BTS guideline. Interstitial Lung Disease Unit, London, UK; 2 Royal Infirmary Edinburgh, Edinburgh, UK

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1 Additional information is published in the online appendies (2, 5 11) at thorax.bmj.om/ontent/vol63/ issuesupplv 1 Royal Brompton Hospital, Interstitial Lung Disease Unit, London, UK; 2 Royal Infirmary Edinburgh, Edinburgh, UK Correspondene to: Dr N Hirani, Royal Infirmary Edinburgh, Little Frane Cresent, Edinburgh EH16 4SA, UK; n.hirani@ed.a.uk BTS Interstitial Lung Disease Guideline Group Members: A Wells (Co-Chair), B Bradley, H Branley, J Egan (Irish Thorai Soiety), K Harrison, N Hirani (Co-Chair), R Hubbard, A Millar, W Wallae, M Whyte, D Hansell, M Greaves, F Lake (Thorai Soiety of Australia and New Zealand) and M Wilsher (Thorai Soiety of Australia and New Zealand) Reeived 14 May 2008 Aepted 28 May 2008 Interstitial lung disease guideline: the British Thorai Soiety in ollaboration with the Thorai Soiety of Australia and New Zealand and the Irish Thorai Soiety A U Wells, 1 N Hirani, 2 on behalf of the British Thorai Soiety Interstitial Lung Disease Guideline Group, a subgroup of the British Thorai Soiety Standards of Care Committee, in ollaboration with the Thorai Soiety of Australia and New Zealand and the Irish Thorai Soiety 1. INTRODUCTION 1.1 An overview of the ILD guideline Sine the publiation of the first BTS guidelines for diffuse lung disease nearly 10 years ago, 1 the speialty has seen onsiderable hange. The early disussions of the Guideline Group entred upon whether the revised doument might onsist of the 1999 doument with minor adaptations. However, it was onsidered that too muh hange had taken plae in the intervening years to justify a simple editorial approah. The last deade had seen the development of a new onsensus terminology for the idiopathi interstitial pneumonias (IIP) 2 stimulated, in part, by the identifiation of non-speifi interstitial pneumonia (NSIP) as a disrete histologial pattern with inreasingly reognised linial orrelates. 3 The better prognosis seen in fibroti NSIP than in idiopathi pulmonary fibrosis (IPF) 4 5 fuelled a more intense approah to diagnosis in ases of suspeted IPF. This in turn has led to a radial hange in aepted diagnosti gold standards, whih have beome inreasingly multidisiplinary and dependent equally upon the skills of pathologists, radiologists and liniians. 6 NSIP, as a new entity, has posed partiular diffiulties. With more detailed studies of outome speifi to individual IIPs, espeially IPF and fibroti NSIP, the prognosti weighting given to pulmonary funtion impairment has been refined, espeially with regard to longitudinal funtional trends. 7 Most important, with the standardisation of terminology, it beame possible to reruit patients into multientre treatment studies With regard to IPF in partiular, the last 3 years have seen more studies of treatment than in the previous history of the speiality, yet there is no universally aepted best urrent treatment. 1.2 Methodology for onstruting guidelines and making reommendations The overall proess for generating BTS guidelines has been addressed in numerous reently published douments (available at org.uk/guidelines.html). The methodology applied herein is broadly similar and is not therefore desribed in detail. However, there are speifi BTS guideline aspets in the proess of writing the ILD guidelines that merit explanation. 1. These are the first BTS guidelines to have been written in onjuntion with other international bodies, namely the Thorai Soiety of Australia and New Zealand and the Irish Thorai Soiety. It is hoped that, by broadening the ollaborative base, the quality and redibility of the guidelines has been enhaned and the doument will reah a wider readership. Inevitably ertain aspets of the guidelines for example, delivery of speifi healthare resoures are written with the UK in mind, but may be equally appliable internationally. 2. At a very early stage the Guideline Committee anvassed the views of olleagues (hest physiians, radiologists and pathologists) via fous groups. The aim was to determine the spread of opinions with regard to the ideal ontent of a new guideline and speifially on the more ontroversial aspets of ILD inluding nomenlature, delivery of are and optimum management in the absene of evidene. 3. The diagnosis and management of ommon interstitial lung diseases but not rare onditions are omprehensively addressed in these guidelines. Conditions suh as Langerhan s ell histioytosis (LAH), lymphangioleiomoyomatosis (LAM), pulmonary vasulitis and alveolar proteinosis are being addressed by the BTS-endorsed British Orphan Lung Disease projet ( brit-thorai.org.uk/rare_lung_diseases.html) 4. A omprehensive searh of major databases (Medline, PubMed, EmBase and CINAHL) was performed, fousing prinipally on peerreviewed artiles generated sine the publiation of the previous guidelines in Where possible, searhes were performed in response to a speifi question (eg, What is the evidene that pulmonary rehabilitation is benefiial in ILD? ). 5. The levels of evidene and the grading of reommendations are summarised in table 1. The grading of reommendations A D will be very familiar to the reader. However, in the ourse of writing the guidelines it beame apparent that there are many areas of ILD v1

2 Table 1 Grading system for reommendations 11 Levels of evidene 1++ High quality meta-analyses, systemati reviews of randomised ontrolled trials (RCTs) or RCTs with a very low risk of bias 1+ Well onduted meta-analyses, systemati reviews of RCTs or RCTs with a low risk of bias 1- Meta-analyses, systemati reviews or RCTs or RCTs with a high risk of bias 2++ High quality systemati reviews of ase-ontrol or ohort studies or high quality ase-ontrol or ohort studies with a very low risk of onfounding, bias or hane and a high probability that the relationship is ausal 2+ Well onduted ase-ontrol or ohort studies with a low risk of onfounding, bias or hane and a moderate probability that the relationship is ausal 22 Case-ontrol or ohort studies with a high risk of onfounding, bias or hane and a signifiant risk that the relationship is not ausal 3 Non-analytial studies (eg, ase reports, ase series) 4 Expert opinion Grades of reommendations A At least one meta-analysis, systemati review or RCT rated as 1++ and diretly appliable to the target population or a systemati review of RCTs or a body of evidene