Not a diagnosis, not (yet) a phenotype… so what is it?

Admittedly, this can be a bit confusing! The guideline committee avoided the term “phenotype” because they worried it implied an established genotype, and avoided the term “clinical phenotype” because they worried people would drop the modifying term “clinical,” thereby returning to the confusion that prompted the original concern. For my own mental schema, I think of it as a clinical descriptor or clinical phenotype. Regardless of how you file it away, you need to remember it is not a diagnosis and is, in fact, agnostic to the underlying cause, with the exception of excluding IPF. (This is not unheard of in medicine: for example, our use of ARDS and sepsis both function much in the same way. Both describe states that are semi-agnostic to the specifics of an underlying cause and which are still useful for selecting specific management strategies when caring for patients.)

Detailed Definition

Progressive pulmonary fibrosis was defined by a 2022 ATS/ERS/JRS/ALAT Clinical Practice Guideline. Specifically, the term applies to patients with imaging evidence of fibrotic interstitial lung disease, who did not meet criteria for idiopathic pulmonary fibrosis (IPF). Other than excluding patients with IPF, whether the etiology of the patient’s pulmonary fibrosis is known or unknown is not important for assigning the PPF classifier.

To meet criteria, patients had to fit the above description and, within the preceding year, meet at least two of three criteria:

1. Worsening respiratory symptoms
   

2. Physiological evidence of disease progression, defined as either:

   Absolute decline in FVC >5% predicted, or
   Absolute decline in DLCO (corrected for Hb) >10% predicted
   

3. Radiological evidence of disease progression

   Increased extent or severity of traction bronchiectasis and bronchiolectasis
   New ground-glass opacity with traction bronchiectasis
   New fine reticulation
   Increased extent or increased coarseness of reticular abnormality
   New or increased honeycombing
   Increased lobar volume loss

Finally, patients must not have another reason for the observed changes, which the committee noted was especially important if a patient only meets criteria based on a change in symptoms and worsened DLCO, since DLCO is a non-specific measure. When DLCO change is the sole physiologic criteria being met, this should mandate additional evaluation, including repeat HRCT Chest to ensure fibrotic progression is the cause (and not other alveolar destruction, alveolar filling, or pulmonary vascular disease. The latter is especially important since all patients with ILD are at risk for WHO Group III pulmonary hypertension, and patients with underlying autoimmune disease may also be at risk for WHO Group I pulmonary hypertension.)

Background & Nuances

Contrasting the Practice Guideline to Trial Definitions

The guideline committee explicitly noted that to arrive at this definition required combining the definitions from multiple trials, in part “because the committee believed that no single trial should guide antifibrotic therapy.” To highlight this, here are features from three definitions for progressive pulmonary fibrosis from some major trials:

• INBUILD & FIBRONEER-ILD: within 24 months,

  • A relative decline in FVC of 10% predicted, or

  • A relative decline in FVC of 5-10% predicted and changes in symptoms or fibrotic progression on imaging, or

  • A change in symptoms and fibrotic progression on imaging
    

• RELIEF: within the prior 6-24 months,

  • Three FVC values, which, when extrapolated, predicted an absolute decline in FVC of 5% per year

Adding another wrinkle, there may be a need for disease-specificity: the 2024 ATS guideline for SSc-ILD adapted the 2022 PPF criteria specifically for SSc-ILD but eliminated a time requirement altogether. Progressive SSc-ILD was instead defined by the presence, during follow-up, of at least two of three features: worsening respiratory symptoms, physiologic progression (5% absolute decline in FVC or 10% absolute decline in DLCO), or radiographic progression; this change reflects retrospective evidence that patients with SSc-ILD tend to demonstrate non-linear progression and that periods of progression are not necessarily continuous.

As you can see, there are differing positions on many aspects of the PPF definition: among them, whether to use relative or absolute declines in percent-predicted values for FVC and within what duration changes must occur. Trials also largely avoided using DLCO in their definition (which makes some sense for research, given its non-specificity and technical limitations affecting its reproducibility).

Absolutely Relative

The definitions above may have raised a question: what exactly is the difference between a relative change and an absolute change in percent predicted?

We can make this concrete using the same numbers used in the 2022 guideline. Imagine that a patient starts with an FVC of 60% predicted. An absolute decline of 5 percentage points would mean the FVC falls from 60% predicted to 55% predicted. A relative decline of 5%, however, is calculated from the starting value: 5% of 60 is 3. So, a 5% relative decline would mean the FVC falls from 60% predicted to 57% predicted, and a 10% relative decline would mean the FVC falls to 54% predicted.

Clinical Relevance

In practice, progressive pulmonary fibrosis can be operationalized in several ways. Across these definitions, however, a useful first principle is to triangulate three types of data: the patient’s clinical report (i.e., changing respiratory symptoms), physiologic trends (i.e., pulmonary function testing), and radiologic trends (i.e., evidence from CT imaging, which usually should be obtained in a hypothesis-driven manner rather than simply because a fixed interval has elapsed). This approach is useful throughout ILD care.

At their core, these efforts aim to identify patients whose disease continues to evolve and compromise functioning lung through fibrotic change, while establishing guardrails against artifactual or nonspecific changes that could cause clinicians to misclassify quiescent disease as progressive disease. Striking this balance is particularly important in a treatment landscape where antifibrotic therapies can slow further loss of lung function and cannot reverse established fibrotic damage, but frequently come with a meaningful side effect profile.

In practice, many clinicians consider evidence accumulated over approximately 12 to 24 months when determining whether PPF is present. Some institutions use an integrative strategy that borrows elements from both clinical trial definitions and the 2022 ATS/ERS/JRS/ALAT guideline.

• For example, an INBUILD/FIBRONEER-like approach would consider a relative decline in FVC >10% predicted sufficient physiologic evidence of progression, or a relative decline of 5% to 10% when accompanied by worsening respiratory symptoms or radiologic progression.

• However, this approach could be complemented by maintaining awareness of the 2022 guideline criterion for an absolute decline in DLCO >10% predicted.

  • For example, since DLCO is non-specific, an absolute decline in DLCO >10% predicted could trigger further investigation, such as detailed history-taking for alternative explanations, and obtaining a repeat CT Chest.

  • This could also be useful in a clinical context where relief of extra-thoracic restriction increases FVC or offsets an FVC decline. For example, substantial weight loss can improve obesity-related respiratory mechanics and increase FVC, potentially attenuating the FVC decline caused by progressive fibrosis.

  • Alternatively, a decline in DLCO despite a stable FVC could herald onset of pulmonary vascular disease or a separate alveolar filling process (highlighting another clinical use of routine DLCO monitoring and the importance of developing a diagnostic schema for FVC-DLCO discordance).

References

• Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, Kreuter M, Lynch DA, Maher TM, Martinez FJ, Molina-Molina M. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. American journal of respiratory and critical care medicine. 2022 May;205(9):e18-47.