Idiopathic pulmonary fibrosis: an update.

Annals of Medicine, 2015; Early Online: 1–13 © 2015 Informa UK, Ltd. ISSN 0785-3890 print/ISSN 1365-2060 online DOI: 10.3109/07853890.2014.982165

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Idiopathic pulmonary fibrosis: An update Paolo Spagnolo1, Nicola Sverzellati2, Giulio Rossi3, Alberto Cavazza4, Argyris Tzouvelekis5, Bruno Crestani6,7 & Carlo Vancheri8

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1Medical University Clinic, Canton Hospital Baselland, and University of Basel, Switzerland, 2Section of Diagnostic Imaging, Department of

Surgery, University of Parma, Italy, 3Section of Pathology, University Hospital of Modena, Italy, 4Operative Unit of Pathology, Arcispedale S. Maria Nuova/I.R.C.C.S., Reggio Emilia, Italy, 5Department of Internal Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, CT, USA, 6Assistance Publique-Hôpitaux de Paris, Service de Pneumologie A, Centre de Compétences Maladies Rares Pulmonaires, DHU FIRE, Hôpital Bichat, Paris, France, 7Inserm U1152, LabEx Inflamex, Université Paris Diderot, Paris, France, and 8Department of Clinical and Molecular Biomedicine, University of Catania, Italy

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal form of idiopathic interstitial pneumonia. The disease, which occurs primarily in middle-aged and older adults, is thought to arise following an aberrant reparative response to alveolar epithelial cell injury characterized by secretion of excessive amounts of extracellular matrix components, resulting in scarring of the lung, architectural distortion, and irreversible loss of function. A complex interplay between environmental and host factors is thought to contribute to the development of the disease, although the cause of IPF remains elusive and its pathogenesis incompletely understood. Over the last decade, disease definition and diagnostic criteria have evolved significantly, and this has facilitated the design of a number of high-quality clinical trials evaluating novel therapeutic agents for IPF. This massive effort of the medical and industry community has led to the identification of two compounds (pirfenidone and nintedanib) able to reduce functional decline and disease progression. These promising results notwithstanding, IPF remains a major cause of morbidity and mortality and a largely unmet medical need. A real cure for this devastating disease has yet to emerge and will likely consist of a combination of drugs targeting the plethora of pathways potentially involved in disease pathogenesis. Key words: Diagnosis, idiopathic pulmonary fibrosis, nintedanib, pirfenidone, treatment, usual interstitial pneumonia

Definition Idiopathic pulmonary fibrosis (IPF) is the most common and severe of the idiopathic interstitial pneumonia (IIPs), a group of diffuse parenchymal lung diseases of unknown origin characterized by varying patterns of inflammation and fibrosis, but often sharing similar clinical, radiologic, and physiologic abnormalities (1). Contrary to the other IIPs, IPF is associated with a radiologic and/or histopathologic pattern of usual interstitial pneumonia (UIP) (2). The term UIP is often (and erroneously) used interchangeably with IPF. Yet, a number of clinical conditions

Key messages • Idiopathic pulmonary fibrosis is a chronic, progressive, and usually lethal disease for which there is no cure. • Disease definition and diagnostic criteria have significantly evolved in the last few years, and this has allowed the conduction of a number of high-quality clinical trials evaluating novel potential treatments. • Two compounds (pirfenidone and nintedanib) have been shown to reduce functional decline and disease progression in this devastating disease.

are associated with a UIP pattern, including collagen vascular diseases, chronic hypersensitivity pneumonitis, asbestosis, familial IPF, and Hermansky–Pudlak syndrome (2). Thus, UIP is not synonymous with IPF, and the diagnosis of IPF requires the exclusion of all known causes of pulmonary fibrosis (e.g. IPF is defined by idiopathic UIP). The incidence and prevalence of IPF increase markedly with age. Presentation typically occurs in the sixth and seventh decades, whereas patients with IPF aged less than 50 years are rare (2). The disease is more common in men, and the majority of patients have a history of cigarette smoking (3). Patients with IPF usually present with slowly progressive dyspnoea on exertion and dry cough. The disease is inexorably progressive with a median survival time of 3 to 5 years from the time of diagnosis (4–7), although it is difficult to predict the rate of progression in individual patients (8).

Epidemiology Incidence and prevalence The true incidence and prevalence of IPF are not precisely established, mainly due to the lack of uniform definition and

Correspondence: Paolo Spagnolo, Medical University Clinic, Canton Hospital Baselland, and University of Basel, Rheinstrasse 26, 4410 Liestal, Switzerland. Fax: ⫹ 41 61 925 28 04. E-mail: [email protected] (Received 29 July 2014; accepted 27 October 2014)

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diagnostic criteria in older reports, and differences in study methodology and populations (9). In a population-based registry of interstitial lung diseases from 1988 to 1993 in the county of Bernalillo (New Mexico), the incidence and prevalence of IPF were higher in men than in women (13.2 and 20.2 cases per 100,000/ year versus 7.4 and 10.7 cases per 100,000/year, respectively) and increased dramatically with age (10). More than a decade later, in a study using a large US health care claims database, overall incidence and prevalence were greater (14.0 and 42.7 per 100,000 persons, respectively), suggesting that the burden of disease had increased over time (11). More recent data from US Medicare beneficiaries show that the annual incidence of IPF amongst individuals aged 65 years or older remained stable between 2001 and 2011, with an overall estimate of 93.7 cases per 100,000 person-years, whereas the annual cumulative prevalence increased steadily from 202.2 cases per 100,000 people in 2001 to 494.5 cases per 100,000 people in 2011, substantially higher than previously reported (12).

Mortality of IPF IPF-related mortality is higher in men and increases progressively with age (12,13). Recent mortality data from the US show an increase in IPF-related mortality. Specifically, the age-adjusted mortality rate increased 28.4% in men (from 40.2 deaths per 1,000,000 in 1992 to 61.9 deaths per 1,000,000 in 2003) and 41.3% in women (from 39.0 deaths per 1,000,000 in 1992 to 55.1 deaths per 1,000,000 in 2003) (14). Similar trends have been reported in the UK (15). With a 5-year survival rate that is worse than several types of cancer (e.g. breast, ovarian, and colorectal), IPF represents an important public health problem, particularly in elderly people (4,16,17).