onsisting prinipally of studies rated as 1+ diretly appliable to the target population and demonstrating overall onsisteny of results B A body of evidene inluding studies rated as 2++ diretly appliable to the target population and demonstrating overall onsisteny of results or extrapolated evidene from studies rated as 1++ or 1+ C A body of evidene inluding studies rated as 2+ diretly appliable to the target population and demonstrating overall onsisteny of results or extrapolated evidene from studies rated as 2++ D Evidene level 3 or 4 or extrapolated evidene from studies rated as 2+ management for whih there is, at best, sparse data upon whih to base reommendations. This is highlighted where appropriate and should at as a spur for more researh. In other areas suh as the management of aute ILD in the intensive are unit or the management of fibroti NSIP it is lear that ontrolled linial trials may never be feasible. The Committee, based on the disussions with fous groups, felt ompelled to offer some form of guidane in those areas that impat regularly on linial pratie, are immensely hallenging, but for whih there is little or no evidene base. Also, in the ourse of guideline development, there has been a disussion in the literature on the usefulness of guideline reommendations for everyday pratie. 11 Treatment deisions involve a trade-off between the potential benefits and risks, and these deisions need to be individualised on a ase-by-ase basis after disussion with the patient. This model of reommendations is embodied in the GRADE system 12 in whih the quality of evidene is qualified by strength of reommendation (either weak or strong). This allows, for example, a strong reommendation to be made even if the evidene base is weak and visa versa. The Committee felt that this resonated strongly with several management areas in the guideline, best exemplified in the management of IPF. Here there are examples of disordane between the strength of reommendation and level of evidene; interferon- (IFN)-1b is not reommended for the treatment of IPF (pending further data) although there is a published metaanalysis suggesting survival benefit. For this reason, some of the statements for the management and treatment of IPF are qualified where appropriate with a weak or strong reommendation. 6. There are some proposed reommendations in the guideline that were subjet to intense debate within the Committee and upon whih onsensus ould not be ahieved. Again, this is exemplified in the management of IPF with speifi drugs and, in suh ases, a final statement was derived by anonymous voting within the Committee, removing the exerise of undue influene by any single ommittee member. In the remainder of the introdution the reent key ontentious issues in ILD are onsidered in turn. A onstant theme that permeates through the entire guideline is that regional entres are now required to effetively manage ILD, a strong reommendation reahed unanimously by the Guideline Group. 1.3 Terminology of interstitial lung disease The term interstitial lung disease is synonymous with diffuse parenhymal lung disease and, while the latter was used in the 1999 BTS guideline, a deision was made to adopt interstitial lung disease in the urrent doument, onsistent with other international guidelines. A more diffiult issue arose with the terminology embraing subgroups of ILD. Traditionally, in the UK, the term ryptogeni fibrosing alveolitis (CFA) orresponds to a harateristi linial presentation seen typially in IPF but ommon also to many patients with other idiopathi interstitial pneumonias and some ases of hypersensitivity pneumonitis. The use of CFA as an umbrella term in the 1999 BTS guideline refleted the fat that it was not then lear that distintions between IIP subsets were of any true linial value other than the very rude distintion between predominantly inflammatory and predominantly fibroti disease; in short, the historial distintion between desquamative interstitial pneumonia (DIP) and usual interstitial pneumonia (UIP). However, within 2 years of the publiation of the first BTS guidelines, a new onsensus lassifiation had been proposed by a joint Amerian Thorai Soiety (ATS) and European Respiratory Soiety (ERS) ommittee. 2 The new ATS/ERS terminology aptured outome differenes in a number of studies omparing subsets of patients with IIP. The historial outome distintions between predominantly fibroti disease and inflammatory disorders (the latter now expanded to inlude ryptogeni organising pneumonia (COP), lymphoyti interstitial pneumonia (LIP), ellular NSIP, respiratory bronhiolitis with assoiated interstitial lung disease (RBILD) and desquamative interstitial pneumonia (DIP)) were exatly as reported previously. However, the important new outome subgroup to emerge was the entity of fibroti NSIP. These patients made up 20 35% of patients previously diagnosed as IPF or CFA and their long-term survival was substantially better than that seen with a histologial pattern of UIP. On this basis, the ore entity of IPF was redefined: harateristi linial features were required in assoiation with a histologial pattern of UIP at surgial biopsy or a high resolution CT (HRCT) pattern typial of UIP. In addition, the absene of a lymphoytosis on bronhoalveolar lavage (BAL) or the absene of features of an alternative diagnosis on transbronhial biopsy were required in patients not undergoing a surgial biopsy (table 2). 19 These non-biopsy ATS/ERS riteria remain the internationally aepted standard by whih to make a diagnosis of IPF in the absene of a surgial lung biopsy. However, for pragmati reasons, many elderly patients, those with signifiant o-morbidity and patients seen outside referral entres often do not undergo transbronhial lung biopsy or BAL. The role of BAL and transbronhial biopsy is thus urrently under review. The ATS/ERS onsensus statement expliitly stated that CFA and IPF were synonymous terms. 2 The Committee therefore faed a hoie between adopting the ATS/ERS terminology and persisting with the use of CFA as an umbrella term as used in the first BTS guidelines. In an initial onsultative proess in v2

