Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic condition characterised by progressive fibrosis of unknown aetiology with typical imaging and histological findings.

Interstitial lung disease

Interstitial lung disease (ILD) refers to a family of conditions with shared characteristics of interstitial inflammation, fibrosis and/or cellular changes in the absence of infection or malignancy.

In most cases interstitial fibrosis is found and commonly related to sarcoidosis, chronic hypersensitivity pneumonitis, autoimmune disease or in cases with an unknown aetiology, idiopathic interstitial pneumonia.

Idiopathic pulmonary fibrosis

IPF is the most common form of idiopathic interstitial pneumonia. It occurs more commonly with advancing age and is rare before the age of 50.

It often presents with exertional dyspnea and a dry cough, whilst clinical examination classically reveals bilateral inspiratory crackles. Management involves supportive care and pulmonary rehabilitation. Relatively novel therapies (pirfenidone and nintedanib) have been licensed for IPF and lung tranplant is an option for appropriately selected patients.

Unfortunately overall the prognosis remains poor with a median survival from diagnosis of approximately 3 years in the UK.

The incidence of IPF is approximately 3-9 cases per 100,000 person-years.

IPF becomes more common with advancing age and is rare before the age of 45. In the UK the median age at presentation is 70 years old.

Though rates appear to be increasing, it is unclear whether this is a true increase in the incidence or simply a reflection of greater recognition.

Though the majority of cases of IPF occur spontaneously without known cause, a small portion are associated with identifiable genetic predispositions.

• Familial pulmonary fibrosis: this is thought to account for up to 5% of cases of IPF. Suspicion is raised in families with multiple cases of ILD. It appears to be autosomal dominant with variable penetrance.
• Hermansky-Pudlak syndrome: it is characterised by partial cutaneous albinism, ocular albinism, immunodeficiency, nystagmus and pulmonary fibrosis. Depending on the variants and expression, features may vary.
• Telomeropathies: telomeres are sections of non-coding DNA found at the end of chromosomes. There are a number of short telomere syndromes that give rise to a variety of pathologies including pulmonary fibrosis.

Chronic exertional dyspnea is the most common presenting symptom of IPF.

Chronic exertional dyspnea is seen in the vast majority of patients and is commonly accompanied by a chronic dry cough.

Examination frequently reveals bilateral inspiratory crackles. On occasion, clubbing of the fingers or acrocyanosis (peripheral discolouration indicative of cyanosis) may be seen.

Symptoms

• Exertional dyspnea
• Dry cough
• Fatigue

Signs

• Bilateral inspiratory crackles
• Clubbing
• Acrocyanosis

The diagnosis of IPF requires a thorough history, lung function testing, imaging and pathological specimens (where indicated).

Additional tests may be required to rule in/ rule out differentials such as other ILDs or heart failure.

Bloods

• FBC
• Renal function
• LFTs
• CRP

Lung function tests

Spirometry, lung volumes and diffusing capacity of the lung for carbon monoxide (DLCO) are all obtained. Additionally resting versus ambulatory pulse oximetry should be measured.

Though in early disease results may be relatively normal, IPF is associated with a restrictive pattern on spirometry, reduced lung volumes and decreased DLCO.

Imaging

CXR: a key investigation in any patient presenting with shortness of breath or chronic cough. Though relatively non-specific can help to assess for differentials (e.g. signs of heart failure) as well as signs of IPF. In IPF, decreased lung volumes and basal reticulation may be seen.

High-resolution CT: an essential investigation in patients with suspected IPF. Characteristic changes include honeycombing (clusters of cystic air spaces), reticular opacities, traction bronchiectasis, emphysema and loss of lung volume – changes are predominantly seen in the bases and peripheries. The classic radiological appearence is called usual interstitial pneumonia (UIP), a term that may also be used, by some, interchangeably with IPF.

Biopsy and cytology

• Bronchoalveolar lavage and/ or transbronchial biopsy
• Surgical lung biopsy

The diagnosis of IPF may be made with or without pathology samples.

