Pulmonary Fibrosis

Pulmonary fibrosis describes a group of diseases which produce interstitial lung damage and ultimately fibrosis and loss of the elasticity of the lungs. It is a chronic condition characterised by shortness of breath, diffuse infiltrates on chest X-ray and inflammation and/or fibrosis on biopsy.

Pulmonary fibrosis is present worldwide, and is represented equally in all ethnic groups.

• The estimated incidence of idiopathic pulmonary fibrosis (IPF) is 7-16 cases per 100,000 per year.¹
• The incidence of other forms depends on the degree of exposure to causative agents and therefore varies worldwide.
• The peak age of incidence is 50-70 years and males and females appear to be equally affected.

There are many known causes of pulmonary fibrosis:

• Occupational exposure to substances such as asbestos, metal dust, mould spores and other allergens (farmer's lung, mushroom worker's lung, bagassosis etc.)
• Sarcoidosis
• Drugs e.g. amiodarone, bleomycin, busulphan, nitrofurantoin
• Radiation
• Tuberculosis
• Connective tissue diseases: e.g. scleroderma, systemic lupus erythematosus, rheumatoid arthritis
• Idiopathic pulmonary fibrosis (IPF), fibrosing alveolitis²
• Hermansky Pudlak syndrome (type of albinism)

Risk factors

• Smoking
• Environmental exposures
• Gastroesophageal reflux disease
• Commonly prescribed drugs
• Diabetes mellitus
• Infectious agents
• Genetic factors

The most common presentation of pulmonary fibrosis is with shortness of breath or cough and as these are common symptoms of many forms of chest disease, the diagnosis relies on the recognition of a pattern of symptoms and signs followed by more definitive tests.

Symptoms

• Shortness of breath on exertion
• Unproductive cough
• Low grade fever
• Myalgia

Signs

• Fine bilateral basal crackles ("Velcro rales")
• Clubbing (50%)
• Signs of cor pulmonale, pulmonary hypertension and right heart failure occur late in the disease

Numerous other chest diseases can give rise to some of the symptoms and signs of pulmonary fibrosis and other forms of alveolar inflammation may also give a similar histological pattern. This characteristically shows failure of alveolar re-epithelialisation, persistence of fibroblasts, deposition of extracellular matrix and distortion of lung architecture which ultimately results in respiratory failure.

However the diagnosis of IPF requires the histological changes to be separated in both time and place and therefore a large lung biopsy, or several smaller biopsies are required to be certain of the diagnosis.
Other diseases which may mimic pulmonary fibrosis include:

• Bronchitis
• Asthma
• Heart failure

A detailed history is essential, especially with respect to occupational history to rule out exposure to asbestos, silica and other respirable toxins as a cause for the underlying symptoms.

• FBC may show mild anaemia
• Raised CRP or ESR
• Non-specific increases in rheumatoid factor and antinuclear factor are present in 30%

• Restrictive pattern
• Reduced total lung capacity
• Reduced residual capacity
• Reduced residual volume
• Reduced gas transfer

CXR almost always shows changes, although reports have been made of biopsy positive IPF with normal CXR appearances. Bilateral basal and peripheral infiltrates with "honeycombing" peripherally due to progressive fibrosis.

Detailed CT scan may be used to assess the extent of the disease and follow progress.

Large open lung biopsy or several smaller biopsies will give the definitive diagnosis.

Transbronchial biopsies may be used, but are generally too small to make definitive diagnosis of IPF.

• Allergen avoidance.
• At present for IPF, there is no treatment available which has been shown to improve the condition.
• Pulmonary fibrosis due to other causes has a very variable response to therapy.
• Counselling may be required in view of the poor prognosis.
• Supportive therapy may be helpful in the form of oxygen therapy and physiotherapy if bronchiectasis is present.
• Patients should be encouraged to take regular exercise to maintain their exercise tolerance.
• Patients should be encouraged to be vaccinated against influenza and pneumococcus.
• Lung transplant is the only option which improves long-term survival.^3,4

Drug treatment

• Although many studies have been performed looking at the use of anti-inflammatory agents such as steroids, when used in studies which looked at only patients with a secure diagnosis of IPF there was no meaningful response. It is now thought that earlier studies which looked more promising were merely showing improvements in patients with other forms of inflammatory lung disease.⁵
• Only 20% of patients respond to steroids.

IPF is a highly heterogeneous disease process and it is important to accurately phenotype it because individualised and 'combined' therapies may be required.
Although anti-inflammatory agents e.g. azathioprine are often used to treat IPF, current evidence does not support their routine use, although a trial may be useful if the diagnosis is less than certain.⁶

New strategies emerging include agents that inhibit epithelial injury or enhance repair, anti-cytokine approaches and agents that inhibit fibroblast proliferation or induce fibroblast apoptosis.^7,8 A multicentre, randomised, double-blind, placebo-controlled study of pirfenidone versus placebo was performed in 107 Japanese patients with IPF. Although no difference was noted in mortality or in the lowest oxygen saturation during a 6-min walk test between both groups, it showed a significant difference in the decline of forced vital capacity at 9 months and in the rate of acute exacerbations of IPF in favour of the pirfenidone group.⁹
However, pirfenidone has not yet been approved by the FDA for the treatment of IPF.

Another line of research looks is looking at the underlying molecular mechanism of fibrogenesis and ongoing but unpublished clinical trials aim to block single gene targets, which are believed to be important in disease progression.¹⁰

• Pulmonary fibrosis is a progressive illness, producing increasingly severe symptoms, which generally has a poor prognosis.
• The median survival of biopsy proven IPF is less than three years. Most will die as a result of respiratory failure, but others will develop infections secondary to steroid therapy or right heart failure.
• Poor outcome is associated with:
  • Older age
  • Male gender
  • Severe dyspnoea
  • History of cigarette smoking
  • Severe loss of lung function
  • Appearance and severity of fibrosis on radiological studies
  • Lack of response to therapy
  • Prominent fibroblastic foci on histopathological evaluation¹¹