- Email: [email protected]
Pulmonary fibrosis (idiopathic): Diagnostic study with 10 clinical actions
G Model
ARTICLE IN PRESS Med Clin (Barc). 2017;xxx(xx):xxx–xxx
www.elsevier.es/medicinaclinica
Editorial
Pulmonary fibrosis (idiopathic): Diagnostic study with 10 clinical actions夽 Fibrosis pulmonar (idiopática): estudio diagnóstico con 10 actuaciones clínicas Ferran Morell a,b,c,∗ , Ana Villar a,b,c a b c
Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain Servei de Pneumologia, Departament de Medicina, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Intituto de Salud Carlos III, Barcelona, Spain
According to the latest international guidelines based on evidence from 2011, idiopathic pulmonary fibrosis (IPF) is a specific form of chronic progressive pulmonary fibrosis of an unknown cause, which occurs mainly in adults, is limited to the lungs and associated with a histologic and/or radiological pattern of usual interstitial pneumonia (UIP). The definition of IPF requires the exclusion of the other idiopathic interstitial pneumonias and the remainder of interstitial pulmonary diseases (IPD) associated with environmental exposures, medications or systemic diseases. It is characterised by a progressive worsening of dyspnoea, a deterioration of lung function and is associated with a serious prognosis.1 The first classification of IPD was made by Liebow and Carrington in 1969,2 and it was in the international consensus of 2000 when experts in IPD considered IPF as a distinct clinical entity.3 In the aforementioned 2011 guidelines, radiological and histological criteria were published in order to qualify the findings of fibrosis as a pattern of UIP. However, given the variability of the clinical manifestations, these radiological criteria were subdivided into definitive, possible and inconsistent UIP pattern, and the anatomopathological criteria were subdivided into definitive, possible, probable, and not UIP pattern.1 Over the years, it has not been easy to diagnose IPF patients accurately following the 2011 criteria, as only half of the patients qualified as IPF meet them.4 On the contrary, a large majority are diagnosed with possible or probable IPF, by not complying strictly with the definitive UIP criteria, both in the histology and images of the high-resolution computed tomography (HRCT). In addition, for skilled radiologists the degree of diagnostic concordance is moderate5 as maximum and the same happens to pathologists.6,7 The fact of having to resort to sub-classification in definitive, possible, probable, and inconsistent UIP pattern, as well as the current recommendation that the diagnosis is carried out in each
夽 Please cite this article as: Morell F, Villar A. Fibrosis pulmonar (idiopática): estudio diagnóstico con 10 actuaciones clínicas. Med Clin (Barc). http://dx.doi.org/10.1016/j.medcli.2017.04.004 ∗ Corresponding author. E-mail address: [email protected] (F. Morell).
centre in a multidisciplinary manner with the participation of the radiologist, pathologist and pulmonologist, already indicates that the diagnostic criteria can be interpreted differently and, ultimately, it is therefore recommended that the diagnosis be done by consensus. On the other hand, it is widely accepted among experts that, in an appropriate clinical context, a UIP pattern in the HRCT including the presence of images in hive is sufficient to diagnose UIP and, therefore, it is no longer necessary to do a lung biopsy to ascertain the diagnosis of IPF.1,8 This recommendation draws attention when it is known that asbestosis, sarcoidosis, collagenosis and chronic hypersensitivity pneumonitis (CHP) can cause a UIP pattern in the HRCT.1 The recent finding by our group, after a prospective protocol, that at least 43% of patients with HRCT of UIP are actually CHP, whose diagnosis may go unnoticed if a comprehensive study is not carried out,9 is an indication that in case of an HRCT of UIP, carrying out a comprehensive study is vitally important, as we propose in this editorial. Furthermore, a recent study conducted in 2015 on patients with pulmonary fibrosis, using current guidelines,1 classified the HRCT as definitive, possible, probable, and inconsistent UIP pattern and, among other inconsistencies, it was found that in the interpretation of the images “there is only a slight to moderate concordance between the radiologists of the study”, “that there was not a significant association between the images in hive of the HRCT and the images in hive in the microscope” and that “the proportion of histologic diagnoses of UIP, among those classified as probable UIP versus a definitive UIP in the HRCT are not significantly different (12.7% and 9.3%)”. In short, the study concludes that the recommendation of many experts claim that an HRCT of definitive UIP allows obviating that the lung biopsy needs to be modified.10 On the other hand, the evolutionary differences between the patients qualified as definitive or possible UIP pattern are very scarce, judging by the results of the recent post hoc study carried out with the accumulated data of patients in the Impulsis clinical trials. In fact, 726 patients were compared with an HRCT (and/or biopsy) of definitive UIP pattern with 338 patients with HRCT of possible UIP, without surgical lung biopsy, checking that both groups had an evolution of pulmonary function, similar rates