3 Table 2 ATS/ERS riteria for diagnosis of idiopathi pulmonary fibrosis (IPF) in the absene of surgial lung biopsy*{ Major riteria Minor riteria Exlusion of other known auses of ILD suh as Age.50 years ertain drug toxiities, environmental exposures and onnetive tissue diseases Abnormal pulmonary funtion studies that inlude evidene of restrition (redued VC, often with an inreased FEV 1 /FVC ratio) and impaired gas exhange (inreased P(A a)o 2, dereased PaO 2 with rest or exerise or dereased TLCO) Bibasilar, inspiratory rakles (dry or Velro -type in quality) Bibasilar retiular abnormalities with minimal ground glass opaities on HRCT sans Transbronhial lung biopsy or BAL showing no features to support an alternative diagnosis{ whih over 35 hest physiians were anvassed for their opinions, the majority favoured the adoption of the ATS/ERS lassifiation with a signifiant minority (at least 20 25%) stating a preferene for the historial UK definition of CFA. It is worth summarising the rationales for these differing points of view. Those in favour of the new lassifiation tended to stress the advantages of a true international onsensus on terminology that had previously been ontentious; workers in diffuse lung disease now understand eah other better than previously. Furthermore, international agreement on the definition of IPF was thought by some to have atalysed reruitment into large multinational treatment studies. However, the most onsistent argument in favour of the new lassifiation was the prognosti separation between IPF, as redefined, and other forms of fibrosing lung disease. A new syndrome or lassifiation an be justified if it provides added prognosti value to previous terminology; in essene, diagnosis informs prognosis. The diagnosti separation between IPF and fibroti NSIP in patients presenting with a linial piture of CFA provides a prognosti distintion between 5-year survival rates of 10 15% and.50%, respetively. Those in favour of retaining the umbrella term CFA argued, for the most part, from linial pragmatism. For many experiened hest physiians the linial entity of CFA was, and is, a key part of their personal diagnosti algorithms a highly useful starting point in distinguishing between idiopathi interstitial pneumonias and other diffuse lung proesses, espeially saroidosis. Some also questioned whether fibroti NSIP was suffiiently prevalent in older non-referred patients with a linial presentation of CFA to be a linially useful diagnosis, although the atual prevalene of fibroti NSIP is not known. Furthermore, epidemiologial work demanded a linial definition of CFA if the true spetrum of disease was to be studied. Requirements that full ATS/ERS riteria be met for a diagnosis of IPF, inluding bronhosopi riteria, effetively exludes the elderly, those with major o-morbidity and many patients not studied at referral entres. This is likely to remain Insidious onset of otherwise unexplained dyspnoea on exertion Duration of illness.3 months BAL, bronhoalveolar lavage; FEV 1, fored expiratory volume in 1 s; FVC, fored vital apaity; HRCT, high resolution omputed tomography; ILD, interstitial lung disease; P(A a)o 2, differene between alveolar and arterial pressure; PaO 2, arterial oxygen tension; TLCO, arbon monoxide transfer fator; VC, vital apaity. *Modified from Amerian Thorai Soiety/European Respiratory Soiety reommendations. 2 {In the immunoompetent adult the presene of all of the major diagnosti riteria as well as at least three of the four minor riteria inreases the likelihood of a orret linial diagnosis of IPF. {The requirement for transbronhial lung biopsy/bronhoalveolar lavage within the diagnosti riteria for IPF is urrently under review. true to some extent in epidemiologial studies in the foreseeable future. Although HRCT sanning may eventually be used to validate diagnosti labels in patient subsets, this has yet to be attempted despite the widespread availability of HRCT for 15 years or more. While ognisant of the debate within the UK, the urrent guideline has adopted the ATS/ERS lassifiation, and perhaps the most ompelling argument for doing so is that the ATS/ERS system has now been almost universally adopted around the world. However, the term CFA is reognised internationally as being synonymous with IPF as defined in the ATS/ERS lassifiation; the ontinued use of the term CFA in its historial sense would have flown in the fae of a growing international onsensus and would have invalidated the urrent guidelines in many eyes. Other onsiderations aside, the use of the term CFA to desribe two separate entities ould not have been sustained on the grounds of ommon sense. Consequently, the ATS/ERS system has been adopted throughout the guidelines, exept in the setion on epidemiology in whih more inlusive terminology was required: solely for epidemiologial statements, the term CFA linial syndrome was santioned Diagnosti standards in interstitial lung disease The reent hange in lassifiation has led to a reappraisal of the way in whih diagnoses are, and should be, reahed in linial pratie. In the last entury it was widely aepted that the diagnosti gold standard for ILD was a histologial diagnosis made on a surgial biopsy. Clinial and radiologial diagnosti information were seen by many as deeply unsatisfatory surrogates for histology. However, the limitations of diagnoses relying solely on histology are inreasingly reognised. In many patients the disease is too advaned or o-morbidity too severe to allow a surgial biopsy to be performed. The proedure is highly unattrative to patients and physiians alike in the elderly. Furthermore, as with all other diagnosti tests, there is signifiant interobserver variation. In a study undertaken by the UK histopathologial panel 21 the level of agreement on a first hoie diagnosis was at the lower limit of what would be aepted as linially useful. In many ases, histologial appearanes were intermediate (ie, features were ompatible with two or more diagnoses). It should be stressed that interobserver diagnosti variation is equally problemati between experiened HRCT radiologists, partiularly in more diffiult ases referred for surgial biopsy. A further onfounding fator in the histologial evaluation of lung biopsies is the problem of sampling error : the possibility that a biopsy speimen was taken from an area not representative of the predominant disease proess. This problem applies partiularly to the distintion between UIP and NSIP and is disussed in Setions 7.3 and No test an be regarded as a diagnosti gold standard if it (1) annot be performed in a large proportion of patients; (2) is subjet to major interobserver variation; and (3) provides nonrepresentative information in a signifiant minority of ases. However, there are additional grounds for questioning the assertion that all patients with IIP should undergo a surgial biopsy whenever possible. As disussed in the body of the guidelines, a diagnosis of IPF an be reasonably based upon typial HRCT appearanes and a ompatible linial setting in approximately 70% of ases and, in this ontext, a surgial biopsy adds no useful information However, a surgial biopsy is often invaluable in the remaining patients with less v3

