Synonyms: fibrosing alveolitis, cryptogenic fibrosing alveolitis

Introduction¹

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised initially by the presence of inflammatory cells within the alveoli. This is followed by thickening and fibrosis of the alveolar walls. The aetiology and pathogenesis are as yet unknown.

A form called the Hamman-Rich syndrome has a particularly poor prognosis. This is an acute interstitial pneumonia which presents with cough, fever and breathlessness. Histology shows bilateral diffuse alveolar damage. The condition usually progresses rapidly to acute respiratory distress and is often fatal (100% of patients between 5-26 days from admission in one study).²

The condition is part of a spectrum of conditions known as interstitial lung disease. The term cryptogenic fibrosing alveolitis should be reserved for those patients in whom lung histology has shown to demonstrate the pathological changes termed 'usual interstitial pneumonitis' (UIP). This is characterised by patchy interstitial changes, a honeycomb appearance to the lung tissue and eosinophilic infiltration.³

Pathogenesis¹

Theories about the underlying pathological process are changing. It used to be thought that the initial trigger factor for fibrosis was a generalised inflammatory condition of interstitial lung tissue with subsequent scarring. Lack of response to steroids and immune modulators suggested this was unlikely. It is now considered that changes occur at endothelial cell level due to a response to some irritant, such as cigarette smoke, gastro-oesophageal reflux, environmental pollution. In IPF the repair mechanism which subsequently comes into play is impaired, leading to excessive production of myofibroblasts and accumulation of extracellular matrix.

20% of patients have a positive family history, suggesting a genetic cause. Proposed mechanisms are mutations affecting surfactant C production and dysfunction of epithelial regeneration.

Epidemiology^4,5

The incidence of idiopathic pulmonary fibrosis (IPF) appears to be rising, although it is not yet known why. A general practice-based study calculated an overall incidence of 4.6 per 100,000 person-years. The study confirmed the impression that the incidence was rising and found that it had doubled between 1990 and 2003. It was postulated that this could be due either to an ageing population or to increasing recognition of the condition.

One study quoted a European and North American prevalence of 340,000 people.⁶

Exposure to certain airborne agents, such as asbestos and metal alloys, may produce the condition and the great majority of people who develop IPF are, or have been at some time, smokers. It is most common in people in their 50s and affects men to a slightly greater degree than women (M:F 1.7:1).

The disease may show familial clusters but the genetic reason for this is not yet fully understood as it does not occur in a predictable fashion.

An American study found that mortality rates increased from 1992 to 2003.⁷

Risk factors

• The condition is common in certain occupations - for example, in people who work with silica, asbestos, heavy metals or mouldy foliage.
• Environmental factors include pigeon breeding and contaminated ventilation systems.
• It can be an adverse effect of amiodarone.

Presentation¹

Symptoms

• The most common symptoms are progressively increasing shortness of breath and dry cough.
• 5% of patients diagnosed opportunistically have no initial symptoms.
• 50% of patients are systemically unwell and may have a flu like illness, fatigue or weight loss.
• Spontaneous remissions do not occur (in contrast to sarcoidosis).
• Extrapulmonary features may include arthralgia, muscle pains and skin rashes.
• Obstructive sleep apnoea may be a common presenting feature.

Signs

These may include:

• Exertional dyspnoea progressing to breathlessness at rest.
• Tachypnoea.
• Cough.
• Clubbing (50%).
• Cyanosis.
• Fine bilateral basal crepitations particularly at the end of expiration ('Velcro® rales').
• Signs of cor pulmonale and right heart failure in the later stages.

Differential diagnosis^1,8

Due to the nonspecific nature of the presenting symptoms and signs, there are many other diagnoses which must be considered, ranging from very common disorders such as heart failure through to much rarer diseases.

Diagnoses to be considered include:

• Heart failure.
• Chronic obstructive pulmonary disease (COPD).
• Sarcoidosis.
• Pulmonary embolism.
• Lymphangitis carcinomatosis.
• Extrinsic allergic alveolitis.
• Pneumonia.
• Asbestosis.

