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">No significant difference in survival rates was found between IPF patients with and without emphysema&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Median survival was 41 months in slow progressors and 9 months in rapid progressors &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Among slow progressors&#44; lower levels of FVC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; TLC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;012&#41; and 6MWT distance &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;026&#41; were associated to a reduced survival&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">No prognostic factors were found in rapid progressors &#40;reduced statistical power due to a small number of patients&#41;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0190" class="elsevierStylePara elsevierViewall">The evaluation of this cohort of IPF patients from the north of Portugal showed the usual features that characterize this disease&#44; in terms of clinical&#44; functional&#44; radiologic parameters and outcome&#46; Although some baseline prognostic factors were associated with overall survival in this series&#44; the main issue is related with the sort of clinical course&#44; more exactly the distinction between slow progression and rapid progression since their outcome and survival are significantly different&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Mean age at diagnosis was consistent with literature&#44;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;24</span></a> as well as the higher prevalence of males&#46; Familial IPF may be undervalued&#46; In fact&#44; some patients report family deaths from unspecified respiratory diseases&#46; Cigarette smoking is strongly associated with IPF&#44; namely in those patients with heavy smoking history&#44; more precisely more than 20 pack years&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a> In this study&#44; the proportion of smokers and former smokers was lower than expected&#44; as was the case in other series&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;28</span></a> However&#44; in the 15 patients aged under 60 years old&#44; 80&#37; had a history of cigarette smoking&#44; so we can speculate that excluding ageing&#44; smoking history could have been a significant risk factor for IPF in this sample&#46; Twelve months was the median time between beginning of symptoms and diagnosis&#46; Kim et al&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> reported a period of 6 months to 2 years of symptoms preceding diagnosis&#46; In fact&#44; not only patients tend to attribute the initial breathlessness to ageing&#44; but also primary care physicians tend to focus the clinical investigation on cardiac diseases and other respiratory diseases such as COPD&#44; based on their higher prevalence&#46; However&#44; in this cohort of patients there was an increasing number of patients referred by general practice over the last few years&#44; which could be related to the widespread use of CT scans&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Recently&#44; a new syndrome has been described &#8211; Combined Pulmonary Fibrosis and Emphysema &#40;CPFE&#41;&#44; resulting from the association of IPF and emphysema&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> The percentage of CPFE found in this cohort is in line with other publications&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In this study&#44; some previously described distinctive features were observed&#44; namely a stronger association with smoking&#44; lower levels of FEV1&#47;FVC and a higher compromise on diffusion capacity &#40;DLCO&#41;&#46; However&#44; some authors describe a negative impact on prognosis when IPF is associated with emphysema&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> This negative impact is strongly associated to pulmonary hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> In this study we did not find a significant difference in survival or in the occurrence of pulmonary hypertension&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Lymphocytosis was detected in 14 patients &#40;25&#37;&#41;&#46; They presented a mild lymphocytosis &#40;mean of 22&#46;8&#37;&#41; and no exposure to suspected agents was detected&#46; Also&#44; in 50&#37; of these patients a lung biopsy was performed to rule out other differential diagnoses&#46; Moreover no difference on survival was found between patients with or without BAL lymphocytosis&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Clinical course cannot yet be predicted accurately&#46; In this sample&#44; 13&#46;2&#37; of patients experienced an accelerated decline&#44; already described in literature&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> However&#44; criteria for classification of IPF progression are not well established&#46; The definition of rapid progressors is based on a time-period between symptoms and diagnosis of less than 6 months&#44; associated with an accelerated decline&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;10</span></a> The difference in survival between low and rapid IPF progressors is remarkable &#40;41 and 9 months&#44; respectively&#41;&#46; Although this subject is still not clearly understood&#44; these groups must represent different phenotypes in IPF&#46; At a univariate analysis&#44; lower levels of FVC and TLC were associated to a rapidly progressive disease&#46; Non-smokers were also associated to rapid progression&#46; This was already described in other studies&#44; also with a better survival in current smokers&#59;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> and there is no clear explanation for this&#46; Some data suggest that cigarette smoke inhibits lung fibroblast proliferation as well as chemotaxis&#44; and may that way impair lung repair after lung injury&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> A recent study contradicts this fact&#44; showing a better outcome for non-smokers&#44; and assuming that the better outcome previously reported for smokers was compatible with a healthy smoker lead-time effect &#40;reflecting a less severe disease at presentation&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">AE-IPF has been a main focus of interest&#46; The results of this study are in line with publications on this subject&#44; both in terms of incidence and mortality&#46; In fact&#44; incidence of AE-IPF