King's College London

Background: There is marked variability in the symptoms and outcomes of patients with chronic obstructive pulmonary disease (COPD) which are poorly predicted by spirometry/FEV _1%pred. Furthermore, as spirometry requires the performance of potentially distressing respiratory manoeuvres which are to some extent user-effort dependent, there is need for non-invasive and simple-to-perform techniques to identify subtypes of COPD which are more closely related to clinically relevant outcomes. Materials and Methods: The inspired sinewave test (IST) sinusoidally modulates the inspired concentration of a tracer gas (N ₂O) over successive tidal breaths. A singlecompartment tidal-ventilation lung model processes the amplitude/phase of the expired N ₂ O sinewave and estimates cardiopulmonary variables including: effective lung volume and indices of ventilatory heterogeneity (VH; ELV ₁₈₀/FRC _pleth and ELV ₁₈₀/ELV _pred). 83 COPD patients and 53 healthy controls performed the IST test, standard pulmonary function tests (Spirometry, body plethysmography and the single breath test of carbon monoxide uptake), and symptom severity questionnaires (COPD assessment test, CAT; mMRC dyspnoea-scale, mMRC-DS; Cough+Mucus score; C+M score). Results: ELV ₁₈₀/FRC _pleth and ELV ₁₈₀/ELV _pred were significantly lower in patients with COPD vs healthy participants (0.34±0.11 vs 0.68±0.14 and 0.7±0.27 vs 0.98±0.15, respectively; P<0.05). Multivariable regression analysis demonstrated that ELV ₁₈₀/FRC _pleth was a stronger and independent predictor of CAT, mMRC-DS and C+M score vs FEV _1%pred. ELV ₁₈₀/ELV _pred was a stronger and independent and better predictor of C+M score vs FEV _1%pred. Phenotyping patients, based upon ELV ₁₈₀/ELV _pred and FRC _%pred, uncovered significant symptomatic differences between groups. Conclusion: The IST indices of VH were superior and independent predictors of symptom severity vs FEV _1%pred and has potential as a non-invasive and simple-to-perform method to stratify patients into subgroups related to clinically relevant features of COPD.