Investigations¹

Laboratory tests

• FBC may show mild anaemia or may be normal.
• ESR and CRP may be raised in 50% of patients.
• Antinuclear factor and rheumatoid factor may be raised in up to a third of all patients.

Radio-imaging

• CXR will show abnormalities in 95% of patients. The most common finding is bilateral basal and peripheral infiltrates. The fibrosis may also produce a honeycombing effect.
• High-resolution CT (HRCT) scanning. The specificity of this has been questioned in recent years but it is still a useful screening tool to decide whether or not to proceed to lung histology tests. Typically, a ground glass appearance is indicative of idiopathic pulmonary fibrosis (IPF), whereas a reticular pattern is more predominant in other types of interstitial lung disease.^3,9

Lung function tests

These may show:

• A restrictive defect (forced expiratory volume in one second (FEV1) is usually less than 80% of predicted value, forced vital capacity (FVC) is usually less than 3 litres, FEV1/FVC ratio is normal, because both are reduced).
• Reduced gas transfer.
• Reduced lung volumes.

Bronchiolar lavage

This is not vital for the diagnosis of IPF but is sometimes used to exclude other diseases.¹⁰

Histology

Lung biopsy is the definitive method of arriving at the diagnosis but, as the lesions need to be separated both in time and space, a large biopsy, e.g. open lung biopsy or several smaller biopsies, may be required.

Associated diseases

Idiopathic pulmonary fibrosis (IPF) may be found in association with several autoimmune disorders such as:

• Thyroid disease
• Systemic sclerosis
• Rheumatoid arthritis
• Autoimmune liver disease
• Systemic lupus erythematosis

Management^1,10

There is no consensus regarding management.¹¹

Nondrug

• Supportive therapy with oxygen and physiotherapy may be helpful.
• Regular exercise and weight control should be encouraged.
• Vaccinate against influenza and pneumococcus.
• Encourage the patient to stop smoking if he or she continues to do so.

Drug

It has been acknowledged for some time that the effectiveness of current medical therapies has been disappointing and recent research highlighting the likely aetiology of IPF explains why. The search is therefore on for more targeted treatment but standard drug regimes should be offered until these avenues of research come to fruition. Medication should be initiated under specialist supervision.

• The risks and benefits of all options should be discussed with patients and some may prefer not to have any treatment for their IPF in the early stages, particularly if they have significant comorbidities.
• Current British Thoracic Society (BTS) guidelines do not recommend steroids as monotherapy. Systematic reviews suggest that the optimal first-line treatment is is a combination of prednisolone and azathioprine (the latter substituted by colchicine if it cannot be tolerated).
• Pirfenidone - a growth factor inhibitor - has shown promising results in trials and has been approved for use in the UK; the intended launch date is mid-2012.¹²
• The use of N-acetylcysteine - an antioxidant - is currently being investigated as a therapy, either in combination with prednisolone and azathioprine or as monotherapy.
• Bosentan, imatinib and interferon-γ, all once thought to be promising treatments, have proved disappointing in Phase III studies.⁶
• Opiates are useful to control cough in end-stage disease.
• Proton pump inhibitors should be trialled due to the high associated incidence of gastro-oesophageal disease.

Surgical

Lung transplant may be required for patients who fail to respond to medical therapy.

Complications¹

These may include:

• Adverse drug effects (closely monitor).
• Cor pulmonale .
• Pneumothorax.
• Infection.
• Lung cancer.¹³
• Thromboembolic diseases.
• Pulmonary hypertension.

Prognosis¹

The prognosis is poor, with a mean survival in the UK of 3 years from the time of diagnosis.¹⁰ 60% of patients die from an acute exacerbation of the condition itself, whilst the remainder succumb to a condition associated with increased cardiovascular risk or lung cancer. The estimated mortality rates are 64.3 deaths per million in men and 58.4 deaths per million in women.

One study found that idiopathic pulmonary fibrosis (IPF) patients who developed pulmonary hypertension or emphysema had a significantly poorer prognosis than those who did not.¹⁴

A more favourable prognosis is also associated with female sex, younger age and shorter duration of symptoms. The development of pulmonary hypertension indicates a poor prognosis.¹⁵

It is hoped that the advent of emerging therapies will improve the prognosis.

