Case Report
Azithromycin as an adjuvant therapy in cryptogenic organizing pneumonia
A.P. Vaza,
, A. Moraisb, N. Meloa, P. Caetano Motaa, C. Souto Mourac, A. Amorimb
Corresponding author
a Serviço de Pneumologia, Hospital de São João, Porto, Portugal
b Serviço de Pneumologia, Hospital de São João, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Porto, Portugal
c Serviço de Anatomia Patológica, Hospital de São João, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Porto, Portugal
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Jacinto, A. Morais, J.A. Fonseca" "autores" => array:3 [ 0 => array:2 [ "nombre" => "T." "apellidos" => "Jacinto" ] 1 => array:2 [ "nombre" => "A." "apellidos" => "Morais" ] 2 => array:2 [ "nombre" => "J.A." "apellidos" => "Fonseca" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173511511000200?idApp=UINPBA00004E" "url" => "/21735115/0000001700000004/v1_201305151548/S2173511511000200/v1_201305151548/en/main.assets" ] "itemAnterior" => array:20 [ "pii" => "S2173511511000042" "issn" => "21735115" "doi" => "10.1016/j.rppnen.2011.01.003" "estado" => "S300" "fechaPublicacion" => "2011-07-01" "aid" => "3" "copyright" => "Sociedade Portuguesa de Pneumologia" "documento" => "article" "crossmark" => 0 "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "sco" "cita" => "Rev Port Pneumol. 2011;17:182-5" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 8157 "formatos" => array:3 [ "EPUB" => 256 "HTML" => 6549 "PDF" => 1352 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Case report</span>" "titulo" => "A rich and blessed professional illness - organizing pneumonia due to gold dust" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "182" "paginaFinal" => "185" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1016 "Ancho" => 2735 "Tamanyo" => 443483 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Lung histology (A – H&E, B – Cytokeratin): diffuse parenchymal lung changes; marked enlargement of the alveolar septa, foci of edema and mild to moderate lymphocytic infiltrate with rare neutrophils and some eosinophils. 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Vaz, A. Morais, N. Melo, P. Caetano Mota, C. Souto Moura, A. Amorim" "autores" => array:6 [ 0 => array:4 [ "nombre" => "A.P." "apellidos" => "Vaz" "email" => array:1 [ 0 => "vaz.anapaula@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "A." "apellidos" => "Morais" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "N." "apellidos" => "Melo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "P." "apellidos" => "Caetano Mota" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "C." "apellidos" => "Souto Moura" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 5 => array:3 [ "nombre" => "A." "apellidos" => "Amorim" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Serviço de Pneumologia, Hospital de São João, Porto, Portugal" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Serviço de Pneumologia, Hospital de São João, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Porto, Portugal" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Serviço de Anatomia Patológica, Hospital de São João, Porto, Portugal; Faculdade de Medicina da Universidade do Porto, Porto, Portugal" "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 427 "Ancho" => 1496 "Tamanyo" => 76209 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Chest computed tomography</span> - resolution of lung infiltrates.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cryptogenic organising pneumonia (COP) is an inflammatory disease that mainly affects the alveolar airspaces, ducts and small airways, although the interstitium can also be involved.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The histological pattern is that of organizing pneumonia (OP), which can be seen in a wide variety of settings. The term COP is used when the disease is idiopathic.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>Corticosteroids are the first line therapy in the majority of patients, these are usually effective and lead to a good prognosis.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> There are, however, some reports of patients responding to the immunomodulatory properties of chronic low dose therapy with macrolides, providing an alternative in patients with mild disease or for those who cannot tolerate steroids or as adjuvant to standard treatment.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–9</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The authors report a case of a sixty-year-old woman, with controlled intrinsic bronchial asthma, who presented COP and several respiratory exacerbations despite corticosteroid and immunossupressant therapy, being successfully treated with azithromycin as an adjuvant to steroids. A brief review on the literature data about the anti-inflammatory effects of macrolides in chronic airway diseases is included.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Case report</span><p id="par0015" class="elsevierStylePara elsevierViewall">A sixty-year-old female with a controlled intrinsic bronchial asthma (intermittent), diagnosed in childhood, presented with recurrent pneumonias which had led to multiple hospital admissions. She had never smoked and worked as financial administrator.</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the previous five years, as well as chronic treatment with a long acting bronchodilator and corticosteroid (salmeterol 50/fluticasona 250<span class="elsevierStyleHsp" style=""></span>μg), she had had multiple courses of systemic corticosteroids and antibiotics due to respiratory exacerbations consisting of fever, wheeze, dyspnea and sometimes pleuritic chest pain. During these episodes, chest high resolution computed tomography (HRCT) showed peripheral and migratory multifocal consolidations with air bronchogram and a ground glass pattern, sometimes without being completely resolved between crises (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Bronchoalveolar lavage (BAL) performed during one hospital admission, revealed neutrophilia (12.8%) and a slight eosinophilia (2.2%); there was no lymphocytosis (13.6%). No microbiological agents or evidence of malignancy were found. Autoimmunity and serologic blood studies did not point to any specific etiology. Transthoracic core biopsy was inconclusive.