IPF and If It Is a Distinct Clinical Entity

In this podcast, Ganesh Raghu, MD, speaks about idiopathic pulmonary fibrosis and the importance of eliminating all causes and conditions that can cause pulmonary fibrosis with features of usual interstitial pneumonia. He talks about how a distinct clinical entity is defined and what should be included in a clinical evaluation to eliminate all the known causes and clinical conditions that are associated with the manifestation of unusual interstitial pneumonia.

Additional Resource:

  • Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5).

Ganesh Raghu, MD, is a professor of medicine, laboratory medicine, and pathology and the director of the Center for Interstitial Lung Disease at the University of Washington (Seattle, Washington). 

Published in partnership with The American Thoracic Society



Jessica Bard: Hello, everyone, and welcome to another installment of "Podcast 360," your go‑to resource for medical news and clinical updates. I'm your moderator Jessica Bard with Consultant360 Specialty Network.

Idiopathic pulmonary fibrosis is a progressive life‑threatening interstitial lung disease. It is limited to the lungs and characterized by patchy, peripheral lobular fibrosis that progresses to honeycombing and end‑stage fibrosis.

Dr Ganesh Raghu is here to speak with us about that today. Dr Raghu is a professor of medicine, laboratory medicine, and pathology, and the director of the Center for Interstitial Lung Diseases at the University of Washington in Seattle, Washington.

Thank you for joining us today, Dr Raghu. You're speaking on the session conundrums and controversies and diagnosis, and management of the interstitial lung disease at the ATS 2021 Annual Meeting. Your specific debate topic is on idiopathic pulmonary fibrosis or IPF. Firstly, do you think IPF is a distinct clinical entity? Why or why not?

Dr Ganesh Raghu: Jessica the term idiopathic is often used to describe a disease with no identifiable cause and is considered a specific primary entity of unknown cause. On the other hand, pulmonary fibrosis is a stereotypic pathological response in the lung to several occult and systemic factors, and the cause may never be discovered in many.

A distinction from pulmonary fibrosis that could occur without an attributable cause was actually made by a consensus of opinions among international experts in the year 2000, about 21 years ago by coining the term IPF or idiopathic pulmonary fibrosis.

Defined it as a distinct specific primary entity that occurred in adults, predominantly in males over 60 years of age in whom they manifested fibrosis was relentlessly progressed to death to three to five years after the diagnosis.

JB: How is the distinct clinical entity defined and why does an IPF fall into that category?

Dr Raghu: A distinct clinical entity is defined with precise clinical features. In this regards, the clinical practice guidelines in the year 2011 and further in 2018 that I was privileged to be the chair of indeed have refined the specific clinical radiographic and pathological features of IPF.

As it stands now, IPF would fall into this category as a distinct category, but then, despite the precise criteria, developed by ourselves to guideline committee.

The hallmark feature of UIP pattern that is required to ascertain the diagnosis of this distinct clinical entity that we currently believe is a distinct one is, however, nonspecific as it occurs in several heterogeneous groups of interstitial lung disease, in whom the cause is either in the environment or as an association of other clinical conditions.

For thus, it really depends upon how prudent and thorough the confronted clinician is in taking a detailed history, and subject the patient to a very thorough clinical evaluation to eliminate all the known causes and clinical conditions that are associated with this manifestation of what we call UIP.

In other words, if the clinical evaluation is not thorough enough, and the clinician is not thorough enough to pursue the index of the clinical suspicion for other diseases, such as hypersensitivity pneumonitis, occult connective tissue disease, the clinician tends to simply label the diagnosis as IPF, which is what the concern is.

JB: What research has been conducted that supports your stance?

Dr Raghu: Several studies have actually documented that patients who manifest features of idiopathic pulmonary fibrosis, the way we described now, do in fact have connective tissue disease. In fact, the so‑called IPF may precede the overt manifestation of specific connective tissue disease by a few years. That's one.

