Idiopathic pulmonary fibrosis | Medicina Clínica (English Edition)

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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Idiopathic pulmonary fibrosis &#40;IPF&#41; is defined as a chronic&#44; fibrosing interstitial lung pneumonia&#44; of unknown etiology&#44; usually affecting adults over 50 years old and associated with the radiological and&#47;or histological pattern of usual interstitial pneumonia&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> It is the most frequent diffuse interstitial lung disease&#46; The actual incidence and prevalence of IPF is not fully understood&#46; The epidemiological studies performed show very variable figures depending on the criteria used to define the disease&#44; study population&#44; methodology and study design&#46; However&#44; it is estimated that the incidence is 4&#46;6&#8211;7&#46;4 cases&#47;100&#44;000 and the prevalence is 13 cases&#47;100&#44;000 in women and 20 cases&#47;100&#44;000 in men&#46; In Spain&#44; the number of patients with IPF probably ranges from 8000 to 12&#44;000&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">2&#44;3</span></a> It is unknown whether the incidence and prevalence are influenced by ethnic&#44; racial or geographical factors&#46; In recent years&#44; incidence has been reported to be higher&#44; probably due to the improved diagnostic methods and the increased life expectancy&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Etiology</span><p id="par0010" class="elsevierStylePara elsevierViewall">The etiology of IPF is unknown&#44; although it is likely that the disease is the consequence of the action of several factors in subjects with genetic predisposition &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The relevance of the genetic predisposition is based on the existence of familial forms of the disease&#46; From 2&#46;2 to 3&#46;7&#37; IPFs are familial&#46; It should be noted that members of the same family may be affected by various types of interstitial lung disease&#44; such as non-specific interstitial pneumonia and cryptogenic organizing pneumonia&#46; The most significant genetic abnormalities in the predisposition and evolution of the disease are the gene mutations maintaining the telomere length and located in the telomerase complex&#44; such as TERT&#44; TERC&#44; DKC&#44; or RTEL&#44; surfactant protein C and the Mucin 5B promoter &#40;MUC5B&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">4&#44;5</span></a> Smoking&#44; exposure to silica&#44; brass&#44; steel and wood dust&#44; livestock and agriculture work&#44; and the construction of wooden houses are deemed risk factors&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">6</span></a> Gastroesophageal reflux &#40;GER&#41; might play a role in the pathogenesis of IPF and in its natural history since it may lead to aspiration or microaspiration of gastroesophageal content that might be factors triggering the damage of the alveolar epithelial cells that characterizes IPF&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">7</span></a> Although several studies have been conducted&#44; there is no evidence to suggest that viral infections &#40;hepatitis C virus&#44; herpes virus&#44; adenovirus&#41; are etiological factors&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a> The potential contribution of autoimmunity is based on the fact that the histological and radiological pattern of the usual interstitial pneumonia can be associated with connective tissue disorders&#44; especially rheumatoid arthritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">8&#44;9</span></a> In this context&#44; it should be noted that in a recent study usual interstitial pneumonia has been shown to be the main pulmonary condition in the undifferentiated connective tissue disease&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">10</span></a> It has been suggested that IPF is a consequence of lung aging or of some pathogenic mechanisms that occur more easily after a certain age&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">11&#44;12</span></a> Several cases of people over 75 years&#44; with no respiratory symptoms&#44; have shown abnormalities suggestive of interstitial disease when undergoing high-resolution computed tomography &#40;HRCT&#41; for any other reason&#44;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">13</span></a> and it is not clear if these changes are a consequence of lung aging or a true interstitial disease&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Pathogenesis</span><p id="par0015" class="elsevierStylePara elsevierViewall">Historically it was accepted that IPF was the result of an inflammatory process&#46; Currently it is demonstrated that the disruption of lung tissue and the formation of fibrosis are the result of an abnormal repair of alveolar epithelial lesions resulting in progressive accumulation of extracellular matrix proteins&#44; decreased fibroblast&#47;myofibroblast balance and constant death of epithelial cells&#44; without evidence of previous