Idiopathic Pulmonary Fibrosis

Respiratory Medicine

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Take home messages:
1. IPF is a form of interstitial lung disease which presents insidiously and is often misdiagnosed.
2. Patients typically present with chronic dyspnea and a nonproductive cough and have fine bibasal inspiratory crackles on auscultation. Clubbing is only present in half of patients.
3. The findings of IPF may be mimicked by granulomatous disorders, autoimmune diseases, connective tissue diseases and pneumoconiosis.
4. The presence of supportive clinical and HRCT findings (and absence of findings suggestive of other diseases) is sufficient to diagnose IPF.
5. If the clinical and radiological findings result in an uncertain diagnosis, or if the patient is not thought to have IPF, bronchoalveolar lavage and/or lung biopsy is necessary.
5. Medical management is of limited benefit. Lung transplantation is the only definitive therapy.

IPF is a chronic, progressive, irreversible and usually lethal lung disease of unknown cause. There is a mild male predominance, with the frequency increasing with age. Patients typically present in their fifth to sixth decades of life.

The pathogenesis of IPF is incompletely understood. The current hypothesis is that a (still unidentified) stimulus produces repeated episodes of acute lung injury, resulting in activation of processes associated with tissue repair. For unclear reasons, this tissue repair occurs in an aberrant fashion, leading to progressive pulmonary fibrosis.

Patients with IPF typically present with exertional dyspnea and a nonproductive cough. There may also be associated systemic symptoms such as fever, arthralgia, myalgia or fatigue, although these are uncommon. Note however that prominent systemic symptoms should raise the possibility of interstitial lung disease secondary to other disorders.

The physical examination usually reveals fine bibasal inspiratory crackles, while clubbing is seen in up to 50% of patients. With severe disease, evidence of cor-pulmonale may become apparent.

A detailed occupational history, with attention to exposure to asbestos, silica, or other respirable toxins, is critical to rule out a pneumoconiosis, which may mimic the findings of IPF. In addition, frank findings of connective tissue or autoimmune disease such as rashes, inflammatory arthritis or myositis should be actively elicited.

Up to 30% of patients show non-specific laboratory findings such as mild anemia, elevated inflammatory markers (i.e. ESR and CRP), and increases in rheumatoid factor and antinuclear antibodies. Note that in the absence of supportive clinical findings, the presence of antibodies alone does not imply an underlying autoimmune or connective tissue disease.

Lung function tests usually reveal a restrictive pattern of disease, with reduced total lung capacity (TLC), functional residual capacity (FRC) and residual volume (RV) due to decreased lung compliance. In addition, the carbon monoxide diffusing capacity (DLCO) is reduced, indicating impaired gas exchange secondary to thickening of the alveolar-capillary barrier.

Chest x-rays typically show bilateral reticulonodular shadows, which are predominantly localized to the lung peripheries and bases. In addition, the progressive fibrosis leads to cystic dilatation of the distal air spaces, which is visible as peripheral "honeycombing", while the decreased parenchymal compliance may lead to traction bronchiectasis, which is visible as thickened and dilated airways.

Note that the presence of pleural effusions, air bronchograms, or hilar enlargement on the chest x-ray strongly suggests an alternative diagnosis.

High resolution CT (HRCT) typically shows patchy peripheral reticular abnormalities with intralobular linear opacities, irregular septal thickening, subpleural honeycombing and traction bronchiectasis. These findings are most prominent in the lower lung zones, but may involve all lobes in advanced disease.

Earlier, the 2000 American Thoracic Society / European Respiratory Society (ATS/ERS) guidelines on IPF required both suggestive clinical and HRCT findings as well as either a supportive lung biopsy or bronchoalveolar lavage to establish the diagnosis of IPF.

This mandatory requirement for lung biopsy or bronchoalveolar lavage was removed in the 2011 ATS guidelines as several new studies had shown HRCT to be highly specific for diagnosis if certain "pathognomonic" findings were present.

However, if clinical and radiological data result in an uncertain diagnosis, or if the patient is not thought to have IPF, bronchoalveolar lavage or surgical lung biopsy is still necessary.

The main value of bronchoalveolar lavage lies in excluding alternative diagnoses such as sarcoidosis or other granulomatous diseases (for which the diagnostic yield approaches 90%). The most common finding in IPF is only a neutrophilia and/or eosinophilia, which is too non-specific to establish the diagnosis.

Lung biopsy allows definitive diagnosis of IPF. However, the tissue specimen needs to be of sufficient size to allow analysis of the underlying lung architecture, necessitating an open thoracotomy or video assisted thoracoscopic surgery (VATS). Tissue specimens obtained via transbronchial biopsy are inadequate.

Current medical therapy for IPF is poorly effective at best. The combination of N-Acetyl-Cysteine, prednisolone and azathioprine has been shown to reduce the rate of decline of FVC and DLCO as measured by lung function tests, although the clinical significance is uncertain. Numerous other immunosuppressants, cytotoxic agents and antifibrotic agents have been studied, with little or no success.

Note that it is recommended that all patients who are diagnosed with IPF should be enrolled in ongoing high quality clinical trials, if possible.

Lung transplantation is the only therapy that prolongs survival in advanced IPF, although the post-transplantation 5-year survival is only about 44%. Unfortunately, many patients are referred too late and die before receiving a transplant. Therefore, these patients should be referred for evaluation early, ideally at the time of initial diagnosis.

Complications of IPF include recurrent respiratory tract infections and pulmonary hypertension with cor pulmonale, while a higher incidence of bronchogenic carcinoma is also reported. The median survival after the diagnosis of (biopsy-confirmed) IPF is less than 3 years, with the main causes of death being respiratory failure and infections.

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