European Respiratory Society
Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a steadily progressive and ultimately fatal disease of unknown origin. Recent years have seen advances in our understanding of IPF and a number of guidelines have been published. But many questions remain unanswered, particularly surrounding probable versus definite IPF. This Monograph aims to discuss the latest achievements in IPF, and covers key diagnostic issues, staging of the disease, complications and comorbidities, treatment, unmet patient needs and perspectives for the future. This book will be of interest to all clinicians and researchers in this area.

  • ERS Monograph
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    Vidya Navaratnam, Nottingham Respiratory Research Unit, Clinical Sciences Building, Nottingham City Hospital, Hucknall Road, Nottingham NG5 1PB, UK. E-mail:

    The precise global incidence and prevalence of IPF remain unclear, with incidence estimates ranging from 1.2 to 9.6 per 100 000 person-years. In this chapter, we summarise studies of the incidence and prevalence of IPF before discussing risk factors and comorbid illnesses. Many studies have evaluated risk factors for IPF including smoking, environmental factors, gastro-oesophageal reflux, diabetes mellitus, clotting dysfunction and genetics. Through epidemiological studies there has been considerable progress in identifying factors that are likely to be aetiologically important, and further research into the causes and progression of IPF is vital to identify biomarkers and targets for treatments. The most common cause of death in people with IPF is respiratory failure secondary to lung fibrosis. However, the incidence of comorbidities such as cardiovascular disease and lung cancer is increased in people with IPF. The association between these comorbidities may be important in helping understand the pathogenesis of IPF and the need for a holistic approach to the care of patients.

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    Bruno Crestani, Service de Pneumologie, Hôpital Bichat, 46 Rue Henri Huchard, Paris, 75018, France. E-mail:

    The occurrence of pulmonary fibrosis in numerous individuals from the same family suggests a genetic cause for the disease. During the last 10 years, mutations involving proteins from the telomerase complex and from the surfactant system have been identified in association with pulmonary fibrosis. Mutations of TERT, the gene encoding the telomerase reverse transcriptase, are the most frequently identified and are present in 15% of cases of familial pulmonary fibrosis. More recently, mutations in RTEL1 and PARN have each been described in 5–10% of cases. Other mutations (TERC, surfactant proteins genes) are only rarely found in adults. Patients with mutations involving the telomerase complex may present with pulmonary fibrosis or haematological, cutaneous or hepatic diseases. Rare syndromes including pulmonary fibrosis have recently been characterised on a genetic level involving original pathways. Evidence for mutations associated with the development of pulmonary fibrosis raises numerous clinical questions, from establishing a diagnosis and providing counselling to deciding on therapy, and requires specific studies. Other genetic variations, such as a polymorphism in the promoter of MUC5B, have also been described in pulmonary fibrosis, and may be considered to be part of a polygenic transmission. From a pathophysiological point of view, the function of the genes involved highlights the central role of alveolar epithelium and ageing in fibrogenesis.

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    Andreas Günther, Dept of Internal Medicine II, Justus-Liebig-University Giessen, Klinikstrasse 36, Giessen D-35392, Germany. E-mail:

    The pathogenesis of IPF is characterised by a defective interplay between the epithelium and mesenchyme. The early events are thought to take place in epithelial cells with an initial injury, followed by a stress response that is linked to endoplasmic reticulum stress and apoptosis. Impaired regenerative capacities lead to defective re-epithelisation. Mesenchymal cells then proliferate and form large amounts of extracellular matrix. The origin of these cells can be diverse. They can result from epithelial-to-mesenchymal transition, circulating fibrocytes or activation of resident cells by factors such as inflammatory cytokines. These alterations eventually result in a gradual exchange of normal lung parenchyma with fibrotic tissue.

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    Dominique Valeyre, Assistance publique hôpitaux de Paris, Hôpital Avicenne, 125 rue de Stalingrad, 93009 Bobigny, France. E-mail:

    Early and accurate IPF diagnosis is essential in order to offer patients the best treatment. The 2011 guidelines significantly improved IPF diagnosis. The diagnosis relies, in a specific context, on either a UIP pattern on CT or the combination of adequate CT and pathological findings after a multidisciplinary discussion. The diagnosis may remain difficult due to: unclear honeycombing on CT; unclear pathology; discrepancies between CT and pathology; possible confusion with UIP secondary to a known cause; and surgical lung biopsy contraindicated when it is indispensable. In difficult cases the diagnosis might be supported by taking into account age, subtle CT findings, BAL, transbronchial cryobiopsy results or the observed behaviour of the disease. Advances in the near future may stem from new biomarkers, which might overhaul the diagnosis and even lead to more personalised medicine. An important challenge will be to shorten the delay between initial symptoms and confirmed IPF diagnosis.