Risk factors Although IPF is a condition of unknown origin, several exposures have been shown to increase the risk of developing the disease.

Cigarette smoking Smoking is strongly associated with IPF (18). In a multicentre case–control study, more cases (72%) than matched controls (63%) had a history of ever smoking (OR 1.6) (19). The risk was higher for smokers with a history of 21–40 pack-years (OR 2.3) but did not increase further for those with a history greater than 40 pack-years.

Environmental exposures An increased risk for IPF has been observed following exposure to several environmental/occupational agents, particularly metal and wood dust (20,21). Farming, raising birds, stone cutting/ polishing, and exposure to livestock and to vegetable/animal dust have also been associated with IPF (22). However, since epidemiologic studies of environmental risk factors are subject to a number of biases and limitations, these associations should be interpreted with caution.

Microbial agents The putative role of infectious agents in the aetiology of IPF has been investigated in several studies. Positive associations include Epstein–Barr virus, cytomegalovirus, hepatitis C virus, human herpes viruses (HHV)-7 and HHV-8, as well as herpesvirus saimiri (23), although these findings have not been consistently replicated (24). More recent data suggest that IPF is characterized by an increased bacterial burden (e.g. specific members

within the Staphylococcus and Streptococcus genera, Haemophilus, Neisseria and Veillonella spp.) in bronchoalveolar lavage (BAL) that also predicts disease progression and death (25,26). In addition, co-trimoxazole (added to standard treatment) has been shown to reduce mortality in patients with fibrotic idiopathic interstitial pneumonia including IPF, an effect possibly related to a reduction of respiratory infections (27). The study of putative associations of microbial agents with IPF is hindered by several confounding factors (e.g. patients receiving immunosuppressive drugs are more prone to infections). Thus, at present firm conclusions about the role of infection in the pathogenesis of IPF cannot be drawn.

Gastroesophageal reflux Emerging data support a role for chronic microaspiration secondary to gastroesophageal reflux (GER) in the pathogenesis of IPF (28). Abnormal GER is present in up to 90% of IPF patients, though clinically silent in a significant minority of them (29). In addition, symptoms of reflux are a poor predictor of acid reflux as measured by esophageal pH monitoring (30). Animal studies suggest that aspiration of acid into the lung can induce a number of pulmonary abnormalities, including parenchymal changes, pneumonitis, increased epithelial permeability and damage, as well as fibrotic proliferation (31). Nevertheless, the precise relationship between chronic microaspiration and IPF remains unknown.

Genetic factors A genetic basis for IPF is suggested by several lines of evidence, the most persuasive being familial clustering of the disease. Familial IPF, which accounts for ⬍ 5% of all cases (2), is clinically and histologically indistinguishable from sporadic IPF, although familial forms tend to present at an earlier age and may display some differences in radiological pattern (32). Transmission is autosomal dominant, with variable and reduced penetrance (33). A number of genetic abnormalities have been associated with IPF. Mutations within surfactant protein C (SFTPC) and A2 (SFTPA2), which are expressed by alveolar epithelial cells (AECs), result in abnormal protein precursors that accumulate in the endoplasmic reticulum (ER) and causes ER stress (34–37). This, in turn, activates the unfolded protein response (UPR), a cascade of events that, although designed to protect the cell, may lead to AEC apoptosis in case of long-standing or severe activation (38,39). Variations within the two major telomerase components hTERT and hTR are observed in approximately 10% of familial and 1%–3% of sporadic IPF cases (40–43). Since telomerase is expressed by stem cells and progenitor cells, telomerase-associated mutations may impact on AEC turn-over and repair after injury, thus predisposing to the initiation of IPF. The recent observation that telomere shortening correlates with worse survival in IPF lends further support to the hypothesis that telomere abnormalities contribute to disease pathogenesis, progression, and outcome (44). MUC5B—a gene expressed in bronchiolar epithelium— encodes one of the major gel-forming proteins as well as exerting pulmonary anti-infectious activities (45). A common variant in the promoter region of MUC5B (rs35705950) has been strongly associated with both familial pulmonary fibrosis and sporadic IPF (46). Interestingly, carriage of the mutant MUC5B allele is also associated with a better prognosis (47). While the functional consequences of this polymorphism, if any, remain to be elucidated, the MUC5B association with IPF suggests that abnormalities in proteins uniquely expressed in the lung may contribute to disease pathogenesis. More recently, two large genome-wide

Idiopathic pulmonary fibrosis association studies in sporadic cases of IPF have confirmed association with MUC5B and have identified multiple novel susceptibility loci, suggesting that defects in innate immune system regulation, host defence, cell–cell adhesion, and DNA repair may represent additional contributors to disease risk (48,49).


Pathogenesis In the last decade, the increasing number of studies investigating the pathogenesis of IPF has significantly improved the comprehension of the mechanisms underlying this disease. The old concept of pulmonary fibrosis being a direct consequence of chronic inflammation has been replaced by the idea of an aberrant wound-healing process involving the interstitial and alveolar spaces of the lung (50). According to the ‘non-inflammatory’ pathogenic hypothesis, unknown environmental and/or occupational factors, cigarette smoking, viral infections, or even tractional injury to the peripheral lung may cause, in susceptible individuals, the fibrotic changes observed in IPF. These result from a repeated and chronic damage of the alveolar epithelium followed by an abnormal repair process characterized by an uncontrolled and disorganized proliferation of myofibroblasts that leads to the gradual distortion of the pulmonary architecture (51). Myofibroblasts mainly derive from the differentiation of resident lung mesenchymal cells (such as resident fibroblasts, or pericytes) although, at least in part, they may also result from epithelial–mesenchymal transition (EMT) (52). In both cases, transforming growth factor-β (TGF-β), the pro-fibrotic cytokine ‘par excellence’, plays a critical role. Under the influence of TGF-β, normal lung fibroblasts differentiate into myofibroblasts whereas AECs progressively lose epithelial markers such as cytokeratin and acquire instead markers specific of mesenchymal cells such as alpha-SMA, vimentin, and type I collagen (53). Another source of myofibroblasts is bone marrowderived cells named fibrocytes. These cells co-express markers of hematopoietic cells and mesenchymal cells. Their pathogenic role in IPF is still debated although a number of recent evidence supports their role in promoting the fibrotic process (54). Under normal circumstances, when damage of the alveolar surface occurs, injured type I AECs are replaced by type II AECs. These cells proliferate to cover the exposed basement membrane and eventually differentiate into type I AECs, thus repairing the alveolar injury. In IPF, the repairing process is instead driven by myofibroblasts that accumulate into the alveolar sites of injury, producing collagen and extracellular matrix (ECM) components. The activation, differentiation, and recruitment of myofibroblasts result from the development in the lung of a microenvironment where the imbalance between anti-fibrotic and pro-fibrotic mediators promotes an excessive and redundant process of wound healing. For instance, the reduced capacity to produce the anti-fibrotic prostaglandin E2 and the parallel increased production of TGF-β described in IPF are considered responsible for the ‘apoptosis paradox’, characterized by the enhanced sensitivity and increased resistance to apoptosis of epithelial cells and fibroblasts, respectively (55). The scientific essence of the ‘non-inflammatory’ hypothesis remains persuasive even though recent evidence has added new elements to the pathogenesis of IPF, making this process particularly complex and multi-faceted. Ageing and genetic and epigenetic changes are only some of the factors that may alter lung homeostasis, leading to the aberrant behaviour of epithelial cells and fibroblasts observed in IPF. Incidence and prevalence of IPF increases with age, and IPF is commonly considered an agerelated condition associated with distinctive features of degenerative disorders such as telomerase dysfunction and shortening and

