The Annual Scientific Meeting for leaders in Lung Health & Respiratory Science, held in March/April 2022, featured an update on the management of interstitial lung disease (ILD), including new definitions and advances in the diagnosis and monitoring of ILD. Associate Professor Nicole Goh moderated the session. She was joined by Consultant Respiratory Physician Associate Professor Tamera Corte, Director of Interstitial Lung Disease in the Department of Respiratory Medicine at Royal Prince Alfred Hospital Sydney, and Professor Luca Richeldi, head of the Division of Respiratory Disease, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Progressive Fibrosing interstitial lung disease (PF-ILD): shifting focus from diagnosis to progression

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia, accounting for up to 30% of cases.^1,2 It is characterised by increasing fibrosis noted on high-resolution computed tomography (CT), and a decline in lung function, quality of life and survival.³ Progression is common even in non-IPF ILD, with as many as one-third of non-IPF ILD patients at risk of developing a progressive fibrosing phenotype: data from a survey of 486 physicians who regularly manage ILD patients estimated that 18-32% of patients diagnosed with non-IPF ILD develop progressive fibrosis.⁴

A/Prof. Corte explained, “When we move to the relatively new concept of progressive pulmonary fibrosis, we need to start thinking of all interstitial lung disease or pulmonary fibrosis lumped together and instead of splitting conditions based on specific ILD diagnosis, we need to split them into whether they are progressive or non-progressive – an exception here is idiopathic pulmonary fibrosis, which is mostly progressive.”⁵

Honing in on responsiveness to therapy

A/Prof. Corte explained that fibrotic ILDs may be classified into three categories based on disease behaviour: non-progressive; progressive and responsive (at least in the short term) to initial therapy (i.e., immune suppression or antigen avoidance); and progressive regardless of appropriate treatment.⁴  “Typically, we see a gradual progression over a number of months from ILD symptom onset to death over a mean time of 61-80 months” said A/Prof Corte. “That is from initial symptoms of ILD, diagnosis, development of progressive fibrosing ILD, progressive fibrosing ILD detected by physician, and death. Given the time frame, this provides valuable opportunity to diagnose, intervene and delay disease progression,” she said.

Identifying progression demands a clear definition

A/Prof. Corte noted that the definition of progression has been a recurrent theme of clinical discussion. “Disease progression can be complex, as it often consists of assessments made by the physician, other carers in the health team and patient feedback,” she said. “Typical progression measures may include changes in lung capacity, worsening of cough, dyspnoea, reduced physical function – that is, a decrease in exercise capacity – decline in Forced Vital Capacity (FVC) and/or diffusing capacity of the lungs for carbon monoxide (DLco), increase in radiological abnormalities, and physician or patient impression that disease has worsened. For clinical trials there are more defined criteria, as stated in the literature, which when looking at drug accessibility becomes important,”⁵she said.

According to A/Prof. Corte, there are a number of reasons why it makes clinical sense to classify ILD according to whether it’s progressive fibrosing: “Patients with progressive ILD have a common pathobiology: as ILD patients progress, there is a common pathobiology of end stage fibrosis. Secondly is for prognostic reasons. That is, if you take patients from any different ILD and look at patients who progress over a 6-month period, they are in a worse category – patients who progress are bound together by their poor prognosis. The third reason is there are clear indications for management.”

The role of antifibrotics in PF-ILD

A/Prof. Corte provided an overview of the evidence for use of the antifibrotics such as nintedanib for PF-ILD.^7-10 The INBUILD trial was a randomised, double- blind, placebo-controlled, parallel-group trial conducted at 153 sites in 15 countries (n= 663) to assess the efficacy and safety of nintedanib in patients with PF-ILD. Its primary endpoint was the annual rate of decline in the FVC, as assessed over the 52-week period. The adjusted rate of decline in the overall population was −80.8 mL per year with nintedanib and −187.8 ml per year with placebo, for a between-group difference of 107.0 mL per year (95% confidence interval [CI], 65.4 to 148.5; P<0.001). For those patients with a UIP-like fibrotic pattern, the adjusted rate of decline in the FVC was −82.9 ml per year with nintedanib and −211.1 mL per year with placebo, for a difference of 128.2 ml (95% CI, 70.8 to 185.6; P<0.001). The most commonly reported adverse event was diarrhoea, as reported in 66.9% and 23.9% of patients treated with nintedanib and placebo, respectively. Abnormalities on liver-function testing were more common in the nintedanib group than in the placebo group yet the study showed that for patients with progressive fibrosing interstitial lung diseases, the annual rate of decline in the FVC was significantly lower among patients who received nintedanib than among those who received placebo.⁸

