Elsevier

The Lancet

Volume 378, Issue 9807, 3–9 December 2011, Pages 1949-1961
The Lancet

Seminar
Idiopathic pulmonary fibrosis

https://doi.org/10.1016/S0140-6736(11)60052-4Get rights and content

Summary

Idiopathic pulmonary fibrosis is a devastating, age-related lung disease of unknown cause that has few treatment options. This disease was once thought to be a chronic inflammatory process, but current evidence indicates that the fibrotic response is driven by abnormally activated alveolar epithelial cells (AECs). These cells produce mediators that induce the formation of fibroblast and myofibroblast foci through the proliferation of resident mesenchymal cells, attraction of circulating fibrocytes, and stimulation of the epithelial to mesenchymal transition. The fibroblast and myofibroblast foci secrete excessive amounts of extracellular matrix, mainly collagens, resulting in scarring and destruction of the lung architecture. The mechanisms that link idiopathic pulmonary fibrosis with ageing and aberrant epithelial activation are unknown; evidence suggests that the abnormal recapitulation of developmental pathways and epigenetic changes have a role. In this Seminar, we review recent data on the clinical course, therapeutic options, and underlying mechanisms thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis.

Introduction

Idiopathic pulmonary fibrosis (IPF), the most common form of the idiopathic interstitial pneumonias, is a chronic, progressive, irreversible, and usually lethal lung disease of unknown cause. IPF occurs in middle-aged and elderly adults (median age at diagnosis 66 years, range 55–75 years), is limited to the lungs, and is associated with a histopathological or radiological pattern typical of usual interstitial pneumonia.1, 2, 3

The main histopathological features of usual interstitial pneumonia, best seen at low magnification, is a heterogeneous appearance with areas of subpleural and paraseptal fibrosis and honeycombing (ie, cystic fibrotic airspaces lined by bronchiolar epithelium and often filled by mucin and variable numbers of inflammatory cells) alternating with areas of less affected or normal parenchyma (spatial heterogeneity). Small areas of active fibrosis (fibroblast foci) are present in the background of collagen deposition, and they reflect the temporal heterogeneity of the process and indicate current ongoing disease. Inflammation is usually mild and consists of a patchy lymphoplasmacytic interstitial infiltrate (figure 1). The presence of a usual-interstitial-pneumonia pattern on high-resolution CT is characterised by reticular opacities, often associated with traction bronchiectasis, with little or no ground-glass opacifications (figure 1). Honeycombing, manifested as subpleural, clustered cystic airspaces with well-defined walls (typically 3–10 mm in diameter), is common and is critical for making a definite diagnosis.1, 2, 3

Patients with IPF usually seek medical attention because they suffer chronic and progressive exertional dyspnoea and cough. Bibasilar inspiratory crackles are heard on chest auscultation and frequently finger clubbing is found. The natural history of IPF has been characterised as a steady or slowly progressive lung disorder, and most patients follow this pattern. However, recent findings indicate that IPF is a heterogeneous disease and new clinical phenotypes with distinct patterns of survival are being described. The pathogenic mechanisms are unclear, but a growing body of evidence indicates that the disease is the result of an abnormal behaviour of the alveolar epithelial cells that provoke the migration, proliferation, and activation of mesenchymal cells, with the formation of fibroblast and myofibroblast foci. Activated myofibroblasts secrete exaggerated amounts of extracellular matrix molecules with the subsequent destruction of the lung architecture.

Section snippets

Epidemiology and risk factors

The annual incidence of IPF is rising and is estimated to be between 4·6 and 16·3 per 100 000 people and the prevalence is 13 to 20 cases per 100 000.3, 4, 5, 6 There is a higher predominance of the disease in men (1·5 to 1·7:1) than in women and the frequency increases with age.4 The most important environmental risk factors are cigarette smoking and exposure to metal and wood dust.1, 3 Genetic transmission occurs in about 0·5–3·7% of patients with IPF,5 although this frequency might be higher.

Diagnosis

The diagnosis of IPF often requires a multidisciplinary approach, involving pulmonologists, radiologists, and pathologists experienced in the field of interstitial lung diseases.15 A pattern indicative of usual interstitial pneumonia on high-resolution CT (figure 1) or on lung tissue obtained by surgical lung biopsy (figure 1) is crucial for the final diagnosis.1, 2, 3 The major differential diagnostic consideration is fibrotic nonspecific interstitial pneumonia, and other forms of idiopathic

Clinical phenotypes and prognosis

IPF has a heterogeneous clinical course, and patients have a median survival of 2·5–3·5 years after diagnosis. Clinical phenotypes with distinct patterns of comorbidities and survival are being defined (figure 2). Worse prognosis is associated with old age (>70 years of age), smoking history, low body-mass index, severe physiological impairment, large radiological extent of disease, and pulmonary hypertension.17

From an inflammatory-driven to an epithelial-driven disease

Inflammation has a pivotal role in most interstitial lung diseases and, if chronic, evolves to fibrosis. However, with the redefinition of IPF as a distinct condition characterised by the pattern typical of usual interstitial pneumonia,1, 2 the progressive fibrotic reaction in IPF was associated with an epithelial-dependent fibroblast-activated process (figure 4) and a poor response to anti-inflammatory therapy.41 However, deregulated adaptive immune mechanisms and subsequent inflammation could

Treatment approaches

In clinical trials of novel drugs (etanercept,127 IFNγ,24, 128 bosentan,129 imatinib mesilate130) in patients with IPF who have mild-to-moderate functional impairment, no significant benefit was reported with these interventions. In general, patients with IPF who have moderate-to-severe functional impairment and associated co-morbidities (eg, pulmonary hypertension) have been excluded from trials. Consequently, many patients seen in clinical practice have not been studied. Several clinical