inflammation&#46; Therefore&#44; epithelial cells&#44; fibroblasts and myofibroblasts are considered the main effectors in the progression of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">14&#44;15</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Anatomical pathology</span><p id="par0020" class="elsevierStylePara elsevierViewall">The histological pattern of usual interstitial pneumonia has been defined with 4 criteria&#58; a&#41; evidence of marked honeycomb or non-honeycomb fibrosis&#44; with subpleural and paraseptal predominance&#59; b&#41; presence of patches where fibrotic areas are combined with areas of healthy lung&#59; c&#41; presence of fibroblastic foci in areas of fibrosis interface with healthy parenchyma&#44; and d&#41; absence of histopathological findings inconsistent with usual interstitial pneumonia&#46; Integrating the HRCT findings with the histopathological pattern is meant to establish the diagnosis of IPF&#44; to exclude it or&#44; if the data are inconclusive&#44; to maintain it as probable or possible&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">16&#44;17</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Signs and symptoms</span><p id="par0025" class="elsevierStylePara elsevierViewall">The signs and symptoms are of insidious onset and are characterized by progressive effort dyspnea and persistent dry cough&#46; The presence of systemic symptoms should be suspicious of an alternative diagnosis&#46; In the advanced stages&#44; chronic respiratory failure is common&#46; Physical examination shows crackles in 90&#37; cases and nail clubbing in 50&#37;&#46; There are no specific modifications in blood tests&#46; SVR&#44; C-reactive protein &#40;CRP&#41; and IgG may be slightly higher&#46; Antinuclear antibodies and rheumatoid factor are positive in 10&#8211;20&#37; cases&#44; but at low titers&#46; Familial pulmonary fibrosis is a form of fibrosis that affects 2 or more members of the same family&#46; The symptomatology is similar&#44; although it is usually diagnosed at younger ages&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Chest X-ray shows reticular opacities associated or not with honeycomb images&#44; of basilar peripheral and bilateral distribution&#46; The presence of alveolar images should raise the possibility of an alternative diagnosis&#46; HRCT shows the typical findings of usual interstitial pneumonia&#44; consisting of basilar and subpleural predominant pulmonary involvement&#44; and presence of reticular and honeycomb images with or without traction bronchiectasis&#47;bronchiolectasis&#46; There should be little or none ground glass images&#44; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46; Its diagnostic sensitivity is over 90&#37;&#46; Bronchoalveolar lavage is characterized by neutrophilia&#44; with or without eosinophilia&#44; in 85&#37; cases&#46; In some cases the cell is normal&#46; In case of lymphocytosis &#40;over 20&#37;&#41;&#44; other diagnoses should be ruled out&#44; particularly chronic hypersensitivity pneumonitis&#46; Respiratory function tests show a restrictive abnormality in ventilatory activity with lower pulmonary volumes and diffusing capacity for carbon monoxide &#40;DLco&#41;&#46; The 6-minute walk test is a simple stress test used to assess exercise tolerance&#46; Hypoxemia occurs in the advanced stages of the disease and hypercapnia&#44; in the final stages&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">18&#44;19</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis</span><p id="par0035" class="elsevierStylePara elsevierViewall">Diagnostic criteria include&#58; a&#41; exclusion of other causes of interstitial lung disease and b&#41; presence of the histological pattern of usual interstitial pneumonia in lung biopsy samples or evidence of pattern of usual interstitial pneumonia in HRCT or both&#46; Biopsy is indicated in cases where HRCT does not reveal the typical findings of usual interstitial pneumonia&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;2</span></a> The diagnosis of IPF is clinicopathological&#46; A multidisciplinary assessment involving pulmonologists&#44; radiologists and pathologists&#44; experts in IPF&#44; increases diagnostic accuracy and is currently a widely accepted recommendation for establishing a diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;2</span></a> Serological analysis of connective tissue diseases should be performed in every case since the pattern of usual interstitial pneumonia can occur in these diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">20</span></a> In addition&#44; specific IgGs in serum should be determined against the antigens that may most frequently cause hypersensitivity pneumonitis&#44; since their clinical manifestations are sometimes similar to those of IPF&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">21</span></a> Conventional transbronchial biopsy is not useful for diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">22</span></a> However&#44; transbronchial biopsy using cryobiopsy has been shown to be a potentially useful