˜ S.L.U. All rights reserved. 2387-0206/© 2017 Elsevier Espana,
MEDCLE-4056; No. of Pages 3
G Model 2
ARTICLE IN PRESS F. Morell, A. Villar / Med Clin (Barc). 2017;xxx(xx):xxx–xxx
of exacerbations and a similar response to treatment. These and other experiences have led to the conclusion that both forms have a similar evolutionary course.11 Before the diagnostic difficulties and recent data mentioned, it seems prudent to ask ourselves whether IPF is an entity with its own characteristics and different from the remainder of pulmonary fibroses. In particular, if IPF is truly different, from the point of view of the aetiology, the evolution and the response to the treatment, for fibrosis which are currently qualified as possible UIP, not UIP or unclassifiable idiopathic interstitial pneumonia. In the face of these difficulties of clinical differentiation, one might deduce that all fibroses of the lung may be due to the same causes and clinical presentations may be somewhat different, either due to a different mode of entry of the noxa/antigen to the lung, for example in minimal quantities, but persistent (that would not cause an initial inflammatory reaction in the lung),12 either by the (small) size of the particle that reaches the alveoli, or perhaps because the inhalation of noxae has occurred, in some cases, in combination with other particles, such as tobacco smoke,13 pollution, etc.; also because the form of clinical presentation is conditioned by the time (long) elapsed from the initial inhalations and the clinic, in this case, has been barely symptomatic during this time. Finally, it may also happen that, for genetic reasons, the immune responses of each individual are different, resulting in slightly different histological lesions: with criteria of any of the subdivisions of UIP, not UIP, undifferentiated, etc. In fact, when Liebow and Carrington established the classification of IPF,2 they considered as UIP those biopsies of idiopathic interstitial pneumonias which had no specific histologic features to be included in any of the other groups (acute interstitial pneumonia, interstitial lymphoid pneumonia, pneumonia with bronchiolitis, scaly pneumonia or giant cell pneumonia); that is to say, that the usual was regarded as the catchall differentiated from the remainder of interstitial pneumonias. The classifications of the different entities are made by humans, with the aim of understanding each other when referring to a type of disease or set of clinical manifestations, but, given the similarity of images and lesions of the fibrosis, it should be recalled that in biology, when a pathogenic bacterium or fungus, a protein or a chemical agent enters the respiratory system, it does not always produce the same type of injury in the bronchi, bronchioles, alveoli, the interstitial tissue or arterioles, but the type of these lesions may be different as a result of, among others, the time, the mode of inhalation or other factors previously commented on. In conclusion, we propose, and this is our direction for years, that instead of attempting to distinguish, not without falling into large inaccuracies, between definitive, possible, probable, and not UIP pattern, all lung fibroses should be considered from a nosological and aetiologic point of view. This direction, in the case of finding the cause, is going to report, on one hand, an improvement in the evolution of the patient to be able to separate them from the causal noxa,14 and also a contribution to the prevention of further cases by knowing the circumstances of the exposure to these causes. It will also lead to the development of studies to assess the efficacy of certain treatments, not based on the specific diagnosis of UIP or not UIP, but depending on the fibrosing nature of the disease itself. In fact, as we have discussed before, pulmonary fibroses are not watertight compartments between images and injuries which meet the criteria (of UIP) and images and injuries which do not meet the criteria (not UIP), but merely that they are a continuum of biological injuries that occur in individuals with a certain genetic predisposition after inhalation of certain noxae. In particular, we will try to attribute the cause to a trigger of CHP (birds, bird feathers, fungi, mycobacteria, or others), to
