Methacholine-Induced Variations in Airway Volume and the Slope of the Alveolar Capnogram Are Distinctly Associated with Airflow Limitation and Airway Closure

<div><p>Mechanisms driving alteration of lung function in response to inhalation of a methacholine aerosol are incompletely understood. To explore to what extent large and small airways contribute to airflow limitation and airway closure in this context, volumetric capnography was performed before (n = 93) and after (n = 78) methacholine provocation in subjects with an intermediate clinical probability of asthma. Anatomical dead space (VDaw), reflecting large airway volume, and the slope of the alveolar capnogram (slope3), an index of ventilation heterogeneity linked to small airway dysfunction, were determined. At baseline, VDaw was positively correlated with lung volumes, FEV₁ and peak expiratory flow, while slope3 was not correlated with any lung function index. Variations in VDaw and slope3 following methacholine stimulation were correlated to a small degree (R² = -0.20). Multivariate regression analysis identified independent associations between variation in FEV₁ and variations in both VDaw (Standardized Coefficient-SC = 0.66) and Slope3 (SC = 0.35). By contrast, variation in FVC was strongly associated with variations in VDaw (SC = 0.8) but not Slope3. Thus, alterations in the geometry and/or function of large and small airways were weakly correlated and contributed distinctly to airflow limitation. While both large and small airways contributed to airflow limitation as assessed by FEV1, airway closure as assessed by FVC reduction mostly involved the large airways.</p></div

Multivariate analysis of relationships between the FEV1 and FVC dose-response and Mch-induced variations in capnographic variables.

<p>SC: Standardized coefficient.</p

Characteristics of subjects before methacholine testing.

<p>*: p < 0.05,</p><p>**: p<0.001,</p><p>***: p<0.0001 between subjects with and without BHR.</p><p>FEV1: Forced expiratory volume in 1 second. FVC: Forced vital capacity. FEF25-75: Mean forced expiratory flow between 25% and 75% of FVC. PEF: Peak expiratory flow. TLC: Total lung capacity. RV: Residual volume. Raw: Airway resistance. sRaw: Specific airway resistance. VDaw: Airway volume. Slope3: Slope of the alveolar capnogram.</p

Correlation between baseline lung function parameters and baseline airway volume (VDaw) and the slope of the alveolar capnogram (slope3) in 93 subjects.

<p>Linear regression was performed with VDaw and slope3 as dependent variables.</p

Relationships between methacholine-induced variations in volumetric capnography variables and the FEV1 dose-response curve in patients without BHR (empty circles) and in patients with BHR (filled grey circles).

<p>A: Variations in airway volume (VDaw). B: Variation in the slope of the alveolar capnogram (slope3). Scales are linear to a value of 100 and exponential thereafter. ΔVDaw / Mch: Fractional change in aiway volume reported to the methacholine dose, expressed as -% / mg. Δslope3 / Mch: Fractional change in the slope of the alveolar capnogram reported to the methacholine dose, expressed as % / mg.</p

Table_1_Disease patterns and specific trajectories of anti-MDA5-related disease: a multicentre retrospective study of 70 adult patients.docx

IntroductionThis study aimed to provide an updated analysis of the different prognostic trajectories of patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies.MethodsAmong a cohort of 70 patients, baseline characteristics and phenotypes, treatments and outcomes were analyzed. A Cox proportional hazards model was used to identify factors associated with poor outcomes, i.e., death or progressive disease at the last follow-up.ResultsAmong the 70 patients, 45 were women, and 54 were Caucasian. A dermatologic involvement was observed in 58 (83%) patients, including 40 with MDA5 vasculopathy-related skin lesions. Muscular involvement was observed in 39 (56%) patients. Interstitial lung disease (ILD) was observed at baseline in 52 (74%) patients, including 23 (44%) who developed rapidly progressive (RP) ILD. Seven (10%) patients showed thromboembolic complications within the first weeks of diagnosis, and eight (11%) other patients developed a malignancy (4 before the diagnosis of anti-MDA5 disease). Poor outcomes were observed in 28 (40%) patients, including 13 (19%) deaths. Among the 23 patients with RP-ILD, 19 (79%) showed poor outcomes, including 12 (63%) who died. In multivariate analyses, RP-ILD (hazard ratio (HR), 95% CI: 8.24 [3.21–22], pDiscussionThis new independent cohort confirms the presence of different clinical phenotypes of anti-MDA5 diseases at baseline and the poor prognosis associated with RP-ILD. Thromboembolic events and malignancies were also identified as prognostic factors.</p