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Clinical Challenges: Diagnosing Idiopathic Lung Fibrosis

Approval of two antifibrotic drugs for idiopathic pulmonary fibrosis (IPF) — pirfenidone (Esbriet) and nintedanib (Ofev) — represented a paradigm shift in the management of the progressive fibrotic disease and potentially other interstitial lung diseases, ushering in the era of therapies that can slow lung scarring progression.

But the therapeutic progress has focused new attention on significant remaining challenges in the management of IPF and the broad and diverse group of lung disorders that encompass interstitial lung disease (ILD).

First and foremost among these challenges is the accurate and timely diagnosis of idiopathic pulmonary disease.

Questions also remain about the optimal timing of treatment initiation and duration, assessment of treatment response and disease progression, and the management of non-IPF ILDs.

Presenting IPF symptoms — including shortness of breath on exertion, dry cough, and decline in pulmonary function — mimic those of far more common chronic respiratory diseases, including asthma, pneumonia, COPD, and bronchitis.

Accurate diagnosis involves excluding these alternative conditions, as well as careful interpretation of findings from clinical, radiologic, and pathologic examinations.

While international diagnostic guidelines outline specific features characteristic of IPF, identifying these patterns on high resolution CT scans (HRCT), lung biopsies, and other testing may require a high level of expertise due to the frequency of mixed or discordant patterns in patients.

“When a patient presents with very common symptoms such as cough and breathlessness, idiopathic pulmonary fibrosis is often not something a primary care doctor is thinking about,” said pulmonologist Gregory Cosgrove, MD, assistant director of the Interstitial Lung Disease Program at National Jewish Health in Denver.

A nationwide survey of ILD patients conducted by Cosgrove and colleagues, published in 2018, illustrated the scope of the problem, with a high frequency of delayed and missed diagnosis.

Among 600 patients surveyed — 46.5% with a final diagnosis of IPF — 55% reported one or more misdiagnoses and 38% reported two or more before ending their odyssey.

The median time from symptom onset to the diagnosis of IPF or non-IPF interstitial lung disease was 7 months, but in 29% of patients the diagnosis took 2 years or more and in 19% at 3 years elapsed between symptom onset and ultimate diagnosis.

The most common wrong diagnoses were asthma (13.5%), pneumonia (13.0%), and bronchitis (12.3%).

Most surveyed patients who reported delays in receiving an accurate diagnosis said the delay negatively impacted their quality of life.

In an interview with MedPage Today, Cosgrove said raising awareness about IPF and other interstitial lung diseases among patients and general practitioners is critical to reducing the time from symptom onset to accurate diagnosis.

“I would argue that diagnosis is not that complicated once there is an enhanced level of awareness,” he said. “An understanding of the importance of taking a careful history and ordering the right tests may be the difference between a prompt diagnosis and imperially treating a patient for asthma or COPD or some other condition for months and months.”

Timely referral to a subspecialist who routinely treats ILD patients can also dramatically shorten time to diagnosis and initiation of effective treatments, Cosgrove said.

In the survey of patients with ILD, 68% reported that referral to a subspecialist was the most important contributing factor in obtaining their diagnosis.

Delayed referral to subspecialty care was shown to be a risk factor for earlier death in patients with IPF in a 2011 study involving 129 patients.

The median delay was 2.2 years (interquartile range 1.0-3.8 years), and longer delay was associated with an increased risk of death independent of other recognized risk factors (adjusted hazard ratio per doubling of delay was 1.3, 95% CI 1.03-1.60).

Diagnostic delays can not only slow the initiation of therapies that can slow disease progression, they can also delay evaluation for lung transplant which could cause some patients to be considered ineligible due to advanced age or frailty, Cosgrove said.

“It is more important than ever to make a timely and accurate diagnosis,” he said.

Additional challenges in managing IPF and other progressive ILDs were highlighted in a review published early in 2020 by Michael Kreuter, MD, and colleagues from the University of Heidelberg Center for Interstitial and Rare Lung Diseases in Germany.

They noted that, besides imaging and histological testing, analysis of bronchoalveolar lavage fluid may be useful in the diagnostic work-up of suspected IPF, “specifically to exclude alternative diagnoses.”

“Serological testing, particularly for antinuclear antibodies, rheumatoid factor, myositis panel and anticyclic citrullinated peptide levels can specifically help in the differential diagnosis of ILDs associated with connective tissue disorders,” they wrote.

They concluded that important questions remain about the optimal timing of treatment initiation and treatment duration, as well as the management of non-IPF progressive fibrosing ILD.

“Real-world data suggest that many patients are not treated with approved IPF therapies immediately after diagnosis, despite the insidious, progressive nature of IPF,” Kreuter and colleagues wrote.

Another 2016 European survey found that more than half (53.5%) of patients with IPF received neither nintedanib nor pirfenidone.

Kreuter and colleagues noted that while the treatment landscape for IPF “is growing increasingly favorable, many challenges and unmet needs remain.”

“The diagnosis of IPF is still complex, but research into new techniques that could improve the sensitivity of diagnosis and reduce the burden of histological procedures is ongoing,” they wrote. “Lung function tests are, to date, the best measure of disease progression and, although prediction of disease progression in individual patients using pulmonary function testing remains problematic, exploration of quantification of disease progression and treatment response using HRCT, digital lung auscultation and blood biomarkers show promise.”

Last Updated October 23, 2020

Disclosures

Researcher Gregory Cosgrove reported serving as an investigator or collaborator in industry-sponsored clinical trials from Boehringer Ingelheim, Bristol Myers Squibb, FibroGen, Genentech, Gilead Sciences, Global Blood Therapeutics, and Intermune. He also reported serving as an advisor to Boehringer Ingelheim, InterMune, Genentech, and Global Blood Therapeutics and serving as chief medical officer for the Pulmonary Fibrosis Foundation.

Source: MedicalNewsToday.com