Idiopathic pulmonary fibrosis: new approaches to diagnosis and treatment

Idiopathic pulmonary fibrosis (IPF) is a form of interstitial lung disease (ILD) that results in scarring of the lung tissue, progressive lung restriction, breathlessness and, ultimately, death, with a median survival of two to five years.¹ It has traditionally been considered a rare disease; however, the incidence appears to be increasing worldwide. Although IPF can occur in any adult, it is more common in older males; often with a history of smoking.

The diagnosis of IPF can be challenging as symptoms are often vague, and include cough, breathlessness and fatigue. In an elderly population, these symptoms are often attributed to comorbidities such as heart failure and chronic obstructive pulmonary disease. IPF also shares many features with other ILDs. The classification of ILDs is complex. ILDs are often classified according to their associations such as connective tissue diseases, drugs or smoking. Figure 1 shows the current ILD classification, with the classification of IPF highlighted. Early referral to a specialised ILD centre is recommended for accurate diagnosis and treatment.

The early consideration of an IPF diagnosis is important as treatments that can slow the progression of this disease are now available. Unfortunately, there is still no treatment that can stop or reverse the disease and therefore early initiation of treatment to preserve lung function and quality of life is of great importance.

This article provides an overview of the approach to diagnosis of IPF as well as the management options available. It also discusses two case studies and how to diagnose and manage them:

Paul, aged 60 years, presents with a four-month history of breathlessness and dry cough. Chest x-ray shows patchy changes bilaterally with no response to multiple courses of oral antibiotics (Box 1).

Steven, aged 75 years, presents with a three-year history of worsening breathlessness. GP review finds severe exercise limitation, with hypoxia and bibasilar crackles (Box 2).

Diagnosing IPF

Clinical features

A thorough clinical history is required not only to diagnose idiopathic pulmonary fibrosis (IPF) but also to exclude other causes of ILD (Table 1). It is important to identify any occupational, environmental or medication exposures as these may cause ILD, and cessation of exposure is critical to management. Although most instances of IPF are sporadic, familial IPF does occur and a detailed family history should be taken.

It is also important to ask about specific symptoms of connective tissue disease, a major differential diagnosis for IPF. These symptoms include Raynaud’s phenomenon, morning stiffness, joint pain/swelling and muscle pain/weakness. Connective tissue disease-related ILD should be suspected in patients who are female and are younger.

Clinical examination should focus on features of IPF including fine inspiratory crackles, usually at the base of the lungs, as well as clubbing of fingernails (Figure 2). Hypoxia should be assessed for, with oxygen saturations and the presence of peripheral or central cyanosis. Cardiovascular and rheumatological examinations should also be done.

Investigations

Serology

Serological testing is recommended for all patients to assess for underlying connective tissue disease. Connective tissue diseases that are commonly associated with ILD include rheumatoid arthritis, Sjögren’s syndrome, scleroderma and polymyositis-dermatomyositis. Serology to look for these diseases is recommended including, at a minimum, rheumatoid factor, anticyclic citrullinated peptide and antinuclear antibody titre and pattern.

Lung function testing

Lung function tests of patients with IPF will most commonly show a restrictive pattern. Spirometry will show a normal to high forced expiratory volume in one second (FEV₁) to forced vital capacity (FVC) ratio, and a reduced FVC. These patients will also have a reduced total lung capacity (TLC) and diffusing capacity of the lungs the lungs for carbon monoxide (D_LCO). Lung function has important implications in predicting a patient’s prognosis, with patients who present with more severe impairment usually having worse outcomes.

High-resolution CT

High-resolution CT (HRCT) plays a central role in the diagnosis of IPF. The presence of a definite usual interstitial pneumonia (UIP) pattern on HRCT is adequate to diagnose IPF in the correct clinical context, without the need for tissue biopsy. A definite radiological UIP pattern shows honeycombing with or without traction bronchiectasis and reticular abnormality in a subpleural, basal distribution (Figure 3).

Lung biopsy

Lung biopsy is sometimes required when the above testing is insufficient for a diagnosis. This decision requires discussion at an ILD multidisciplinary team (MDT) meeting. Lung biopsies, however, are invasive procedures that can be associated with significant morbidity including pain, bleeding, exacerbation of ILD and, in rare cases, death.

Management

The comprehensive management of IPF involves disease-specific therapies and management of comorbidities, disease-related symptoms, pulmonary rehabilitation as well as palliative care and/or lung transplantation (Flowchart 1). Management requires a variety of health professionals, with the local general practitioner vital in co-ordinating care.

Interstitial lung disease multidisciplinary team meeting

Early referral is critical for both the diagnosis and management of IPF. Multiple studies have shown that using an ILD MDT improves accuracy and confidence of IPF diagnosis compared with doctors working individually.⁴ In order to confirm a diagnosis of IPF and access medical treatment via PBS, all IPF patients need to be discussed at an ILD MDT meeting. These meetings are typically attended by respiratory physicians, radiologists, pathologists +/- rheumatologists, ILD-specific nurses and allied health staff. In order to co-ordinate referral to an ILD MDT, a GP can either directly refer to the ILD outpatient service or, if not available, can refer to their closest respiratory physician (Flowchart 2).