4 typial radiologial features. With further experiene it is likely that the repertoire of lassial linioradiologial profiles that obviate diagnosti surgial biopsy will be expanded. For example, it is inreasingly aepted that a diagnosis of RBILD is seure when based upon typial HRCT findings in a urrent smoker, espeially when BAL findings are also ompatible. 25 Surgial biopsy may also be misleading if onsidered in isolation and without the integration of linial and radiologial information. In hypersensitivity pneumonitis (HP) it is now known that the typial histologial appearanes are absent in a signifiant minority of ases, with both UIP- and NSIP-type patterns of disease enountered UIP may our in onnetive tissue disease but the outome, in ontrast to IPF, is not uniformly poor Thus, it is inreasingly aepted that diagnosis of diffuse lung disease requires a multidisiplinary approah with the reoniliation of linial, radiologial and histologial information. Suh an approah was first formally evaluated in a study of over 50 patients with suspeted IPF involving leading liniians, radiologists and pathologists. 6 Key onlusions relate to omparisons between linioradiologial diagnoses made by liniians and radiologists, histologial diagnoses made by pathologists and final diagnoses reahed after joint disussion of all information by all partiipants. In patients without typial linial and HRCT features of IPF, the linioradiologial diagnosis hanged approximately half the time and the histologial diagnosis hanged in 25% of ases ompared with the final onsensus diagnosis. Thus, while histologial information was more influential, no single mode of evaluation was uniformly pre-eminent. This study aords with widespread anedotal experiene that, when linial, HRCT and histologial information are examined together, the final diagnosis is often a matter of negotiation and onsensus formation with a frequent need to reonile apparently ontraditory findings. The multidisiplinary approah is now onsidered the gold standard for diagnosing diffuse lung disease. This has profound impliations for routine linial pratie. Historially in the UK and in other healthare systems represented in these BTS guidelines, diffuse lung disease has largely been managed loally with oasional referral of diffiult ases to tertiary entres. The provision of a multidisiplinary approah will require an expansion of expert entres in diffuse lung disease with the fostering of regional expertise in linial, HRCT and histopathologial skills alike, as disussed later. 1.5 The problem of NSIP A good deal of diagnosti diffiulty in the last few years has related to the entity of NSIP, urrently identified in the ATS/ ERS lassifiation as a single disorder. Herein lies the problem. A onfident diagnosis of idiopathi NSIP requires a surgial biopsy. However, based upon multidisiplinary evaluation and, to some extent, upon geneti fingerprinting, it is inreasingly reognised that the term NSIP overs a number of separate linioradiologial entities expressed as a ommon histologial pattern of NSIP. Hene, without a multidisiplinary approah, little sense an be made of NSIP as a single disorder. A areful perusal of linial and HRCT statements on NSIP reveals a true diversity of linioradiologial profiles assoiated with a histologial diagnosis of NSIP. Although it is tempting to onlude that NSIP is not a true entity but merely a waste-basket term to over unlassifiable histologial appearanes, there are now suffiient data to justify the onept of several linioradiologial syndromes of NSIP; these inlude NSIP with an IPF-like profile or overlap (NSIP/ IPF), NSIP with an organising pneumonia profile (NSIP/OP) and NSIP with a hypersensitivity profile (NSIP/HP). This onept has been broadly reognised by an ATS/ERS expert group whih has yet to submit a final report and, for this reason, no final statement of the sublassifiation of idiopathi NSIP an be made in urrent guidelines, inluding the definition of a ore entity for NSIP. Nonetheless, a framework for managing NSIP in the urrent era is required. Coneptualising NSIP as most losely resembling IPF, COP or HP may help to rationalise treatment, but this an only be ahieved in a multidisiplinary forum. This integrated approah should failitate realisti therapeuti goals and treatment strategies to be set in individual ases. As suh, a dogmati guideline-entred approah, laying down a single treatment strategy for NSIP, will inevitably prove to be too inflexible and will fail to meet the needs of many patients. Guidane on the management of NSIP, based on ategorising ases with a histologial pattern of NSIP into NSIP/ IPF, NSIP/OP and NSIP/HP profiles, is provided in Setion Staging the severity and progression of disease Evaluation of the hest radiograph provides, at best, a rude approximation of disease extent in ILD. Pulmonary funtion tests usually reflet the severity of disease more aurately than hest radiography. However, the wide variation in the normal range of pulmonary funtion tests (generally ranging from 80% to 120% of values predited from age, sex, rae and height) is a major onstraint in the staging of mild disease. For example, apparently minor impairment in levels of fored vital apaity (FVC) to 75% of predited an represent anything from a 5% to 45% deline from premorbid values. Moreover, pulmonary funtion tests are readily onfounded by onurrent disease proesses. The most widely studied example is the frequent admixture of emphysema and fibrosis seen in up to 40% of patients with IPF in some series, and produing a spurious preservation in spirometri and plethysmographi lung volumes but a disproportionate redution in gas transfer. In the onnetive tissue diseases a variety of abnormal proesses, inluding interstitial, pulmonary vasular, pleural and musle disease, ommonly oexist but, without an independent means of evaluating the morphologial extent of eah, liniians fae diffiulty in understanding and deonstruting patterns of lung funtion