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the burden and prevalence of severe exacerbations remain high&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The &#8220;frequent exacerbator&#8221; COPD patient is a well identified phenotype defined by consensus by the presence of 2 or more exacerbations or one hospital admission during the preceding year&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">1&#44;7</span></a> Patients with more severe COPD had more frequent AECOPD&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">8</span></a> Moreover&#44; history of previous exacerbation is an important predictor of subsequent exacerbations&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">8&#44;9</span></a> Severe exacerbations leading to hospital admissions have an important impact on the quality of life and mortality of these patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">10&#8211;12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In the last decade&#44; the importance of providing special care to the frequent-exacerbator COPD patient was emphasized&#46; Various care models targeting these patients reported a reduction of health-care resources utilization in terms of emergency room &#40;ER&#41; visits and hospital admission as well as improvement of quality of life among this group of patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">13&#8211;16</span></a> The majority of these programs provided schedule visits and on-demand visits<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">14&#8211;16</span></a>&#59; while other programs considered further telemonitoring through medical call centers&#46;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">13&#44;15</span></a> However&#44; it has been claimed that future models of care should be personalized &#8211; providing patient education aiming at behavior changes&#44; identifying and treating co-morbidities&#44; and including outcomes that measure quality of care rather than focusing only on readmission quantity within 30 days&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">17</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">We hypothesized that a personalized and integrated care model &#40;ICM&#41; for frequent-exacerbator COPD patients &#40;fe-COPD&#41; could provide a sustained and better quality of care for this group of patients and reduce the overuse of healthcare resources&#46; Accordingly&#44; we aimed to&#58; &#40;a&#41; evaluate longitudinally the impact of a long-term fe-COPD ICM on ER visits&#44; hospital admissions&#44; and days of hospitalization&#59; &#40;b&#41; investigate the effects of the ICM on health status and all-causes of mortality&#59; &#40;c&#41; evaluate the risk factors of mortality among the whole studied population and ICM group&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study design and subjects</span><p id="par0025" class="elsevierStylePara elsevierViewall">Prospective controlled study that recruited patients from outpatient&#39;s respiratory clinics after being discharged from the hospital due to AECOPD in a tertiary teaching hospital between 2012 and 2019&#46; Patients were identified after two or more hospital admissions per year due to AECOPD and were offered to join a fe-COPD ICM if they fulfilled the following inclusion criteria&#58; &#40;1&#41; patients with diagnosis of COPD according to GOLD criteria&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">1</span></a> able to attend scheduled visits to hospital&#44; &#40;2&#41; able to contact the ICM team by phone and&#44; &#40;3&#41; able to follow the treatment instructions&#46; Patients were excluded if they &#40;1&#41; had non-respiratory comorbidity that substantially affected the prognosis of the disease&#44; &#40;2&#41; lived out of the area of influence of the hospital&#44; &#40;3&#41; lived in a nursing home or jail&#44; &#40;4&#41; suffered from deteriorative cognitive function or psychiatric illness that affected their mental capacity&#44; or &#40;5&#41; had socio-familial conditions that affected the access to the hospital or to attend the scheduled visits&#46; The control group were similarly COPD patients diagnosed according to GOLD criteria with history of &#8805;2 AECOPD required hospitalization and fulfilled inclusion criteria with no exclusion criteria for ICM but they were unwilling to be included in the ICM&#44; or refused to contact the program team through the phone and preferred to come directly to ER&#44; or preferred to continue with their primary physician of care&#46; The control group underwent standard care in the same hospital with scheduled outpatient visits in Primary and Specialized Care and were included in a database as controls and analyzed retrospectively&#46; Exacerbations were defined&#44; and all patients received treatment&#44; according to GOLD recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">1</span></a> The study was approved by the research board of the participating hospital and all the participants signed a written informed consent&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Frequent-exacerbator COPD integrated care model</span><p id="par0030" class="elsevierStylePara elsevierViewall">The fe-COPD patients enrolled in the ICM were assigned to a nurse-led program under medical supervision that included personalized-structured visits with social&#44; nutritional&#44; rehabilitation&#44; educational &#40;including smoking cessation when required&#41; and functional assessment&#46; Also&#44; patients were provided with a fast-track access to medical care in case of new respiratory symptoms by a direct telephone call with the ICM team&#46; The evaluation and