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    Venerino Poletti, Ospedale GB Morgagni, Forlì, Via Carlo Forlanini 34, Forlì, Italy. E-mail:

    The IIPs represent a subset of ILDs of unknown cause. Different histological patterns are linked to these entities. The UIP pattern is associated with IPF. Other histological patterns are: NSIP, respiratory bronchiolitis, desquamative interstitial pneumonia, organising pneumonia and diffuse alveolar damage. Lymphoid interstitial pneumonia is significantly rarer and the idiopathic form has been removed from the IIP category. New entities such as pleuroparenchymal fibroelastosis, acute fibrinous and organising pneumonia, and bronchiolocentric interstitial pneumonia have been recently considered. The “unclassifiable category” is nowadays also used in recognition of the difficulties that pathologists may meet. These patterns are usually identified on samples provided by surgical lung biopsy. Recently, new immunohistochemical analyses have better defined the boundaries of these patterns and a new endoscopic transbronchial approach using cryoprobes has been introduced in clinical practice. Using this approach, large samples are retrieved and identification of the UIP pattern or other complex patterns seems feasible on these samples. The complications are significantly less than those observed after a surgical lung biopsy and transbronchial cryobiopsy seems a promising diagnostic tool in patients with suspected IIP.

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    Carlos Robalo Cordeiro, Centre of Pneumology, Coimbra University Hospital, Rua Mota Pinta, 3000 Coimbra, Portugal. E-mail:

    In this chapter we will discuss the role of BAL in IPF from clinical and research perspectives, presenting a review of the most recent advances in both areas. Although guidelines on the diagnosis and management of IPF do not recommend the use of BAL, its use is argued in excluding differential diagnosis and in patients without a confident diagnosis on HRCT, which is driven by the centre's experience and expertise. As a research tool, BAL has been useful in the study of the pathogenesis of pulmonary fibrosis, as well as in the identification of disease subtypes and response to therapy. After discussing the safety of the technique and less invasive alternatives, we will highlight some areas where further research is needed.

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    Simon L.F. Walsh, King's College Hospital Foundation Trust, Denmark Hill, London SE5 9RS. E-mail:

    HRCT is central to the evaluation of patients with suspected IPF. Based on the most up-to-date diagnostic guidelines, which were published as a collaborative effort by American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and the Latin American Thoracic Association (ALAT) in 2011, in the correct clinical setting a pattern of UIP on HRCT allows a diagnosis of IPF to be made without the need for surgical lung biopsy. An important difficulty applying these guidelines is that a significant proportion of patients with IPF, do not present with typical HRCT appearances and, at the same time, are unable to undergo surgical lung biopsy. Recognising this limitation, there have been several recent attempts to expand the range of HRCT appearances, which are considered sufficiently accurate for IPF to preclude the need to proceed to biopsy. Detection and diagnosis of early IPF also represents an important challenge for the radiologist particularly given the recent licensing of new therapeutic agents for IPF. Finally, there is a growing perception that the initial HRCT appearances of patients with suspected IPF are best considered the starting point of a diagnostic process which is dynamic, rather than representing an immutable diagnosis in the absence of biopsy material.

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    Jim J. Egan, Dept of Lung Transplantation and Interventional Pulmonology, Mater Misericordiae University Hospital, Eccles St, Dublin 7, Ireland. E-mail:

    The natural history of IPF is poorly defined and has a variable clinical course. There has been debate in the international literature as to the appropriate clinically meaningful end-points for clinical trials. Recent US Food and Drug Administration approval for pirfenidone and nintedanib was granted primarily based on showing efficacy in stabilising or reducing the decline in FVC. However, there is some controversy over the use of nonvalidated end-points that have not definitively been proven to be clinically meaningful, such as the use of FVC, 6MWD or DLCO for clinical trials in IPF. Some IPF experts have suggested that all-cause mortality and hospitalisation rates are the most appropriate clinically meaningful end-points for clinical trials in IPF. Single clinical end-point measurements have their own limitations, including effect measure modification, the concept that a therapy may only influence a single part of a process but have less of an effect at a different stage of the same process. To date, the international guidelines have not implemented a standardised staging system in IPF. This chapter reviews the evidence and background for a number of staging systems described for patients with IPF.

