Criteria for Progression in Fibrotic Non-IPF Interstitial Lung Disease

Progressive Pulmonary Fibrosis in Non-IPF ILD Patients 

A significant portion of patients with fILD other than idiopathic pulmonary fibrosis (IPF) experience disease progression despite initial treatment. This disease phenotype is referred to as progressive pulmonary fibrosis (PPF). PPF is associated with high morbidity and mortality. Most patients with PPF have diagnoses of fibrotic hypersensitivity pneumonitis (fHP), interstitial lung diseases associated with systemic connective tissue diseases (CTD-ILD), or idiopathic interstitial pneumonias (IIP) other than IPF (including fibrotic non-specific interstitial pneumonia and unclassifiable interstitial lung disease). The proportion of patients with PPF falling among fibrotic non-IPF ILD over 24 months excluding fibrotic sarcoidosis was retrospectively estimated at 30%. However, the prevalence of PPF varies depending on the definition of progression.

Signs of PPF Progression and Their Prevalence 

In the INBUILD trial with nintedanib, progression in patients with PPF was defined as a relative decline in forced vital capacity (FVC) by ≥ 10% or a combination of a relative decline in FVC by > 5% and worsening of respiratory symptoms or progression of fibrosis on high-resolution CT (HRCT) over the preceding 24 months. In the observed cohort, PPF most commonly manifested as a relative decline in FVC by ≥ 10% (332/663, or 50.1% of patients).

Hambly et al. examined the prevalence and characteristics of disease progression according to INBUILD criteria in a prospective registry of patients with fILD of all subtypes, including IPF (n = 2746). PPF was found in 50.1% of patients. The frequency of occurrence of PPF in major non-IPF subgroups varied: 58% in fHP, 51% in unclassified ILD, 45% in CTD-ILD, and 39% in other non-IPF diseases. The prevalence of PPF in all patients with non-IPF ILD (excluding sarcoidosis patients) was 47.5% (919 out of 1936 patients), while the prevalence of progression in IPF patients was 59.5% over the same period. The criterion of a relative decline in FVC by ≥ 10% was met by 49.1% of patients with PPF or IPF progression in the entire cohort. The time to progression during the 24-month follow-up was similar across major subgroups and practically the same in IPF and fibrotic hypersensitivity pneumonitis (fHP). 

Large testing (n = 754) and validation cohorts (n = 473) of patients with fHP, CTD-ILD, or non-IPF IIP were included in a multicenter retrospective study (Oldham et al.), which evaluated the prevalence and prognostic significance of various PPF criteria, including INBUILD criteria, their individual components, and other potential criteria over 10 years of follow-up. The most commonly identified progression criterion was the relative decline in FVC by ≥ 5%, noted in 69.7% of patients. The median time to progression in individual cohorts was 10.6−12.9 months. A relative decline in FVC by ≥ 10% was observed in 56.2% of patients, with a median time to progression of 15.3 months in the testing cohort and 24 months in the validation cohort.

Prognostic Significance of PPF Criteria 

Criteria for the early identification of PPF established based on their prevalence and short time to progression include a relative decline in FVC by > 10% and combinations of lower thresholds of FVC decline with symptomatic worsening or progression of fibrosis on HRCT. The prognostic significance of these criteria has been widely validated in terms of mortality, and their prognostic accuracy appears to be higher than alternative criteria. However, results are inconsistent regarding the prognostic significance of these criteria for subsequent FVC decline progression. Criteria may need to be slightly adjusted for patients with CTD-ILD and especially for those with inflammatory myopathy.

Conclusion 

Recently published results from large cohort studies based on the prevalence and prognostic significance of PPF criteria show that the INBUILD study criteria are suitable for the early identification of progression in non-IPF ILD. Parameters used to determine the presence of PPF cited in recent international recommendations largely do not derive from data observed in prior or subsequent real-world cohorts.

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Sources: 
1. Wells A. Patterns of progression in non-IPF fibrotic interstitial lung disease. Curr Opin Pulm Med 2023; 29 (5): 459–464, doi: 10.1097/MCP.0000000000000981. 
2. Oldham J. M., Lee C. T., Wu Z. et al. Lung function trajectory in progressive fibrosing interstitial lung disease. Eur Respir J 2022; 59 (6): 2101396, doi: 10.1183/13993003.01396-2021.
3. Current insights into progressive fibrosis in interstitial lung disease. proLékaře.cz, Sept. 8, 2022. Available at: www.prolekare.cz/tema/progredujici-ipp/detail/aktualni-poznatky-k-progresivni-fibroze-u-intersticialni-plicni-nemoci-131728 
4. SPC Ofev. Available at: www.ema.europa.eu/en/documents/product-information/ofev-epar-product-information_cs.pdf