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cellular senescence (56). While the exact role and to what extent ageing may influence the mechanisms regulating normal tissue repair needs to be further explored, age-related cellular changes may increase the susceptibility of lung tissue to injury, thus facilitating abnormal tissue repair and fibrosis (56). Epigenetic alterations occurring in response to ageing but also to environmental exposures or tobacco smoke have recently been hypothesized in IPF. The hypermethylation of the Thy-1 promoter region causes a reduced expression of the glycoprotein Thy-1 that is normally expressed by fibroblasts (57). In IPF, within the fibroblastic foci, the loss of this molecule is linked to the differentiation of fibroblasts into myofibroblasts. More recently, the altered expression of short non-protein coding RNAs (microRNAs), which regulates the expression of target genes involved in the control of cell activation and proliferation, has been also associated with the pathogenesis of IPF (58). In IPF, microRNAs such as let-7, mir-29, mir-30, and mir-200 are significantly down-regulated, while mir-155 and mir21 are instead up-regulated (59–61). In both cases their changes are linked to groups of genes related to fibrosis and able to affect EMT induction, regulation of apoptosis, and ECM remodelling. Interestingly, some of these microRNAs are capable of increasing the expression of TGF-β, which in turn causes their altered expression, thus creating a sort of ‘vicious circle’ (58).

Clinical features At presentation, virtually all IPF patients report a history of slowly progressive dyspnoea (initially on exertion) and non-productive cough. Dyspnoea is commonly attributed to cardiac disease, ageing, or chronic obstructive pulmonary disease (COPD), thus delaying the diagnosis. In fact, the median duration of symptoms before diagnosis is 24 months (62). Symptoms such as weight loss, fever, and joint pain or swelling are uncommon in IPF, and should suggest an alternative diagnosis (e.g. pulmonary fibrosis associated with connective tissue disease [CTD]). In most patients chest auscultation reveals end-inspiratory fine crackles (‘velcro-like’) most prevalent at the lung bases. Finger clubbing is present in 25%–50% of patients (63). Cyanosis, cor pulmonale (e.g. augmented P2, right-sided lift, and S3 gallop) and peripheral oedema are indicative of advanced disease.

Laboratory findings The laboratory abnormalities that can be observed in patients with IPF are limited and non-specific. In fact, the major utility of laboratory investigations is to rule out known causes of lung fibrosis. A mild elevation of the erythrocyte sedimentation rate, and low-positive antinuclear antibody and rheumatoid factor titres are not uncommon in IPF, whereas high titres of autoantibodies suggest alternative diagnoses, primarily CTD (64). However, many patients with interstitial lung disease (ILD) who are suspected to have a systemic autoimmune disease (based on the presence of circulating autoantibodies, specific histopathologic features, or subtle extrathoracic manifestations) are commonly labelled as idiopathic because they do not meet the diagnostic criteria for a defined CTD (65,66). This represents a clinical dilemma (with inevitable therapeutic and prognostic implications), and there is currently an American Thoracic Society/European Respiratory Society panel of experts working on a new classification scheme for this subset of patients.

Physiologic findings Pulmonary function test (PFT) typically reveals a restrictive physiology (e.g. reduced forced vital capacity [FVC] and total lung capacity [TLC]) reflecting the increased lung stiffness (and

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reduced lung compliance) caused by the accumulation of scar tissue and the subsequent architectural distortion of the lung parenchyma. Diffusing capacity for carbon monoxide (DLCO) is almost invariably reduced due to both a contraction of the pulmonary capillary volume and ventilation and perfusion mismatching. The decline in DLCO may represent the only functional abnormality in early or mild disease. In addition to its diagnostic role, PFT is useful in quantifying disease severity and predicting outcome (67). In this regard, a prognostic staging system for IPF using gender, age, FVC, and DLCO as variables has recently been developed and validated in three large, geographically distinct cohorts of patients (68). Resting arterial oxygen saturation is usually normal, but with exercise widening of the alveolar-arterial oxygen gradient (P(A-a)O2), oxygen desaturation, and hypoxemia are commonly observed.


Diagnostic procedures and criteria Imaging The vast majority of symptomatic patients have abnormal chest radiographs. Chest X-ray shows a reticular pattern of disease, characterized by interstitial opacities and small cystic spaces in a predominantly peripheral distribution and best appreciated in the costophrenic angles and in the lower lung zones (Figure 1) (69). However, though rarely, mild reticular changes can be observed in asymptomatic patients. Subclinical incidental radiographic abnormalities should be further investigated by computed tomography (CT). Occasionally, chest radiograph may reveal IPF-related complications (e.g. pneumomediastinum or pneumothorax). CT is pivotal for the assessment of IPF, but optimal quality images require the use of the high-resolution technique—which produces thin sections (⬍ 2 mm)—with high spatial resolution reconstruction. IPF is frequently diagnosed based on clinical and radiologic features, without the need for a surgical lung biopsy, because of the high diagnostic accuracy of CT in many cases. CT may show the characteristic morphologic features of IPF, namely those of UIP pattern, which consist of a reticular pattern with honeycombing, often associated with traction bronchiectasis

Figure 1. Idiopathic pulmonary fibrosis. The chest radiograph reveals bilateral, peripheral, and basilar predominant abnormalities consisting of reticulonodular infiltrates. Note also the decrease in lung volumes.