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    Jürgen Behr, Dept of Internal Medicine V, University of Munich Marchioninstr.15, 81377 Munich, Germany. E-mail:

    Monitoring patients with IPF is crucial to proactively identify those with progressive disease and determine the development of comorbidities to initiate appropriate and timely treatment. Variables whose longitudinal changes predict survival and that are established surrogate markers of disease progression comprise: clinical symptoms (most prominently dyspnoea), PFT (especially DLCO and FVC), and exercise tolerance assessed by 6MWD. Other valuable measures of progression include arterial blood gas exchange measures at rest and during exercise as well as HRCT, but their longitudinal validity and minimal clinically important difference have yet to be fully established. Molecular biomarkers and the composition of the lung microbiome are newly identified, promising predictors that need further investigation. Additionally, acute exacerbations and hospital admission are marker events correlating with mortality. Several composite scoring systems that integrate some of these variables have been developed for a more reliable and valid assessment of disease progression. As the individual disease course and treatment response is variable, so must be the monitoring schedule.

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    Francesco Bonella, Interstitial and Rare Lung Disease Unit, Ruhrlandklinik, Tüschener Weg 40, 45239, Essen, Germany. E-mail:

    IPF is characterised by a complex pathobiology, which progressively leads to irreversible architectural distortion of the lungs and impaired respiratory function. The management of IPF patients is difficult and still inadequate. Existing assessment tools, including PFTs, are poorly predictive of disease progression and response to treatment. In the last decade, biomarker research in IPF has grown consistently. The multiple pathways involved in the pathogenesis of IPF provide a plethora of molecules, some of which appear to play a role in biological processes rather than simply representing epiphenomena, and could have a role as biomarkers. Selected biomarkers appear to be repeatable, easy to detect and correlated with prognosis, but inter- and intra-individual variability, including variation linked to genetic polymorphisms, has been observed. A number of promising, although not yet fully validated, circulating biomarkers are close to utilisation in routine clinical practice, and encouraging data are emerging from genetic and epigenetic investigations. Confirmation of the results of potential genetic variants linked to prognosis and/or response to treatment should lead to their inclusion into future clinical trials and to their use in clinical practice in the near future.

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    Antje Prasse, Dept of Respiratory Medicine, Hanover Medical School, Carl-Neuberg-Strasse 1, 30625 Hanover, Germany. E-mail:

    This chapter summarises recent advances regarding definition, clinical features, underlying mechanisms, and management of acute exacerbation of IPF. Whilst recent studies suggest risk modulation for acute exacerbations may become feasible with treatment, shortcomings in the current definition and a need for standardised diagnostic algorithms have become apparent.

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    Carlo Vancheri, Regional Referral Centre for Rare Lung Diseases, University Hospital “Policlinico – Vittorio Emanuele”, Dept of Clinical and Experimental Medicine, University of Catania, Sofia 78, Catania 95123, Italy. E-mail:

    IPF and cancer share similar risk factors and have a number of pathogenic mechanisms in common, which makes the two diseases very similar. This aetiopathogenic commonality may explain the relative frequency of the occurrence of lung cancer in IPF patients. Both diseases find their origin in the continuous exposure of alveolar and bronchiolar epithelial cells to microinjuries caused by exogenous agents that, depending on individual susceptibility, may lead to fibrosis and/or cancer. Based on that, lung cancer can be considered a true comorbidity for patients with IPF in which a proper screening programme based on annual HRCT might be helpful in disclosing lung cancer at early stages. However, the presence of IPF, even if an early diagnosis of lung cancer is made, virtually precludes the possibility of an effective treatment of cancer. The lack of effective and safe therapeutic options for patients with IPF and lung cancer, and the poor prognosis that characterises this association of diseases makes the therapeutic strategy extremely complicated. The best approach is to treat these patients on a case-by-case basis, trying to find a balance between the possibility of cure or practising palliation on one hand, and the potential complications that may be induced by diagnostic procedures and therapeutic approaches on the other hand.

