Case series
Diagnosis of alpha1-antitrypsin deficiency not just in severe COPD
A. Nuñez, M. Barrecheguren, E. Rodríguez, M. Miravitlles, C. Esquinas
Corresponding author
Pneumology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
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Reis, C. Alves, S. Furtado, J. Ferreira, M. Drummond, C. Robalo-Cordeiro" "autores" => array:7 [ 0 => array:2 [ "nombre" => "A.J." "apellidos" => "Reis" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Alves" ] 2 => array:2 [ "nombre" => "S." "apellidos" => "Furtado" ] 3 => array:2 [ "nombre" => "J." "apellidos" => "Ferreira" ] 4 => array:2 [ "nombre" => "M." "apellidos" => "Drummond" ] 5 => array:2 [ "nombre" => "C." "apellidos" => "Robalo-Cordeiro" ] 6 => array:1 [ "colaborador" => "on behalf of the GI DPOC-Grupo de Interesse na Doença Pulmonar Obstrutiva Crónica" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2531043718301077?idApp=UINPBA00004E" "url" => "/25310437/0000002400000006/v2_201902120618/S2531043718301077/v2_201902120618/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Case series</span>" "titulo" => "Diagnosis of alpha1-antitrypsin deficiency not just in severe COPD" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "351" "paginaFinal" => "353" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "A. Nuñez, M. Barrecheguren, E. Rodríguez, M. Miravitlles, C. Esquinas" "autores" => array:5 [ 0 => array:2 [ "nombre" => "A." "apellidos" => "Nuñez" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Barrecheguren" ] 2 => array:2 [ "nombre" => "E." "apellidos" => "Rodríguez" ] 3 => array:2 [ "nombre" => "M." "apellidos" => "Miravitlles" ] 4 => array:4 [ "nombre" => "C." "apellidos" => "Esquinas" "email" => array:1 [ 0 => "crise4@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Pneumology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Alpha1-antitrypsin deficiency (AATD) is a well known genetic risk factor for pulmonary disease and is the most frequent hereditary disease diagnosed in adults. AATD has a prevalence of less than 5 cases per 10,000 habitants, accounting for 1–2% of patients with emphysema.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">1,2</span></a> Despite being one of the most common hereditary diseases, AATD remains under-diagnosed because of its variable clinical presentation and the poor knowledge that physicians have of this disease. Tobacco exposure is the most important risk factor for the development of emphysema in AATD.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although forced expiratory volume in the first second (FEV1) and diffusing lung capacity for carbon monoxide (DLCO) are the usual parameters used in clinical practice to follow disease progression,<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">5</span></a> their great variability makes them less suitable to be used as outcomes in clinical trials.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">6</span></a> Loss of lung density measured by quantitative computed tomography has demonstrated to be a more accurate outcome measure<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">7–9</span></a> and has a good long-term correlation with FEV1, DLCO, and survival.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">10,11</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Despite the data reported from patient registries, the evolution of lung disease associated with AATD is not fully understood.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">12,13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Since this is a progressive disease, early diagnosis and treatment may change the natural course of the disease.</p><p id="par0025" class="elsevierStylePara elsevierViewall">With the aim of identifying clinical differences that could influence early diagnosis, we consecutively selected patients from our database of AATD patients, and we compared two groups according to the severity of the disease. Severe disease defined as FEV1<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>45% at diagnosis and then we found patients with FEV1<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>65% paired by age and gender.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Clinical observations</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Moderate group</span><p id="par0030" class="elsevierStylePara elsevierViewall">Six AATD Pi*ZZ patients with relatively preserved lung function at diagnosis (FEV1<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>65%) were included. The mean age at diagnosis was 51 years (SD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4) and four of patients were men. Two patients were never smokers and 4 were former smokers. The mean FEV1 at diagnosis was 93% (SD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>29). Regarding comorbidities, one patient had bronchiectasis, another cardiovascular disease and one had severe liver disease requiring liver transplantation. None of the six patients had had more than one exacerbation during the previous year. Two patients had radiologically confirmed emphysema with a FEV1 of 65 and 67% respectively and intravenous augmentation treatment was initiated after diagnosis (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Severe group</span><p id="par0035" class="elsevierStylePara elsevierViewall">Six AATD Pi*ZZ patients with impaired lung function at diagnosis (FEV1≤45%) were analyzed. The mean age was 43 years (SD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6.4) and four were men. Two patients were current smokers and 4 were former smokers. The mean FEV1 at diagnosis was 44% (SD<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6.7). We observed bronchiectasis in one patient and cardiovascular disease in two patients and none presented significant liver disease. All had had two or more exacerbations during the last year. Four patients initiated intravenous augmentation treatment after diagnosis, the two remaining patients were active smokers and therefore augmentation treatment was not indicated.