Diagnosis and management of idiopathic pulmonary fibrosis: Thoracic Society of Australia and New Zealand and Lung Foundation Australia position statements summary

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and idiopathic interstitial lung disease (ILD) which, while demonstrating a heterogeneous clinical course, carries a universally poor prognosis that is worse than many forms of malignancy.1 IPF is more common in older men, and most patients have a history of cigarette smoking.2 The mean survival from diagnosis is only 2–5 years.3

Patients usually experience progressive worsening of dyspnoea on exertion, often with a debilitating dry cough, resulting in significant limitation in their ability to perform activities of daily living and reduction in their quality of life.1

Accurately diagnosing IPF can be challenging, as the pathognomonic, radiological and histopathological findings of usual interstitial pneumonia seen in patients with IPF may also be present in other ILDs, such as connective tissue disease-related ILD, chronic hypersensitivity pneumonitis, asbestosis and drug toxicity.4-6 In 2011, the American Thoracic Society and European Respiratory Society published guidelines for the diagnosis of IPF, recommending that, given these difficulties, IPF be diagnosed within the context of an expert ILD multidisciplinary meeting.7

Until recently, treatment of IPF was limited to lung transplantation in suitable candidates, while the majority of patients could only be offered best supportive or palliative care. However, in 2014, two new antifibrotic medications (nintedanib and pirfenidone) were shown to have a clinically meaningful impact on the natural history of mild to moderate IPF.8,9 Their availability for patients has revolutionised the approach to this once largely untreatable condition.

This article summarises two recently published position statements from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia, outlining the diagnosis10 and treatment of IPF.11 They do not represent guidelines per se but are based on current evidence as well as expert opinion.

For each position statement, a panel of experts contributed to the comprehensive literature review, writing and editing. The statements were independently peer reviewed and endorsed by the Thoracic Society of Australia and New Zealand. All authors had the opportunity to review this summary statement.

Diagnosis

The clinical presentation of IPF is usually insidious and non-specific, resulting in a significant delay from symptom onset to diagnosis.12 Cardinal symptoms include dyspnoea on exertion, non-productive cough, decreased exercise tolerance13 and weight loss.3 Physical examination may reveal bibasal crackles and, in 30–50% of patients, digital clubbing may be present.14,15 It is essential to assess patients thoroughly for other potential causes of fibrotic lung disease, via a comprehensive history and examination (Box 1). Common differential diagnoses include connective tissue disease, drug-induced or occupational lung disease, and hypersensitivity pneumonitis.

High resolution computed tomography has revolutionised the diagnosis of IPF as it allows for detailed assessment of the lung parenchyma, which may eliminate the need for an open lung biopsy.16,17 Based on international guidelines (Box 2), the presence of features consistent with a usual interstitial pneumonia pattern, including subpleural, reticular changes and honeycombing (Box 3), is diagnostic of IPF when other causes for ILD have been excluded.7 In the absence of honeycombing, the predictive value of these features for the presence of usual interstitial pneumonia is reduced and, depending on clinical factors, a surgical lung biopsy may be required to confirm a diagnosis of IPF (Box 4).

Role of the multidisciplinary meeting

Current international guidelines recommend a dynamic multidisciplinary discussion between expert respiratory physicians, radiologists and pathologists as the gold standard for IPF diagnosis.7 Several studies suggest that the use of ILD-specific multidisciplinary meetings leads to greater accuracy and confidence in IPF diagnosis than clinicians working in isolation,18-20 and frequently leads to a change in diagnosis from that proffered by the referring physician.21

Expert ILD multidisciplinary meetings may display considerable heterogeneity in final diagnoses.18,22 To achieve standardisation, based on relatively limited and evolving data supplemented by expert opinion, we have produced a statement10 outlining the conduct of the multidisciplinary meeting regarding core clinical input, discussion and diagnostic outputs.

Data that should be presented at an ILD multidisciplinary meeting are described in Box 5. A detailed and systematic consideration of all diagnostic material is essential to maximise diagnostic confidence from an ILD multidisciplinary meeting. Where data are inadequate for diagnosis to occur, as is common when the history is incomplete or imaging is suboptimal, repeat or further investigation before re-presentation may be required (online Appendix 1).