plans with every patient were shared with their Primary Care nurse through a web-based chronic disease management package included in the local health care electronic record system&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">At first visit&#44; patients were subjected to&#58; &#40;1&#41; complete medical history with assessment of comorbidities and evaluation of health status with COPD assessment test &#40;CAT&#41;&#44; the modified Medical Research Council &#40;mMRC&#41; dyspnea scale&#44; smoking history&#44; and history of previous exacerbations&#59; &#40;2&#41; forced spirometry&#44; lung volumes and DLCO &#40;if there was not a previous one within the 6 months prior to admission to the program&#41;&#44; ADO index &#40;age&#44; dyspnea and airway obstruction&#41;&#44; 6-minute walking test&#44; arterial blood gases and BODE index was calculated&#59; &#40;3&#41; sputum sample for microbiological evaluation&#59; &#40;4&#41; revision of inhalation techniques and compliance by pharmacy refills in the electronic prescription records&#59; &#40;5&#41; education about healthy habits&#44; alert signs of exacerbations and aiming at behavior changes including smoking cessation&#59; &#40;6&#41; nutritional status and need of dietary assessment&#59; &#40;7&#41; physical activities and need of rehabilitation&#59; and &#40;8&#41; assessment of psychosocial support and identification care-givers with coaching with patient and family support&#46; All patients were followed-up on regular basis at scheduled visits every 3 months &#40;or earlier if required&#41; with evaluation of symptoms&#44; vital signs&#44; mMRC dyspnea scale&#44; CAT score&#44; O<span class="elsevierStyleInf">2</span> saturation and re-checking of inhalation techniques by specialized nurse at each single visit&#46; Identification and treatment of new comorbidities&#44; compliance of treatments&#44; physical activity and psychosocial needs were also assessed in every scheduled visit&#46; Moreover&#44; patients included in the program were able to contact the ICM team from Monday-to-Friday through telephone calls for consultation about their symptoms outside the scheduled visits&#46; Based on their new presenting symptoms&#44; the team decided whether the patient needed to come to hospital for medical evaluation and accordingly further action was considered &#40;online supplement fig&#46; 1&#41;&#46; Out-of-hours&#44; patients requiring urgent medical attention had to go to the ER at their Primary Care center or hospital&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Variables and outcomes</span><p id="par0040" class="elsevierStylePara elsevierViewall">New hospital admissions&#44; domiciliary hospitalization&#44; ER visits&#44; courses of antibiotic and systemic corticosteroids as well as mortality were recorded for every patient during follow-up for further analysis&#46; All variables were analyzed as cumulative variables throughout the whole follow-up duration not as annual frequency&#46; Average days of hospitalization were recorded for each patient and analyzed&#46; Patients with AECOPD who were managed by the ICM team as outpatient were considered as avoided ER visits&#46; When patients fulfilled criteria for hospitalization&#44; providing that they were not on acute respiratory failure&#44; and were conscious with good home support&#44; they were managed as outpatient instead with close monitoring by the program team&#46; This was considered as avoided admissions&#46; Baseline and follow-up values of mMRC and CAT were collected prospectively in the ICM group&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">The data were expressed as median and interquartile range &#40;IQR&#41; or number and percentage &#40;&#37;&#41; as appropriate unless otherwise stated&#46; Mann&#8211;Whitney&#44; unpaired <span class="elsevierStyleItalic">t</span>-test and chi-square tests were used in the comparison between both groups as appropriate&#46; A percentage of reduction of new hospital admissions and ER visits was calculated to study the effect of the ICM as the relation between measured new hospital admission or ER visits&#47;expected hospitalizations or emergency visits &#40;i&#46;e&#46; actual new hospital admission or emergency visits<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>avoided admissions or ER visits&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">C-statistic was used to identify the best cut-off point for CAT score as predictor of mortality among fe-COPD ICM patients&#46; Logistic univariate and multivariate analysis were used to evaluate the risk factors for new hospital admissions and mortality among fe-COPD ICM patients&#46; Odd ratio &#40;OR&#41; and confidence interval 95&#37; &#40;CI95&#37;&#41; were calculated&#46; Cumulative mortality within 7 years of enrollment in the ICM was estimated using Kaplan&#8211;Meier survival analysis&#46; A two-tailed <span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered statistically significant&#46; SPSS package &#40;Version 22&#46;0&#46; Armonk&#44; NY&#58; IBM Corp&#41; was used for all analyses&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Characterization of the population</span><p id="par0055" class="elsevierStylePara elsevierViewall">280 fe-COPD patients were followed-up for a median of 37 months &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#8211;65 months&#41; and maximally 7 years&#46; 148 fe-COPD patients were assigned to fe-COPD ICM&#44; and 132 fe-COPD were unwilling to join the program and considered as a control group receiving standard medical care&#46; Seven fe-COPD from the ICM group &#40;4&#46;7&#37;&#41; abandoned the program due to the occurrence of