(Figure 2). Ground-glass opacities may also be present, but they are not the predominant abnormality and are less extensive than reticulation. All of these abnormalities predominate in the lower lung zones (2). Since most patients with IPF are current or former smokers, a variable amount of emphysema may be seen in the upper lobes. Enlarged mediastinal lymph nodes represent another common finding on CT and may reflect a hyperplastic reaction secondary to a coexisting chronic inflammatory process (70). A confident diagnosis of UIP based on CT data results in a diagnosis of IPF (thus obviating the need for a lung biopsy) in more than 90% of patients (71). However, a confident CT diagnosis of UIP can be made only in about half of the cases, mainly due to the difficulties in recognizing honeycombing, the key CT feature of UIP. As defined by the 2008 Fleischner Society statement, honeycombing represents ‘clustered cystic air spaces, typically of comparable diameters on the order of 3–10 mm but occasionally as large as 2.5 cm’, with a typically subpleural distribution (72). However, a number of mimickers of honeycombing on CT exist. For instance, peripheral traction bronchiectasis or emphysematous areas surrounded by ground-glass and/or reticular opacity may mimic honeycombing, thus making it difficult to distinguish UIP from other disease patterns such as non-specific interstitial pneumonia (NSIP) (73). Yet, a sizeable proportion of biopsy-proven UIP cases do not display honeycombing on CT or may show atypical findings (e.g. extensive ground-glass opacity). Therefore, the most recent guidelines on IPF distinguish three levels of certainty for CT findings: definite UIP, possible UIP, and inconsistent with UIP (Table I) (2). For instance, the presence of calcified pleural plaques in the context of a UIP pattern or profuse areas of decreased attenuation would be in keeping with a diagnosis of asbestosis and chronic hypersensitivity pneumonitis (HP), respectively. Chronic HP and CTD, particularly rheumatoid arthritis, may be associated with a UIP pattern indistinguishable from IPF (74,75). CT may also be used to appreciate the progressive nature of IPF. Reticular opacities tend to increase in extent and may progress to honeycombing over time, whereas honeycomb cysts may increase in size or remain stable (76). Furthermore, CT is helpful in diagnosing acute complications of IPF, including infection, heart failure, and rapid disease progression (also termed ‘acute exacerbation’), although the differential diagnosis may be problematic since they all tend to manifest on CT with extensive and rapidly progressive ground-glass opacities (77).

Figure 2. Idiopathic pulmonary fibrosis. High-resolution CT showing a characteristic combination of peripheral, subpleural, and predominantly bibasilar reticular abnormalities with associated honeycomb change and traction bronchiectasis.

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Table I. High-resolution computed tomography criteria for usual interstitial pneumonia (UIP) pattern (2). UIP pattern (all four features) Subpleural, basal predominance Reticular abnormality Honeycombing with or without traction bronchiectasis Absence of features inconsistent with UIP

Possible UIP pattern (all three features) Subpleural, basal predominance Reticular abnormality Absence of features inconsistent with UIP


Histological findings Open lung biopsy Histopathology is no longer the diagnostic gold standard in IPF, since CT may be diagnostic in around 50% of cases. In other words, the accuracy of CT in typical cases is such that histologic confirmation of the diagnosis is not necessary. Conversely, histology plays a key role when CT findings are not typical, since the differential diagnosis between UIP and NSIP (78), the most common mimicker of UIP, and between idiopathic and secondary UIP has important therapeutic and prognostic implications (79–83). In cases of suspected IPF, histologic evaluation is commonly performed on surgical lung biopsy. Appropriate sites for deep and large biopsies should be selected based on CT appearances (biopsies should be taken from at least two different lobes) in order to prevent sampling errors and misdiagnosis (84,85). IPF is a heterogeneous disease often arising in current or former smokers, therefore features of NSIP or smoking-related changes may coexist with the UIP pattern (86). However, the prognosis depends pretty much on the presence of the UIP pattern, even when it does not represent the major fibrotic component (86,87). Considerable inter-observer variability exists among pathologists evaluating diffuse parenchymal lung disease (DPLD). Indeed, inter-observer agreement is only moderate to good (mean weighted κ coefficient for agreement ⫽ 0.58) even among expert pathologists (88). Significant disagreement in the diagnosis of DPLD also exists between academic and community pathologists (kappa range ⫽ 0.12–0.48), as well as between general and pulmonary pathologists (kappa ⫽ 0.21) (89,90). Histologically, the UIP pattern is defined by: 1) patchy involvement of lung parenchyma (e.g. alternating areas of scarred and normal tissues); 2) architectural distortion with/without honeycombing; and 3) presence of active fibroblastic foci adjacent to areas of dense fibrosis (Table II) (91,93). The UIP pattern is also characterized by subpleural and paraseptal fibrosis irregularly and abruptly juxtaposed to normal lung (‘spatial heterogeneity’ with patchwork pattern) (Figure 3), a finding particularly evident at low magnification. Lung architecture is distorted by scar