impairment. The advent and appliation of HRCT sanning has provided liniians with a sensitive means of staging disease severity in diffuse lung diseases but has its own limitations. The formal soring of disease extent applied in linial researh is not user friendly in routine pratie. The linial signifiane of subtle HRCT abnormalities is often unertain, espeially in patients with onnetive tissue disease and minor lung funtion impairment. In other ases it is diffiult to distinguish between normal HRCT appearanes and subtle diffuse ground glass attenuation. In all these senarios pulmonary funtion tests omplement HRCT, helping the liniian to disount trivial disease on HRCT sans but to reognise espeially with estimation of gas transfer that HRCT may underestimate widespread and linially important pulmonary infiltration. Muh the same priniple applies to the interpretation of serial hanges in pulmonary funtion tests. The prognosti value of short-term serial funtional hange has been widely investigated in IPF and fibroti NSIP However, serial data need to be integrated with baseline linial, HRCT and, when appliable, histologial information in order to ahieve the most aurate estimation of the likely long-term outome. Thus, the reoniliation of HRCT findings and pulmonary funtion tests v4

5 is an important part of the multidisiplinary proess and repetition of the multidisiplinary proess, integrating longitudinal observations, may be as informative as initial evaluation. 1.7 Advanes in the treatment of diffuse lung disease Historially there has been a pauity of therapeuti linial trials for ILDs and, in partiular, IPF. However, reent studies, although inonlusive, have indiated possible therapeuti benefits in IPF with the use of IFN-1b, 41 pirfenidone, 8 bosentan (unpublished at the time of writing), warfarin 42 and, more onviningly, with the use of N-aetylysteine in ombination with low dose prednisolone and azathioprine. 9 These and other data are reviewed in detail later in this doument. However, three points deserve partiular emphasis. First, these guidelines were written during a time of rapid hange, making it diffiult to distil reommendations on best urrent treatment. The role of antioxidant therapy is a good example of this problem. There was a wide range of strongly held views within the group, ranging from septiism to optimism and refleting the urrent range of views in editorial statements. The amiable reoniliation of these differenes was greatly helped by an anonymised vote on key reommendations. Seond, at present there is no speifi therapy that an be onsidered best urrent treatment for IPF, the most prevalent of the hroni fibrosing lung diseases and that with the poorest prognosis. However, onfirmation and extension of urrent data on, for example, antioxidant therapy, perhaps emerging from a large imminent study in the USA, might make it inreasingly diffiult to undertake plaebo ontrolled studies in the fae of inreasing aeptane of a best urrent regimen. The Guideline Committee felt that that point has not yet been reahed, but the impliations are potentially profound. IPF has an outome similar to lung aner and is more prevalent than many of the less frequent malignanies. If a real differene in outome an be ahieved with treatment, there is likely to be an inreasing pereption that the disease should be managed in speialist linis, exatly as has ourred in the onologial world. If more than one benefiial treatment emerges, best management may require therapies to be ombined to ahieve therapeuti synergism, and this also is likely to require speialist expertise. Finally, liniians urrently fae a therapeuti division between IPF in whih the pathogeneti role of inflammation has been questioned and an epithelial-fibroti model is inreasingly favoured 45 and other fibrosing lung diseases in whih inflammation is believed to preede and indue fibrosis. Highdose ortiosteroid therapy, now onsidered to be ontraindiated in IPF, may have an important role in some of the other diseases presenting with the traditional linial piture of CFA linial syndrome (disussed in Setion 13.2). The optimal use of traditional therapies therefore requires aurate multidisiplinary diagnosis. 1.8 Struture of healthare delivery for interstitial lung disease The importane of multidisiplinary evaluation by expert liniians, radiologists and pathologists is a onstant theme throughout this doument. In partiular, multidisiplinary evaluation allows a more aurate appliation of disease lassifiation, diagnosis, staging, prognosis and a more informed appliation of therapeuti advanes. Historially, most patients with ILD have been managed by respiratory physiians in general respiratory linis. Within this model, eah physiian looks after relatively few patients with ILD and arues linial experiene only slowly. The aumulation of linial, radiologial and histopathologial expertise will require the development of designated ILD linis using a model similar to that in ysti fibrosis or lung aner. The multidisiplinary team (MDT) model requires that a lini dediated to patients with ILD should be led by a onsultant hest physiian with a speialist interest in ILD and supported by a regular loal multidisiplinary meeting with a onsultant radiologist and, ideally, a onsultant pathologist with an interest in ILD. In most ases the team would work losely with a thorai surgeon and with loal palliative are, rheumatology and primary are servies using models reminisent of those developed for lung aner and ysti fibrosis. Suh a system should allow equality of aess to ommon standards of high quality are while allowing loal hest physiians to retain ownership of day-today patient management. An essential requirement would be lose ollaboration between loal and speialist entres as well as rapid and effetive ommuniation (inluding image transfer) between the two. It is envisaged that some regional linis will evolve into speialist (tertiary) entres, oordinating regional linis and ollaborating with other entres to form a national ILD network able to deliver the large-sale studies urgently required in this field. Streamlining of the referral, diagnosti and management pathway of patients with ILD may be enhaned through the development of regional do one and share programmes, a proess already underway in many parts of the UK for a number of linial onditions ( engagement/linial/doas). At present, few studies have addressed the utility of the