We suggest that the diagnosis of IPF should take place in a dedicated ILD multidisciplinary meeting. The suggested governance and structure of the multidisciplinary meeting is outlined in online Appendix 2. We recommend that an ILD-dedicated meeting involve at least two respiratory physicians (including the treating physician), a radiologist and a histopathologist, each with ILD expertise, and that the meeting adopt a consensus approach to diagnosis.

Diagnostic outputs from the ILD multidisciplinary meeting should include the final ILD diagnosis, the differential diagnosis and the level of diagnostic certainty. Secondary outputs, such as prediction of disease behaviour as well as treatment goal and management recommendations, may be useful but their value greatly depends on the constitution of the multidisciplinary meeting. Standardised correspondence of the multidisciplinary meeting discussion should be communicated to the treating clinician(s).

As multidisciplinary meetings are complex in their structure and governance, adequate infrastructure and human resource support are vital. In Australia and New Zealand, the location of ILD multidisciplinary meetings may be biased towards larger tertiary centres where core members from various disciplines are more likely to be co-located. Tele- and video-conferencing is an invaluable tool to overcome the geographic separation of ILD experts, enabling access for outer metropolitan, regional and remote centres, as well as for patients who are cared for in the private sector.

Treatment

Until recently, there were no effective therapies for IPF. With the publication of two landmark clinical trials in 2014, antifibrotic therapies have gained widespread approval.8,9 However, the generalisability of these clinical trials is uncertain, especially in the broader IPF disease spectrum.

Despite these advances in pharmacological therapy, IPF remains a progressive and fatal disease. Non-pharmacological interventions including pulmonary rehabilitation, supplemental oxygen, and management of comorbidities and disease-related symptoms are vital to the holistic care of patients with IPF. A suggested treatment algorithm is shown in Box 6.

In phase 3 double-blind randomised clinical trials, pirfenidone8,23 (a pleotrophic novel antifibrotic) and nintedanib9 (an intracellular tyrosine kinase inhibitor) were separately shown to slow disease progression in IPF compared with placebo. In the ASCEND (assessment of pirfenidone to confirm efficacy and safety in IPF) study, there was a 47.9% relative reduction in the proportion of patients who died or had a decline in forced vital capacity (FVC) ≥ 10% at 52 weeks on treatment compared with patients receiving placebo.8 Similarly, in the INPULSIS studies of nintedanib, patients receiving nintedanib had an approximately 50% reduction in annual fall in FVC, with a fall in FVC of 114.7 mL/year and 113.6 mL/year in INPULSIS studies 1 and 2 compared with 239.9 mL/year and 207.3 mL/year in the respective placebo groups.9

In each of these clinical trials, patients had mild to moderate disease, with patients with an FVC < 50% excluded from all trials. The ASCEND study8 of pirfenidone also excluded patients with an FVC > 90%, while the INPULSIS9 studies of nintedanib did not specify an upper FVC limit. Importantly, in post-hoc analyses, patients with very mild disease (FVC > 90% for nintedanib, FVC > 80% for pirfenidone)24,25 had an attenuation of FVC decline similar to that of patients with moderate physiological impairment. However, in severe disease (FVC < 50%), there is very little controlled data to guide treatment. Cohort studies of pirfenidone in real-world populations26,27 suggest that treatment of patients with severe IPF with pirfenidone may be beneficial. A controlled study of nintedanib in patients with severe disease is currently recruiting (NCT02802345).

Other fibrosing lung diseases such as connective tissue disease-related ILD, chronic hypersensitivity pneumonitis and asbestosis may present with a usual interstitial pneumonia pattern on radiology and/or histopathology. A minority of patients (about 10%) remain unclassifiable despite thorough investigation and discussion at an ILD multidisciplinary meeting.28,29 As there is currently no evidence to support the use of antifibrotic medications in patients with non-IPF usual interstitial pneumonia or unclassifiable disease, a clinical trial, if available, should be considered.