NICE CG 163 outlines how the diagnosis of IPF can be made. Key to this is an appropriately specialised MDT that reviews the merits of each case. Where the MDT can make a ‘confident diagnosis’ based on the clinical features, lung function tests and radiological findings, this may be considered sufficient.

However where an appropriate MDT is unable to make a ‘confident diagnosis’ based on the history, examination, lung function and imaging results the following is considered:

• bronchoalveolar lavage or transbronchial biopsy and/or
• surgical lung biopsy, with the agreement of the thoracic surgeon

Management involves supportive care, pulmonary rehabilitation as well as medical therapies and lung transplant in appropriate candidates.

Supportive care

Patients should be counselled on their condition and offered additional sources of information. Optimisation of modifiable risk factors is advised. Where appropriate patients should be given advice and support on improving their diet and quitting smoking.

If and when appropriate palliative care input should be sought to aid with symptomatic relief and ensure a holistic approach is taken to each individual patients needs.

Pulmonary rehabilitation

Pulmonary rehabilitation should be offered to appropriate patients. It consists of an exercise and education programme aimed at helping patients, in particular those affected by breathlessness, better manage their symptoms and improve their underlying health.

Oxygen therapy

Breathlessness on exertion

Patients suffering with breathlessness on exertion should be reviewed to ensure there are no other contributory causes and to characterise the degree of hypoxia. They should be considered for ambulatory oxygen, long term oxygen therapy and pulmonary rehabilitation.

Breathlessness at rest

Patients suffering with breathlessness at rest should be reviewed to ensure there are no other contributory causes and to characterise the degree of hypoxia. They should be assessed for ambulatory oxygen and long term oxygen therapy. Benzodiazepines and opioids may also offer symptomatic relief.

In addition NICE advise tending to their psychosocial needs and considering referral to palliative care.

Disease modifying medical therapies

There are two main disease modifying therapies licensed for use in IPF; pirfenidone and nintedanib. Each of these two medications are subject to NICE technological appraisals:

• NICE TA 504: Pirfenidone for treating idiopathic pulmonary fibrosis (2018)
• NICE TA 379: Nintedanib for treating idiopathic pulmonary fibrosis (2016)

Pirfenidone is an anti-inflammatory and anti-fibrotic whose mechanism of action is incompletely understood. According to TA 504, pirfenidone may be used to treat adults with IPF if:

• the person has a forced vital capacity (FVC) between 50% and 80% predicted
• the company provides pirfenidone with the discount agreed in the patient access scheme and
• treatment is stopped if there is evidence of disease progression (an absolute decline of 10% or more in predicted FVC within any 12-month period)

Nintedanib acts on 3 growth factor receptors implicated in the development of IPF and has been shown to slow the rate of fibrosis. According to TA 379, nintedanib may be used to treat IPF if:

• the person has a forced vital capacity (FVC) between 50% and 80% of predicted
• the company provides nintedanib with the discount agreed in the patient access scheme and
• treatment is stopped if disease progresses (a confirmed decline in percent predicted FVC of 10% or more) in any 12-month period

Lung transplant

In appropriately selected patients lung transplantation can offer a survival benefit and improve quality of life.

In the US 66% percent survive 3 years or more following transplant, with 53% surviving 5 years or more. It remains a major operation with significant post-operative risks including graft rejection and immunosuppressant (necessary post-transplant) related infections and malignancies.

In the UK the median survival is approximately 3 years after diagnosis.

Disease progression and prognosis varies greatly between individuals and is difficult to predict. Though there is a median survival of 3 years, approximately 20% survive 5 years or more.

Death often results from progressive disease and respiratory failure. Others may die during an acute exacerbation – a sudden worsening of symptoms that may be secondary to a specific trigger (e.g. infection) or idiopathic in nature. IPF is also associated with pulmonary hypertension, lung cancer and blood clots.