exclusion criteria during follow-up&#59; accordingly&#44; 141 patients completed the program and were analyzed &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the baseline clinical and functional characteristics of the studied population&#46; All included fe-COPD patients were predominantly GOLD D in both groups with similar proportion of patients with airway colonization by <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> between both groups&#46; Further&#44; the ADO index was similar between both groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;550&#44; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Noteworthy&#44; patients in the fe-COPD ICM group were slightly younger &#40;72 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>66&#46;0&#8211;77&#46;0&#41; vs 76 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>69&#46;5&#8211;83&#46;0&#41; years&#41;&#44; with more severe airway obstruction and lower BMI than the control group &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Seventy-five patients &#40;56&#46;8&#37;&#41; of control group were on domiciliary oxygen therapy versus 104 patients &#40;73&#46;8&#37;&#41; of ICM group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#59; while 23&#46;5&#37; versus 21&#46;3&#37; respectively used nocturnal non-invasive ventilation &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Effectiveness of ICM for frequent-exacerbator COPD</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Hospital admissions and emergency visits</span><p id="par0065" class="elsevierStylePara elsevierViewall">The median number of AECOPD was 6 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#8211;11&#41; among the ICM group&#59; however&#44; the ICM produced a reduced number of new hospital admissions due to AECOPD compared to standard care &#40;3 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#8211;6&#41; vs&#46; 5 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#8211;8&#41; median admissions respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; over the period of the study&#46; This resulted in a 38&#46;2&#37; reduction of new hospital admissions among the fe-COPD ICM group &#40;online supplement Table 1&#59; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#41;&#46; Also&#44; the median days of hospitalizations were significantly lower among the ICM group vs&#46; control group &#40;7&#46;4 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;95&#8211;10&#46;43&#41; vs&#46; 8&#46;65 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#46;0&#8211;12&#46;15&#41; days respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Moreover&#44; the new ER visits were significantly less frequent among the ICM group vs&#46; control group &#40;1 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#8211;2&#41; vs&#46; 1 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#8211;3&#41; visit respectively&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;017&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; with a reduction of 69&#46;7&#37; of the expected ER visits &#40;online supplement <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#59; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>b&#41;&#46; However&#44; there were no statistically significant differences regarding domiciliary hospitalization&#44; hypercapnic respiratory failure admissions&#44; number of positive sputum cultures during admission&#44; number of corticosteroid or antibiotic courses between both groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">When comparing the number of hospital admissions in the intervention group before and after enrolling the ICM program&#44; there was a statistically significant reduction of hospital admissions&#47;year among fe-COPD ICM patients when compared to the admissions 1 year before enrollment &#40;median 1&#46;09 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;27&#8211;2&#46;57&#41; vs&#46; 3 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#8211;5&#41; admissions&#47;year&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001 respectively&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>a&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">In the multivariate analysis&#44; last follow-up CAT score<span class="elsevierStyleHsp" style=""></span>&#62;17 was the unique independent risk factor associated to two or more new hospital admissions during follow-up among fe-COPD ICM group &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;61&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013&#44; online supplement Table 2&#41;&#46; Moreover&#44; admissions 1 year before enrollment in ICM program were not a statistically significant risk factor for further admissions in the same multivariate analysis &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;43&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;056&#44; online supplement Table 2&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Health status</span><p id="par0080" class="elsevierStylePara elsevierViewall">The ICM program had a significant beneficial impact on health status&#44; with a reduction in CAT score from 19 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>14&#8211;25&#41; to 15 &#40;IQR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>11&#8211;20&#41; after 1 year of follow-up &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>b&#41;&#46; Moreover&#44; this effect was maintained or improved over 3 years of follow-up &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#44; online supplement Fig&#46; 2&#41;&#59; however&#44; mMRC dyspnea scale did not show statistically significant changes over follow-up &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;449&#44; online supplement Fig&#46; 3&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Mortality</span><p id="par0085" class="elsevierStylePara elsevierViewall">More than 50&#37; of patients died during the study period&#46; The ICM had no effect on mortality compared to standard care &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;117&#44; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#59; and online supplement Fig&#46; 4&#41;&#46; Female gender&#44; higher baseline mMRC dyspnea scale&#44; <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> infection&#44; domiciliary oxygen therapy&#44; higher ADO&#44; lower BMI&#44; FEV<span class="elsevierStyleInf">1</span> &#40;L&#41;&#44; FVC&#37; predicted and FEV<span class="elsevierStyleInf">1</span>&#47;FVC were risk factors for mortality among the entire fe-COPD population as well as in those included in ICM program using univariate logistic analysis &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#44; online supplement Tables 3 and 4 respectively&#41;&#46; Further among fe-COPD patients included in the ICM program&#44; last follow-up CAT score<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>17 and higher BODE index were also significant risk factors for mortality &#40;online supplement Table 4&#41;&#46; In a multivariate analysis&#44; last follow-up CAT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>17 was the strongest independent risk factor for mortality &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;55&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;029&#44; Table 4 online supplement&#41;&#44; with survival of 20&#37; after 100 months of follow-up compared to those with CAT<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>17 with a survival of 60&#37; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#44; <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion</span><p id="par0090" class="elsevierStylePara elsevierViewall">We have shown that fe-COPD is associated with impaired health status&#44; high consumption of health resources and high mortality&#44; and that it benefits from a personalized integrated care model that decreases hospital admissions and ER visits when compared to standard care&#46; Moreover&#44; the ICM have a direct impact on the quality of care by improving the health status measured by the CAT score during follow-up although it had no effect in dyspnea nor mortality&#46; This long-term effect on CAT is relevant&#44; since the last CAT<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>17 is associated to new admissions and mortality&#46;</p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Previous studies</span><p id="par0095" class="elsevierStylePara elsevierViewall">The effectiveness of integrated care models has been previously demonstrated in uncontrolled studies&#46; Huertas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">15</span></a> found that a day hospital-based care model for severe COPD patients was associated with a reduction of hospital admission by 71&#37;&#46; Similarly&#44; Jain et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">18</span></a> found that there was significant decrease of ER visits and hospitalizations in asthma and COPD patients with frequent exacerbations in a similar ICM&#46; On the other hand&#44; other forms of integrated care using home telemonitoring rather than face-to-face evaluation in frequent COPD exacerbators also reported significant decrease of ER visits&#44; hospital admissions and the number of exacerbations&#47;year&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">13</span></a> Our results are in accordance with these studies&#59; however&#44; our study had the strength of providing a control group of fe-COPD&#46; Further&#44; the previous mentioned studies had an average follow-up of 12 months<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">13&#44;15&#44;18</span></a> and maximum of 24 months&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">15</span></a> whereas in the current study&#44; the median follow-up duration was 31 months with maximum of 7 years&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Interpretation of results and clinical implications</span><p id="par0100" class="elsevierStylePara elsevierViewall">A key objective of COPD management is preventing exacerbations&#44; that have a significant burden on the quality of life especially among severe COPD patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">12&#44;19</span></a> According to our results&#44; we believe that enrolment of fe-COPD in an integrated comprehensive program is associated with significant decrease of AECOPD that required ER visits&#44; hospitalization&#44; and&#44; in case patients needed to be admitted&#44; a reduction of hospitalization days&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Several factors may explain the effectiveness of ICM in the current study&#58; &#40;1&#41; the flexibility of the program that enabled the patient to access to medical care through a direct telephone call and so the early detection of exacerbations and subsequent management&#59; &#40;2&#41; rapid arrangement of follow-up visits after phone calls for evaluation of patients after exacerbations&#59; &#40;3&#41; the health care is provided by the same team who are familiar with the patients&#8217; characteristics&#59; &#40;4&#41; the program is conducted in a tertiary hospital with all facilities for rapid tracking and evaluation of the patients&#59; &#40;5&#41; the care model is coordinated with Primary Care and other hospital departments such as Hospital-at-home&#44; Rehabilitation&#44; Nutrition