Conclusions

IPF is a devastating lung disease whose incidence and prevalence increases markedly with ageing. The disease course is heterogeneous; however, the median survival is about 3 years after diagnosis. The cause of IPF is unknown, but it appears to be a disorder likely arising from the interplay between environmental and genetic factors. Cigarette smoking is the most consistent environmental risk factor. Gene mutations and polymorphisms have been shown in both sporadic IPF and familial pulmonary

Search strategy and selection criteria

We searched PubMed from January, 1996, to April, 2011, using the search terms “pulmonary fibrosis”, “fibrosing alveolitis”, “usual interstitial pneumonia”, and “nonspecific interstitial pneumonia”. We also searched these terms alongside several subsets of terms as follows: definition and epidemiology; risk factors; natural history and acute exacerbation; staging and prognosis; and pathogenesis, treatment, and biomarkers. We mostly selected publications from the past 5 years although we also

References (143)

  • CJ Lettieri et al.

    prevalence and outcomes of pulmonary arterial hypertension in advanced idiopathic pulmonary fibrosis

    Chest

    (2006)
  • K Hamada et al.

    Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis

    Chest

    (2007)
  • CD Fell et al.

    The impact of pulmonary arterial hypertension on idiopathic pulmonary fibrosis

    Chest

    (2007)
  • D Bouros et al.

    Association of malignancy with diseases causing interstitial pulmonary changes

    Chest

    (2002)
  • H Kawasaki et al.

    p53 gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis

    Human pathology

    (2001)
  • K Oshikawa et al.

    Serum anti-p53 autoantibodies from patients with idiopathic pulmonary fibrosis associated with lung cancer

    Respir Med

    (2000)
  • Y Wang et al.

    Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer

    Am J Hum Genet

    (2009)
  • K Williams et al.

    Identification of spontaneous feline idiopathic pulmonary fibrosis: morphology and ultrastructural evidence for a type II pneumocyte defect

    Chest

    (2004)
  • U Hodgson et al.

    ELMOD2 is a candidate gene for familial idiopathic pulmonary fibrosis

    Am J Hum Genet

    (2006)
  • M Chilosi et al.

    Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis

    Am J Pathol

    (2003)
  • DR Coon et al.

    Differential epithelial expression of SHH and FOXF1 in usual and nonspecific interstitial pneumonia

    Exp Mol Pathol

    (2006)
  • DW Walsh et al.

    Extracellular BMP-antagonist regulation in development and disease: tied up in knots

    Trends Cell Biol

    (2010)
  • K Koli et al.

    Bone morphogenetic protein-4 inhibitor gremlin is overexpressed in idiopathic pulmonary fibrosis

    Am J Pathol

    (2006)
  • K Borensztajn et al.

    Factor Xa: at the crossroads between coagulation and signaling in physiology and disease

    Trends Mol Med

    (2008)
  • GS Bogatkevich et al.

    Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway

    J Biol Chem

    (2001)
  • A Andersson-Sjoland et al.

    Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis

    Int J Biochem Cell Biol

    (2008)
  • JP Thiery et al.

    Epithelial-mesenchymal transitions in development and disease

    Cell

    (2009)
  • BC Willis et al.

    Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis

    Am J Pathol

    (2005)
  • B Hinz et al.

    The myofibroblast: one function, multiple origins

    Am J Pathol

    (2007)
  • JM Englert et al.

    A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis

    Am J Pathol

    (2008)
  • Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS)

    Am J Respir Crit Care Med

    (2000)
  • International multidisciplinary consensus classification of the idiopathic interstitial pneumonias

    Am J Respir Crit Care Med

    (2002)
  • G Raghu et al.

    An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management

    Am J Respir Crit Care Med

    (2011)
  • G Raghu et al.

    Incidence and prevalence of idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2006)
  • U Hodgson et al.

    Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland

    Thorax

    (2002)
  • J Gribbin et al.

    Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK

    Thorax

    (2006)
  • CH van Moorsel et al.

    Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a Dutch cohort

    Am J Respir Crit Care Med

    (2010)
  • V Cottin et al.

    Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome

    Eur Respir J

    (2010)
  • KR Flaherty et al.

    Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis?

    Am J Respir Crit Care Med

    (2004)
  • B Ley et al.

    Clinical course and prediction of survival in idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2011)
  • M Selman et al.

    Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern

    PloS One

    (2007)
  • K Boon et al.

    Molecular phenotypes distinguish patients with relatively stable from progressive idiopathic pulmonary fibrosis (IPF)

    PLoS One

    (2009)
  • HR Collard et al.

    Acute exacerbations of idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2007)
  • H Tomioka et al.

    Acute exacerbation of idiopathic pulmonary fibrosis: role of Chlamydophila pneumoniae infection

    Respirology

    (2007)
  • CIS Silva et al.

    Acute exacerbation of chronic interstitial pneumonia: high-resolution computed tomography and pathologic findings

    J Thorac Imaging

    (2007)
  • JW Song et al.

    Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome

    Eur Respir J

    (2011)
  • SC Wootton et al.

    Viral Infection in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

    Am J Respir Crit Care Med

    (2011)
  • K Konishi et al.

    Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2009)
  • A Moeller et al.

    Circulating fibrocytes are an indicator of poor prognosis in idiopathic pulmonary fibrosis

    Am J Respir Crit Care Med

    (2009)
  • DR Silva et al.

    Idiopathic pulmonary fibrosis and emphysema in smokers

    J Bras Pneumol

    (2008)
  • Cited by (1520)

    View all citing articles on Scopus
    View full text