multidisiplinary regional lini model of are in ILD There is therefore an urgent need to demonstrate the value of this model to patients and to ommissioners and those involved in researh and teahing. The preise nature and number of regional ILD linis is likely to be ditated by loal needs. However, the observation that there are a growing number of regional ILD linis already established in the UK bears testimony to their pereived need. Reommendations for referral to regional ILD linis are provided in Setion SUMMARY OF RECOMMENDATIONS FOR ILD History and linial examination in ILD Detailed history taking is required to identify respiratory risk fators both past and present. [D] Lung funtion testing in ILD All patients with ILD should have resting spirometri and gas transfer measurement at presentation, whih together provide a reasonable measure of disease severity. [C] In idiopathi pulmonary fibrosis (IPF) and fibroti nonspeifi interstitial pneumonia (NSIP), arbon monoxide transfer fator (TLCO) levels at presentation are a more reliable guide to outome than other resting lung funtion variables. A TLCO level of less than 40% is indiative of advaned disease in fibroti idiopathi interstitial pneumonia (IIP). [B] In IPF a fall from baseline of >10% in fored vital apaity (FVC) or >15% in TLCO in the first 6 12 months identifies patients with a muh higher mortality. [B] Desaturation during the 6 minute walk test at presentation is a stronger prognosti determinant in IPF than resting lung v5

6 funtion. [C]. However, additional studies are required to define the role of exerise testing in routine staging and follow-up both in IPF and other ILDs. Maximal exerise data probably add little to resting lung funtion in assessing the severity of ILD but are sometimes useful, when normal, in exluding linially signifiant diffuse lung disease. [C] Chest radiography and HRCT Radiologists with an interest in thorai imaging and respiratory physiians should meet regularly to evaluate imaging in patients with ILD. [D] In patients for whom the diagnosis is unertain after hest radiography and linial assessment, HRCT sanning is the next investigation of hoie. [C] HRCT is valuable in deteting ILD in patients with a normal hest radiograph. [B] In the appropriate linial setting, appearanes on the HRCT san may be suffiiently harateristi to prelude the need for BAL or lung biopsy and histopathologial onfirmation. [B] Radiologists involved with determining the protool and interpretation of HRCT sans should have expertise in the tehnique, be responsible for quality assurane and ensure that an appropriate radiation dose protool is used. At least one radiologist in any department should have a delared interest and be trained in hest radiology and HRCT. [D] Consideration should be given to establishing a referene panel of radiologists with partiular expertise in HRCT. [D] Initial blood and other tests Initial tests in all ases of suspeted ILD should inlude a urine dipstik, full differential blood ell ount, serum urea, eletrolytes and reatinine, and liver funtion tests. Other tests are largely dependent upon linial ontext. [D] The serum angiotensin-onverting enzyme (ACE) level has only a limited role in diagnosis and does not ontribute to monitoring patients with pulmonary saroidosis when added to serial lung funtion and imaging. [D] Bronhoalveolar lavage (BAL) and transbronhial lung biopsy (TBLB) BAL or TBLB, when required, should be performed before the initiation of treatment. [D] BAL should be onsidered in all patients with suspeted infetion, malignany and some rare ILDs. In suh ases, BAL may be diagnosti. [C] BAL is not required as a diagnosti tool in patients with linial features and HRCT appearanes typial of IPF. [C] In patients for whom the diagnosis is unertain after linial assessment and HRCT sanning, typial BAL ellular profiles may allow a diagnosis of hypersensitivity pneumonitis or saroidosis to be made with greater onfidene. [C] In ases in whih the diagnosis is unertain and BAL is onsidered, the proedure should be performed in a regional entre with tehnial expertise in the proedure and the analysis of the BAL samples. [D] BAL should be performed in all patients undergoing TBLB. [D] TBLB is the initial proedure of hoie in those patients likely to have ILDs in whih small samples may be diagnosti, partiularly if the disease has a tendeny for bronhoentri involvement. HRCT should be used to guide the biopsy site. [D] Four to six TBLB speimens should be taken. [D] In suspeted saroidosis, endobronhial biopsy samples in addition to TBLB are reommended sine they are frequently positive, are assoiated with low morbidity and inrease the diagnosti yield. [C] TBLB is not reommended as the initial biopsy option in ases of suspeted IPF and is unreliable in the diagnosis of rare lung disease (other than alveolar proteinosis). [C] Surgial lung biopsy in ILD Surgial lung biopsy, when required, should be performed before the initiation of treatment. [D] A onfident pathologial diagnosis of IPF or the other interstitial pneumonias an only be made if a surgial lung biopsy is obtained. [C] A onfident linial diagnosis of IPF an be reliably made in the presene of harateristi HRCT and linial findings. [C] If a surgial biopsy is performed in ases of suspeted interstitial pneumonia, more than one biopsy speimen must be taken from more than one site, preferably from different lobes. [C] Multiple multilobe lung biopsies are tehnially easier by video-assisted thoraosopy (VATS) than by open lung biopsy [D]. VATS is also assoiated with less early postoperative pain than open lung biopsy. [B] It is reommended that the preise biopsy sites are based on HRCT appearanes [D]. In patients with suspeted IIP, areas of intermediate abnormality or omparatively normal lung adjaent to areas of established honeyombing should be targeted with the speifi aim of identifying UIP if present. [D] Care pathway and general management strategies for ILD All patients with ILD should have aess to a multidisiplinary team based in a regional entre with expertise in ILD. [C] Referral to a regional ILD lini should be made if there are pereived diffiulties in diagnosis and/or management, but a tailored shared are model is advoated. [D] Patients with ILD who are urrent smokers should reeive opportunisti smoking essation advie from healthare professionals and this advie should be reorded in the linial notes. Current smokers should be offered speialist support and niotine replaement therapy or bupropion on NHS presription. [B] Patients with ILD should have aess to a loal pulmonary rehabilitation programme. [C] Management and treatment of IPF Best supportive are should be onsidered a speifi and important treatment strategy in all patients with IPF. It is a proative approah to symptomati treatment and may inlude oxygen therapy, pulmonary rehabilitation, opiates, antireflux therapy, withdrawal of steroids and other immunosuppressants, early reognition of terminal deline and liaison with palliative are speialists. [D] To date there is no therapy proven to improve survival or otherwise signifiantly modify the linial ourse of IPF. As suh, it is reommended that all patients be onsidered for v6