technique&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">23</span></a> Bronchoalveolar lavage can be very helpful in the differential diagnosis of other entities&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Natural history</span><p id="par0040" class="elsevierStylePara elsevierViewall">The evolution is variable&#46; The disease can remain asymptomatic for 2&#8211;3 years and is sometimes stable for long periods of time&#46; In some cases the onset of symptoms may occur 6&#8211;24 months prior to diagnosis&#46; The most usual progression is slow progression&#44; although there are accelerated forms leading to respiratory failure within 6&#8211;12 months&#46; In the course of the disease&#44; acute exacerbations may occur&#44; which worsen the prognosis&#46; Mean survival is 2&#8211;5 years from the onset of symptoms&#44; although with the recent introduction of antifibrotic drugs&#44; progression-free disease is increasing&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">25&#8211;27</span></a> It is unknown whether the different forms of natural history account for different phenotypes of the disease&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Monitoring evolution and prognostic factors</span><p id="par0045" class="elsevierStylePara elsevierViewall">The tests to be performed to monitoring evolution&#44; will depend on the patient&#39;s condition&#46; It is generally accepted that it is advisable to perform respiratory function tests &#40;forced vital capacity &#91;FVC&#93; and DLco&#41;&#44; assessment of the degree of dyspnea&#44; pulse oximetry at rest&#44; chest X-ray and 6-minute walk test every 3&#8211;6 months&#46; However&#44; they should be practiced in shorter periods of time if there are symptoms and signs of disease progression&#46; Arterial blood gas tests should be performed only when the disease is progressing&#46; HRCT is not necessary on a systematic and sequential basis during follow-up&#46; It should be performed in cases of disease progression and suspected complications&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The IPF has a variable clinical course&#46; Therefore&#44; it is important to identify factors that can help define the prognosis&#46; Several studies have evaluated the importance of symptoms and function tests&#46;<a class="elsevierStyleCrossRefs" href="#bib0440"><span class="elsevierStyleSup">28&#44;29</span></a> The predictive survival variables are specified in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; It should be noted that the factor that best determines the evolution of the disease is FVC&#46; A decrease of FVC by &#8805;5&#8211;10&#37; is a sign of poor disease progression&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">30</span></a> Multidimensional scales containing clinical data and function tests are currently being developed intended to predict the individual risk of mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">31</span></a> Currently&#44; there are no biomarkers to assess the evolution of the disease&#44; however possible options are being investigated through longitudinal studies&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">32</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Complications and comorbidities</span><p id="par0055" class="elsevierStylePara elsevierViewall">Patients with IPF can report complications and comorbidities that modify the clinical course and prognosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Emphysema</span><p id="par0060" class="elsevierStylePara elsevierViewall">Combined pulmonary fibrosis and emphysema &#40;CPFE&#41; is deemed a different entity representing a clinical syndrome&#46; It is more common in males with a significant smoking-habit&#46; Chest X-ray and HRCT show emphysema of the upper lobes and images of pulmonary fibrosis in the lower lobes&#46; Its prevalence is 30&#8211;47&#37; in patients with IPF&#46; Spirometry and lung volumes are minimally diminished due to the opposite effect between emphysema-induced hyperinflation and volume loss due to fibrosis&#46; However&#44; DLco and severe hypoxemia drop dramatically and disproportionately during exercise due to the additive effect of emphysema and fibrosis&#46; Pulmonary hypertension &#40;PH&#41; is more frequent and marked than in patients with IPF and is the main determinant of poor prognosis&#44; which is worse than in IPF without emphysema&#46; There is no specific therapy&#46; Therapeutic measures are limited to oxygen therapy in cases where indicated and to the conventional treatment for chronic obstructive pulmonary disease &#40;COPD&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">33&#44;34</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Pulmonary hypertension</span><p id="par0065" class="elsevierStylePara elsevierViewall">PH in IPF occurs due to several factors&#44; mainly chronic hypoxia-induced vasoconstriction and destruction of the pulmonary capillary bed induced by fibrosis&#46; PH usually appears in advanced stages of IPF and is generally mild&#44; with a 30&#8211;45&#37; prevalence&#46; However&#44; there