tobacco smoke13 or asbestos.15 We will also try to relate it to the aetiologies associated epidemiologically with IPF: agriculture and livestock, wood dust, stone and sand,16 construction of wooden houses, mobile homes and metal mining,17 as well as the gastroesophageal reflux.18 With all of the above, we propose a ten-point protocol for the study of the entities and the causes of pulmonary fibrosis, which includes: • Exhaustive and repetitive history of exposures, carried out by an expert in IPD. • Auscultation in search of crackling velcro and short meso sibilants or teleinspiratory (chirping rales). • Pulmonary HRCT (observing, in addition, the eventual presence of an oesophageal hernia). • Blood analysis with determination of specific IgG versus serum antigens of dove, parrot, parakeet, canary and chicken; versus duck feathers and versus extract of Aspergillus, Penicillium, Mucor (Rhizopus and Cladosporium). Also versus feathers in duvets or pillows in case of suspicion of this cause. In addition, determination of autoantibodies anti-tissues (drums), angiotensin-converting enzyme, rheumatoid factor and antipeptide citrulline antibodies. • Bronchoscopy with cell count of bronchoalveolar lavage and histological study through criobiopsy. • If a material is suspected to be the cause (feather pillow, humidity of walls), etc. a culture of it will be done for fungi. • Evaluate the possibility that the cause is tobacco in accordance with the criteria established.13 • Specific inhalation test if you suspect a particular antigen as causative agent (provided that FVC > 50% and DLCO > 40%). • Surgical lung biopsy, that will be necessary in a few cases.19 • Follow-up, with evaluation of the data provided by the patient and the results of other biopsies, or tissue of the explant or other. This protocol requires the implementation of the different diagnostic techniques and the participation of professionals skilled in its use. The practical reality is that this comprehensive study will allow us to diagnose the type of clinical entity and the cause of many pulmonary fibroses till now considered idiopathic. A large percentage will be CHP with hidden exposures to common antigens, others will be associated with smoking habits13 and a small group to other causes. With regard to treatment, although we are in an optimistic phase given the recent marketing of two antifibrotic products that have been shown to make a minor loss of lung function at oneyear follow-up, we must insist that if a large percentage of fibroses are CHP,9 and in these, glucocorticoids are considered effective, we must manage them in order to prolong the survival of patients. In fact, the Cochrane20 review, based on 2011 guidelines, not recommending the use of glucocorticoids in IPF means that there are no studies of sufficient quality demonstrating that they are useful to modify the natural history of the disease, but the reverse is also met since there are no studies of sufficient quality to scientifically support that they are not effective. Thus, in the new international guidelines it should be assessed whether or not to keep the name of idiopathic when referring to this entity. References 1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidencebased guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824. 2. Liebow AA, Carrington DB. The interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, editors. Frontiers of pulmonary radiology. New York: Grune and Stratton; 1969. p. 102–41.
G Model
ARTICLE IN PRESS F. Morell, A. Villar / Med Clin (Barc). 2017;xxx(xx):xxx–xxx
3. American Thoracic Society.Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161:646–64. 4. Wuyts WA, Cavazza A, Rossi G, Bonella F, Sverzellati N, Spagnolo P. Differential diagnosis of usual interstitial pneumonia: when is it truly idiopathic? Eur Respir Rev. 2014;23:308–19. 5. Walsh SL, Calandriello L, Sverzellati N, Wells AU, Hansell DM, UIP Observer Consort. Interobserver agreement for the ATS/ERS/JRS/ALAT criteria for a UIP pattern on CT. Thorax. 2016;71:45–51. 6. Nicholson AG, Addis BJ, Bharucha H, Clelland CA, Corrin B, Gibbs AR, et al. Interobserver variation between pathologists in diffuse parenchymal lung disease. Thorax. 2004;59:500–5. 7. Sverzellati N, Wells AU, Tomassetti S, Desai SR, Copley SJ, Aziz ZA, et al. Biopsyproved idiopathic pulmonary fibrosis: spectrum of nondiagnostic thin-section CT. Radiology. 2010;254:957–64. 8. Hodnett PA, Naidich DP. Fibrosing interstitial lung disease. A practical high-resolution computed tomography-based approach to diagnosis and management and a review of the literature. Am J Respir Crit Care Med. 2013;188:141–9. ˜ 9. Morell F, Villar A, Montero MA, Munoz X, Colby TV, Pipvath S, et al. Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir Med. 2013;1: 685–94. 10. Chung JH, Chawla A, Peljto AL, Cool CD, Groshong SD, Talbert JL, et al. CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic interstitial pneumonitis. Chest. 2015;147:450–9.