Research

Blood tests to assist in the diagnosis of idiopathic pulmonary fibrosis (IPF) are being investigated.¹⁶ Ongoing research is looking at the use of stem cells to help repair damaged lung tissue.¹⁷ An international register to help gather data on diagnosis and the effectiveness of emerging therapies has been set up under the auspices of the European IPF Network, a consortium of clinical and non-clinical specialists.

Document references

1. Godfrey A et al; Pulmonary Fibrosis, Idiopathic, Medscape, Aug 2010
2. Avnon LS, Pikovsky O, Sion-Vardy N, et al; Acute interstitial pneumonia-Hamman-Rich syndrome: clinical characteristics and Anesth Analg. 2009 Jan;108(1):232-7. [abstract]
3. Katzenstein AL, Myers JL; Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 1):1301-15.; Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 1):1301-15.
4. Gribbin J, Hubbard RB, Le Jeune I, et al; The incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax. 2006 Jul 14;.; Thorax. 2006 Jul 14;. [abstract]
5. Gustafson T, Dahlman-Hoglund A, Nilsson K, et al; Occupational exposure and severe pulmonary fibrosis. Respir Med. 2007 Oct;101(10):2207-12. Epub 2007 Jul 12. [abstract]
6. Guenther A; The European IPF Network: towards better care for a dreadful disease Eur Respir J. 2011 Apr;37(4):747-748
7. Olson AL, Swigris JJ, Lezotte DC, et al; Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am J Respir Crit Care Med. 2007 Aug 1;176(3):277-84. Epub 2007 May 3. [abstract]
8. Michaelson JE, Aguayo SM, Roman J; Idiopathic pulmonary fibrosis: a practical approach for diagnosis and management. Chest. 2000 Sep;118(3):788-94.; Chest. 2000 Sep;118(3):788-94.
9. Gulati M; Diagnostic assessment of patients with interstitial lung disease. Prim Care Respir J. 2011 Apr 20. pii: pcrj-2010-07-0078. doi: [abstract]
10. Interstitial lung disease guideline, British Thoracic Society (September 2008)
11. Collard HR, Loyd JE, King TE Jr, et al; Current diagnosis and management of idiopathic pulmonary fibrosis: a survey of academic physicians. Respir Med. 2007 Sep;101(9):2011-6. Epub 2007 May 16. [abstract]
12. Pirfenidone, New Drugs Online, 2011
13. Le Jeune I, Gribbin J, West J, et al; The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med. 2007 Dec;101(12):2534-40. Epub 2007 Sep 17. [abstract]
14. Mejia M, Carrillo G, Rojas-Serrano J, et al; Idiopathic pulmonary fibrosis and emphysema: decreased survival associated with Chest. 2009 Jul;136(1):10-5. Epub 2009 Feb 18. [abstract]
15. Noth I, Martinez FJ; Recent advances in idiopathic pulmonary fibrosis. Chest. 2007 Aug;132(2):637-50. [abstract]
16. Prasse A, Muller-Quernheim J; Non-invasive biomarkers in pulmonary fibrosis. Respirology. 2009 Aug;14(6):788-95. [abstract]
17. Gharaee-Kermani M, Gyetko MR, Hu B, et al; New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis: a potential role for stem cells in the lung parenchyma and implications for therapy. Pharm Res. 2007 May;24(5):819-41. Epub 2007 Mar 1. [abstract]

Internet and further reading

• Tzouvelekis A, Aidinis V, Harokopos V, et al; Down-regulation of the inhibitor of growth family member 4 (ING4) in different Respir Res. 2009 Feb 27;10:14. [abstract]
• Dixon S, Benamore R; The idiopathic interstitial pneumonias: understanding key radiological features. Clin Radiol. 2010 Oct;65(10):823-31. Epub 2010 May 7. [abstract]
• Yamashita M, Yamauchi K, Chiba R, et al; The definition of fibrogenic processes in fibroblastic foci of idiopathic Hum Pathol. 2009 Sep;40(9):1278-87. Epub 2009 Apr 22. [abstract]

Acknowledgements