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In the meanwhile, there was clinical deterioration with the patient presenting a moderate obstructive ventilatory syndrome (FEV1<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>53%) without bronchodilator reversibility, slight hipoxemia (Pa02<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>71.5<span class="elsevierStyleHsp" style=""></span>mmHg) and significant desaturation in the six minute walk test (S02<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>90---95%, 500m). The patient was then referred for pulmonology consultation and a second transthoracic core biopsy was performed revealing features compatible with OP, namely chronic inflammation and intra-alveolar organizing fibromyxoid polyps (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The diagnosis of COP was established, since no aetiology related to OP was found. The patient started high dose of corticosteroid therapy (equivalent dose of prednisolone 1<span class="elsevierStyleHsp" style=""></span>mg/Kg/day), but as there was no clinical improvement and tapering glucocorticoid therapy was not possible, four months later, azathioprine was added. The dose of azathioprine was not increased above 150<span class="elsevierStyleHsp" style=""></span>mg/day, and the cytotoxic drug was stopped, due to persistent exacerbations and hospital admission. Following discharge, azithromycin, 500<span class="elsevierStyleHsp" style=""></span>mg on alternate days, was started as an adjuvant to steroid therapy (0,75<span class="elsevierStyleHsp" style=""></span>mg/kg/day). Clinical and functional improvement followed and HRCT showed clearing of lung infiltrates (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). It was possible to withdraw steroid therapy within a year and there was no evidence of relapse in the six months of the follow up. Azithromycin was maintained, and at this point the frequency of administration was reduced (500<span class="elsevierStyleHsp" style=""></span>mg, three times per week). No adverse side effects were observed.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">Spontaneous remission of COP is rare and, therefore, the majority of symptomatic patients with lung infiltrates will need treatment.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> The prominent histological finding is OP with patchy involvement of the pulmonary parenchyma by fibromyxoid, polypoid plugs of granulation tissue, within the alveoli and occasionally the bronchioles.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–3</span></a> Intra-alveolar fibrosis of OP represents a unique model of inflammatory lung disease, since it is not associated with progressive irreversible fibrosis.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Corticosteroids are, thus, the standard therapy, resulting in complete recovery in up to 80% of patients within a few weeks to three months.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Relapses are common (13% to 58%), usually associated with tapering or withdrawal of corticosteroids. Even so, the prognosis of the disease is generally good.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> Immunosuppressive agents, such as cyclophosphamide and azatioprine, can be used in refractory COP, although data concerning the use of these drugs are scarce.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The patient described presented further relapses with high dose of corticosteroid therapy and even with the addition of an immunosuppressant agent. Therefore, based on observational studies and case series reporting efficacy of chronic low-dose macrolide therapy with a 14 (erythromycin, clarithromycin) and 15 (azithromycin) member-ring in COP, azithromycin was started as an adjuvant to corticotherapy.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Besides antibacterial actions, these macrolides seem to have immune modulating effects that appear to be the rationale for clinical benefit in several chronic inflammatory airway diseases.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Much of the evidence that macrolides have immunomodulatory effects comes from Japan, where these antibiotics have proved effective in treating diffuse panbronchiolitis (evidence 1A).<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10–12</span></a> In cystic fibrosis, the most recent recommendations suggest that they should be reserved for those with chronic <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> infection when controlling symptoms and maintaining pulmonary function has been difficult (evidence 2A).<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,13</span></a> The evidence for a role of macrolides in other inflammatory airway diseases, such as idiopathic bronchiectasis (evidence 2B), obliterative bronchiolitis (evidence 2B), chronic obstructive pulmonary disease (evidence 2B), COP (evidence 2C) and asthma (evidence 1B, against), is less clear.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>Macrolides in COP have been described as an alternative therapy in patients with minimal symptoms and/or minimal physiologic impairment.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–6</span></a> In the majority of cases, patients were started on macrolides for suspected bacterial infection and subsequently received the diagnosis. Other patients either refused corticosteroid therapy or could not tolerate the side effects and were administered macrolides. The use of macrolides as adjuvant therapy in patients receiving steroids is also considered in the literature.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–9</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In general, macrolides are assumed to reduce airway inflammation by several mechanisms such as modulation of host-pathogen interactions, signalling pathways, cytokine responses, oxidative stress, innate immunity and others, such as decrease in mucus secretion and methylprednisolone clearance.