</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion</span><p id="par0040" class="elsevierStylePara elsevierViewall">Diagnosis of lung disease in AATD is usually delayed for some years after the first clinical manifestations.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> We compared two groups of patients diagnosed with lung disease of different severity to try to understand factors associated with early diagnosis.</p><p id="par0045" class="elsevierStylePara elsevierViewall">On comparing the two groups, we observed a younger mean age at diagnosis and more exacerbations in the severe group, but the percentage of smokers did not statistically differ between the two groups.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Our results suggest that AATD continues to be a disease which is suspected in younger patients with a worse lung function. In addition these findings confirm the clinical variability of the disease and that there are still unknown factors that contribute to its development. Therefore, early diagnosis may modify the prognosis of this disease. It is estimated that a total of 253,404 ZZ individuals are distributed mainly in Europe and North America.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">2</span></a> Nevertheless AATD is under-diagnosed because of the poor knowledge of this disease by physicians. Indeed, in the study by Greulich et al. only 18 and 25% of physicians in Italy and Germany, respectively, stated that they tested all their patients with chronic obstructive pulmonary disease (COPD) and asthma.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">15</span></a> Likewise, in another survey conducted by Esquinas et al. in Spain and Portugal only 15.8% of physicians tested all of their COPD patients for AATD, and only 45.2% knew the AAT serum concentrations needed to consider severe deficiency.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">16</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">These data are in contrast with the worldwide recommendation of testing all COPD patients at least once in their lives.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">1,17,18</span></a> A population-based study performed in primary care in our region demonstrated that requests for AAT determinations were low compared to the number of COPD patients diagnosed per year.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">19</span></a> In addition, an important number of determinations were not prescribed because of pulmonary disease.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusion</span><p id="par0060" class="elsevierStylePara elsevierViewall">In conclusion, lung disease associated with AATD may evolve in different ways and predisposing factors are not completely understood, which makes its early diagnosis even more important. Early diagnosis would help to improve strategies such as tobacco cessation, vaccination, initiation of optimum COPD treatment and augmentation therapy with AAT when indicated, to prevent disease progression. In addition, physicians should have a broader knowledge of the disease which would facilitate early diagnosis and thereby implement more efficient health care interventions.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflicts of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">Marc Miravitlles has received speaker or consulting fees from (in alphabetical order) Bial, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Laboratorios Esteve, Gebro Pharma, GlaxoSmithKline, Grifols, Menarini, Mereo Biopharma, Novartis, pH Pharma, Rovi, TEVA, Verona Pharma and Zambon, and research grants from GlaxoSmithKline and Grifols.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:3 [ "identificador" => "xres1148536" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1077802" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:3 [ "identificador" => "sec0010" "titulo" => "Clinical observations" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Moderate group" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Severe group" ] ] ] 4 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 5 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusion" ] 6 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflicts of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-11-17" "fechaAceptado" => "2018-05-10" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1077802" "palabras" => array:3 [ 0 => "COPD" 1 => "Alpha1-antitrypsin deficiency" 2 => "Diagnosis" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Alpha1-antitrypsin deficiency (AATD) is a well known genetic risk factor for pulmonary disease and is the most frequent hereditary disease diagnosed in adults. Despite being one of the most common hereditary diseases, AATD remains under-diagnosed because of its variable clinical presentation and the poor knowledge of this disease by physicians. With the aim of identifying clinical differences that could influence early diagnosis, we compared two groups of six AATD Pi*ZZ patients with different lung function severity and clinical expression at diagnosis. On comparing the two groups, we observed a younger mean age at diagnosis and more exacerbations in the severe group, but the percentage of smokers did not statistically differ between the two groups. Our results suggest that AATD continues being a disease suspected on younger patients with a worse lung function. In addition these findings confirm the clinical variability of the disease and that there are still unknown factors that contribute to its development. Therefore, early diagnosis may modify the prognosis of this disease.</p></span>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Data are expressed as mean and percentages.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variables \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Moderate <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Severe <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6 \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Current age</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">61.7 (7.