or social assistant&#46; All of these factors also increased the adherence of the patients to the ICM visits and the given instructions which positively enhanced the impact of the program&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">However&#44; despite the impact of this model of care on hospital utilization&#44; we did not find differences in mortality when comparing to standard care&#46; This could be explained on the basis that fe-COPD patients enrolled in the ICM were more severe in terms of lower FEV<span class="elsevierStyleInf">1</span> and higher basal mMRC dyspnea scale compared to control group &#40;although there was a similar proportion of GOLD D and C in both groups as well as ADO index&#41;&#46; We found that ADO index was a significant risk factor of mortality in the entire fe-COPD population that was not superior than mMRC dyspnea scale &#40;online supplement Table 3&#41;&#46; Other studies have shown that basal mMRC dyspnea scale is a good predictor of mortality and AECOPD&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">20</span></a> mMRC was also a good predictor of mortality in our cohort that was not influenced by the ICM&#46; However&#44; dyspnea is a complex symptom that can be explained by different pathophysiological mechanisms&#44; especially in a more severe and frequent-exacerbator population like ours&#46; When we evaluated a multidimensional score such as the BODE index&#44; an important predictor of survival among stable COPD irrespective of their ABCD grouping&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">21</span></a> we found that it was a significant risk factor of mortality&#46; However&#44; in our population of fe-COPD receiving ICM&#44; BODE index was not superior to CAT score for the prediction of mortality&#46; CAT is a simple questionnaire that has been validated as a multi-dimension assessment tool for COPD patients and can be used for the evaluation of treatment response&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">22</span></a> Further&#44; there was a significant decrease of CAT score after 1 year and 3 years of follow-up among fe-COPD patients enrolled in the program denoting better control of the disease and improving health status&#46; Not surprising&#44; we found that last follow-up CAT score<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>17 was the strongest predictor for new admissions and mortality among fe-COPD&#46; CAT score<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>17 has been used as cutoff value for the identification of poor health status and moderate-severe exacerbations leading to death&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">20&#44;23</span></a> Rassouli et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">24</span></a> also reported a significant positive association between CAT score changes and risk of AECOPD&#46; In our understanding&#44; this finding may have important prognostic implications since the ICM have a direct impact on CAT&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The high mortality rate observed in the studied COPD population could be explained by the severity of the underlying COPD disease especially FEV<span class="elsevierStyleInf">1</span><a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">25</span></a>&#44; but also by patients&#8217; demographics&#46; Morevover&#44; COPD is associated to a persistent underlying systemic inflammatory process that could be a mediator of extra-pulmonary complications and a risk factor for mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">26&#44;27</span></a> Moreover&#44; still there is a percentage of COPD who die during their sleep or in whom death was unexpected&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">28</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Interestingly&#44; we found that female gender was associated to mortality in our fe-COPD cohort&#46; Ringbaek et al&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">29</span></a> found that women with COPD had double risk for mortality compared to men&#46; Further&#44; Stolz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">30</span></a> found that females with COPD were at greater risk for moderate-to-severe AECOPD than males&#46; Moreover&#44; <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> infection was also a significant risk factor for mortality but other bacterial infections were not&#46; <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> infection was shown to be a predictor of 3-year mortality after hospitalization for AECOPD<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">31</span></a> and in outpatient stable COPD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">32</span></a> However&#44; age&#44; gender or <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> infection were not independent risk factors in the multivariate analysis among fe-COPD included in the ICM program&#44; which we think that can be explained by the interactions among all these factors on the severity of the disease&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Study limitations</span><p id="par0125" class="elsevierStylePara elsevierViewall">The current study has some limitations&#46; Firstly&#44; there could be a selection bias since the control group was not randomly assigned&#46; However&#44; the population enrolled in the ICM was more severe than the control group which reinforces the conclusions&#46; Moreover we thought that it was unethical to choose a randomized control group when we have a specialized program of care for this group of patients&#46; Secondly&#44; the data of hospitalizations&#44; AECOPD and treatments