3
11. Raghu G, Wells AU, Nicholson AG, Richeldi L, Flaherty KR, Le Maulf F, et al. Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am J Respir Crit Care Med. 2017;195:78–85. 12. Selman M, King TE, Pardo A, American Thoracic Society, European Respiratory Society, American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134:136–51. 13. Flaherty KR, Fell C, Aubry MC, Brown K, Colby T, Costabel U, et al. Smoking-related idiopathic interstitial pneumonia. Eur Respir J. 2014;44: 594–602. 14. Fernández Pérez ER, Swigris JJ, Forssén AV, Tourin O, Solomon JJ, Huie TJ, et al. Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest. 2013;144:1644–51. 15. Bledsoe JR, Christiani DC, Kradin RL. Smoking-associated fibrosis and pulmonary asbestosis. Int J Chron Obstruct Pulmon Dis. 2014;10:31–7. 16. Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc. 2006;3:293–8. 17. Pinheiro GA, Antao VC, Wood JM, Wassell JT. Occupational risks for idiopathic pulmonary fibrosis mortality in the United States. Int J Occup Environ Health. 2008;14:117–23. 18. Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy. Eur Respir J. 2012;39:242–5. ˜ X, Cruz MJ. Hypersensitivity pneumonitis: 19. Morell F, Villar A, Ojanguren I, Munoz challenges in diagnosis and management, avoiding surgical lung biopsy. Semin Respir Crit Care Med. 2016;37:395–405. 20. Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2003;3:CD002880.
ARTICLE IN PRESS Med Clin (Barc). 2017;xxx(xx):xxx–xxx
www.elsevier.es/medicinaclinica
Editorial
Pulmonary fibrosis (idiopathic): Diagnostic study with 10 clinical actions夽 Fibrosis pulmonar (idiopática): estudio diagnóstico con 10 actuaciones clínicas Ferran Morell a,b,c,∗ , Ana Villar a,b,c a b c
Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain Servei de Pneumologia, Departament de Medicina, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Intituto de Salud Carlos III, Barcelona, Spain
According to the latest international guidelines based on evidence from 2011, idiopathic pulmonary fibrosis (IPF) is a specific form of chronic progressive pulmonary fibrosis of an unknown cause, which occurs mainly in adults, is limited to the lungs and associated with a histologic and/or radiological pattern of usual interstitial pneumonia (UIP). The definition of IPF requires the exclusion of the other idiopathic interstitial pneumonias and the remainder of interstitial pulmonary diseases (IPD) associated with environmental exposures, medications or systemic diseases. It is characterised by a progressive worsening of dyspnoea, a deterioration of lung function and is associated with a serious prognosis.1 The first classification of IPD was made by Liebow and Carrington in 1969,2 and it was in the international consensus of 2000 when experts in IPD considered IPF as a distinct clinical entity.3 In the aforementioned 2011 guidelines, radiological and histological criteria were published in order to qualify the findings of fibrosis as a pattern of UIP. However, given the variability of the clinical manifestations, these radiological criteria were subdivided into definitive, possible and inconsistent UIP pattern, and the anatomopathological criteria were subdivided into definitive, possible, probable, and not UIP pattern.1 Over the years, it has not been easy to diagnose IPF patients accurately following the 2011 criteria, as only half of the patients qualified as IPF meet them.4 On the contrary, a large majority are diagnosed with possible or probable IPF, by not complying strictly with the definitive UIP criteria, both in the histology and images of the high-resolution computed tomography (HRCT). In addition, for skilled radiologists the degree of diagnostic concordance is moderate5 as maximum and the same happens to pathologists.6,7 The fact of having to resort to sub-classification in definitive, possible, probable, and inconsistent UIP pattern, as well as the current recommendation that the diagnosis is carried out in each
夽 Please cite this article as: Morell F, Villar A. Fibrosis pulmonar (idiopática): estudio diagnóstico con 10 actuaciones clínicas. Med Clin (Barc). http://dx.doi.org/10.1016/j.medcli.2017.04.004 ∗ Corresponding author. E-mail address: [email protected] (F. Morell).