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    David Montani, Service de Pneumologie, Université Paris-Sud, Hôpital Bicêtre, 78 Rue du général Leclerc, 94270 Le Kremlin Bicêtre, France. E-mail:

    IPF is often associated with PH, which principally develops due to fibrotic destruction of the vasculature and pulmonary vascular remodelling. The presence of PH worsens prognosis, especially when associated with right ventricular dysfunction. The extent of PH is not closely associated with the extent of lung fibrosis, as assessed by pulmonary lung function or radiological features, suggesting that the severity of fibrosis is not the only driving factor for PH. The term “out of proportion PH” has now been abandoned and replaced with “IPF with severe PH” in the minority of patients with a mean pulmonary artery pressure >35 mmHg. Although echocardiography is a useful indicator, right heart catheterisation remains the gold standard for PH in IPF. There is no current recommendation for PH-specific therapies in IPF, and patients should be included in clinical trials. Current treatment recommendations are optimisation of treatment of the underlying IPF, oxygen supplementation when necessary and lung transplantation, despite the increase in transplantation complications when PH is associated with IPF.

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    Athol U. Wells, Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney St, London, SW3 6NP, UK.E-mail:

    Emphysema is highly prevalent in patients with IPF. However, the question of whether CPFE should be viewed as a syndrome or merely as the coincidental existence of two disease processes remains uncertain. Distinctive pathogenetic features have yet to be demonstrated in CPFE. It is unclear whether observed mortality trends and the reported high prevalence of PH are specific CPFE characteristics or merely reflect a greater reduction in pulmonary reserve due to the coexistence of two processes. No data currently exist to suggest that, in CPFE, pulmonary fibrosis is more progressive or that the presence of PH results from a unique microvascular phenotype. Thus, CPFE syndrome designation is not, at this stage, justified by proven pathogenetic insights or prognostic utility. The strongest current argument for a CPFE syndrome relates to the definition of disease progression in treatment trials and clinical practice, with emerging data suggesting that CPFE has an important confounding effect on serial FVC trends.

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    Michael Kreuter, Centre for Interstitial and Rare Lung Diseases, Pneumology and Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, Röntgenstr. 1, D-69126 Heidelberg, Germany. E-mail:

    IPF is a chronic, progressive disease that has a significant impact on QoL. It is also associated with poor survival. Several comorbidities have been reported to be more common in IPF than in the general population; these may additionally worsen QoL and prognosis. Important comorbidities include cardiovascular and thromboembolic diseases, depression, sleep disorders, and diabetes. For some of these (e.g. GERD), a possible association between the comorbid condition and IPF may exist and specific treatment of the comorbidity might influence the course of IPF. In GERD, retrospective data suggested a possible positive effect of antacid therapy (AAT) leading to a conditional recommendation for AAT in the current IPF guidelines; for several reasons this is highly debatable and demonstrates that prospective trials are needed to determine the interactions of treatments for comorbidities and IPF. Currently, patients with IPF should be actively screened for comorbidities; these comorbidities should then be treated as in non-IPF patients.

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    Vincent Cottin, Hôpital Louis Pradel – Batiment Aile A4 pneumologie, Service de Pneumologie, 28 Avenue Doyen Lepine, 69677 Lyon Cedex, France. E-mail:

    Recently, two drugs have been approved in a number of countries for the treatment of IPF. Pirfenidone and nintedanib, the first antifibrotic pharmacological drugs to treat IPF, target downstream pathways of the fibrogenesis process. Randomised controlled trials have demonstrated that treatment of IPF patients with pirfenidone reduces lung function decline and improves progression-free survival. Pooled data demonstrate that pirfenidone significantly reduces the risk of all-cause mortality at 1 year. Randomised controlled trials have demonstrated that treatment of IPF patients with nintedanib reduces disease progression. Nintedanib reduces the risk of adjudicated confirmed or suspected acute exacerbations. Both pirfenidone and nintedanib have a manageable safety and tolerability profile in patients with IPF, and have a consistent effect across a variety of baseline characteristics in subgroup analysis. The primary treatment-related adverse events associated with pirfenidone therapy are gastrointestinal upset, rash and photosensitivity, and that of nintedanib is diarrhoea. Management of adverse events through treatment interruption, dose reduction, symptomatic treatment and patient education is critical to help patients remain on treatment over the long term. Pirfenidone, nintedanib and antiacid therapy are recommended (conditional recommendation) for the treatment of IPF in the 2015 update of international clinical practice guidelines.