Number two, we also know that interstitial lung abnormalities precedes the manifestation of UIP or IPF. In fact, that position paper by the Fleischner Society recently published this issue in the Lancet respiratory medicine that discusses this concept.

Third, a prospective study done in Barcelona, a few years ago, actually documented that 40 percent of patients who were diagnosed as IPF by a central review of experienced ILD‑IPF experts utilizing the same guidelines, turned out to have hypersensitivity pneumonitis when the same cases were re‑evaluated.

Fibrotic hypersensitivity pneumonitis is always in the differential diagnosis of IPF and often missed by the clinician, as there were no guidelines available to make the diagnosis of hypersensitivity pneumonitis until now.

An evidence‑based guidelines for the diagnosis of hypersensitivity pneumonitis has just been published by the ATF. I'm very hopeful that clinicians will now be able to pursue the diagnosis of HP, the hypersensitivity pneumonitis, rather than concluding the diagnosis as IPF without pursuing other causes.

Also, genetic factors are becoming an important known factors, such as telomere biology disorders. Other genetic polymorphisms are now discovered in about 30 percent of patients with what we currently believe to have IPF.

Thus, genetic, environmental factors besides connective tissue disease and other clinical conditions, including some known inherited diseases are being recognized as associated manifestation of pulmonary fibrosis, and disease behavior, similar to IPF.

Finally, there is an rapidly evolving concept in knowledge that pulmonary fibrosis is progressive in several of the heterogeneous group of interstitial lung diseases. This is yet another supporting argument that IPF is not a distinct entity anymore.

JB: You briefly touched on this, but how might this research aid healthcare providers in making a diagnosis of IPF more quickly?

Dr Raghu: Jessica, it is my hope that this debate or increasing awareness will awaken the minds of healthcare providers to be more diligent and prudent in thorough evaluation as I have explicitly stated by eliciting a very detailed medical history that includes family history, genetic factors, environmental factors, clinical assessment that requires multidisciplinary discussions.

Be constantly on the lookout for systemic diseases, such as connective tissue disease, and be confronted with patients with interstitial lung disease before concluding the patient has IPF.

In my opinion, making a diagnosis of IPF, as you call it more quickly or even early is too late. In my opinion, as the current criteria to make the diagnosis of IPF requires the lung to have advanced disease called honeycomb features, which is now a hallmark characteristic feature of IPF, as it stands today.

JB: Dr Raghu, what is the overall key take‑home message for our audience today?

Dr Raghu: The overall key take‑home message is that UIP that is currently required feature to make a diagnosis of IPF does not equate to the diagnosis of IPF. It is nonspecific manifestation of many clinical entities.

Therefore, it is crucial for the clinician to investigate for this, and engage other experts in multi‑disciplines to make the diagnosis before diagnosing IPF. If they do that, the prevalence of true IPF is likely to be substantially lower than the current estimate of only 20 percent.

JB: Is there anything else that you'd like to add today? Anything that we missed?

Dr Raghu: Not really, but I think it is time to acknowledge, maybe changing the I in the IPF to I as irreversible, pulmonary fibrosis irreversible, as it relates to honeycomb lung because honeycomb long cannot be reversed, at least to current knowledge, and that is irreversible permanent causes to multiple causes.

This is likely to shift the clinical understanding and therapeutic strategies can then target the cascade, or the fibrotic pathways, regardless of the cause. This shift would provoke both the clinician and the patient to be more prudent and diligent in exploring all current causes that led to the manifestation of UIP, with the hope that the UIP will become a rare manifestation in the future.

The term idiopathic in the context of idiopathic pulmonary fibrosis will soon be a historical term. Basically, Jessica, I think time has come for us to concede that IPF is not a primary entity of unknown cause anymore. It simply represents a delayed diagnosis of irreversible pulmonary fibrosis, meaning honeycomb lung of multiple causes.

JB: Thank you so much for your time today. I really appreciate you being here.

Dr Raghu: You're welcome, Jessica. Thank you for having me.