centre in a multidisciplinary manner with the participation of the radiologist, pathologist and pulmonologist, already indicates that the diagnostic criteria can be interpreted differently and, ultimately, it is therefore recommended that the diagnosis be done by consensus. On the other hand, it is widely accepted among experts that, in an appropriate clinical context, a UIP pattern in the HRCT including the presence of images in hive is sufficient to diagnose UIP and, therefore, it is no longer necessary to do a lung biopsy to ascertain the diagnosis of IPF.1,8 This recommendation draws attention when it is known that asbestosis, sarcoidosis, collagenosis and chronic hypersensitivity pneumonitis (CHP) can cause a UIP pattern in the HRCT.1 The recent finding by our group, after a prospective protocol, that at least 43% of patients with HRCT of UIP are actually CHP, whose diagnosis may go unnoticed if a comprehensive study is not carried out,9 is an indication that in case of an HRCT of UIP, carrying out a comprehensive study is vitally important, as we propose in this editorial. Furthermore, a recent study conducted in 2015 on patients with pulmonary fibrosis, using current guidelines,1 classified the HRCT as definitive, possible, probable, and inconsistent UIP pattern and, among other inconsistencies, it was found that in the interpretation of the images “there is only a slight to moderate concordance between the radiologists of the study”, “that there was not a significant association between the images in hive of the HRCT and the images in hive in the microscope” and that “the proportion of histologic diagnoses of UIP, among those classified as probable UIP versus a definitive UIP in the HRCT are not significantly different (12.7% and 9.3%)”. In short, the study concludes that the recommendation of many experts claim that an HRCT of definitive UIP allows obviating that the lung biopsy needs to be modified.10 On the other hand, the evolutionary differences between the patients qualified as definitive or possible UIP pattern are very scarce, judging by the results of the recent post hoc study carried out with the accumulated data of patients in the Impulsis clinical trials. In fact, 726 patients were compared with an HRCT (and/or biopsy) of definitive UIP pattern with 338 patients with HRCT of possible UIP, without surgical lung biopsy, checking that both groups had an evolution of pulmonary function, similar rates
˜ S.L.U. All rights reserved. 2387-0206/© 2017 Elsevier Espana,
MEDCLE-4056; No. of Pages 3
G Model 2
ARTICLE IN PRESS F. Morell, A. Villar / Med Clin (Barc). 2017;xxx(xx):xxx–xxx
of exacerbations and a similar response to treatment. These and other experiences have led to the conclusion that both forms have a similar evolutionary course.11 Before the diagnostic difficulties and recent data mentioned, it seems prudent to ask ourselves whether IPF is an entity with its own characteristics and different from the remainder of pulmonary fibroses. In particular, if IPF is truly different, from the point of view of the aetiology, the evolution and the response to the treatment, for fibrosis which are currently qualified as possible UIP, not UIP or unclassifiable idiopathic interstitial pneumonia. In the face of these difficulties of clinical differentiation, one might deduce that all fibroses of the lung may be due to the same causes and clinical presentations may be somewhat different, either due to a different mode of entry of the noxa/antigen to the lung, for example in minimal quantities, but persistent (that would not cause an initial inflammatory reaction in the lung),12 either by the (small) size of the particle that reaches the alveoli, or perhaps because the inhalation of noxae has occurred, in some cases, in combination with other particles, such as tobacco smoke,13 pollution, etc.; also because the form of clinical presentation is conditioned by the time (long) elapsed from the initial inhalations and the clinic, in this case, has been barely symptomatic during this time. Finally, it may also happen that, for genetic reasons, the immune responses of each individual are different, resulting in slightly different histological lesions: with criteria of any of the subdivisions of UIP, not UIP, undifferentiated, etc. In fact, when Liebow and Carrington established the classification of IPF,2 they considered as UIP those biopsies of idiopathic interstitial pneumonias which had no specific histologic features to be included in any of the other groups (acute interstitial pneumonia, interstitial lymphoid pneumonia, pneumonia with bronchiolitis, scaly pneumonia or giant cell pneumonia); that is to say, that the usual was regarded as the catchall differentiated from the remainder of interstitial pneumonias. The classifications of the different entities are made by humans, with the aim of understanding each other when referring to a type of disease or set of clinical manifestations, but, given the similarity of images and lesions of the fibrosis, it should be recalled that in biology, when a pathogenic bacterium or fungus, a protein or a chemical