of the control group were obtained from the recorded files of the hospital&#59; however&#44; we assumed that there was no significant bias in the analysis as all the patients were recruited and followed up in the same hospital&#46; Thirdly&#44; we did not analyze the impact of the ICM in terms of costs&#46; The saving on hospital admissions and ER visits should be counterbalance with the cost of having a structure with a full-time nurse and a respiratory specialist on demand&#46; Since the facilities and personnel were already in place and were reallocated to exert this function&#44; we anticipate that the cost&#47;benefit was high for our institution&#44; although detailed economic analysis is needed&#46; Previous studies considered telemonitoring of COPD had significant reduction of total costs for COPD management&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">33&#44;34</span></a> Fourth&#44; the current program was applied in a single center and all the patients were living in the same geographical area&#59; however&#44; this fact improved the adherence to the program&#44; so enhanced better control of the patients&#46; Lastly&#44; we did not analyze social factors and physical activity as risk factors among our studied population&#46; Physical activity level is considered as an important factor associated with mortality and exacerbations in COPD population&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">35</span></a> however&#44; our ICM program is integrated and personalized offering rehabilitation and social support to our patients as part of their usual care&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conclusions</span><p id="par0130" class="elsevierStylePara elsevierViewall">A comprehensive and personalized integrated care model for fe-COPD patients effectively decreased ER visits and hospital admissions due to exacerbations and improved steadily health status measured by CAT&#46; Since this model of care have no impact on mortality&#44; we demonstrated that our approach helped frequent-exacerbator patients <span class="elsevierStyleItalic">not to live longer but to live better</span>&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Funding</span><p id="par0135" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public&#44; commercial&#44; or not-for-profit sectors&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflict of interest</span><p id="par0140" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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              "titulo" => "Frequent-exacerbator COPD integrated care model"
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              "titulo" => "Characterization of the population"
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              "titulo" => "Effectiveness of ICM for frequent-exacerbator COPD"
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                  "identificador" => "sec0050"
                  "titulo" => "Hospital admissions and emergency visits"
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    "fechaRecibido" => "2020-11-03"
    "fechaAceptado" => "2021-01-25"
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            1 => "Long-term mortality"
            2 => "CAT score"
            3 => "Hospitalization"
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            0 => "EPOC con agudizaciones frecuentes"
            1 => "Mortalidad a largo plazo"
            2 => "Puntuaci&#243;n CAT&#169;"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Frequent-exacerbator COPD &#40;fe-COPD&#41; associated with frequent hospital admissions have high morbidity&#44; mortality and use of health resources&#46; These patients should be managed in personalized integrated care models &#40;ICM&#41;&#46; Accordingly&#44; we aimed to evaluate the long-term effectiveness of a fe-COPD ICM on emergency room &#40;ER&#41; visits&#44; hospital admissions&#44; days of hospitalization&#44; mortality and improvement of health status&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Prospective-controlled study with analysis of a cohort of fe-COPD patients assigned to ICM and followed-up for maximally 7 years that were compared to a parallel cohort who received standard care&#46; All patients had a confirmed diagnosis of COPD with a history of &#8805;2 hospital admissions due to exacerbations in the year before enrollment&#46; The change in CAT score and mMRC dyspnea scale&#44; hospital admissions&#44; ER visits&#44; days of hospitalization&#44; and mortality were analyzed&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">141 patients included in the ICM were compared to 132 patients who received standard care&#46; The ICM reduced hospitalizations by 38&#46;2&#37; and ER visits by 69&#46;7&#37;&#44; with reduction of hospitalizations for COPD exacerbation&#44; ER visits and days of hospitalization &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; compared to standard care&#46; Further&#44; health status improved among the ICM group after 1 year of follow-up &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; effect sustained over 3 years&#46; However&#44; mortality was not different between groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;117&#41;&#46; Last follow-up CAT score<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>17 was the strongest independent risk factor for mortality and hospitalization among ICM patients&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">An ICM for fe-COPD patients effectively decreases ER and hospital admissions and improves health status&#44; but not mortality&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducci&#243;n</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La