Beyond Diffusion Capacity: Continuous Exercise Oximetry Reveals Phenotype-Related Cardiopulmonary Signals in...

Background: Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) are defined and monitored without definite exercise-based criterion, despite exertional desaturation being among the earliest functional signs of disease and an established independent predictor of mortality in IPF. The 6 min walk test (6MWT) provides robust prognostic information in IPF, yet whether it can kinetically distinguish IPF from PPF under sustained submaximal loading has not been systematically examined. We hypothesised that second-by-second oximetry during the 6MWT and the 1 min (min) sit-to-stand test (1STST) would expose phenotype-specific kinetic signatures invisible to static endpoints, and that test modality would matter. Methods: Fifty-one patients with IPF, 12 with PPF, and 100 with non-IPF/non-PPF ILD (reference cohort) from the European ILD Registry (eurILDreg) participated in this pilot study and completed both tests with continuous 1 Hz SpO₂ and pulse-rate recording. Phenotype-specific desaturation and recovery slopes were derived from random-effects panel regression models. Multivariable linear regression tested whether IPF and PPF phenotypes carried kinetic and static-endpoint signatures independent of DLCO, age, sex, and BMI. Results: Despite substantially lower DLCO in fibrosing phenotypes (IPF 45 ± 17%, PPF 38 ± 11%, reference 55 ± 19%; p < 0.001), conventional exercise performance metrics did not differ significantly between groups (6MWD p = 0.099; 1STST repetitions p = 0.351). The 6MWT produced statistically indistinguishable per-second desaturation slopes in IPF and PPF (both ≈ -0.016%/s versus -0.011%/s in the reference), whereas the 1STST exposed a clear phenotype gradient (PPF -0.044%/s, IPF -0.027%/s, reference -0.016%/s; a 2.75-fold spread). PPF additionally showed a blunted chronotropic response during the 6MWT (PR slope +0.014 vs. +0.032 and +0.033 bpm/s in IPF and reference). Likelihood-ratio tests confirmed significant phenotype effects on seven of eight time-resolved trajectories (all p < 0.001). IPF was independently associated with greater cumulative oxygenation deficit during the 1STST (SpO₂ AUC β = +669, p = 0.022), indicating excess dynamic burden beyond what diffusion capacity predicts. Conclusions: In this pilot analysis, continuous high-resolution oximetry identified two phenotype-related signals that were robust to the principal confounders. IPF was independently associated with a greater cumulative oxygenation impairment during the 1STST after DLCO adjustment, and PPF showed a blunted chronotropic response during sustained walking that, being pulse-rate based, was unaffected by supplemental oxygen and was not attributable to pulmonary hypertension. A phenotype gradient in per-second desaturation measurements during the 1STST was also observed but should be interpreted as hypothesis-generating, as the small PPF subgroup (n = 12), its greater disease severity, and supplemental oxygen use in half of its patients preclude firm attribution to phenotype. Taken as exploratory, these observations support the prospective evaluation of kinetic exercise parameters as candidate monitoring components for PPF.