Usefulness of a disease severity staging classification system for IPF in Japan: 20 years of experience from empirical evidence to randomized control trial enrollment.

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Since 1991, the severity of idiopathic pulmonary fibrosis (IPF) has been classified into 4 stages-stage I (characterized by a resting PaO2 ≥ 80 Torr), stage II (70-79 Torr), stage III (60-69 Torr), or stage IV (<60 Torr)-to aid decisions on medical care subsidization in Japan. Among patients with stage II/III IPF, the severity should be increased by one stage if the lowest oxygen saturation on pulse oximetry (SpO2) is <90% during a 6-min walk test. Patients with stage III/IV IPF receive Japanese government subsidies for incurable diseases. This classification system highly correlates with serial changes in the percentage of vital capacity (%VC), the diffusing capacity for carbon monoxide, the incidence of acute exacerbation, and survival. A phase III trial of pirfenidone showed that IPF patients with an SpO2 on exertion of <90% and either a %VC ≥ 70% or a PaO2 ≥ 70 Torr (which includes most patients with stage III disease) at baseline would benefit from pirfenidone treatment. Recent post-marketing surveillance of 1370 patients--67.3% of whom had stage III/IV IPF--showed that pirfenidone was well-tolerated among those treated for longer than 6 months (63% of patients). A Japanese randomized controlled trial (RCT) demonstrated that inhaled N-acetylcysteine monotherapy benefitted patients with early IPF (stage I/II, with no desaturation on exertion). Thus, N-acetylcysteine monotherapy is suitable for early IPF, and pirfenidone is indicated for advanced disease. The classification of IPF severity is important in identifying clinically responsive patients and those suitable for RCT enrollment.