Idiopathic pulmonary fibrosis

In 1868, Flint described a respiratory condition called “chronic pneumonitis” and noted the bulbous appearance of one patient’s fingertips, later known as finger clubbing.1 This was probably the first recorded case of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a devastating form of interstitial lung disease of unknown cause. With a median survival of three years after diagnosis, it carries a prognosis worse than many cancers.2 At a conservative estimate, there are 5000 new cases each year in the United Kingdom, and at least 14 000 new patients diagnosed annually in the United States.3 4 5 Median age of onset is 70 years and about two thirds of patients are smokers.6 Once thought of as a chronic inflammatory condition, the disease is more likely to be a fibrotic response driven by abnormally activated alveolar epithelial cells.7

This year, the National Institute for Health and Care Excellence (NICE) published documents on the diagnosis and management of this condition and an appraisal of a new antifibrotic drug, pirfenidone, now approved for use in the UK.6 8 These documents supplement recent management guidelines.9 10 11

The NICE guidance highlights low awareness of the disease among healthcare professionals, with the condition often being missed because clinicians do not consider it as a diagnosis.6 General practitioners play a pivotal role, screening large numbers of patients with exertional dyspnoea and cough, most of whom have diseases such as chronic obstructive pulmonary disease or asthma. A GP practice with a catchment population of 10 000 may see only two or three cases of idiopathic pulmonary fibrosis every three years.3 Diagnostic clues include older age (uncommon <45 years) and the key clinical finding of persisting “Velcro”-like crackles, audible over lower lobes and the axillae.12 Finger clubbing is found in only 40% of patients.13 Diagnostic delay is common; referral to secondary care often comes only after unsuccessful trials of diuretics or antibiotics prompt a chest radiograph.14

Ideally, these patients should be promptly referred to a dedicated interstitial lung disease service. The NICE guidelines reinforce the need for a confident diagnosis based on multidisciplinary assessment. High resolution computed tomography imaging has largely replaced the need for surgical lung biopsies (usually thoracoscopic).10 The disease is characterised by a radiological pattern termed usual interstitial pneumonia. Features include subpleural reticular interstitial shadowing with a basal predominance, honeycombing, and often traction bronchiectasis. If clinical doubt remains, or imaging results are atypical, surgical lung biopsies should be considered.10

Importantly, the label “idiopathic” requires active exclusion of known causes of pulmonary fibrosis. Such causes include underlying connective tissues diseases (in which respiratory symptoms can occasionally precede other systemic manifestations), domestic or environmental exposures (such as organic and inorganic dusts), and pro-fibrotic drugs, including nitrofurantoin and amiodarone.14

Idiopathic pulmonary fibrosis has no cure, although much can be done to help these patients, including pulmonary rehabilitation, oxygen therapy, and palliative care as the disease progresses.9 Lung transplantation is recommended in selected patients, but patients are often too frail or old, or they have serious comorbidity.15 The past decade has seen an increase in well designed clinical drug trials, but most drugs tested (interferon γ, bosentan, macitentan, ambrisentan, sildenafil, imatinib, and warfarin) have shown no benefit.16 Cochrane reviews have established that popular treatments—oral corticosteroids and immunosuppressants—are similarly ineffective.17 18

What might work? N-acetyl cysteine, an antioxidant, has shown promise. A phase III study found that it significantly reduces the rate of decline in lung function compared with placebo, although both groups received concurrent treatment with prednisolone and azathioprine.19 However, as with all drug treatments, no effect on mortality has been shown, and the results of a placebo controlled study will be announced in 2014. Another potentially promising drug is nintedanib, a triple kinase inhibitor. One study reported a trend towards a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life.20 Two phase III studies will report next year. There is mounting interest in co-trimoxazole. In a recent UK study, when added to standard treatment in patients with fibrotic interstitial lung disease (about 90% of whom had idiopathic pulmonary fibrosis), co-trimoxazole had no effect on lung function but improved quality of life and reduced mortality in those adhering to treatment.21 A host of other novel drugs are currently being assessed.16

The biggest advance in treatment has been the recent approval by NICE of pirfenidone. This orally administered drug has antifibrotic, anti-inflammatory, and antioxidant properties, although its precise mechanism of action remains elusive.22 A recent Cochrane review found that pirfenidone reduces the risk of disease progression by 30% (hazard ratio 0.70, 95% confidence interval 0.56 to 0.88), although no effect on mortality was found.18 Although side effects, including photosensitivity and nausea, are common, the drug is well tolerated, and these adverse effects have not been associated with high rates of treatment discontinuation in clinical trials. NICE has now approved its use in patients with “mild-moderate” disease (forced vital capacity of 50-80% predicted), with discontinuation advised if vital capacity falls by 10% or more in any 12 month period.8

Pirfenidone has been the subject of much debate,23 24 given its expense. Initially estimated at £26 000 (€30 362; $41 693) a year per patient, a new patient access scheme reduces this cost.8 Although currently available in Europe, pirfenidone awaits approval in the US, where additional clinical trial data are required. The results of a further phase III trial are expected next year.

Nearly 150 years after Flint’s initial observations, we are at last starting to make some progress in our understanding and treatment of this devastating and lethal disease.