is 10&#8211;15&#37; of all IPF patients&#44; according to two large randomized clinical trials <a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a> and its mortality is high&#44; ranging between 50 and 100&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;36&#8211;38</span></a> Excluding patients who received lung transplant&#44; this study registered an in-hospital mortality of 66&#46;7&#37; in AE-IPF&#46; There have been several attempts to identify acute exacerbations predictors&#44; without success&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> In fact&#44; the occurrence of AE-IPF does not appear to be related to the severity of pulmonary function impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> It was the same for this study&#44; no factor was identified which could predict its occurrence&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">Median survival in this sample is in line with other studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;40</span></a> Predictors of mortality in IPF have been divided in baseline and dynamic predictors&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> In fact&#44; prognosis in IPF should involve the integration of baseline and longitudinal data&#46; This study only meant to evaluate baseline predictors&#46; Factors associated with a poorer survival in this cohort at univariate analysis are related to higher functional decline &#40;FVC&#44; TLC&#41;&#44; worse oxygenation &#40;PaO<span class="elsevierStyleInf">2</span>&#41;&#44; reduced tolerance to exercise &#40;distance in 6MWT&#41; and higher neutrophil count on BAL&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">When reviewing the literature&#44; what is remarkable is the great variability in prognostic factors&#46; There are several reasons for this&#44; such as series with a small number of patients or the inclusion of patients with co-morbidities which act as confounding factors&#46; Most studies have different diagnostic and therapeutic approaches relating to the patients included&#59; although when we consider the lack of effective pharmacologic therapeutics&#44; this latter factor is hardly likely to affect the accuracy of the results&#46; Moreover this cohort of patients was divided according to their phenotypes&#44; since the prognostic factors must be adapted to each of the three types of outcome as their outstanding different clinical course&#46; The prognostic factors concerned&#44; that is lower levels of FVC&#44; TLC and 6MWT distance&#44; are all significantly associated with the low progression subgroup&#46; The lack of any association with rapid progressors may be explained by the fact that the sample size was too small to give a significant result&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Several studies have tended to ascribe prognostic values to baseline pulmonary function tests&#44; giving the impression that a higher functional decline is significantly associated with a reduced survival&#46; The factors concerned are usually FVC<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;42&#8211;44</span></a> and TLC&#44;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;44</span></a> with higher evidence supporting the first parameter&#46; The association of DLCO with reduced survival rates is a consistent finding across the literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#8211;45</span></a> It is a fact that lower diffusion capacity reflects a greater extent of fibrosis and increased severity of the disease&#46; However&#44; in this sample there was no prognostic impact&#46; There are some studies which show baseline PaO<span class="elsevierStyleInf">2</span> at rest as a predictor of mortality&#44;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;27&#44;43&#44;46</span></a> although there are also some contradictory results&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">44&#44;47</span></a> Higher degrees of hypoxemia occur in more advanced stages of the disease but whether this can be considered as a prognostic factor or not&#44; is yet to be established&#46; There are studies which have ascribed prognostic significance in relation to survival rates to 6MWT parameters&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#8211;51</span></a> either linked to the walking distance or to desaturation peak&#44; but these results are underestimated due to lack of standardization and reproductability of this test&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">BAL neutrophilia has been associated with severity as in other diffuse lung disease such as sarcoidosis&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> There is also some evidence that a higher level of neutrophilia may be associated with lower survival rates&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> Although neutrophilia is usually described as a baseline prognostic factor in univariate analysis&#44; multivariate analysis does not confirm this association according to studies published in peer-review literature&#46;<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">54&#44;55</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Pulmonary hypertension should have a multifactorial pathogenesis for IPF&#46; Several studies point out pulmonary hypertension to be a predictor of mortality&#44;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;57</span></a> but usually in longitudinal studies&#46; In our sample&#44; pulmonary hypertension at baseline did not act as a prognostic factor&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Some coefficients<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;58</span></a> have been proposed in order to combine different parameters&#46; For instance&#44; the Composite Physiologic Index&#44; which includes FVC&#44; FEV1&#44; DLCO and fibrosis extension on HRCT scan&#44; has been successfully tested at baseline and longitudinal studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;59</span></a> This could be a way to predict outcome more accurately and to provide a more precise timing of the progression of the disease&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">In conclusion&#44; IPF is inevitably associated with a poor prognosis&#46; However&#44; different phenotypes seem to be emerging&#44; based on the striking differences in clinical course&#46; A more accurate prediction of the outcome at the moment of diagnosis would improve patient management&#44; particularly in the time to reference to lung transplant&#44; which is the only therapy with demonstrated survival benefit&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of interest</span><p id="par0255" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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              "titulo" => "Patients&#8217; characterization at diagnosis"