<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11,14–16</span></a> The mechanism of the action of macrolides in COP is not yet clear. However, it is known that some patients with the disease show a mixed BAL pattern with increased neutrophils, eosinophils and lymphocytes, with a decrease in CD4/CD8 ratio due to an increase in cytotoxic T-cells. Aoki and Kao<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> demonstrated that erythromycin may exert anti-inflammatory effects on T-cells by inhibiting cytokine gene expression at the level of transcription activation, demonstrating that the beneficial effects of macrolides in COP may occur due to their immunosuppressive effect on polymorphonuclear cells and their products and also to their influence on T-cells.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Our patient did not however present lymphocytosis on BAL. In fact, the absence of BAL lymphocytosis, the presence of comorbilities and the late diagnosis, the three factors considered to have the worst prognosis, were recorded in this case. Nevertheless, there seemed to be a correlation between administration of the drug and the end of the recurrent episodes, with radiologic resolution and clinical and functional improvement.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Like the corticosteroids, macrolides were continued for a prolonged period of time, and were then empirically tapered after the withdrawal of the former. As with the majority of other case studies, we did not find any complications during long term therapy with macrolides.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Although this case may reinforce the role of macrolide anti-inflammatory properties in COP as corticosteroids adjuvant therapy, further studies are required in order to clarify potential benefits and possible side effects, in particular the most serious ones, related to antimicrobial resistance. In addition, information about which patients would be likely to respond, proper dosage and duration of macrolide therapy is needed.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a></p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:2 [ "identificador" => "xres173244" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec161526" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres173245" "titulo" => "Resumo" ] 3 => array:2 [ "identificador" => "xpalclavsec161527" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case report" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2010-12-29" "fechaAceptado" => "2011-03-21" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec161526" "palabras" => array:4 [ 0 => "Cryptogenic organizing pneumonia" 1 => "Macrolides" 2 => "Azithromycin" 3 => "Antibiotic therapy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec161527" "palabras" => array:4 [ 0 => "Pneumonia organizativa criptogénica" 1 => "Macrólidos" 2 => "Azitromicina" 3 => "Antibioterapia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">There are data about the immunomodulatory properties of some macrolides in cryptogenic organizing pneumonia (COP) as an alternative to corticosteroids in mild disease or as adjuvant to standard therapy.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A sixty-year-old female, with a controlled intrinsic asthma, presented with COP and recurrent respiratory exacerbations despite corticosteroid and immunossupressant therapy. Azithromycin (500<span class="elsevierStyleHsp" style=""></span>mg, on alternate days) as an adjuvant to steroids was then started, with clinical and functional improvement and regression of lung infiltrates. Withdrawal of steroids was possible in one year, without evidence of relapse in the next six months. Azithromycin was maintained (three times per week) with no documentation of adverse side effects.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">This clinical case reinforces the potential role of macrolides anti-inflammatory properties in COP as corticosteroids adjuvant therapy.</p>" ] "es" => array:2 [ "titulo" => "Resumo" "resumen" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Existem dados na literatura sobre o uso das propriedades imunomoduladoras de alguns macrólidos no tratamento da pneumonia organizativa criptogénica (COP) como alternativa aos corticoesteróides na doença ligeira ou como adjuvantes da terapêutica padrão.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Os autores descrevem o caso de uma mulher de 60 anos de idade, com asma intrínseca controlada, que apresentou uma COP e exacerbações respiratórias de repetição, apesar da corticoterapia e terapêutica imunossupressora instituídas. Após início de azitromicina (500<span class="elsevierStyleHsp" style=""></span>mg, dias alternados), como adjuvante da corticoterapia, verificou-se melhoria clínica e funcional e regressão dos infiltrados pulmonares. A suspensão dos corticoesteróides foi possível no período de um ano, sem evidência de recidiva nos seis meses seguintes. A azitromicina foi mantida (3 vezes/semana) sem documentação de efeitos laterais adversos.</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Este caso clínico reforça o potencial papel das propriedades anti-inflamatórias dos macrólidos na COP, como terapêutica adjuvante dos corticoesteróides.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Vaz AP, et al. Azitromicina como terapêutica adjuvante na pneumonia organizativa criptogénica. Rev Port Pneumol. 2011; 17: 186–189.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 412 "Ancho" => 1496 "Tamanyo" => 83184 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Chest high resolution computed tomography</span> - peripheral and multifocal consolidations with air bronchogram and a ground glass pattern.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 761 "Ancho" => 950 "Tamanyo" => 259508 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Histopathologic slide (hematoxylin and eosin, 200x)</span> - septal thickening with lymphocytic infiltration involving polymorphonuclear eosinophils. Proteinaceous exudate and, focally, fibrosis and inflammatory cells in a myxoid stroma in intra-alveolar location.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 427 "Ancho" => 1496 "Tamanyo" => 76209 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">Chest computed tomography</span> - resolution of lung infiltrates.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. 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