Inconsistent with UIP pattern (any of the seven features) Upper or mid-lung predominance Peribronchovascular predominance Extensive ground-glass abnormality (extent ⬎ reticular abnormality) Profuse micronodules (bilateral, predominantly upper lobes) Discrete cysts (multiple, bilateral, away from areas of honeycombing) Diffuse mosaic attenuation/air trapping (bilateral, in three or more lobes) Consolidation in bronchopulmonary segment(s)/lobe(s)

tissue and honeycomb changes, which appear as enlarged airspaces lined by metaplastic bronchiolar-type epithelium and filled by mucus, neutrophils, macrophages, and/or giant cells with intracytoplasmic cholesterol cleft (Figure 4). The fibrotic process is initiated by the fibroblastic foci (Figure 5), which are clusters of actively proliferating fibroblasts/myofibroblasts embedded into a myxoid stroma. The ‘young’ active fibrosis is easily appreciated as small spots of ‘grey-to-blue’ hematoxylinophilic colour in a background of ‘old’ fibrosis, which typically has a ‘pink’ eosinophilic appearance. The concept of temporal heterogeneity refers to the alternation of ‘old’ (fibrotic scars and honeycombing) and ‘young’ (fibroblastic foci) fibrosis. Notably, the recognition of a UIP pattern, a crucial step in the pathologic evaluation of an ILD, is not diagnostic per se as it may be observed in a number of conditions (2). Yet, the first task for the pathologist is to differentiate UIP from non-UIP pattern. Other critical points introduced by the 2011 guidelines on IPF relate to the level of confidence for a diagnosis of UIP. Based on four main histopathologic criteria (1: architecture distortion by scarred fibrosis ⫾ honeycombing; 2: patchwork pattern; 3: fibroblastic foci; 4: lack of features inconsistent with UIP pattern), the 2011 guidelines define four categories/levels of confidence: 1) definitive UIP; 2) probable UIP; 3) possible UIP; and 4) not UIP (Table III). However, these levels of confidence, which essentially indicate how certain the pathologist is about a diagnosis of UIP, are of limited value in clinical practice and should be used with caution outside the setting of clinical trials.

Table II. Distinguishing histologic features in usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) pattern. Patchwork pattern (spatial heterogeneity) Distorted architecture Honeycombing Fibroblastic foci (temporal heterogeneity)

UIP

NSIP

Yes Yes Yes Yes

No No No No (very few)

Figure 3. UIP pattern as seen at low magnification. Subpleural/paraseptal scars disrupting the alveolar architecture alternate with normal lung (‘patchy fibrosis’).

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P. Spagnolo et al. Table III. Histologic criteria for usual interstitial pneumonia (UIP) pattern. Definite UIP

Probable UIP

Possible UIP pattern

Not UIP

1 ⫹ 2⫹ 3 ⫹ 4

1 ⫹ 4 or end-stage honeycombing only

2⫹4

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Modified from Raghu et al. (2). 1 ⫽ architectural fibrotic distortion ⫾ honeycombing; 2 ⫽ patchwork pattern; 3 ⫽ fibroblastic foci; 4 ⫽ lack of features inconsistent with UIP; 5 ⫽ presence of hyaline membranesa/organizing pneumoniaa,b/granulomasb/marked inflammatory infiltrate away from honeycombing/airway-centred changes/ other features favouring an alternative diagnosis. aThese features may be present in acute exacerbation of idiopathic pulmonary fibrosis (IPF). bFew/occasional granulomas or minimal organizing pneumonia may be rarely seen in UIP pattern.


Figure 4. Honeycomb change appearing as enlarged alveolar spaces lined by bronchiolar metaplastic epithelium and filled with mucus and inflammatory cells.

Bronchoscopic techniques Bronchoalveolar lavage According to current guidelines, the main role of BAL in the evaluation of patients with suspected IPF is the exclusion of alternative diagnosis, primarily chronic HP, which is characterized by prominent lymphocytosis (⬎ 30%) (2,94,95). Similarly, the presence in the BAL of asbestos bodies suggests a diagnosis of asbestosis (96). In patients with IPF, BAL is non-specific, being characterized by the presence of macrophages and neutrophils with or without eosinophils (Figure 6).

Transbronchial biopsy Lung specimens obtained through transbronchial biopsies are considered too small to appreciate the spatial (patchy fibrosis) and temporal (abrupt transition from normal lung to fibroblastic foci and established fibrosis) heterogeneity that defines the UIP pattern (84,85). However, in our experience and according to published data, occasionally a transbronchial biopsy can be virtually diagnostic of UIP (Figure 7). In the only study comparing transbronchial biopsies with surgical lung biopsies in a series of patients with different ILDs (97), the combination of at least two findings (patchy fibrosis, fibroblastic foci and honeycombing) on transbronchial biopsy had a specificity and a sensitivity for the

Figure 5. A fibroblastic focus consisting of a dome-shaped collection of actively proliferating fibroblasts/myofibroblasts embedded in a myxoid, pale matrix and covered by hyperplastic pneumocytes.

presence of UIP in the subsequent surgical biopsy of 100% and 20%, respectively. Similarly low sensitivity has been observed in two other studies evaluating transbronchial biopsies in patients with known UIP (32% and 0%, respectively) (98,99). Interestingly, in the study by Tomassetti et al. (97) the presence of even one feature (patchy fibrosis or fibroblastic foci or honeycombing) on transbronchial biopsy had a specificity for UIP in the subsequent surgical lung biopsy of 85%. Conversely, transbronchial biopsy has very limited power to exclude UIP (97).

Cryobiopsy Transbronchial cryotherapy probes (cryobiopsy) represent a promising diagnostic tool in patients with ILD (100). The rationale behind its use in the diagnostic work-up of patients with suspected IPF is that cryobiopsy, as compared with transbronchial biopsy with forceps, provides larger and higher-quality specimens owing to the lack of crush artefacts due to forceps. In a recent prospective study on cryobiopsies obtained from 69 patients with fibrotic ILDs (101), two experienced pulmonary pathologists were able to define a specific pattern (including UIP) in the majority of cases with a high level of confidence and inter-observer agreement (kappa 0.83). Cryobiopsy represents a potential alternative to surgical lung biopsy in patients with fibrotic ILD, but its specificity and specificity need to be validated in larger populations of patients.

Natural history and clinical course The rate of functional decline and disease progression in IPF is highly heterogeneous and unpredictable. Data from the placebo

Figure 6. Bronchoalveolar lavage (BAL) fluid in a patient with idiopathic pulmonary fibrosis (IPF) showing macrophages, neutrophils, and eosinophils.

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cyclophosphamide, and broad-spectrum antibiotics are commonly used, but the results are disappointing (108).

Co-morbidities and complications A number of common conditions frequently accompany (or complicate) IPF and contribute to its poor prognosis and impaired quality of life. In addition, the presence of co-morbidities impacts on both the eligibility of IPF patients for lung transplantation and their survival while on the waiting list (109).