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              "titulo" => "Clinical course"
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    "fechaRecibido" => "2011-09-19"
    "fechaAceptado" => "2012-05-02"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec164111"
          "palabras" => array:3 [
            0 => "Idiopathic Pulmonary Fibrosis"
            1 => "Survival"
            2 => "Prognosis"
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          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec164110"
          "palabras" => array:3 [
            0 => "Fibrose Pulmonar Idiop&#225;tica"
            1 => "Sobreviv&#234;ncia"
            2 => "Progn&#243;stico"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Idiopathic Pulmonary Fibrosis &#40;IPF&#41; is the most common disease in the subgroup of idiopathic interstitial pneumonias&#46; It is inevitably associated to a bad prognosis&#44; although assuming a highly variable clinical course&#46;</p> <span class="elsevierStyleSectionTitle">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Patients with IPF&#44; observed at Interstitial Lung Diseases outpatient clinic of Centro Hospitalar de S&#227;o Jo&#227;o &#8211; Porto&#44; Portugal&#44; were identified and clinical&#44; functional&#44; radiological and bronchoalveolar lavage &#40;BAL&#41; parameters were reviewed&#46; Their clinical course and survival were analyzed in order to identify prognostic factors&#46;</p> <span class="elsevierStyleSectionTitle">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Eighty-one patients were included&#44; with a mean age at diagnosis of 63&#46;8 years old&#46; At diagnosis&#44; the main functional abnormalities were restrictive physiology&#44; reduced lung diffusion and exercise capacity impairment&#46; Clinical course was mainly slowly progressive &#40;72&#46;3&#37;&#41;&#46; Ten patients &#40;13&#46;2&#37;&#41; had a rapid progression and 11 &#40;14&#46;5&#37;&#41; patients had an acute exacerbation during the course of the disease&#46; IPF&#39;s rapid progression was associated to a higher functional impairment at diagnosis&#44; namely in what is related with Functional Vital Capacity &#40;FVC&#41; and Total Lung Capacity &#40;TLC&#41;&#46; Median survival was 36 months&#46; A significant difference in survival was observed among different types of clinical course &#8211; 41 months for slow progressors and 9 months for rapid progressors&#46; Lower levels of FVC&#44; TLC&#44; six-minute walk test &#40;6MWT&#41; distance and rest PaO<span class="elsevierStyleInf">2</span>&#44; and higher BAL neutrophil count were associated with poorer survival in univariate analysis&#46;</p> <span class="elsevierStyleSectionTitle">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The analysis of this group of IPF patients confirms two clearly different phenotypes&#44; slow and rapid progressors&#46; Those phenotypes seem to have different presentations and a remarkably different natural history&#46; These results could mean different physiopathologic pathways&#44; which could implicate different therapeutic approaches&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle">Introdu&#231;&#227;o</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A Fibrose Pulmonar Idiop&#225;tica &#40;FPI&#41; &#233; a patologia mais comum no subgrupo das Pneumonias Intersticiais Idiop&#225;ticas&#46; Apesar de uma grande variabilidade no tipo de evolu&#231;&#227;o cl&#237;nica&#44; est&#225; inexoravelmente associada a um mau progn&#243;stico&#46;</p> <span class="elsevierStyleSectionTitle">Material e m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Foram identificados doentes com FPI&#44; observados na consulta de Doen&#231;as Pulmonares Difusas do Centro Hospitalar de S&#227;o Jo&#227;o&#44; Porto&#44; e revistos os seus par&#226;metros cl&#237;nicos&#44; funcionais&#44; radiol&#243;gicos e do lavado broncoalveolar &#40;LBA&#41;&#46; A evolu&#231;&#227;o cl&#237;nica e sobreviv&#234;ncia foram avaliadas&#44; tendo sido igualmente identificados factores progn&#243;sticos&#46;</p> <span class="elsevierStyleSectionTitle">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Foram inclu&#237;dos 81 doentes com uma m&#233;dia de idade de 63&#46;8 anos&#46; Na altura do diagn&#243;stico&#44; as principais altera&#231;&#245;es funcionais identificadas foram restri&#231;&#227;o&#44; redu&#231;&#227;o da difus&#227;o pulmonar e da capacidade de exerc&#237;cio&#46; A maioria dos doentes &#40;72&#46;3&#37;&#41; apresentou uma evolu&#231;&#227;o cl&#237;nica lentamente progressiva&#46; Em 10 doentes &#40;13&#46;2&#37;&#41;&#44; foi observada uma evolu&#231;&#227;o rapidamente progressiva e 11 &#40;14&#46;5&#37;&#41; apresentaram exacerba&#231;&#227;o aguda&#46; Verificou-se uma associa&#231;&#227;o entre a evolu&#231;&#227;o rapidamente progressiva e uma maior gravidade funcional ao diagn&#243;stico&#44; nomeadamente na Capacidade Vital For&#231;ada &#40;CVF&#41; e Capacidade Pulmonar Total &#40;CPT&#41;&#46; A sobreviv&#234;ncia mediana foi de 36 meses&#46; Verificou-se uma diferen&#231;a estatisticamente significativa na sobreviv&#234;ncia entre os diferentes grupos de evolu&#231;&#227;o cl&#237;nica - 41 meses para os doentes com evolu&#231;&#227;o lentamente progressiva e 9 meses para os doentes com evolu&#231;&#227;o rapidamente progressiva&#46; Valores inferiores de CVF&#44; CPT&#44; dist&#226;ncia na Prova da marcha dos 6 minutos e PaO2 em repouso&#44; bem como o maior grau de neutrofilia no LBA estiveram associados a uma sobreviv&#234;ncia inferior em an&#225;lise univariada&#46;</p> <span class="elsevierStyleSectionTitle">Conclus&#227;o</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">A an&#225;lise deste grupo de doentes com FPI confirma a exist&#234;ncia de 2 fen&#243;tipos claramente distintos&#44; o de evolu&#231;&#227;o lenta e o de evolu&#231;&#227;o rapidamente progressiva&#46; Estes fen&#243;tipos t&#234;m uma diferente apresenta&#231;&#227;o cl&#237;nica e uma hist&#243;ria natural da doen&#231;a claramente distinta&#44; sugerindo a presen&#231;a de diferentes mecanismos fisiopatol&#243;gicos&#44; os quais poder&#227;o implicar diferentes abordagens terap&#234;uticas&#46;</p>"