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">61.0 (10.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.937 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age at diagnosis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">51.2 (4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42.7 (6.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.041 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Gender</span></td><td class="td" title="table-entry " align="left" valign="top">0.999 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-Men \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (66.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (66.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-Women \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (33.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (33.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Number of smokers</span></td><td class="td" title="table-entry " align="char" valign="top">0.135 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-Never smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (33.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-Current smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (33.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-Former smoker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (66.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (66.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">FEV1% at diagnosis</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">93 (29) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44 (6.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.002 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleItalic">Other comorbidities</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-Bronchiectasis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (16.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (16.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.098 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-Cardiovascular disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (16.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (33.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.125 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-Liver disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (16.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Bronchodilator treatment</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (66.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.225 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-β2 agonists \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (66.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.065 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-Inhaled corticosteroids \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6 (100%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.025 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Exacerbations per year (≥2)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (66.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.049 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Intravenous augmentation treatment with AAT</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (33.3%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4 (66.7%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.248 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1959763.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Demographic and clinical characteristics.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Indications for active case searches and intravenous alpha-1 antitrypsin treatment for patients with alpha-1 antitrypsin deficiency chronic pulmonary obstructive disease: an update" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 1 | 9 |
| 2024 October | 22 | 18 | 40 |
| 2024 September | 21 | 15 | 36 |
| 2024 August | 53 | 58 | 111 |
| 2024 July | 39 | 54 | 93 |
| 2024 June | 51 | 33 | 84 |
| 2024 May | 36 | 32 | 68 |
| 2024 April | 36 | 28 | 64 |
| 2024 March | 39 | 21 | 60 |
| 2024 February | 44 | 31 | 75 |
| 2024 January | 47 | 29 | 76 |
| 2023 December | 34 | 22 | 56 |
| 2023 November | 58 | 52 | 110 |
| 2023 October | 24 | 38 | 62 |
| 2023 September | 25 | 40 | 65 |
| 2023 August | 24 | 20 | 44 |
| 2023 July | 34 | 40 | 74 |
| 2023 June | 26 | 18 | 44 |
| 2023 May | 71 | 49 | 120 |
| 2023 April | 34 | 27 | 61 |
| 2023 March | 73 | 27 | 100 |
| 2023 February | 54 | 26 | 80 |
| 2023 January | 24 | 15 | 39 |
| 2022 December | 57 | 29 | 86 |
| 2022 November | 51 | 36 | 87 |
| 2022 October | 77 | 43 | 120 |
| 2022 September | 30 | 43 | 73 |
| 2022 August | 39 | 36 | 75 |
| 2022 July | 49 | 65 | 114 |
| 2022 June | 27 | 41 | 68 |
| 2022 May | 40 | 41 | 81 |
| 2022 April | 35 | 47 | 82 |
| 2022 March | 40 | 62 | 102 |
| 2022 February | 29 | 39 | 68 |
| 2022 January | 34 | 49 | 83 |
| 2021 December | 37 | 49 | 86 |
| 2021 November | 29 | 48 | 77 |
| 2021 October | 38 | 68 | 106 |
| 2021 September | 32 | 44 | 76 |
| 2021 August | 23 | 29 | 52 |
| 2021 July | 31 | 19 | 50 |
| 2021 June | 40 | 39 | 79 |
| 2021 May | 35 | 34 | 69 |
| 2021 April | 121 | 99 | 220 |
| 2021 March | 52 | 42 | 94 |
| 2021 February | 27 | 22 | 49 |
| 2021 January | 31 | 32 | 63 |
| 2020 December | 26 | 24 | 50 |
| 2020 November | 27 | 22 | 49 |
| 2020 October | 35 | 39 | 74 |
| 2020 September | 51 | 47 | 98 |
| 2020 August | 32 | 30 | 62 |
| 2020 July | 74 | 43 | 117 |
| 2020 June | 39 | 30 | 69 |
| 2020 May | 36 | 29 | 65 |
| 2020 April | 30 | 13 | 43 |
| 2020 March | 39 | 26 | 65 |
| 2020 February | 27 | 19 | 46 |
| 2020 January | 34 | 26 | 60 |
| 2019 December | 42 | 28 | 70 |
| 2019 November | 25 | 19 | 44 |
| 2019 October | 26 | 20 | 46 |
| 2019 September | 39 | 18 | 57 |
| 2019 August | 33 | 21 | 54 |
| 2019 July | 34 | 24 | 58 |
| 2019 June | 35 | 18 | 53 |
| 2019 May | 41 | 19 | 60 |
| 2019 April | 42 | 48 | 90 |
| 2019 March | 63 | 47 | 110 |
| 2019 February | 103 | 97 | 200 |
| 2019 January | 106 | 68 | 174 |
| 2018 December | 37 | 35 | 72 |
| 2018 November | 1 | 0 | 1 |
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