Idiopathic Pulmonary Fibrosis

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.

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.

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.

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 D_LCO 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.

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.

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.

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.

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.

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.

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.