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        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Pires FS&#44; et al&#46;&#44; Fibrose Pulmonar Idiop&#225;tica &#8211; Apresenta&#231;&#227;o cl&#237;nica&#44; evolu&#231;&#227;o e factores progn&#243;sticos basais numa coorte portuguesa&#46; Rev Port Pneumol&#46; 2010&#46; <span class="elsevierStyleInterRef" href="http://dx.doi.org/10.1016/j.rppneu.2012.05.002">http&#58;&#47;&#47;dx&#46;doi&#46;org&#47;10&#46;1016&#47;j&#46;rppneu&#46;2012&#46;05&#46;002</span>&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Kaplan&#8211;Meier survival curves for all IPF patients &#40;left&#41; and for slow and rapid progressors &#40;right&#41; &#8211; months&#46;</p>"
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                  """
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Physiological assessment in IPF patients at time of diagnosis&#46;</p>"
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        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">&#37; Lymph &#8211; percentage of lymphocytes at BAL differential count&#59; &#37; Neutroph &#8211; percentage of neutrophils at BAL differential count&#59; &#37; Eosinoph &#8211; percentage of eosinophils at BAL differential count&#46; Significant results are presented in bold&#46;</p>"
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                  \t\t\t\t" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">N</span> &#40;&#37;&#41; or mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>SD</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31 &#40;59&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 &#40;11&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">FVC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">76&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>21&#46;0&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">57&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">72&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">44&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14&#46;7&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">38&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">73&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">377&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>131&#46;2&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">265&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>226&#46;4&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="left" valign="\n
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                  \t\t\t\t">0&#46;318&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6MWT Min SatO<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">81&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;9&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">77&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;242&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibrotic score&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;192&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Meters&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;00 &#40;0&#46;99&#8211;1&#46;00&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " colspan="3" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">6MWT</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Lowest SatO<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;00 &#40;0&#46;95&#8211;1&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;894&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>SatO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;63 &#40;0&#46;38&#8211;6&#46;98&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;512&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>SatO<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VO<span class="elsevierStyleInf">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;97 &#40;0&#46;91&#8211;1&#46;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;244&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HRCT fibrotic score&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;08 &#40;0&#46;90&#8211;1&#46;29&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;407&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Pulmonary hypertension</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>No&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;10 &#40;0&#46;39&#8211;3&#46;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;854&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lymph &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;00 &#40;0&#46;95&#8211;1&#46;05&#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;999&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;03 &#40;1&#46;00&#8211;1&#46;06&#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;039&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Eosinoph &#37;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;97 &#40;0&#46;90&#8211;1&#46;05&#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;398&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46;S&#46; Kim"
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                      "doi" => "10.1513/pats.200601-005TK"
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                  "contribucion" => array:1 [
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                      "titulo" => "American Thoracic Society&#47;European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias"
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                          "etal" => false
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                  "contribucion" => array:1 [
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                      "titulo" => "An official ATS&#47;ERS&#47;JRS&#47;ALAT statement&#58; idiopathic pulmonary fibrosis&#58; evidence-based guidelines for diagnosis and management"
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                          "etal" => true
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                            0 => "S&#46;K&#46; Frankel"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46;W&#46; Visscher"
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                        "paginaInicial" => "322"
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                          "etal" => false
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