Pulmonary hypertension


Figure 7. Transbronchial biopsy showing UIP pattern (patchy fibrosis, fibroblastic foci, and honeycombing).

arms of large clinical trials show that the mean annual rate of decline in FVC ranges from 0.13 to 0.21 litres (102). Five-year survival is only 20%–30% with most deaths occurring from progression of lung fibrosis, although ischemic heart disease, heart failure, bronchogenic carcinoma, infection, and pulmonary embolism are also important causes of mortality in IPF (8). Several clinical phenotypes of IPF have been described. The classic clinical course of IPF is one of slowly progressive disease, with patients reporting a history of worsening dyspnoea and/or dry cough lasting for months to years. A subgroup of patients, mainly male heavy smokers, experience a rapidly progressive disease course (referred to as accelerated IPF) characterized by shortened survival (103). Notably, accelerated IPF differs from the typical slowly progressive form in terms of outcome and gene expression profile, despite having similar lung function, chest imaging, and histological findings at the time of the diagnosis. Patients with IPF may also suffer sudden deterioration of their condition during a relatively stable disease course (acute exacerbation). It remains uncertain whether acute exacerbations of IPF (AE-IPF) represent an acceleration of the underlying fibroproliferative lung process or the sequelae of clinically unrecognized triggers (e.g. infection or occult microaspiration). The diagnostic criteria for AE-IPF have recently been defined by an international working group combining the efforts of the Idiopathic Pulmonary Fibrosis Clinical Research Network (IPFnet) and experienced individual pulmonologists and include previous or concurrent diagnosis of IPF; worsening or development of dyspnoea within 30 days; new bilateral ground-glass opacities and/or consolidation superimposed on a UIP pattern on CT; and absence of infection, heart failure, pulmonary embolism, or other identifiable causes (104). Studies evaluating the clinical significance of AE-IPF have provided discordant incidence rates, likely due to differences in study design, patient populations, and definition of AE. Indeed, while in a large retrospective study the 1-year and 3-year incidences of AE-IPF were as high as 14.2% and 20.7%, respectively, (105), data from the placebo arms of most large clinical trials suggest that AE-IPF are infrequent events in patients with mild-to-moderate disease (106). Importantly, the risk of an exacerbation does not appear to be linked to the level of lung function impairment, age, or smoking history (107). The significance of AE-IPF rests on its poor prognosis, with mortality exceeding 60% during hospital stay and 90% within 6 months after discharge (104,105). Treatment is supportive. High-dose corticosteroids, with or without immunosuppressants such as

Pulmonary hypertension (PH) is defined as an increase in mean pulmonary artery pressure of 25 mmHg or more at rest, with normal pulmonary capillary wedge pressure as assessed by right heart catheterization (110). Pulmonary hypertension is more common among patients with advanced disease and is present in about 20% to 40% of IPF patients who are evaluated for or are awaiting lung transplantation (111). In patients with IPF, PH is associated with lower DLCO, reduced exercise capacity, desaturation during exercise, and worse survival (112). Pulmonary hypertension has also been associated with the development of acute exacerbation of IPF and, in turn, with poor prognosis (113). The best method to detect PH in patients with IPF remains unsettled. In fact, while a reduced DLCO, supplemental oxygen requirement, or poor 6-minute exercise performance raise suspicion of PH, their absence does not rule out PH (111). Similarly, echocardiography is inaccurate in estimating pulmonary hemodynamics in patients with fibrotic lung disease and should not be relied upon to assess the presence and severity of PH (114,115). Right heart catheterization represents the diagnostic gold standard for PH, but the implementation of such an invasive procedure is difficult to justify in the absence of data demonstrating the benefit of treating IPF-associated PH (2,64,116). Patients with IPF appear to have an increased risk of developing lung cancer. The exact prevalence is unknown but is likely to range between 5% and 17% (117,118). Most of the patients are men with a history of cigarette smoking (119).The mechanisms underlying this association remain unclear, but three pathogenetic hypotheses have been proposed: IPF contributing to the development of lung cancer, lung cancer playing a role in the development of IPF, and common mediators causing both lung cancer and IPF (120). Management of lung cancer in patients with IPF is problematic. In fact, while IPF is not a contraindication for lung cancer treatment, AE-IPF/acute lung injury has been reported following tumour resection, radiation therapy, radiofrequency ablation, and chemotherapy (109).

Emphysema The coexistence of IPF and emphysema is well established, and the term combined pulmonary fibrosis and emphysema (CPFE) syndrome has been coined to describe this association (121). Patients with CPFE, primarily male heavy smokers, have characteristic radiographic features (e.g. upper lobe predominant centrilobular or paraseptal emphysema and lower lobe predominant fibrosis), whereas lung function tests reveal relatively preserved lung volumes but markedly impaired diffusion capacity (122). The incidence of CPFE remains unknown, but this subgroup may comprise up to 35% of patients with IPF (123,124). There are conflicting data on survival in CPFE versus IPF with some reports demonstrating worse course—with PH being the main determinant of mortality—and others that show longer survival (121,122,124).

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Whether CPFE represents a distinct clinical phenotype or a coincidence of two pulmonary diseases related to cigarette smoking is as yet unclear.


Coronary artery disease and venous thromboembolic disease Several epidemiological studies have found an increased risk of both venous thromboembolic disease (VTE) and coronary artery disease (CAD) among patients with IPF. A cross-sectional study of 630 patients referred for lung transplantation showed that patients with IPF have an increased risk of CAD compared with patients with other chronic lung diseases (125). In addition, a case–control study revealed that, compared with controls, IPF patients are more likely to have a history of cardiovascular disease before their diagnosis of IPF and are more likely to have an acute coronary event during follow-up (126). In the same study, patients with IPF were also shown to have increased risk of angina, atrial fibrillation, deep venous thrombosis, and stroke. On the other hand, data analysis from a large Danish patient registry demonstrated that individuals with a history of VTE have a significantly increased risk of developing idiopathic interstitial pneumonia, including IPF (127).

