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 CXR and inflammation and/or fibrosis on biopsy. Pulmonary fibrosis may be secondary to a wide range of diseases or may be idiopathic with no known underlying cause. There are three types of lung fibrosis:¹

• Replacement fibrosis secondary to lung damage - e.g. infarction, tuberculosis and pneumonia.
• Focal fibrosis in response to irritants - e.g. coal dust and silica.
• Diffuse parenchymal lung disease (DPLD), which occurs in fibrosing alveolitis (idiopathic pulmonary fibrosis (IPF)) and extrinsic allergic alveolitis.

Although the prognosis for patients with IPF is generally poor, some patients may remain stable for a number of years and careful monitoring is important to provide optimal care and support.

Epidemiology

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.²
• The incidence of other forms depends on the degree of exposure to causative agents and therefore varies worldwide.
• Many causes of pulmonary fibrosis develop over many years and are therefore often seen in older adults. The peak age of incidence is 50-70 years and males and females appear to be equally affected.
• However, some forms of interstitial lung disease - e.g. sarcoidosis, connective tissue diseases and inherited forms of lung disease - usually present in younger adults.¹

Risk factors

• Some forms of pulmonary fibrosis are caused by drugs and environmental causes, including occupational.
• Some forms of diffuse pulmonary fibrosis are mainly seen in current smokers or ex-smokers.¹
• Gastroesophageal reflux disease.
• Diabetes mellitus.
• Infectious agents.
• Genetic factors.

Aetiology¹

Idiopathic pulmonary fibrosis (IPF) is the most common cause of interstitial lung disease.³ There are many known causes of pulmonary fibrosis:

• Replacement fibrosis secondary to lung damage, e.g. infarction, tuberculosis and pneumonia.
• Pneumoconioses - e.g. silicosis, asbestosis, berylliosis, coal worker's pneumoconiosis.
• Extrinsic allergic alveolitis - e.g. farmer's lung, bird fancier's lung, mushroom worker's lung, cheese worker's lung, etc.
• Exposure to toxic gases, fumes, aerosols, and vapours, e.g. silo filler's disease (lung exposure to oxides of nitrogen).
• Granulomatous diseases, e.g. sarcoidosis.
• Exposure to drugs - e.g. amiodarone, bleomycin, busulfan, nitrofurantoin, methotrexate, gold, penicillamine, and also illicit drugs - e.g. crack cocaine, heroin.
• Radiation exposure.
• Connective tissue diseases - e.g. scleroderma, systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease.
• Other systemic illnesses, including hepatitis C, inflammatory bowel disease, acquired immunodeficiency syndrome.
• IPF.⁴
• Inherited causes - e.g. familial IPF, tuberous sclerosis, neurofibromatosis, Niemann-Pick disease, Gaucher's disease, Hermansky-Pudlak syndrome (a type of albinism).

Presentation

• The presentation is variable and related to the underlying disease process.
• The presentation may be:¹
  • Acute, with a fulminant, progressive, remitting, or resolving course.
  • Subacute, with a resolving, remitting, relapsing, or progressive course.
  • Chronic, insidious, and slowly progressive.
• Most patients with idiopathic pulmonary fibrosis (IPF) present with a gradual onset of dyspnoea and/or a nonproductive cough.⁵
• Diagnosis may be made by the incidental findings on CXR, spirometry, or as a result of screening for high-risk occupational exposure, such as asbestos.
• The main symptoms include dyspnoea, chronic cough, wheezing, haemoptysis and chest pain.
• Examination findings may include central cyanosis, fine end-inspiratory pulmonary rales (Velcro rales).
• Nonspecific features may include low-grade fever and myalgia.
• Finger clubbing is common with some causes of pulmonary fibrosis, especially with advanced disease - e.g. idiopathic pulmonary disease and asbestosis.¹
• Signs of cor pulmonale, pulmonary hypertension and right heart failure occur late in the disease.

Differential diagnosis

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. Other diseases which may mimic pulmonary fibrosis include:

• Chronic obstructive pulmonary disease.
• Asthma.
• Bronchiectasis.
• Congestive heart failure.
• Atypical pneumonia (including Pneumocystis jirovecii).
• Lung cancer.

Investigations

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.
• Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) may be raised.
• Autoantibodies including antinuclear antibodies, rheumatoid factor.
• Arterial blood gases: oxygen desaturation is common.
• Lung function tests may be used to aid diagnosis and to follow disease progress. They show:
  • Restrictive pattern (but obstruction of airways may also be present).
  • Reduced total lung capacity.
  • Reduced residual capacity.
  • Reduced residual volume.
  • Reduced gas transfer.
• CXR:
  • This may show no abnormality.
  • Reticular and/or nodular opacities.
  • Honeycombing is a late finding and correlates with severe disease.
• High-resolution chest CT scanning is more sensitive than chest radiography and may reveal characteristic findings. It may be used to assess the extent of the disease and to follow progress.
• Bronchoalveolar lavage has been used as a research tool in idiopathic pulmonary fibrosis (IPF) but the role in clinical diagnosis is limited. There is often an increased number of neutrophils in the bronchoalveolar lavage fluid, and also an increased number of eosinophils may be present.⁵
• Patients may require open or thoracoscopic lung biopsy to establish a definitive diagnosis. Video-assisted thoracoscopic lung biopsy is the preferred method. The role of lung biopsy when there are high-resolution CT scan findings characteristic of specific diseases remains controversial.¹

Management

Treatment of the underlying cause when applicable.