is a subgroup of patients with mild to moderate IPF and severe PH&#46; The development of PH is associated with significant dyspnea&#44; function impairment &#40;particularly DLco&#41; and decreased exercise capacity&#46; In addition&#44; the prognosis of the disease worsens significantly&#46; Pharmacological treatment is controversial&#46; In 2015&#44; 2 clinical practice guidelines were published mentioning the therapy<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;35&#44;36</span></a> and where the use of drugs approved for pulmonary arterial hypertension is not recommended for any other causes&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Sildenafil is a phosphodiesterase 5 inhibitor&#44; which in patients with right ventricular systolic dysfunction improves the distance covered in the 6-minute walk test and the quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">37</span></a> Therefore&#44; treatment should be individualized in patients with IPF and PH or severe right ventricular dysfunction in a center experienced in PH&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Acute exacerbation</span><p id="par0075" class="elsevierStylePara elsevierViewall">The exacerbation of IPF is defined as an acute worsening of respiratory symptoms&#44; with no clear trigger&#44; leading to severe hypoxemia and worsening prognosis in the short term&#46; Mortality is over 50&#37; and in those cases requiring mechanical ventilation&#44; close to 100&#37;&#46; The annual incidence varies by series but is around 15&#37;&#46; Several studies have established potential risk factors&#44; such as impaired lung function &#40;FVC &#60;70&#37;&#41;&#44; the presence of GER and PH&#46; The etiology of IPF exacerbations is unknown&#44; although several mechanisms have been suggested as initiators of the symptomatology&#58; infectious agents&#44; pollution or pharmacological toxicity&#46; Lung surgery associated with diagnostic tests &#40;bronchoscopic techniques&#41; have also been admitted as predisposing factors&#46; The diagnostic criteria are as follows&#58; 1&#41; diagnosis prior to or concurrent with IPF&#44; 2&#41; worsening dyspnea below 30 days of evolution&#44; 3&#41; HRCT with the occurrence of new ground glass infiltrates with or without consolidations adjacent to the usual interstitial pneumonia pattern&#44; 3&#41; in the absence of pulmonary infection&#44; heart failure and other diseases that occur with a similar clinical symptomatology &#40;sepsis&#44; aspiration&#41;&#46; It is not related to the previous evolution of the disease&#44; since it may be the form of presentation&#46; Histological examination of the lung parenchyma shows diffuse alveolar damage in most cases&#44; although organizational pneumonia or accumulation of fibroblasts may occur&#44; in addition to the modifications typical of the usual interstitial pneumonia&#46; There are no established therapeutic guidelines&#46; The most commonly used treatment is high-dose glucocorticoid boluses &#40;methylprednisolone 500&#8211;1000<span class="elsevierStyleHsp" style=""></span>mg&#47;day iv&#41; for 3 days&#44; followed by prednisone &#40;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#41;&#44; which are progressively decreased&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">38&#44;39</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Sleep apnea&#8211;hypopnea syndrome</span><p id="par0080" class="elsevierStylePara elsevierViewall">Over one-third of patients with IPF suffer from sleep apnea&#8211;hypopnea syndrome and other sleep disorders that influence the patients&#8217; quality of life&#46; No association has been reported between the severity of sleep apnea&#8211;hypopnea syndrome and abnormalities in pulmonary function tests&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">1&#44;2</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Gastroesophageal reflux</span><p id="par0085" class="elsevierStylePara elsevierViewall">As discussed above&#44; GER has a role in the pathogenesis of IPF and its natural history&#46; It has been proven that the prevalence of GER in IPF is 90&#37;&#44; although only half of the patients report symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">40</span></a> In a retrospective study of 204 patients with IPF&#44; survival has been increased in patients treated with antacid therapy&#44; mainly proton pump inhibitors &#40;PPIs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">41</span></a> In a data analysis from 242 patients included in the placebo arms of 3 randomized clinical trials it has been reported that patients receiving PPIs or antagonist of histamine-2 receptors &#40;H2R&#41; had lower drop in FVC&#46; Given the reasonable cost and poor morbidity that might result from PPI-induced side effects&#44; it is reasonable to prescribe them in patients with IPF and GER&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">42</span></a> However&#44; the most effective procedure for treating GER is postural and dietary measures&#44; which should never be forgotten when considering an