Based on the results of the INBUILD trial, the Pharmaceutical Benefits Advisory Committee gave a positive recommendation for nintedanib in patients with PF-ILD, and the Pharmaceutical Benefits Scheme (PBS) OFEV^® (nintedanib) listing was expanded in May 2022 from the initial IPF listing to the broader PF-ILD listing.^11,12

A/Prof. Corte summarised a 3-stage approach for clinical disease management of PF-ILD: 1) ensure accurate diagnosis, 2) treat with standard-of-care 3) consider antifibrotic therapy if there is evidence of progression despite conventional treatment.¹³

Personalised management in pulmonary fibrosis: what’s in store for the future?

Prof. Richeldi described pulmonary fibrosis as a prototypic disease of the larger group of fibrotic disorders with fibrosis a common pathway to organ injury and organ failure.¹⁴ He noted three important points on fibrosis:¹⁴

• Fibrosis and resultant organ failure accounts for at least one third of deaths worldwide, making it an important medical problem.
• Fibrosis is common and can affect any organ, making it an attractive therapeutic target.
• Whilst it is believed that scar tissue is permanent, fibrosis is reversible, with available evidence pointing to the highly plastic nature of organ ¹⁴

At present, diagnosis is mostly made by exclusion of idiopathic causes of PF and Hi-Res Computer Tomography (HRCT) of the chest.¹⁵ In 2018, three papers were published that tried to remove some of the ambiguity in diagnosis, but the quest to introduce more objective tests to further reduce ambiguity is ongoing.^3,16,17  “Accurate diagnosis is important, yet it is still a challenge, given it can come down to clinician experience. There is now a large field of study to develop accurate objective tests, this is to provide confirmation independent to interpretation of a radiologist, which may improve accuracy in diagnosis. The earlier detection, the quicker the patient can be treated,”^18,19 Prof. Richeldi said.

Developments in technologies such as machine learning are now assisting clinicians in making an accurate diagnosis.¹⁹ One study has assessed the ability of a machine-learning algorithm to identify a interstitial pneumonia pattern from diagnostic histopathology and RNA sequence data.¹⁹ The classifier was able to identity interstitial pneumonia in transbronchial lung biopsy samples with 88% specificity (95% CI 70–98) and 70% sensitivity (95% CI 47–87).¹⁹

Early detection and treatment is key

Prof. Richeldi highlighted how digital auscultation is a useful screening and subsequent monitoring tool, as there is a clear sound pattern of a healthy person compared to someone with pulmonary fibrosis.^20-22“In the case of catching the disease early this is very important as [antifibrotic] drugs nintedanib and pirfenidone do not stop or reverse disease, but simply reduce disease progression,” he explained.

The official American Thoracic Society (ATS/ERS/JRS/ALAT) guideline states that suspected patients are likely to have bibasilar inspiratory crackles which may be picked up through accurate listening.^16,23 In this area, Prof. Richeldi briefly touched on a clinical trial that investigated the use of digital acoustic analysis of lung sounds as a valid metric of disease severity.^22,24 It was shown that lung sounds are a reproducible and valid metric of disease severity in IPF patients.²²

“Whilst other methods of investigation and diagnosis such as surgery biopsy, chest HRCT pattern, and molecular classifiers are important, digital auscultation should also now be taken up as it also offers the advantage that it can be used at the beginning and end of diagnosis, it’s safe, at point of care, and cheap,”²⁵ said Prof Richeldi

The session panel agreed that the PBS listing of nintedanib for PF-ILD and the use of more enhanced diagnostic tools may help improve treatment of patients and allow clinicians to make more accurate diagnoses in the future. It was suggested that the proposed PBS clinical criteria for nintedanib may need further discussion, especially around observation time frames and meaningful progression. However, with this new listing there are now other options available for clinicians to manage and monitor interstitial lung disease.

Disclosure

This article was sponsored by Boehringer Ingelheim. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the OFEV product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

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