General supportive measures¹

• Smoking cessation.
• Avoidance of any other environmental (including occupational) causes.
• Stopping any medication thought to be causing or contributing to pulmonary fibrosis.
• Treating any respiratory tract infections promptly.
• Patients should be encouraged to receive influenza vaccination and pneumococcal vaccine.⁵
• Good pulmonary hygiene is important; may require advice and treatment from a physiotherapist to help clear secretions from the lungs.
• Oxygen therapy may be useful for any patients who demonstrate significant hypoxaemia.
• Encourage exercise. Pulmonary rehabilitation may improve exercise tolerance and quality of life.

Drug treatment

• Corticosteroids and/or cytotoxic drugs (e.g. cyclophosphamide, azathioprine, methotrexate) may be indicated for specific diagnoses.
• Other immunosuppressive or antifibrotic agents, such as colchicine, ciclosporin, and D-penicillamine, may have a role in specific cases.
• 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 idiopathic pulmonary fibrosis (IPF), there is currently no drug proven to have significant benefit.⁶
• Although anti-inflammatory agents, e.g. azathioprine, have no proven benefit in the treatment of IPF, a trial may be useful if the diagnosis is less than certain.⁷
• Interferon-gamma-1b, pirfenidone, and N-acetylcysteine have been studied for the treatment of IPF. Interferon-gamma-1b initially appeared to have a favourable effect but this was not supported in a larger follow-up study. Some evidence suggests that pirfenidone may have some benefit in IPF.^1,8,9

Future drug treatments

• 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.^10,11
• Another line of research 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.¹²

Lung transplantation¹

• Lung transplantation is a treatment option for selected patients with advanced disease refractory to medical therapy. Lung transplant improves long-term survival.^13,14
• Survival rates worldwide after single lung transplantation are approximately 74% at 1 year, 58% at 3 years, 47% at 5 years, and 24% at 10 years.

Complications¹

• Progressive respiratory failure.
• Pulmonary hypertension, cor pulmonale.
• Pulmonary embolism.
• Pneumothorax.
• Pneumonia.
• Acute coronary syndrome.
• There is an increased incidence of lung cancer.

Prognosis

• The prognosis is variable and depends on the specific diagnosis and severity. Some diseases are insidious in onset and gradual progression, while other diseases are acute in onset but responsive to therapy.
• Idiopathic pulmonary fibrosis (IPF) is a progressive illness, producing increasingly severe symptoms, and generally has a poor prognosis. Mortality data for 3-year and 5-year mortality rates are approximately 50% and 80%, respectively. Although IPF occurs in older patients with comorbid diseases, most patients with IPF die as a direct consequence of the lung fibrosis.¹⁵ However, some patients with IPF remain stable for a number of years.
• The median survival rate 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:¹⁶
  • 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 evaluation.

Document references

1. Summerhill EM; Pulmonary Fibrosis, Interstitial (Nonidiopathic), eMedicine, Oct 2010
2. Raghu G, Weycker D, Edelsberg J, et al; Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006 Oct 1;174(7):810-6. Epub 2006 Jun 29. [abstract]
3. Mallick S; Outcome of patients with idiopathic pulmonary fibrosis (IPF) ventilated in Respir Med. 2008 Oct;102(10):1355-9. Epub 2008 Jul 17. [abstract]
4. Khalil N, O'Connor R; Idiopathic pulmonary fibrosis: current understanding of the pathogenesis and the status of treatment. CMAJ. 2004 Jul 20;171(2):153-60. [abstract]
5. Godfrey A et al; Idiopathic Pulmonary Fibrosis, eMedicine, Aug 2010
6. Ryu JH, Colby TV, Hartman TE; Idiopathic pulmonary fibrosis: current concepts. Mayo Clin Proc. 1998 Nov;73(11):1085-101. [abstract]
7. No authors listed; American Thoracic Society. 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 Feb;161(2 Pt 1):646-64.
8. Azuma A, Nukiwa T, Tsuboi E, et al; Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005 May 1;171(9):1040-7. Epub 2005 Jan 21. [abstract]
9. Spagnolo P, Del Giovane C, Luppi F, et al; Non-steroid agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev. 2010 Sep 8;(9):CD003134. [abstract]
10. Thannickal VJ, Flaherty KR, Martinez FJ, et al; Idiopathic pulmonary fibrosis: emerging concepts on pharmacotherapy. Expert Opin Pharmacother. 2004 Aug;5(8):1671-86. [abstract]
11. Antoniu SA; Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert Opin Investig Drugs. 2006 Jul;15(7):823-8. [abstract]
12. Ask K, Martin GE, Kolb M, et al; Targeting genes for treatment in idiopathic pulmonary fibrosis: challenges and opportunities, promises and pitfalls. Proc Am Thorac Soc. 2006 Jun;3(4):389-93. [abstract]
13. Dempsey OJ, Kerr KM, Gomersall L, et al; Idiopathic pulmonary fibrosis: an update. QJM. 2006 Sep 6. [abstract]
14. Noth I, Martinez FJ; Recent advances in idiopathic pulmonary fibrosis. Chest. 2007 Aug;132(2):637-50. [abstract]
15. Klingsberg RC, Mutsaers SE, Lasky JA; Current clinical trials for the treatment of idiopathic pulmonary fibrosis. Respirology. 2010 Jan;15(1):19-31. [abstract]
16. Zisman DA, Keane MP, Belperio JA, et al; Pulmonary fibrosis. Methods Mol Med. 2005;117:3-44. [abstract]

Internet and further reading

• Pulmonary Fibrosis Foundation.
• Orens JB, Estenne M, Arcasoy S, et al; International guidelines for the selection of lung transplant candidates: 2006 update--a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006 Jul;25(7):745-55.

Acknowledgements