effective treatment since PPIs control stomach acidity&#44; not reflux&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Lung cancer</span><p id="par0090" class="elsevierStylePara elsevierViewall">The prevalence of lung cancer ranges from 15 to 20&#37;&#44; and increases over time of disease evolution and in CPFE patients&#46; Smoking and an increased expression of p53 and p21 molecules in alveolar epithelial cells might influence carcinogenesis&#46; Tumors predominate in the lower lobes&#44; where fibrotic lesions are located&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">43</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Other complications</span><p id="par0095" class="elsevierStylePara elsevierViewall">Patients with IPF have a hypercoagulable state with a higher incidence of stroke&#44; pulmonary thromboembolism and coronary diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">44</span></a> Pneumothorax may cause worsening of IPF&#46; Its prevalence is 11&#37;&#46; In most cases it is not resolved with thoracic drainage because of the stiffness of lung parenchyma&#44; which prevents lung reexpansion&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">1</span></a> IPF has been associated with anti-neutrophil cytoplasmic antibody-positive &#40;ANCA&#41; vasculitis&#44; mainly anti-myeloperoxidase &#40;MPO&#41;&#46; The diagnosis of IPF is prior to vasculitis&#44; which in most cases is a microscopic polyangiitis&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">45</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Treatment</span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Pharmacotherapy</span><p id="par0100" class="elsevierStylePara elsevierViewall">For many years&#44; IPF was treated with glucocorticoids&#44; without any scientific evidence&#46; In 2003&#44; a Cochrane meta-analysis of the studies conducted to date&#44; concluded that there was no clinical evidence to justify the use of this drug&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">46</span></a> The IFIGENIA clinical trial&#44; which evaluated the effect of N-acetylcysteine &#40;NAC&#41;&#44; found that the use of this drug&#44; in combination with glucocorticoids and azathioprine&#44; showed a reduction in the decrease of DLco&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">47</span></a> This study led to the use of this triple therapy in IPF by many clinical groups&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The PANTHER study&#44; which evaluated the effect of this triple therapy compared to placebo and NAC monotherapy&#44; demonstrated that azathioprine and glucocorticoid therapy and NAC monotherapy did not show any beneficial effect&#46; Therefore&#44; there is evidence that glucocorticoids&#44; azathioprine and NAC should not be used in the treatment of IPF&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">48&#44;49</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In recent years&#44; 2 antifibrotic drugs have been included for the treatment of IPF&#58; pirfenidone and nintedanib&#46;<a class="elsevierStyleCrossRefs" href="#bib0550"><span class="elsevierStyleSup">50&#8211;52</span></a> Both drugs decrease the progression of the disease and improve its evolution&#46; They are indicated for the treatment of mild-moderate IPF defined by FVC &#62;50&#37; and DLco &#62;30&#37;&#46; The duration of the treatment will depend on the evolution of the disease&#46; Once the diagnosis of IPF has been established it is reasonable to begin antifibrotic treatment as soon as possible in order to slow down the worsening of its function which&#44; inexorably&#44; occurs without treatment&#46; Expectant and close clinical&#8211;functional surveillance management might be used in asymptomatic patients with minimal functional or radiological repercussion&#46; However&#44; only after weighing the risk-benefit of such an attitude&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">53</span></a> In severe disease&#44; defined by FVC &#60;50&#37; and DLco &#60;30&#37;&#44; the possibility of lung transplantation should be considered or patients should be included in clinical trials&#46; There are currently several ongoing trials available online &#40;<a href="http://www.clinicaltrials.gov/">www&#46;clinicaltrials&#46;gov</a>&#41;&#46; For the treatment of persistent dry cough&#44; dimemorfan phosphate or codeine phosphate are indicated&#46; Prednisone in low doses &#40;5&#8211;10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; may be effective for antitussive-resistant cough&#46; In a clinical trial it has been shown that thalidomine improves cough and respiratory quality of life&#46; Low doses of morphine improve the feeling of dyspnea and cough in patients with advanced disease&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Non-pharmacological treatment</span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Home oxygen therapy</span><p id="par0115" class="elsevierStylePara elsevierViewall">Home oxygen therapy&#44; indicated in patients with IPF and hypoxemia&#44; is based mainly on the studies conducted