Pharmacological treatment The management of patients with IPF is largely based on the recommendations of current evidence-based guidelines (2). These recommendations are based on the quality of available evidence as assessed by the American Thoracic Society GRADE methodology (128). According to current guidelines, no treatment is recommended for patients with IPF (e.g. no treatment received a ‘strong yes’ recommendation). Conversely, the guideline document makes strong recommendations against the use of most therapies due to either lack of sufficient-quality data or clear evidence of inefficacy. Some pharmacological agents (combination of N-acetylcysteine [NAC]/prednisone/azathioprine; NAC monotherapy; warfarin; and pirfenidone) received a weak recommendation against their use (e.g. the majority of patients would not want the intervention, but it could represent a reasonable therapeutic choice in a minority of them). However, because at present there is no standard of care for IPF, a weak negative recommendation could be interpreted as actually endorsing the use of that particular treatment, even if only in a minority of patients. Nevertheless, since the publication of the guidelines in 2011, more robust and better-quality data have become available, and some ‘weak no’ recommendations are likely to change in the near future. In fact, combination of NAC/prednisone/azathioprine (129) and warfarin (130) has been recently shown to be harmful in patients with IPF, whereas NAC monotherapy appears to be ineffective in preserving lung function (131).

Pirfenidone Pirfenidone, a compound with anti-fibrotic, anti-inflammatory, and antioxidant properties, (132), is currently the only drug approved for clinical use in IPF, at least in Japan, Europe, Canada, and India (133). The first phase III randomized controlled trial (RCT) of pirfenidone in IPF, which was conducted in Japan, showed that pirfenidone 1800 mg/day slowed the decline of vital capacity (VC) compared to both low-dose pirfenidone (1200 mg/ day) and placebo (134). The CAPACITY (Clinical Studies Assessing Pirfenidone in Idiopathic Pulmonary Fibrosis: Research of Efficacy and Safety Outcomes) programme consisted of two almost identical trials (PIPF-004 and PIPF-006) (135). However, while study 004 met its primary end-point (e.g. pirfenidone 2403 mg/ day reduced the decline in FVC compared to both pirfenidone

1197 mg/day and placebo), study 006 did not. These studies had sufficient methodological quality to be included in a Cochrane systematic review and meta-analysis which showed that pirfenidone significantly reduces both the rate of decline in lung function and the risk of disease progression in patients with IPF (136). The ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis) study has recently confirmed the beneficial effect of pirfenidone on disease progression in patients with IPF (137). In fact, pirfenidone treatment as compared with placebo significantly reduced the proportion of patients who had a decline of 10% or more in the percentage of the predicted FVC or who died (16.5% versus 31.8%, respectively; P ⬍ 0.001), and significantly increased the proportion of patients with no decline in FVC (22.7% versus 9.7%, respectively; P ⬍ 0.001). In addition, in a pre-specified pooled analysis incorporating results from two previous phase III studies (004 and 006 studies), pirfenidone as compared with placebo reduced both all-cause mortality and IPF-related mortality at 1 year by 48% and 68%, respectively.

Nintedanib Nintedanib is an oxindole derivative that suppresses signalling by platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptors (VEGFR) 1 and 2, and fibroblast growth factor receptors (FGFR) 1, 2, and 3 (138). Originally developed as an angiostatic factor for cancer treatment, nintedanib also exerts anti-fibrotic activities both in vitro in human lung fibroblasts and in vivo in bleomycin-induced pulmonary fibrosis in rodents (139,140). Following a phase II study—the TOMORROW (To Improve Pulmonary Fibrosis With BIBF 1120)—which showed that nintedanib 150 mg twice daily reduces the decline in FVC by 68.4% as compared to placebo (–0.06 litres versus 0.19 litres) (141), two parallel, placebo-controlled phase III trials (INPULSIS-1 and INPULSIS-2) were designed to evaluate further the efficacy and safety of nintedanib (at the dose of 150 mg twice daily) in patients with IPF. Both studies confirmed that nintedanib treatment significantly reduces the decline in FVC over the 52-week study period (the primary end-point) (142). In addition, a nonsignificant decrease in death from any cause was observed in the nintedanib-treated group (5.5%) compared to the placebo group (7.8%, P ⫽ 0.14). The effect of nintedanib on the exacerbation rate was inconsistent, as in INPULSIS-1 there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio 1.15, P ⫽ 0.67), whereas in INPULSIS-2 there was a significant increase in the time to the first acute exacerbation favouring nintedanib (hazard ratio 0.38, P ⫽ 0.005). Furthermore, a pre-specified sensitivity analysis of pooled data on the time to the first adjudicated acute exacerbation (confirmed or suspected) showed that nintedanib had a significant benefit as compared with placebo. The observation that both pirfenidone and nintedanib are pleiotropic in their action suggests that a plethora of mediators and signalling pathways are likely to be involved in the pathogenesis of IPF and that truly effective therapies will need to target pro-fibrotic signalling pathways at multiple levels.

N-acetylcysteine N-acetylcysteine (NAC) is a precursor of the endogenous antioxidant glutathione. Based on the assumption that an oxidant–antioxidant imbalance plays a role in the pathogenesis of IPF (143), the IFIGENIA trial (Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine) evaluated the efficacy over one year of high-dose NAC (600 mg three times


Idiopathic pulmonary fibrosis daily) added to prednisone and azathioprine (triple therapy) in patients with IPF (144). As compared with standard therapy (the ‘placebo’ arm), triple therapy (NAC/prednisone/azathioprine) significantly slowed the decline of both VC and DLCO (the primary end-points). However, this study had important limitations, mainly related to the lack of a true placebo arm (e.g. patients not taking any potentially effective drug), the use of the last observation carried forward (LOCF) method of analysis, which may overestimate treatment effect, and the high rate of patients who did not complete the treatment period (about 30%). The IPFnetsponsored PANTHER study (Prednisone, Azathioprine, and N-acetylcysteine: A Study That Evaluates Response in IPF) was specifically designed to address some of the issues raised by the IFIGENIA trial (129). Patients were randomized in a 1:1:1 ratio to NAC/prednisone/azathioprine (triple therapy), NAC alone, or placebo. Unexpectedly, a pre-specified efficacy and safety interim analysis revealed that triple therapy, as compared with placebo, was associated with a statistically significant increase in all-cause mortality, all-cause hospitalizations, and treatmentrelated severe adverse events. As such, the triple therapy arm was terminated early. The PANTHER study, which continued as a two-group study (e.g. NAC versus placebo), showed that NAC is not superior to placebo in reducing the rate of decline in FVC (–0.18 litres versus –0.19 litres, respectively; P ⫽ 0.77) (131).