EPOC con agudizaciones frecuentes &#40;EPOC-AF&#41;&#44; que se asocia a ingresos hospitalarios recurrentes&#44; presenta altas tasas de morbilidad y mortalidad&#44; y un importante uso de los recursos sanitarios&#46; Estos pacientes deber&#237;an ser tratados en modelos de atenci&#243;n integral &#40;MAI&#41; personalizada&#46; Por este motivo&#44; nuestro objetivo fue evaluar la efectividad a largo plazo de un MAI para EPOC-AF valorando las visitas a urgencias&#44; los ingresos hospitalarios&#44; los d&#237;as de hospitalizaci&#243;n&#44; la mortalidad y la mejora del estado de la salud&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">M&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Estudio prospectivo controlado que analiz&#243; una cohorte de pacientes con EPOC-AF incluidos en un MAI y en seguimiento durante un m&#225;ximo de 7 a&#241;os en comparaci&#243;n con una cohorte paralela que recibi&#243; atenci&#243;n est&#225;ndar&#46; Todos los pacientes ten&#237;an diagn&#243;stico confirmado de EPOC y antecedentes de &#8805;<span class="elsevierStyleHsp" style=""></span>2 ingresos hospitalarios por agudizaciones durante el a&#241;o anterior a su inclusi&#243;n en el estudio&#46; Se analizaron los cambios en la puntuaci&#243;n del CAT&#169; y en la escala de disnea del MRC&#44; en los ingresos hospitalarios&#44; las visitas a urgencias&#44; los d&#237;as de hospitalizaci&#243;n y la mortalidad&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se compararon 141 pacientes incluidos en el MAI con 132 pacientes que recibieron atenci&#243;n est&#225;ndar&#46; El MAI redujo las hospitalizaciones en un 38&#44;2&#37; y las visitas a urgencias en un 69&#44;7&#37;&#44; mostrando reducci&#243;n de las hospitalizaciones por exacerbaci&#243;n de la EPOC&#44; las visitas a urgencias y los d&#237;as de hospitalizaci&#243;n &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41; en comparaci&#243;n con la atenci&#243;n est&#225;ndar&#46; Adem&#225;s&#44; el estado de salud mejor&#243; en los pacientes del grupo del MAI despu&#233;s de un a&#241;o de seguimiento &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;&#44; un efecto que se mantuvo durante 3 a&#241;os&#46; Sin embargo&#44; la mortalidad no fue diferente entre ambos grupos &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;117&#41;&#46; Una puntuaci&#243;n en el CAT&#169;<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>17 en el &#250;ltimo control de seguimiento fue el factor independiente de riesgo m&#225;s fuertemente asociado a la mortalidad y la hospitalizaci&#243;n de los pacientes en el MAI&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusiones</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Un MAI para pacientes con EPOC-AF reduce eficazmente los ingresos hospitalarios y en urgencias&#44; y mejora el estado de salud&#44; pero no la mortalidad&#46;</p></span>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Reduction of median new hospital admissions among the fe-COPD ICM group&#59; &#40;B&#41; Reduction of median new emergency visits among the fe-COPD ICM group&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Differences between admissions per year before and after the program in the ICM group&#59; &#40;B&#41; Differences between CAT at baseline and CAT after 1 year of follow-up among the fe-COPD ICM group&#46;</p>"
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                  \t\t\t\t">101 &#40;71&#46;6&#41;&#47;40 &#40;28&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;286&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 ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">mMRC dyspnea scale&#59; mean</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#177;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">SD</span>&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">2&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;83&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">2&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;76&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;044<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">28&#46;9 &#40;23&#46;95&#8211;31&#46;53&#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="left" valign="\n
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                  \t\t\t\t">26&#46;7 &#40;23&#46;6&#8211;30&#46;72&#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;047<a class="elsevierStyleCrossRef" href="#tblfn0005">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;922&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>FEV<span class="elsevierStyleInf">1</span>&#37; predicted&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">36 &#40;27&#46;5&#8211;46&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">13 &#40;9&#46;8&#41;&#47;109 &#40;82&#46;6&#41;&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">&#60;0&#46;0001<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;117&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Follow up duration &#40;in months&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;023<a class="elsevierStyleCrossRef" href="#tblfn0010">&#42;</a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Female gender&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">5&#46;58&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pseudomonas Aeruginosa infection&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;163&nbsp;\t\t\t\t\t\t\n
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Vol. 57. Issue 9.
Pages 577-583 (September 2021)
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Vol. 57. Issue 9.
Pages 577-583 (September 2021)