Respiratory effort in IPF patients during unassisted spontaneous breathing: a prospective monocentric study on its quantification and clinical implications at rest and after 6MWDT

Background. Preclinical evidence suggests that respiratory effort may play a pathogenic role in the progression of pulmonary fibrosis, mediated by mechanotransduction mechanisms, in patients with idiopathic pulmonary fibrosis (IPF). Although IPF represents the paradigmatic and most common form of fibrotic interstitial lung disease (F-ILD), other forms of progressive pulmonary fibrosis (PPF) also share similar clinical phenotypes and evolutionary outcomes. In particular, the tomographic pattern of usual interstitial pneumonia (UIP), which is typical of IPF, appears to act as a risk factor for fibrotic progression through focal overdistension phenomena, which can also be induced during spontaneous breathing. Objectives. The primary objective of the study is to quantify respiratory effort using nasal manometry in patients with mild to moderate F-ILD presenting a UIP radiological pattern. Furthermore, the study aims to correlate breathing effort with the clinical and functional outcomes of these patients. Materials and methods. In this prospective monocentric study, patients with F-ILD and a UIP pattern documented by HRCT scan performed within 6 months from first assessment were considered eligible for enrollment. These patients were consecutively admitted to the Center for Rare Lung Diseases of the University Hospital of Modena between June 1st, 2023, and May 31th, 2025. Nasal pressure (Pnose) was measured at rest (Pnose_rest), at the end of the 6MWDT (Pnose_effort), and following 2 minutes of recovery (Pnose_recovery). Demographic, clinical, and functional data were collected, including pulmonary function tests and the 6MWDT. The correlation between these variables and Pnose at different time-point was analyzed. A longitudinal exploratory analysis was also conducted to assess the correlation between Pnose and changes in forced vital capacity (FVC) at 6 months. Results. A total of 71 patients with F-ILD were enrolled. Nasal manometry showed that the median value of Pnose_rest was 1.4 cmH₂O, then it increased to 3.8 cmH2O, p<0.0001 under submaximal effort (Pnose_effort), and decreased only partially to 2.6 cmH₂O after 2 minutes of recovery (Pnose_recovery, p<0.0001). Pnose measured in each condition showed a significant inverse correlation with the distance walked during the 6MWDT (r=-0.21, p=0.04, r=-0.37, p=0.01; r=-0.23, p=0.04). Only Pnose_effort was inversely correlated with nadir SpO₂ reached during the 6MWDT (r=-0.34, p=0.005). Dyspnea reported by patients using the BORG scale was positively correlated with Pnose_rest, Pnose_effort and Pnose_recovery (r=0.3, p=0.01, r=0.32, p=0.01, and r=0.38, p=0.003 respectively). In patients who completed the second evaluation at 6 months (n=54), baseline Pnose_effort was inversely correlated with the relative decline in FVC (r=-0.39; p=0.01) and DLCO (r=0.4; p=0.02). Conclusions. The measurement of respiratory effort through nasal manometry in a cohort of patients with F-ILD and a UIP radiological pattern showed that submaximal effort generates values close to the threshold associated with potentially harmful mechanical stress, which may contribute to fibrosis progression through mechanotransduction mechanisms. Moreover, the correlations observed between respiratory effort measurements and variables describing patient functional reserve (6MWD and nadir SpO₂), as well as functional decline (relative changes in FVC and DLCO), suggest a potential prognostic value of this parameter and its application in clinical practice.