in patients with COPD and chronic respiratory failure&#46; There are no conclusive data supporting the use of ambulatory oxygen therapy in patients with only exercise-induced oxygen desaturation&#44; without respiratory failure at rest&#46; Lacking specific data&#44; administering chronic home oxygen therapy is currently accepted in patients with arterial oxygen saturation &#8804;88&#37; at rest or during the 6-minute walk test&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Lung transplant</span><p id="par0120" class="elsevierStylePara elsevierViewall">Lung transplantation is the only treatment in advanced stages of the disease&#44; causes significant function improvement and increases survival&#46; Survival at year 1 is 81&#37;&#44; 64&#37; at year 3&#44; and 51&#37; at year 5&#46; Survival is similar either in unilateral or bilateral transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">54</span></a> The International Society for Heart and Lung Transplantation defined the criteria for lung transplantation&#58; DLco &#60;40&#37;&#44; FVC drop &#62;10&#37; over the course of 6 months&#44; arterial oxygen saturation &#60;88&#37; during the 6-minute walk test&#46; From a practical point of view&#44; patients with advanced disease&#44; progressive worsening of lung function and not responding to pharmacotherapy should be referred to a transplant center&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Pulmonary rehabilitation</span><p id="par0125" class="elsevierStylePara elsevierViewall">The review by The Cochrane Collaboration of 2008&#44; updated in 2010&#44; indicates that pulmonary rehabilitation is effective in patients with diffuse interstitial lung diseases&#44; including IPF&#44; since it improves the distance covered in the 6-minute walk test and the health-related quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">55</span></a> Recent studies show that the most lasting effects are reported in mild-moderate disease&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">56</span></a> It is advisable to include patients with IPF in a pulmonary rehabilitation program before the disease reaches advanced stages&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Cell therapy and gene therapy</span><p id="par0130" class="elsevierStylePara elsevierViewall">Both cell therapy and gene therapy in IPF are undergoing experimental study&#46; Therefore&#44; we should still wait some time to know its effectiveness as an alternative treatment or associated with pharmacotherapy&#46; IPF is characterized by the death of alveolar epithelial cells that are replaced by fibroblasts&#46; Therefore&#44; the therapeutic approaches based on cellular therapies are aimed at replacing the alveolar cells responsible for regenerating the alveolar epithelial cells&#46; Implanting stem cells&#44; able to proliferate and differentiate into alveolar cells&#44; has been considered as a therapeutic strategy&#46; To date&#44; 2 studies have been published in which stem cells have been implanted in IPF patients&#46; In the first study&#44; autologous adipose stem cells have been implanted in 14 patients with mild-moderate disease&#46; After a 12-month follow-up with fiberoptic bronchoscopy&#44; no side effects or worsening of the disease were reported&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">57</span></a> In the second study&#44; placental stem cells from donors were implanted intravenously in 8 patients with moderate-to-severe IPF&#46; After a 6-month follow-up&#44; no side effects or worsening of the disease were reported&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">58</span></a> One option is administering type II alveolar cells&#44; which has been shown to reverse bleomycin-induced pulmonary fibrosis in animal testing&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">59</span></a> In one study&#44; type <span class="elsevierStyleSmallCaps">II</span> pneumocytes isolated from deceased donors were implanted through fiberoptic bronchoscopy in 16 patients with mild-to-moderate and progressive IPF&#46; No complications were reported and after 12 months of follow-up&#44; the disease remained stable without functional impairment&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">60</span></a> Gene therapy has only been performed experimentally&#44; inhibiting or administering micro RNAs that regulate gene expression in animal testing&#46;</p></span></span></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors report no conflict of interest&#46;</p></span></span>"
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    "fechaAceptado" => "2016-11-01"
    "PalabrasClave" => array:2 [
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec818204"
          "palabras" => array:3 [
            0 => "Idiopathic pulmonary fibrosis"
            1 => "Treatment"
            2 => "Interstitial pneumonia"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec818203"
          "palabras" => array:3 [
            0 => "Fibrosis pulmonar idiop&#225;tica"
            1 => "Tratamiento"