agent enters the respiratory system, it does not always produce the same type of injury in the bronchi, bronchioles, alveoli, the interstitial tissue or arterioles, but the type of these lesions may be different as a result of, among others, the time, the mode of inhalation or other factors previously commented on. In conclusion, we propose, and this is our direction for years, that instead of attempting to distinguish, not without falling into large inaccuracies, between definitive, possible, probable, and not UIP pattern, all lung fibroses should be considered from a nosological and aetiologic point of view. This direction, in the case of finding the cause, is going to report, on one hand, an improvement in the evolution of the patient to be able to separate them from the causal noxa,14 and also a contribution to the prevention of further cases by knowing the circumstances of the exposure to these causes. It will also lead to the development of studies to assess the efficacy of certain treatments, not based on the specific diagnosis of UIP or not UIP, but depending on the fibrosing nature of the disease itself. In fact, as we have discussed before, pulmonary fibroses are not watertight compartments between images and injuries which meet the criteria (of UIP) and images and injuries which do not meet the criteria (not UIP), but merely that they are a continuum of biological injuries that occur in individuals with a certain genetic predisposition after inhalation of certain noxae. In particular, we will try to attribute the cause to a trigger of CHP (birds, bird feathers, fungi, mycobacteria, or others), to
tobacco smoke13 or asbestos.15 We will also try to relate it to the aetiologies associated epidemiologically with IPF: agriculture and livestock, wood dust, stone and sand,16 construction of wooden houses, mobile homes and metal mining,17 as well as the gastroesophageal reflux.18 With all of the above, we propose a ten-point protocol for the study of the entities and the causes of pulmonary fibrosis, which includes: • Exhaustive and repetitive history of exposures, carried out by an expert in IPD. • Auscultation in search of crackling velcro and short meso sibilants or teleinspiratory (chirping rales). • Pulmonary HRCT (observing, in addition, the eventual presence of an oesophageal hernia). • Blood analysis with determination of specific IgG versus serum antigens of dove, parrot, parakeet, canary and chicken; versus duck feathers and versus extract of Aspergillus, Penicillium, Mucor (Rhizopus and Cladosporium). Also versus feathers in duvets or pillows in case of suspicion of this cause. In addition, determination of autoantibodies anti-tissues (drums), angiotensin-converting enzyme, rheumatoid factor and antipeptide citrulline antibodies. • Bronchoscopy with cell count of bronchoalveolar lavage and histological study through criobiopsy. • If a material is suspected to be the cause (feather pillow, humidity of walls), etc. a culture of it will be done for fungi. • Evaluate the possibility that the cause is tobacco in accordance with the criteria established.13 • Specific inhalation test if you suspect a particular antigen as causative agent (provided that FVC > 50% and DLCO > 40%). • Surgical lung biopsy, that will be necessary in a few cases.19 • Follow-up, with evaluation of the data provided by the patient and the results of other biopsies, or tissue of the explant or other. This protocol requires the implementation of the different diagnostic techniques and the participation of professionals skilled in its use. The practical reality is that this comprehensive study will allow us to diagnose the type of clinical entity and the cause of many pulmonary fibroses till now considered idiopathic. A large percentage will be CHP with hidden exposures to common antigens, others will be associated with smoking habits13 and a small group to other causes. With regard to treatment, although we are in an optimistic phase given the recent marketing of two antifibrotic products that have been shown to make a minor loss of lung function at oneyear follow-up, we must insist that if a large percentage of fibroses are CHP,9 and in these, glucocorticoids are considered effective, we must manage them in order to prolong the survival of patients. In fact, the Cochrane20 review, based on 2011 guidelines, not recommending the use of glucocorticoids in IPF means that there are no studies of sufficient quality demonstrating that they are useful to modify the natural history of the disease, but the reverse is also met since there are no studies of sufficient quality to scientifically support that they are not effective. Thus, in the new international guidelines it should be assessed whether or not to keep the name of idiopathic when referring to this entity. References 1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidencebased guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788–824. 2. Liebow AA, Carrington DB. The interstitial pneumonias. In: Simon M, Potchen EJ, LeMay M, editors. Frontiers of pulmonary radiology. New York: Grune and Stratton; 1969. p. 102–41.