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    Wim A. Wuyts, Unit for Interstitial Lung Diseases, Dept of Pulmonary Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail:

    Emerging information on the pathogenesis of IPF has led to the first specific treatments for this disease. These agents only have an effect on FVC decline, although pirfenidone also has a positive effect on survival. None of these agents seems to significantly alter symptoms that are crucial for patients, such as dyspnoea and cough. Dyspnoea seems to be directly related to disease progression but is also determined by comorbidities such as cardiac disease and PH. Treatment of dyspnoea includes lung transplantation and symptom-based therapies such as supplemental oxygen, pulmonary rehabilitation, the use of opioids and treatment of comorbidities such as PH. Cough is also a cardinal feature of IPF. There are some animal data on the use of pirfenidone, but convincing treatment evidence for both pirfenidone and nintedanib is lacking. Thalidomide and codeine have shown promising effects, but it is obvious that new tools and an innovative trial design will be crucial to detect the activity of new agents on the critical determinants of QoL in patients with IPF.

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    Klaus Kenn, Dept of Respiratory Medicine and Pulmonary Rehabilitation, Schoen Klinik Berchtesgadener Land, Malterhoeh 1, 83471 Schoenau am Koenigssee, Germany. E-mail:

    Only a limited number of pharmacological treatments are available for IPF patients. However, a variety of nonpharmacological options are beneficial in such patients. Pulmonary rehabilitation is one of the most effective nonpharmacological interventions used to increase exercise capacity, reduce dyspnoea, and improve QoL. Furthermore, long-term oxygen therapy and, in some patients, even nocturnal noninvasive ventilation may be supportive in reducing the burden of disease. Lung transplantation (LTx) can be the most effective treatment in highly selected patients with IPF. However, early consideration for LTx and close monitoring of disease progression are mandatory because of the highly variable nature of the disease.

    Although IPF patients report symptoms of psychosocial stress, including anxiety and depression, palliative care is delayed or even neglected because of various reasons, such as discomfort with discussing end of life fears.

    Thus, all nonpharmacological options should be implemented as early as possible when treating IPF patients.

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    Although the needs of IPF patients vary, some are cited frequently. Needs are being met differently in various centres but satisfaction, unsurprisingly, is highest at the specialist centres. Communication and information is an overarching theme. This ensures that informed decisions are made interactively, such that the patient feels they have participated fully.

    The important specific needs include the following. 1) Reducing under, or inconclusive, diagnosis, and speeding up the diagnostic process. 2) Better prognostic information. 3) Clearer articulation of the severity of the patient's IPF and its interaction with various aspects of their QoL. 4) Integrated care, ideally with one, easily accessible, point of contact, managing all aspects of the patient journey. 5) Quick approval of effective new drugs. 6) The opportunity to participate in clinical trials. 7) Understanding the criteria for lung transplantation, their personal chances of receiving a transplant, and confidence that access is determined fairly.

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    Luca Richeldi, National Institute for Health Research Southampton Respiratory Biomedical Research Unit, Mailpoint 813, E Level, South Academic Block, University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton SO16 6YD, UK. E-mail:

    Recently significant progress has been made in the therapeutic targeting of IPF. This has culminated in the worldwide approval of the first antifibrotic therapies, nintedanib and pirfenidone. Whilst an important first step, patients continue to progress and better therapies are urgently required. However, there is an increasing number of potential obstacles in the design of new trials; at the same time, new potential opportunities are emerging from the advancement of our scientific knowledge. The recent advances in our understanding of genetics, biomarkers and study design are particularly relevant. In this chapter, we discuss future priorities if we are to continue to increase the length and QoL of patients with IPF, and describe some possible approaches to increase the efficiency of future trials.

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    Toby M. Maher, National Heart and Lung Institute, Imperial College, Sir Alexander Fleming Building, Exhibition Road, London, SW7 2AZ, UK. E-mail:

    The recent establishment of two effective therapies for IPF is a remarkable achievement for patients and clinicians alike. However, the unmet medical need for patients with IPF remains substantial, and a number of issues need to be urgently addressed if we are to move IPF research forward. One such priority is the establishment of well-characterised cohorts of patients with standardised, comprehensive and longitudinally collected clinical and biological data. Equally important are the establishment of centralised open-access biorepositories of samples from patients (and appropriate controls), the validation of an IPF-specific patient-reported outcome tool, and the development and validation of biomarkers to facilitate the design and efficiency of future therapeutic trials. Several pharmacological agents with high potential are currently being tested in trials and many more are ready to be evaluated in the near future. However, only through a continued, concerted partnership between all stakeholders will the ultimate goal of curing patients with this terrible disease be achieved.