During the ILD MDT meeting, key elements of the patient’s case are discussed including the clinical history and examination, as above, pulmonary function tests and HRCT scans. A consensus diagnosis is reached and suggestions for management are made (Box 3).

Antifibrotic treatments

Until recently, there were no effective treatments available for IPF. In 2014, two landmark trials of the antifibrotic therapies nintedanib and pirfenidone, respectively, were published. These studies resulted in both medications becoming available in Australia through the PBS in 2017.^2,3

PBS criteria in Australia for use of antifibrotics include MDT diagnosis of IPF, HRCT consistent with UIP pattern within 12 months, FVC greater than 50%, FEV₁/FVC more than 0.7, D_LCO more than 30% and ILD not a result of another known cause.

There is little evidence to support the use of antifibrotics in patients with severe disease outside the PBS criteria (FVC less than 50%, D_LCO less than 30%). Due to absence of trial data at this stage, there is no evidence to support the use of antifibrotic therapy in other ILDs.

Gastrointestinal side effects are commonly associated with both nintedanib and pirfenidone (Table 2). In most cases, side effects with both medications are mild and rarely require cessation of treatment. Both antifibrotic medications can cause liver function abnormalities and thus liver function tests should be done regularly, usually monthly for the first six months, then quarterly while undergoing treatment. For patients experiencing diarrhoea, antidiarrhoeal medications including loperamide can be used. If diarrhoea is significant (more than six stools daily/affecting activities of daily living/requiring intravenous fluids), interruption of treatment may be required.

Treating comorbidities

Smoking cessation is of critical importance and all smokers should be offered nicotine replacement therapy, specialist support and psychological support as required. Gastro-oesophageal reflux is common in patients with IPF and may contribute to chronic cough. Growing evidence suggests that antacid therapy may not be beneficial in patients with IPF and reflux-directed therapy should be considered on an individual basis.⁴

All patients with IPF should be offered the yearly influenza vaccine and the pneumococcal vaccine. These infections are poorly tolerated in patients with IPF and can result in significant morbidity and/or mortality.

In patients with suspected disordered breathing during sleep, referral to a sleep physician and sleep studies should be considered. Disordered breathing during sleep can cause pulmonary hypertension because of nocturnal hypoxia. Pulmonary hypertension in ILD is a strong predictor of poor survival.

Oxygen

Recommendations for supplemental oxygen in IPF are currently the same as those for chronic obstructive pulmonary disease. Oxygen is suggested for patients with resting hypoxaemia (PaO2 less than 55 mmHg, or less than 60 mmHg in the presence of end-organ damage). Nocturnal oxygen can be considered in patients who desaturate below 88% for at least one-third of total sleep time.

Pulmonary rehabilitation

There is growing evidence that pulmonary rehabilitation has important effects on symptoms, functional capacity and wellbeing in patients with IPF. Studies show that an eight- to 12-week pulmonary rehabilitation program leads to improvements in breathlessness and health-related quality of life. Patients with milder disease appear to have a prolonged benefit and thus early referral should be considered. Maintenance programs after six to 12 months should also be considered to continue the benefit of pulmonary rehabilitation.

Lung transplant

Lung transplant remains the only definitive cure for IPF. Age is no longer a contraindication in Australia but instead disease severity (with evidence of end-organ damage) and the patient’s overall health are the main criteria used. As a general rule, patients are considered for transplant when they develop respiratory failure despite optimal medical/surgical management and/or a poor quality of life with intractable symptoms or repeat hospital admissions. Exclusion criteria include active malignancy, irreversible dysfunction of other organs (though combined transplants may be considered), noncurable chronic infection, documented nonadherence, or substance addiction within the previous six months.⁵ It should be noted that patient appropriateness for lung transplantation is a complex decision and requires extensive input from a specialist lung transplant team.

Palliative care

Palliative care is a key part of IPF management and should be addressed at all stages of the disease. Palliative care focuses on symptom management, advance care directives and end-of-life planning. It aims to improve the quality of life of patients  and their families. Nonpharmacological therapies that can be considered for dyspnoea in patients with advanced lung diseases include pursed lip breathing, facial cooling with fans, relaxation therapy and noninvasive positive pressure ventilation. Opioid medications have proven efficacy in the management of breathlessness and should be considered for patients with refractory breathlessness. The medications should be dosed and titrated for each patient based on multiple factors including patient renal and hepatic function, lung function and current/previous use of opioids.⁶

Patient support

A diagnosis of IPF creates a significant physical and mental burden on patients and their carers. There are several resources available in Australia to provide further information and support. These include the Lung Foundation Australia website or its information and support centre (https://lungfoundation.com.au/patients-carers/living-with-a-lung-disease/ipf/overview/), and other websites (also accessible via the Lung Foundation).

Conclusion

IPF is a progressive disease that requires extensive investigation, with an MDT the key to successful diagnosis and management. The GP has an essential role in the early diagnosis, co-ordination of care and ongoing management of symptoms and medication side effects resulting from this disease.        RMT

References

Further reading