            2 => "Neumon&#237;a intersticial"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Idiopathic pulmonary fibrosis is a fibrosing interstitial pneumonia associated with the radiological and&#47;or histological pattern of usual interstitial pneumonia&#46; Its etiology is unknown&#44; but probably comprises the action of endogenous and exogenous micro-environmental factors in subjects with genetic predisposition&#46; Its diagnosis is based on the presence of characteristic findings of high-resolution computed tomography scans and pulmonary biopsies in absence of interstitial lung diseases of other etiologies&#46; Its clinical evolution is variable&#44; although the mean survival rate is 2&#8211;5 years as of its clinical presentation&#46; Patients with idiopathic pulmonary fibrosis may present complications and comorbidities which modify the disease&#39;s clinical course and prognosis&#46; In the mild-moderate disease&#44; the treatment consists of the administration of anti-fibrotic drugs&#46; In severe disease&#44; the best therapeutic option is pulmonary transplantation&#46; In this paper we review the diagnostic and therapeutic aspects of the disease&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La fibrosis pulmonar idiop&#225;tica es una neumon&#237;a intersticial fibrosante asociada al patr&#243;n radiol&#243;gico y&#47;o histol&#243;gico de la neumon&#237;a intersticial usual&#46; No se conoce su etiolog&#237;a&#44; aunque es probable que consista en la acci&#243;n de diversos factores microambientales ex&#243;genos y&#47;o end&#243;genos en sujetos con predisposici&#243;n gen&#233;tica&#46; El diagn&#243;stico se basa en los hallazgos caracter&#237;sticos en la tomograf&#237;a axial computarizada de alta resoluci&#243;n y biopsia pulmonar en ausencia de enfermedades pulmonares intersticiales de otras causas&#46; La evoluci&#243;n es variable&#44; aunque la supervivencia media es de 2-5 a&#241;os desde el inicio de los s&#237;ntomas&#46; Los pacientes con fibrosis pulmonar idiop&#225;tica pueden presentar complicaciones y comorbilidades&#44; que modifican el curso cl&#237;nico y el pron&#243;stico&#46; En la enfermedad leve-moderada el tratamiento consiste en la administraci&#243;n de f&#225;rmacos antifibr&#243;ticos&#44; y en la enfermedad grave&#44; la mejor opci&#243;n terap&#233;utica es el trasplante pulmonar&#46; En el presente art&#237;culo&#44; se revisan los aspectos diagn&#243;sticos y terap&#233;uticos de la enfermedad&#46;</p></span>"
      ]
    ]
    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Xaubet A&#44; Ancochea J&#44; Molina-Molina M&#46; Fibrosis pulmonar idiop&#225;tica&#46; Med Clin &#40;Barc&#41;&#46; 2017&#59;148&#58;170&#8211;175&#46;</p>"
      ]
    ]
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">HRCT&#46; Pattern of usual interstitial pneumonia&#46; Reticular images and subpleural&#44; bibasilar and peripheral honeycomb changes&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Genetic predisposition&nbsp;\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">Smoking&nbsp;\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">Exposure to lead&#44; brass and steel&nbsp;\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">Exposure to wood dust&nbsp;\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">Livestock and agriculture work&nbsp;\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">Construction of wooden houses&nbsp;\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">Viral infections&nbsp;\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">Gastroesophageal reflux&nbsp;\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">Autoimmunity&nbsp;\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">Aging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Factors associated with the etiology of idiopathic pulmonary fibrosis&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \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>DLco &#8804;40&#37;&nbsp;\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>Oxygen saturation &#60;88&#37; in 6MWT&nbsp;\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>Extension of fibrosis in HRCT&nbsp;\t\t\t\t\t\t\n
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                  \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="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
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                  \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>FVC drop &#8805;10&#37;&nbsp;\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>DLco drop &#8805;15&#37;&nbsp;\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>Drop &#62;50<span class="elsevierStyleHsp" style=""></span>m in 6MWT&nbsp;\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>Worsening fibrosis in HRCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Prognostic factors of idiopathic pulmonary fibrosis&#46;</p>"
