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Introduction and objectives: The human congenital central hypoventilation syndrome (CCHS) is caused by mutations in the PHOX2B (paired-like homeobox 2B) gene. Genetically engineered PHOX2B rodents exhibit defective development of the brainstem retrotrapezoid nucleus (RTN), a carbon dioxide sensitive structure that critically controls expiratory muscle recruitment. This has been linked to a blunted exercise ventilatory response. Whether this can be extrapolated to human CCHS is unknown and represents the objective of this study.

Materials and methods: Thirteen adult CCHS patients and 13 healthy participants performed an incremental symptom-limited cycle cardiopulmonary exercise test. Responses were analyzed using guideline approaches (ventilation V'_E, tidal volume V_T, breathing frequency, oxygen consumption, carbon dioxide production) complemented by a breathing pattern analysis (i.e. expiratory and inspiratory reserve volume, ERV and IRV).

Results: A ventilatory response occurred in both study groups, as follows: V'_E and V_T increased in CCHS patients until 40 W and then decreased, which was not observed in the healthy participants (p<0.001). In the latter, exercise-related ERV and IRV decreases attested to concomitant expiratory and inspiratory recruitment. In the CCHS patients, inspiratory recruitment occurred but there was no evidence of expiratory recruitment (absence of any ERV decrease, p<0.001).

Conclusions: Assuming a similar organization of respiratory rhythmogenesis in humans and rodents, the lack of exercise-related expiratory recruitment observed in our CCHS patients is compatible with a PHOX2B-related defect of a neural structure that would be analogous to the rodents' RTN. Provided corroboration, ERV recruitment could serve as a physiological outcome in studies aiming at correcting breathing control in CCHS.

Approximately 400 million people live at high altitudes worldwide, yet reference equations for spirometry in these populations are inadequately documented. This study aims to develop reference equations for spirometry and assess their applicability to residents at altitudes ranging from 2,100 to 4,700 metres above sea level. This extensive cross-sectional study encompassed healthy non-smokers aged 15 years or older living at Xinjiang and Tibet autonomous region, which covered eight high-altitude areas by a multistage stratified sampling procedure. All individuals underwent pre- and post-bronchodilator measurement. We used the Lambda-Mu-Sigma (LMS) method to establish reference equations for various spirometry parameters. We assessed model fit using mean absolute error (MAE), mean absolute percentage error (MAPE), and residual values (standard deviation), relative to established benchmarks such as GLI, ECSC, and NHANES III, to evaluate the applicability of our equations to high-altitude residents. Between June 2015 and August 2016, 3174 healthy subjects were included. The reference equations utilise age and height as independent variables, with improved accuracy achieved through spline functions. Our spirometry reference equations demonstrate minimal MAE, MAPE, and residual values (standard deviation) for most of the analysed spirometry parameters, stratified by gender. Our spirometry reference equations are more applicable to residents of high-altitude regions.

Spirometry is used to determine what is "unusual" lung function compared with what is "usual" for healthy non-smokers. This study aimed to investigate regional variation in the forced vital capacity (FVC) and in the forced expiratory volume in one second to FVC ratio (FEV₁/FVC) using cross-sectional data from all 41 sites of the multinational Burden of Obstructive Lung Disease study. Participants (5,368 men; 9,649 women), aged ≥40 years, had performed spirometry, had never smoked and reported no respiratory symptoms or diagnoses. To identify regions with similar FVC, we conducted a principal component analysis (PCA) on FVC with age, age² and height², separately for men and women. We regressed FVC against age, age² and height², and FEV₁/FVC against age and height², for each sex and site, stratified by region. Mean age was 54 years (both sexes), and mean height was 1.69 m (men) and 1.61 m (women). The PCA suggested four regions: 1) Europe and richer countries; 2) the Near East; 3) Africa; and 4) the Far East. For the FVC, there was little variation in the coefficients for age, or age², but considerable variation in the constant (men: 2.97 L in the Far East to 4.08 L in Europe; women: 2.44 L in the Far East to 3.24 L in Europe) and the coefficient for height². Regional differences in the constant and coefficients for FEV₁/FVC were minimal (<1%). The relation of FVC with age, sex and height varies across and within regions. The same is not true for the FEV₁/FVC ratio.

Introduction and objectives: The fractional exhaled fraction of nitric oxide (FeNO) is used in clinical practice for asthma diagnosis, phenotyping, and therapeutic management. Therefore, accurate thresholds are crucial. The normal FeNO values over lifespan in a respiratory healthy population and the factors related to them remain unclear.

Materials and methods: We determined FeNO levels in 2,251 respiratory healthy, non-atopic, and non-smoking participants from the Lung, hEart, sociAl, boDy (LEAD) cohort, a general population, observational cohort study of participants aged 6-82 years in Austria.

Results: The median FeNO value in the total study population was 13.0 [interquartile range: 9.0, 20.0] ppb, increases with age, and, except in young participants (<18 years: 9.0 [7.0, 12.0], ≥18 years: 15.0 [11.0, 22.0]), it was significantly lower in females versus males. Multiple regression analyses showed that body height and blood eosinophil counts were associated with higher FeNO levels, both in children/adolescents and adults. In children/adolescents, FeNO values were positively associated with total IgE levels, FEV1/FVC ratio, and urban living. In adults, FeNO was positively associated with age and negatively associated with the presence of cardiovascular and ischaemic vascular disease.

Conclusions: We identified the normal FeNO ranges within a respiratory healthy population at different age ranges and associated factors. Collectively, they serve as a reference to frame FeNO values in clinical practice.

Background: Traditionally, Venturi-based flow generators have been preferred over mechanical ventilators to provide continuous positive airway pressure (CPAP) through the helmet (h-CPAP). Recently, modern turbine-driven ventilators (TDVs) showed to be safe and effective in delivering h-CPAP. We aimed to compare the pressure stability during h-CPAP delivered by Venturi devices and TDVs and assess the impact of High Efficiency Particulate Air (HEPA) filters on their performance.

Methods: We performed a bench study using an artificial lung simulator set in a restrictive respiratory condition, simulating two different levels of patient effort (high and low) with and without the interposition of the HEPA filter. We calculated the average of minimal (Pmin), maximal (Pmax) and mean (Pmean) airway pressure and the time product measured on the airway pressure curve (PTPinsp). We defined the pressure swing (Pswing) as Pmax - Pmin and pressure drop (Pdrop) as End Expiratory Pressure - Pmin.

Results: Pswing across CPAP levels varied widely among all the tested devices. During "low effort", no difference in Pswing and Pdrop was found between Venturi devices and TDVs; during high effort, Pswing (p<0.001) and Pdrop (p<0.001) were significantly higher in TDVs compared to Venturi devices, but the PTPinsp was lower (1.50 SD 0.54 vs 1.67 SD 0.55, p<0.001). HEPA filter addition almost doubled Pswing and PTPinsp (p<0.001) but left unaltered the differences among Venturi and TDVs systems in favor of the latter (p<0.001).

Conclusions: TDVs performed better than Venturi systems in delivering a stable positive pressure level during h-CPAP in a bench setting.