7 reruitment to high quality linial trials of therapy and/or for lung transplantation if appropriate. [C] High-dose steroid monotherapy (0.5 1 mg/kg) does not improve survival or otherwise modify the linial ourse of the disease and is assoiated with signifiant morbidity. It is therefore strongly reommended that high-dose steroids not be used to treat patients with IPF. [C] Prednisolone (tapering from 0.5 mg/day to mg/day) with azathioprine (2 mg/kg, maximum150 mg/day) and N- aetylysteine (NAC, 600 mg three times a day) has been shown to have a signifiantly better treatment effet than prednisolone and azathioprine alone. However, further studies are required and this regime urrently arries a weak reommendation [C]. Prednisolone and azathioprine without NAC is not reommended. Variations from the above regimens, suh as lower dose steroids (20 mg or less) or omission of azathioprine are very likely to be better tolerated but are entirely without evidene base. Appropriate ounselling should be given to all patients started on speifi regimes. Treatment, if started, ould be equally reasonably initiated at presentation or following objetive evidene of disease progression or in moderate/severe disease. Referral for lung transplantation in patients with IPF The following apply only to patients who fulfil established seletion riteria for transplant, thus generally exluding those over the age of 65 years and/or those with signifiant omorbidity. Referral to a transplant entre should be made if the disease is advaned (TLCO,40% predited) or progressive (>10% deline in FVC or >15% deline in FVC during 6 months of follow-up). [C] Cryptogeni organising pneumonia (COP) COP usually responds to ortiosteroid therapy but the optimum dose and length of treatment is not known. Initial doses of mg/kg, weaning over 6 12 months, are reasonable. [C] Relapses of COP are ommon but are only rarely assoiated with poor outome. The risk versus benefit of prolonged ortiosteroid therapy should be arefully onsidered in patients with relapsing COP. [D] Respiratory bronhiolitis ILD (RBILD) and desquamative interstitial pneumonia (DIP) Patients with RBILD or DIP should reeive appropriate smoking essation advie and treatment. [C] Hypersensitivity pneumonitis The diagnosis of hypersensitivity pneumonitis requires a high index of suspiion and in diffiult ases an integrated multidisiplinary approah is essential. [D] Avoidane of the ausative antigen, when identified, is the most important and effetive aspet of management. [C] Cortiosteroids may have a role in treating severe or progressive disease. [C] Connetive tissue disease (CTD)-assoiated ILD In general, the threshold for starting treatment in the hope of preventing progression of pulmonary fibrosis in CTDassoiated ILD is redued when disease is severe (as judged by HRCT or pulmonary funtion tests), reently progressive, or there is a short duration of systemi disease. [C] In many patients the potential benefits of therapy will be outweighed by the risks. For the majority of CTD, with the exeption of systemi slerosis (SS), reommended initial treatment for ILD is oral prednisolone at an initial dose of mg/kg with the aim of tapering to a maintenane dose of 10 mg/day or less, often in assoiation with an immunosuppressive agent (usually oral or intravenous ylophosphamide or oral azathioprine). [C] ILD assoiated with polymyositis/dermatomyositis often warrants early treatment with oral prednisolone ( mg/kg) and ylophosphamide or other immunosuppressive therapy to prevent disease progression. [C] In SS-assoiated ILD, reommended treatment, if required, is with low-dose oral steroids (10 mg/day) and/or ylophosphamide (oral or intravenous). [C] High-dose ortiosteroid treatment (daily prednisolone dose.10 mg) should be avoided if at all possible beause of the risk of renal risis. [C] Saroidosis Beause of the high rate of spontaneous remission, treatment is not indiated for asymptomati stage I disease. [B] Beause of high rates of remission, treatment is not indiated in asymptomati stage II or III disease with mildly abnormal lung funtion and stable disease. [D] Oral ortiosteroids are the first line of therapy in patients with progressive disease determined by radiology or on lung funtion, signifiant symptoms or extrapulmonary disease requiring treatment. [B] Treatment with prednisolone (or equivalent) 0.5 mg/kg/day for 4 weeks, then redued to a maintenane dose whih will ontrol symptoms and disease progression, should be used for a period of 6 24 months. [D] Bisphosphonates should be used to minimise steroidindued osteoporosis. [D] Inhaled ortiosteroids, either as initial treatment or maintenane therapy, are not of signifiant benefit. [B] Inhaled ortiosteroids may be onsidered for symptom ontrol (ough) in a subgroup of patients. [D] Other immunosuppressive or anti-inflammatory treatments only have a limited role in saroidosis, but should be onsidered in patients when ortiosteroids are not ontrolling the disease or side effets are intolerable. At present, methotrexate is the treatment of hoie. [C] Lung transplantation should be onsidered in end stage pulmonary saroidosis. [D] Pulmonary hypertension Pulmonary hypertension in ILD Pulmonary hypertension should be onsidered in patients with ILD who have either breathlessness or lung dysfuntion (redued TLCO or desaturation on exerise) that seem disproportionate to the extent of parenhymal lung disease. [D] Transthorai ehoardiography is a suitable sreening tool for the detetion of pulmonary hypertension in patients with ILD. [B] Long-term oxygen therapy should be presribed in patients with ILD, hroni hypoxia (,8 kpa) and or pulmonale. [D] v7