The suggestions from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia position statement on IPF treatment for the use of antifibrotic medications are listed in Box 7. The criteria for government-funded IPF treatment in Australia and New Zealand are also summarised in Box 8. In Australia, funding is approved for patients with mild to moderate IPF (FVC ≥ 50% and diffusion capacity of the lungs for carbon monoxide [DL_co] ≥ 30%); however, in New Zealand, funding has been restricted to patients with moderate IPF only (FVC ≥ 50% but ≤ 80%, and DL_co ≥ 30%).

The main adverse events associated with pirfenidone are gastrointestinal, including nausea, diarrhoea, dyspepsia and vomiting. The other common adverse event is a photosensitive rash, which occurs in 25% of patients. Diarrhoea is the most common adverse event with nintedanib, occurring in about 60% of patients. Other common adverse events are nausea, vomiting and decreased appetite. In most cases, adverse events with both medications are mild and rarely lead to treatment discontinuation. Both antifibrotic medications may cause liver function abnormalities and liver function tests should therefore be regularly monitored.

A summary of suggestions for other pharmacological therapies is provided in Box 7.

Management of comorbidities

Comorbidities are common in patients with IPF and include cardiovascular disease, gastroesophageal reflux disease, pulmonary hypertension and sleep-disordered breathing.2 The optimisation of comorbidities has the potential to prolong and improve quality of life, and therapies to target these diseases should therefore be considered (Box 9).

Gastroesophageal reflux disease

Gastroesophageal reflux disease is highly prevalent in patients with IPF and is thought to contribute to its pathogenesis (through microaspiration resulting in alveolar epithelial injury) or perhaps be exacerbated by IPF (via changes in intrathoracic pressures). While there have been no randomised controlled trials, initial retrospective studies suggested a possible therapeutic benefit of antacid therapy.30,31 However, a more recent post-hoc analysis of the pooled data from the placebo arms of the pirfenidone and nintedanib studies found no benefit and possible increased harm resulting from an increased risk of generalised and respiratory infections with antacid therapy.32

Pulmonary hypertension

The presence of pulmonary hypertension in IPF is associated with increased mortality.33 Despite multiple randomised controlled trials, treatment with pulmonary vasodilators including sildenafil, bosentan, ambrisentan, macitentan and riociguat have failed to demonstrate benefit in people with IPF.34-37 A recent network meta-analysis, however, has suggested that sildenafil may extend survival in selected patients with IPF.38 Therapy with sildenafil could be considered in specific cases in consultation with a pulmonary hypertension specialist centre.

Sleep-disordered breathing

Nocturnal hypoxaemia, with or without apnoea, is common in IPF, with higher nocturnal desaturation events and lower nadir oxygen saturation linked to increased mortality in patients with ILD.39 In a non-randomised study, compliance with continuous positive airway pressure in patients with IPF with moderate to severe sleep apnoea was associated with improved daytime functioning and sleep quality, as well as improved survival at 2 years.40

Combined pulmonary fibrosis and emphysema

Combined pulmonary fibrosis and emphysema refers to the coexistence of pulmonary fibrosis and radiological emphysema. The therapeutic options for patients with combined pulmonary fibrosis and emphysema are limited, as there is a paucity of data on this subset of patients. A post-hoc analysis of patients with emphysema less than the extent of fibrosis and a forced expiratory volume in 1 second/FVC ratio above 80% suggests that treatment with nintedanib confers therapeutic benefit with a similar effect size as for patients without emphysema.41 While there are no data on antifibrotic therapy in patients with emphysema extent greater than fibrosis, standard bronchodilator therapy and supplemental oxygen for those with airflow limitation could be of benefit in selected patients.

Non-pharmacological therapy

Non-pharmacological therapies are important in the management of IPF; patients often have a high burden of symptoms, marked exercise intolerance and poor quality of life, which often persist despite antifibrotic therapy. Early introduction of pulmonary rehabilitation, palliative measures and referral for lung transplantation in selected patients are important, as IPF remains an incurable and fatal disease (Box 10).

