PF-ILD
Diagnosis
Progressive fibrosis is an important characteristic of several Interstitial lung diseases (ILDs) that is strongly linked with morbidity and mortality. Although individual ILDs that may present a progressive-fibrosing phenotype have distinguishing features in terms of their clinical, radiological and histopathological presentations, they also have many overlapping characteristics that are similar to the classical fibrosing ILD with a progressive phenotype, IPF. Antifibrotic therapy is currently being investigated in these diseases. Accurate and early diagnosis is challenging but crucial to ensure that each patient receives treatment that is appropriate for the rate of progression seen with their particular disease.1
Diagnostic criteria1,2,3
The differential diagnosis of ILDs requires a multidisciplinary approach, usually involving pulmonologists, radiologists and pathologists.1 Evaluations include clinical presentation, specific history assessment, smoking status, lung function evolution, serological test results, imaging and, if required, lung biopsy.1 ILD diagnosis should be categorized as confident, provisional or unclassifiable depending on the level of diagnostic confidence.2 Based on current knowledge, Cottin proposed the algorithm in Figure 12 for diagnosing ILDs that may present a progressive-fibrosing phenotype; clinical data are needed to refine and validate this approach.1 Recently, several clinical trials have included patients with a progressive fibrosing phenotype, with the eligibility criteria for these studies helping to further guide a standardized definition of progressive fibrosing interstitial lung diseases (PF-ILD) (Table 1).3
Forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) 3, 4
To define PF-ILD, Cottin proposed the following criteria: a relative decline in FVC ≥ 10%, a relative decline in DLCO ≥ 15%, or a relative decline in FVC ≥ 5% but < 10% in combination with worsening of symptoms or radiographic findings in the past 24 months.4 Several criteria have been used to define progression in patients with IPF, with most of these based on an absolute or relative decline in FVC and DLCO ≥5–10% or ≥ 10–15% respectively, a decline in 6-min walk distance (6MWD) > 50 m, or worsening dyspnea and quality of life scores. In patients with systemic sclerosis-associated ILD (SSc-ILD), an absolute 1-year decline in FVC ≥ 10% or 5-9% plus a decline in DLCO ≥ 15% are strong predictors of mortality. In rheumatoid arthritis (RA)-ILD, an absolute FVC decline of ≥ 10% has been used as evidence of progression based on the increased mortality in patients meeting this threshold.3
High-resolution computed tomography (HRCT)1,3
Despite these associations in large cohort studies, FVC and DLCO trajectories can be unpredictable and are less reliable among individual patients given important intra- and interpatient variability.3 As a result, physicians typically use a combination of patient-reported symptoms, trends in pulmonary function tests, and the evolution of fibrosis on imaging to decide if there is clinically relevant ILD progression (Figure 2).3 HRCT help determine the prognosis in ILDs, and quantitative CT analysis may be useful for evaluating disease progression.1
Figure 1. Diagnosis of fibrosing ILDs that may present a progressive phenotype.2
Figure 2. Computed tomography imaging of the chest in a patient with progressive unclassifiable interstitial lung disease.*
Table 1. Disease severity and definition of progression used in eligibility criteria for selected recently completed and ongoing clinical trials evaluating PF-ILD
| Clinical trial |
Disease severity | Minimum definition of progression |
||||
|---|---|---|---|---|---|---|
| Pulmonary function |
HRCT | Time frame | Pulmonary function |
Symptom | HRCT | |
| Pirfenidone in unclassifiable ILD | FVC ≥ 45% DLCO ≥ 30% 6MWD ≥ 150m |
Fibrosis affecting > 10% of lung volume | 6 months | FVC > 5% decline (absolute) | Worsening symptoms |
|
| Pirfenidone in progressive non-IPF ILD (RELIEF) | FVC 40-90% DLCO 25-75% 6MWD ≥ 150m |
12 months | FVC ≥ 5% decline (absolute) | |||
| Nintedanib in non-IPF PF-ILD (INBUILD) | FVC ≥ 45% DLCO 30-80% |
Fibrosis affecting > 10% of lung volume | 24 months | FVC ≥ 10% decline (relative) At least two of: FVC 5-10% decline (relative) | Worsening symptoms |
Increasing extent of fibrosis |
| Pirfenidone in Patients With RAILD (TRAIL1) | FVC ≥ 40% DLCO ≥ 30% |
Fibrosis affecting > 10% of lung volume | 12 months | FVC ≥ 10% decline (relative) or FVC 5–10% decline (relative) and DLCO ≥ 15% decline (relative) | ||
Footnotes:
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* Serial apical (a, c, e) and basal (b, d, f) axial images at baseline (a, b); at 36 months (c, d); and at 42 months (e, f). Images show upper lobe predominant pulmonary fibrosis
with progressive reticulation, traction bronchiectasis, and honeycombing. 6MWD, 6-min walk distance; BAL, bronchoalveolar lavage; DLCO, diffusing capacity of the lungs for
carbon monoxide; ILDs, Interstitial lung diseases; IPF, idiopathic pulmonary fibrosis,; FVC, forced vital capacity; HRCT, high-resolution computed tomography; MDD,
multidisciplinary diagnosis; PF-ILD, progressive fibrosing ILD; RA, rheumatoid arthritis; SSc-ILD, sclerosis-associated Interstitial lung diseases.
References:
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Cottin V et al. Eur Respir Rev. 2018. 27(150).
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Cottin V. Eur Respir Rev. 2019. 28(153).
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Wong A. W et al. Respir Res. 2020. 21(1): 32.
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Makino S. Mod Rheumatol. 2021. 31(1): 13-19.