G Model
ARTICLE IN PRESS F. Morell, A. Villar / Med Clin (Barc). 2017;xxx(xx):xxx–xxx
3. American Thoracic Society.Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161:646–64. 4. Wuyts WA, Cavazza A, Rossi G, Bonella F, Sverzellati N, Spagnolo P. Differential diagnosis of usual interstitial pneumonia: when is it truly idiopathic? Eur Respir Rev. 2014;23:308–19. 5. Walsh SL, Calandriello L, Sverzellati N, Wells AU, Hansell DM, UIP Observer Consort. Interobserver agreement for the ATS/ERS/JRS/ALAT criteria for a UIP pattern on CT. Thorax. 2016;71:45–51. 6. Nicholson AG, Addis BJ, Bharucha H, Clelland CA, Corrin B, Gibbs AR, et al. Interobserver variation between pathologists in diffuse parenchymal lung disease. Thorax. 2004;59:500–5. 7. Sverzellati N, Wells AU, Tomassetti S, Desai SR, Copley SJ, Aziz ZA, et al. Biopsyproved idiopathic pulmonary fibrosis: spectrum of nondiagnostic thin-section CT. Radiology. 2010;254:957–64. 8. Hodnett PA, Naidich DP. Fibrosing interstitial lung disease. A practical high-resolution computed tomography-based approach to diagnosis and management and a review of the literature. Am J Respir Crit Care Med. 2013;188:141–9. ˜ 9. Morell F, Villar A, Montero MA, Munoz X, Colby TV, Pipvath S, et al. Chronic hypersensitivity pneumonitis in patients diagnosed with idiopathic pulmonary fibrosis: a prospective case-cohort study. Lancet Respir Med. 2013;1: 685–94. 10. Chung JH, Chawla A, Peljto AL, Cool CD, Groshong SD, Talbert JL, et al. CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic interstitial pneumonitis. Chest. 2015;147:450–9.
3
11. Raghu G, Wells AU, Nicholson AG, Richeldi L, Flaherty KR, Le Maulf F, et al. Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am J Respir Crit Care Med. 2017;195:78–85. 12. Selman M, King TE, Pardo A, American Thoracic Society, European Respiratory Society, American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med. 2001;134:136–51. 13. Flaherty KR, Fell C, Aubry MC, Brown K, Colby T, Costabel U, et al. Smoking-related idiopathic interstitial pneumonia. Eur Respir J. 2014;44: 594–602. 14. Fernández Pérez ER, Swigris JJ, Forssén AV, Tourin O, Solomon JJ, Huie TJ, et al. Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest. 2013;144:1644–51. 15. Bledsoe JR, Christiani DC, Kradin RL. Smoking-associated fibrosis and pulmonary asbestosis. Int J Chron Obstruct Pulmon Dis. 2014;10:31–7. 16. Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an environmental disease? Proc Am Thorac Soc. 2006;3:293–8. 17. Pinheiro GA, Antao VC, Wood JM, Wassell JT. Occupational risks for idiopathic pulmonary fibrosis mortality in the United States. Int J Occup Environ Health. 2008;14:117–23. 18. Raghu G, Meyer KC. Silent gastro-oesophageal reflux and microaspiration in IPF: mounting evidence for anti-reflux therapy. Eur Respir J. 2012;39:242–5. ˜ X, Cruz MJ. Hypersensitivity pneumonitis: 19. Morell F, Villar A, Ojanguren I, Munoz challenges in diagnosis and management, avoiding surgical lung biopsy. Semin Respir Crit Care Med. 2016;37:395–405. 20. Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2003;3:CD002880.