8 Patients with ILD and pulmonary hypertension that is judged to be ontributing to symptoms and is disproportionate to the extent of ILD or is severe (systoli pulmonary artery pressure.50 mm Hg) should be onsidered for referral to a regional speialist pulmonary hypertension entre for assessment and reruitment to high quality linial trials. [D] Pulmonary artery hypertension assoiated with onnetive tissue disease Patients with systemi slerosis should have annual lung funtion testing and transthorai ehoardiography should be performed in those with delining TLCO or TLCO,50% predited. [C] Long-term warfarin therapy should be presribed in patients with CTD-assoiated pulmonary artery hypertension. [D] ILD presenting with aute respiratory failure Early aurate and seure diagnosis is ritially dependent upon onsidering a broad differential diagnosis inluding new-onset ILD and ILD progression, and non-ild proesses suh as pulmonary oedema, malignany, drug-indued lung disease and infetion. [D] Aurate diagnosis in ILD with borderline respiratory failure often requires BAL to exlude infetion and is best performed in seleted patients on the intensive are unit (ICU) before ventilation is required, or with ventilatory support immediately available. [D] Deisions on transbronhial and surgial lung biopsy must be individualised to the linial senario. Both proedures are often justifiable, despite inreased risk, if there is a realisti possibility that the additional information will influene management. [D] ICU support for patients with IPF and respiratory failure is usually not appropriate due to the very high assoiated mortality. [C] In most rapidly progressive ILDs presenting with respiratory failure, intravenous ortiosteroid therapy is the initial treatment of hoie. Intravenous ylophosphamide is the seond-line treatment of hoie and is usually administered to patients not responding to parenteral ortiosteroids. [D] In ases of known or suspeted vasulitis, intravenous ylophosphamide should be onsidered as first-line treatment. [C] 3. EPIDEMIOLOGY 3.1 Idiopathi pulmonary fibrosis (IPF) and ryptogeni fibrosing alveolitis (CFA) The data available on the epidemiology of IPF are very limited and most of the studies predate the new ATS/ERS relassifiation of IIPs and need to be onsidered in this light. For this reason, we have deliberately retained the term CFA for this setion of the guidelines and used it interhangeably with the CFA linial syndrome, the entity diagnosed by hest physiians and studied in epidemiologial studies prior to the new lassifiation system. Historially, most studies of CFA have relied on linial riteria (eg, the presene of basal inspiratory pulmonary rakles, bilateral interstitial shadowing on the hest radiograph, no doumented exposure to asbestos or other fibrogens, no evidene of ollagen vasular disease and no other oexisting ause of interstitial lung disease). 47 For this reason, it is possible that some mislassifiation of NSIP as CFA is present in the older epidemiologial studies. The extent of this mislassifiation will depend on the relative inidene of NSIP and IPF in the general population, and this is not urrently known. One previous epidemiologial study has reported that the median survival of newly diagnosed patients with the CFA linial syndrome is 3 years, a figure whih is similar to that urrently reported for patients with IPF. This provides some reassurane that there are unlikely to be extensive problems of mislassifiation in the historial studies. Future epidemiologial studies are likely to inlude data from HRCT sans, and this should redue problems of mislassifiation further. Information on the frequeny of the CFA linial syndrome omes from a variety of soures inluding population-based disease registries, omputerised general pratie data (espeially from the UK) and death registrations. In the New Mexio registry, 48 CFA had the highest inidene of all the ILDs (9/ person-years) and similar findings have been reported from European registries Data from omputerised UK general pratie reords 51 suggest that the 12-month period prevalene of CFA is 15 18/ person-years and, based on a median survival from diagnosis in the UK of approximately 3 years, this equates with an estimated inidene of 5/ personyears. This, in turn, suggests that there are at least 2000 new ases of CFA eah year in England and Wales, whih is ompatible with death ertifiate registration data. There is evidene from death ertifiate data that the inidene of the CFA linial syndrome is inreasing in the UK and a number of other ountries inluding Canada, Australia and New Zealand. General population-based data in the UK and the USA suggest that the median age of presentation of the CFA linial syndrome is 70 years, with the disease unommon below the age of 50 years. It is more ommon in men with a male:female ratio of : The CFA linial syndrome ours throughout the world and in most ethni groups, but there are insuffiient data to allow meaningful inter-ountry omparisons of inidene or prevalene. The median survival is 3 years in the UK and 4 years in New Mexio, 59 with patients losing an average of 7 years of life ompared with the general population. 53 Patients with the CFA linial syndrome appear to have a markedly inreased risk of developing lung aner. 3.2 Saroidosis Exluding patients with stage I disease, saroidosis is the seond most ommon ILD. 48 In the UK, general pratie data suggest an inidene of approximately 3/ person-years 51 (assuming a mean disease duration of 2 years), similar to the figure derived from the New Mexio registry 48 and from Japan 62 but lower than other estimates from the USA. 63 The inidene of saroidosis appears to be higher in Sandinavian ountries and in Afro-Caribbean people, and also marginally higher in women. In general, inidene peaks between the ages of 20 and 50 years, with a seond smaller peak after the age of The lungs are involved in most ases and are affeted without other organ disease in approximately 50% of patients; the skin, liver and eyes are the most frequent extrapulmonary sites. 64 The prognosis is generally good, but a few patients die from progressive disease. 67 USA data suggest that females and Afro- Caribbean people have an inreased mortality Hypersensitivity pneumonitis (HP) Data on the frequeny of HP are limited, but it is less prevalent than the CFA linial syndrome or saroidosis in disease registry populations. Some studies have been onduted within v8