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                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Emphysema&nbsp;\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">Pulmonary hypertension&nbsp;\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">Acute exacerbation&nbsp;\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">Sleep apnea&#8211;hypopnea syndrome&nbsp;\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">Gastroesophageal reflux&nbsp;\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">Lung cancer&nbsp;\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">Blood clotting&nbsp;\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">Pneumothorax&nbsp;\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">ANCA positive vasculitis&nbsp;\t\t\t\t\t\t\n
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      "titulo" => "References"
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          "identificador" => "bibs0005"
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              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "An Official ATS&#47;ERS&#47;JRS&#47;ALAT clinical practice guideline&#58; treatment of idiopathic pulmonary fibrosis&#46; An update of the 2011 clinical practice guideline"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46; Raghu"
                            1 => "B&#46; Rochwerg"
                            2 => "Y&#46; Zhang"
                            3 => "C&#46;A&#46; Garcia"
                            4 => "A&#46; Azuma"
                            5 => "J&#46; Behr"
                          ]
                        ]
                      ]
                    ]
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                    0 => array:2 [
                      "doi" => "10.1164/rccm.201506-1063ST"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Respir Crit Care Med"
                        "fecha" => "2015"
                        "volumen" => "192"
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                        "link" => array:1 [
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26177183"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "2"
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                  "contribucion" => array:1 [
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                      "titulo" => "Normativa SEPAR sobre el diagn&#243;stico y tratamiento de la fibrosis pulmonar idiop&#225;tica"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
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                            0 => "A&#46; Xaubet"
                            1 => "J&#46; Ancochea"
                            2 => "E&#46; Bollo"
                            3 => "E&#46; Fern&#225;ndez-Fabrellas"
                            4 => "T&#46; Franquet"
                            5 => "M&#46; Molina-Molina"
                          ]
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            2 => array:3 [
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              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "G&#46; Raghu"
                            1 => "D&#46; Weycker"
                            2 => "J&#46; Edelsberg"
                            3 => "W&#46;Z&#46; Bradford"
                            4 => "G&#46; Oster"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                            "web" => "Medline"
                          ]
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            ]
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              "etiqueta" => "4"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Short telomeres are a risk factor for idiopathic pulmonary fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;K&#46; Alder"
                            1 => "J&#46;J&#46; Chen"
                            2 => "L&#46; Lancaster"
                            3 => "S&#46; Danoff"
                            4 => "S&#46;C&#46; Su"
                            5 => "J&#46;D&#46; Cogan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1073/pnas.0804280105"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18753630"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A common MUC5B promoter polymorphism and pulmonary fibrosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "M&#46;A&#46; Seibold"
                            1 => "A&#46;L&#46; Wise"
                            2 => "M&#46;C&#46; Speer"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1056/NEJMoa1013660"
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                            "web" => "Medline"
                          ]
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                          "pii" => "S001502820800592X"
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              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Is idiopathic pulmonary fibrosis environmental disease&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "V&#46;S&#46; Taskar"
                            1 => "D&#46;B&#46; Coultas"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
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                        "fecha" => "2006"
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