Oxygen

Resting oxygen requirements, as well as the degree of sleep and exercise-induced hypoxaemia, have been associated with adverse outcomes in IPF; however, it is unknown whether prevention of hypoxaemia assuages this risk. Currently, recommendations for supplemental oxygen in IPF have been extrapolated from trials in chronic obstructive pulmonary disease.42,43 In Australia and New Zealand, oxygen therapy is suggested for patients with resting hypoxaemia (Pao₂ < 55 mmHg, or < 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, and intermittent ambulatory oxygen may be considered in hypoxaemic individuals who have improvement in exercise capacity or dyspnoea with oxygen therapy. However, evidence to support this approach is equivocal, and factors such as cost, physical challenges of transporting devices and the limited duration of oxygen cylinders should be considered when suggesting oxygen therapy, particularly in the ambulatory setting.

Pulmonary rehabilitation

There is growing evidence that pulmonary rehabilitation has important effects on symptoms, functional capacity and wellbeing in patients with IPF. A recent Cochrane review showed that an 8–12-week pulmonary rehabilitation program, including whole body endurance and resistance training as well as education and psychosocial support, led to improvements in 6-minute walk distance, dyspnoea and health-related quality of life. However, gains in exercise capacity often diminish over 6–12 months.44 Patients with milder disease appear to have more sustained benefit and early referral should therefore be considered.45

Lung transplantation

Lung transplantation remains the only definitive cure for IPF, and it is recommended that appropriate patients be referred at the time of IPF diagnosis, regardless of disease severity.46 This recommendation reflects the phenotypic heterogeneity and thus difficulties of predicting the individual course. The overall prognosis for IPF is poor compared with other indications for lung transplantation, illustrated by the fact that IPF has the greatest waiting list mortality, despite the shortest median waiting list time.47

Chronological age is no longer an absolute contraindication to transplant; rather, the comorbidities with end-organ damage and physiological reserve are the main criteria used. Indications for lung transplant listing include desaturation to < 88% or distance < 250 m on 6-minute walk testing or > 50 m decline in 6-minute walk distance over a 6-month period, a fall in FVC ≥ 10% and/or in DL_co ≥ 15% during 6-month follow-up, the presence of pulmonary hypertension, or hospitalisation for acute exacerbation, respiratory decline or pneumothorax.46

Palliative care

Palliative care is an integrated, dynamic and individualised process which should be addressed at all stages of disease, with goals shifting to meet the changing needs of patients. Palliative care focuses on symptom management, advance care directives and end-of-life planning, aiming to improve the quality of life of patients and their families.

The use of oral opioids to reduce dyspnoea, a common and debilitating symptom in IPF, has been reported; however, there is limited evidence for the use of benzodiazepine or oxygen. While opioids and over-the-counter cough suppressants have been used to treat cough in IPF, there is little evidence that these measures are effective, and a thorough search for reversible causes of cough should be undertaken in all patients with IPF.

Conclusion

It is a promising time in the history of IPF, with advances in both the diagnostic process and management of this condition. Accurately diagnosing IPF is critically important, given the positive outcomes with correct use of antifibrotic therapies in a subgroup of patients. The next decade will see further evolution such as advances in high resolution computed tomography technology, newer methods of sampling lung tissue, biomarkers and genetic testing, which will refine the multidisciplinary meeting diagnostic process, improve our ability to provide prognosis for patients, and further optimise and personalise management pathways.

Box 3 – Radiological features of usual interstitial pneumonia

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High resolution computed tomography scan showing reticular abnormality and honeycombing, and (A) subpleural predominance (axial view) and (B) apicobasal predominance (coronal view).

Box 4 – Histopathological features of usual interstitial pneumonia

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Surgical lung biopsy showing (A) gross architectural destruction of lung parenchyma and (B) honeycombing with fibroblastic foci (haemotoxylin–eosin stain).

Box 6 – Suggested treatment algorithm for idiopathic pulmonary fibrosis (IPF)∗

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FVC = forced vital capacity; ILD = interstitial lung disease; MDM = multidisciplinary meeting. ∗ Adapted from Jo et al.11