Treatment of concomitant conditions There is increasing awareness of complications and co-morbidities associated with IPF. However, it is unknown whether they are related to the underlying pathobiology of IPF or whether they simply reflect concurrent diseases of ageing. Similarly, it is unclear whether IPF patients should be screened for these conditions and whether treatment of co-morbidities affects disease outcome. At present there are no solid, prospective data on which to make definitive recommendations for treatment of concomitant conditions in patients with IPF.

Anti-gastroesophageal reflux drugs Abnormal acid gastroesophageal reflux (GER) is common in patients with IPF and is considered a risk factor for the development of the disease (28,145). Retrospective studies have shown longer survival in patients given anti-acid treatment (146). A more recent study analysed change in FVC in patients assigned to placebo arms in three large randomized-controlled trials. After adjustment for gender, and baseline FVC and DLCO, patients taking anti-acid treatment at baseline (proton-pump inhibitors or H2 blockers) had a smaller decrease in FVC at 30 weeks compared to those not taking anti-acid treatment (P ⫽ 0.05) (147). Current guidelines recommend treatment of GER in patients with IPF (‘weak yes’ recommendation, very low-quality evidence). However, to date no randomized controlled trial has evaluated the effect of GER medications on morbidity and mortality in IPF.

Non-pharmacological treatment Lung transplantation Current guidelines advocate lung transplantation (LTx) as the most effective treatment for patients with IPF (2). In a series of 46 IPF patients the risk of death following LTx was reduced by 75% (148). Five-year survival rates range from 50% to 56%, while 10-year survival rates drop to 30% (2). Whether single or double LTx represents the most beneficial approach remains a matter

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of controversy. Bilateral LTx is associated with longer survival (but increased short-term mortality), whereas cancer is a more common cause of death among patients undergoing unilateral transplantation (149). However, patients put on a waiting list for bilateral LTx have to wait longer, and this may outweigh any survival benefit (150). The introduction of the lung allocation score (LAS), which prioritizes transplant candidates based on survival probability, has led to a significant reduction of mortality on the waiting list (151). However, preoperative and postoperative mortality rates remain unacceptably high, thus necessitating further refinement of LAS by incorporation of prognostic markers. It has been proposed that symptomatic patients younger than 65 years should be referred for LTx in the presence of a DLCO ⬍ 39% predicted and/or a FVC decline ⬎ 10% over 6 months (152), but there are no clear data to guide the precise timing of LTx.

Pulmonary rehabilitation Pulmonary rehabilitation (PR) has been proven effective in alleviating symptoms and improving exercise tolerance, functional capacity, and dyspnoea scores in patients with IPF (153–155). In addition, PR may improve symptoms such as anxiety and depression (156). Furthermore, PR has been associated with a significant improvement in 6-minute walk test and quality of life in patients with IPF (157,158). It was originally indicated for patients with end-stage disease and limited daily activities. However, more recent data support early referral. Benefits of PR expand also to preoperative and postoperative LTx procedures (156). Successful PR may include behavioural changes, such as weight loss, pacing and energy conservation strategies, as well as adoption of specific breathing and exercise patterns (156). Patients with IPF appear to benefit from home-based pulmonary rehabilitation (159).

Palliative care In advanced disease, dyspnoea may severely affect physical activity and quality of life. In a small case series, Allen and colleagues reported that low-dose diamorphine reduces dyspnoea, anxiety, and cough, without significant decrease in oxygen saturation (160). With disease progression patients may experience fear, anxiety, and depression; psychological counselling and, in selected cases, pharmacological treatment should therefore be considered. In a recent cross-sectional study of outpatients with ILD, including IPF, Ryerson and colleagues reported that depression score, functional status (as assessed by 4-minute walk time), and pulmonary function all contribute to the severity of dyspnoea (161). Notably, this study showed that the relationship between dyspnoea and depression is independent of other clinical variables, suggesting that treating depression may actually improve also dyspnoea.

Cough Cough is a troublesome symptom, which adversely affects quality of life in patients with IPF (162). A recent controlled trial showed that anti-acid treatment did not help control cough in IPF patients despite the prevalence of GER in this population (163). Treatment of cough in IPF remains problematic, particularly in the later stages of the condition in which conventional antitussive agents such as opiate-derived preparations are often of limited benefit. One small, uncontrolled, open-labelled study found that cough sensitivity to capsaicin and cough symptom score was reduced after one month of high-dose oral corticosteroids, although cough recurred after reducing steroid dosage (164). A recent double-blind trial comparing thalidomide with placebo demonstrated a beneficial effect of thalidomide on cough and quality of life (165). However, thalidomide has many

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side effects, including constipation, bradycardia, dizziness, and peripheral neuropathy, which limit its long-term use in IPF patients.


Conclusions IPF is a progressive and almost invariably deadly disease. Over the last decade, our understanding of the mechanisms involved in disease pathobiology has substantially improved, and a number of high-quality clinical trials have been performed and completed. This massive effort of the medical and industry community has produced the approval (at least in Japan, India, Europe, and Canada) of the first drug for IPF, pirfenidone. More recently, nintedanib has also been proven to be effective in reducing functional decline and disease progression, meaning that we may finally have choices for the pharmacological treatment of IPF. Idiopathic pulmonary fibrosis remains a major cause of morbidity and mortality and a largely unmet medical need. Nevertheless, there is genuine optimism that the concerted effort by the scientific, professional, and patient community as well as the pharmaceutical industry will lead soon to the development of a real cure for this devastating disease. Declaration of interest: Paolo Spagnolo serves as consultant for InterMune Inc. and has received consulting fees from Boehringer Ingelheim; Nicola Sverzellati has received speaker fees from InterMune Inc.; Argyris Tzouvelekis has no conflicts of interest to disclose; Giulio Rossi has no conflicts of interest to disclose; Alberto Cavazza has no conflicts of interest to disclose; Bruno Crestani has received consulting fees from Boehringer Ingelheim, InterMune Inc., and Sanofi, and research grants from Boehringer Ingelheim, InterMune Inc., and Roche; Carlo Vancheri has received research grant and consulting and speaker fees from InterMune Inc., Boehringer Ingelheim, Novartis, Astra-Zeneca, Menarini, and Chiesi.

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