Orphanet Journal of Rare Diseases | Oscillometry Reveals Expiratory Phase Lung Function Abnormalities in Patients with Late-Onset Pompe Disease

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This study suggests that respiratory mechanical abnormalities in patients with late-onset Pompe disease may extend beyond the scope of conventional pulmonary function testing. Oscillometry can detect occult expiratory resistance increases, offering a more sensitive, non-invasive tool for evaluating future respiratory intervention strategies.

 

Literature Overview

The article titled 'Expiratory phase lung mechanics in late-onset Pompe disease: a multicenter study using oscillometry to identify specific breathing abnormalities,' published in the journal Orphanet Journal of Rare Diseases, systematically investigates whether unrecognized expiratory phase respiratory mechanical abnormalities exist in patients with late-onset Pompe disease (LOPD), even when conventional pulmonary function is normal or only mildly restricted. Through a multicenter prospective study, the authors applied the forced oscillation technique (FOT) to perform whole-breathing cycle analysis in 16 adult LOPD patients, revealing two distinct mechanical phenotypes. The study further evaluated the immediate effects of air-stacking on respiratory mechanics, finding that despite a significant increase in lung volume, expiratory phase abnormalities did not improve. This work emphasizes that in neuromuscular diseases, pulmonary function assessment must go beyond the limitations of traditional forced vital capacity (FVC) to more sensitively capture respiratory pathophysiology.

Background Knowledge

Late-onset Pompe disease (LOPD) is a lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA), leading to abnormal glycogen accumulation in muscles and the respiratory system. Although respiratory failure is primarily attributed to restrictive ventilatory dysfunction caused by diaphragmatic weakness, animal models show that GAA deficiency also leads to glycogen deposition in distal airways and lung parenchyma, suggesting possible non-myogenic pulmonary involvement. Currently, respiratory management in LOPD mainly relies on metrics such as FVC and MIP/MEP, which cannot capture dynamic airway behavior. Moreover, despite the widespread use of enzyme replacement therapy (ERT), some patients still experience progressive respiratory decline, indicating that current monitoring methods may miss key pathological mechanisms. Therefore, more sensitive tools are urgently needed to characterize early or occult respiratory mechanical abnormalities. This study focuses on using oscillometry to analyze differences in resistance and reactance between inspiration and expiration (e.g., ΔR5, ΔX5), exploring whether regional airway-parenchymal mechanical imbalances exist that do not fully align with muscle weakness, thus offering new insights for refined phenotyping and intervention assessment in LOPD.

 

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Research Methods and Core Experiments

The study enrolled 16 genetically confirmed adult LOPD patients from three medical centers in Italy. All patients had respiratory involvement (FVC < 80% predicted or postural decline in FVC > 25%). A prospective observational design was used, with simultaneous standard pulmonary function tests (including FVC, FEV1/FVC, MIP/MEP) and forced oscillation technique (FOT). FOT measurements were performed at frequencies of 5, 11, and 19 Hz to obtain total respiratory system resistance (R) and reactance (X). Parameters during inspiration and expiration were analyzed separately, and expiratory-inspiratory differences (e.g., ΔR5 = R5exp − R5insp) were calculated. Abnormal thresholds were set at ΔR5 > 0.70 cmH₂O·s/L and ΔX5 < −1.0 cmH₂O·s/L to ensure high specificity. After baseline measurements, all patients underwent standardized air-stacking maneuvers, followed by repeated FOT and pulmonary function tests after 5 minutes. Between-group comparisons used non-parametric tests, and correlation analyses used Spearman’s rho.

Key Conclusions and Insights

• Two oscillometric mechanical phenotypes were identified in LOPD patients: one with significantly increased expiratory resistance (ΔR5 > 0.70), indicating expiratory airway instability, and another with stable mechanics throughout the breathing cycle. This finding shows that traditional FVC cannot differentiate these subtypes, and oscillometry provides additional stratification information.
• Some patients exhibited abnormal ΔR5 despite normal overall resistance (R5), suggesting that expiratory abnormalities may be independent of total airway resistance, possibly reflecting regional dynamic narrowing or airway-parenchymal coupling imbalance, which is important for understanding LOPD respiratory pathophysiology.
• Air-stacking significantly improved FVC (increased from 53.3% to 71.3% predicted, p < 0.001), but did not improve expiratory reactance (X11), and even showed a worsening trend. This indicates that although lung volume recruitment increases volume, it does not resolve underlying expiratory mechanical instability, suggesting that respiratory rehabilitation strategies should consider mechanical quality rather than volume alone.
• Patients without expiratory abnormalities showed lower MEP (p = 0.001), suggesting respiratory muscle strength may influence oscillometric signal expression. However, ΔR5 showed no correlation with FVC%, indicating that mechanical abnormalities are not solely driven by reduced lung volume, warranting further investigation into respiratory muscle coordination mechanisms.

Research Significance and Outlook

This study provides a new non-invasive assessment dimension for respiratory phenotyping in LOPD. Oscillometry can complement traditional pulmonary function testing to enable early identification of high-risk patients and guide individualized respiratory support strategies. Future studies should validate whether these oscillometric phenotypes correlate with symptom progression, ventilatory dependence, or prognosis, promoting their use in clinical monitoring. Additionally, this technique can be used to evaluate the effects of novel therapies (e.g., gene therapy or AAV delivery) on lung microstructure, particularly verifying in animal models whether GAA restoration improves airway-parenchymal mechanics.

 

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Conclusion

This study uses respiratory oscillometry to reveal expiratory phase mechanical abnormalities in patients with late-onset Pompe disease (LOPD) that are undetected by conventional pulmonary function tests, proposing two potential respiratory phenotypes: one with increased expiratory resistance representing a complex restrictive pattern, and another with purely neuromuscular restriction. This finding challenges the current reliance on FVC alone for assessing respiratory status in LOPD, emphasizing the need to incorporate more sensitive mechanical metrics for a comprehensive understanding of disease burden. Although air-stacking increases lung volume, it fails to improve expiratory mechanics, suggesting that therapeutic goals should shift from 'increasing volume' to 'optimizing respiratory efficiency.' From lab to clinic, this technology has the potential to become an important monitoring tool in the long-term management of LOPD, helping identify subgroups requiring more aggressive intervention. Future multicenter longitudinal studies will validate the prognostic value of these oscillometric indices and explore their potential in assessing lung functional recovery following novel GAA-targeted therapies (e.g., mRNA or gene editing), laying the foundation for a more precise LOPD care system.

 

Grazia Crescimanno, Oreste Marrone, Marta Lazzeri, Filippo Brighina, and Marco Confalonieri. Expiratory phase lung mechanics in late-onset Pompe disease: a multicenter study using oscillometry to identify specific breathing abnormalities. Orphanet Journal of Rare Diseases.