Annals of the American Thoracic Society最新文献

Rationale: Elexacaftor/tezacaftor/ivacaftor (ETI) has significantly improved lung function in people with cystic fibrosis (CF), prompting the need for outcome measures that can detect mild disease. In this new era of CFTR (CF transmembrane regulator) modulator therapy, more sensitive endpoints are required to evaluate the progression of early lung disease and to determine the efficacy of new CF therapies. Before the availability of highly effective therapies, xenon-129 magnetic resonance imaging (MRI) was shown to be more sensitive to regional ventilation changes compared with spirometry. Objectives: To evaluate the longitudinal changes in pulmonary function and Xe MRI outcomes after treatment with ETI in children and young people with CF. Methods: Lung function was assessed longitudinally at baseline and 1, 6, and 12 months after ETI treatment initiation in children and young people with CF between the ages of 6 and 18 years at four study sites. Ventilation defect percentage (VDP), reader defect percentage (RDP), lung clearance index (LCI) and forced expiratory volume in 1 second (FEV₁) were reported. Results: A total of 28 participants were enrolled; 25 completed at least baseline and one-month measurements. All four measures (RDP, VDP, LCI, and FEV₁) improved at one month after ETI initiation, with mean (standard deviation) absolute changes of -1.2 (1.7) in LCI, 6.9 (12.3) in FEV₁ % predicted, -4.3 (4.8) in VDP, and -7.8 (9.6) in RDP. Xe MRI outcomes (RDP and VDP) showed the largest relative treatment effects, with mean relative improvements of 43% and 72%, respectively. One-third of participants (8 of 25) had improvements in VDP and RDP but did not show improvements in FEV₁. Conclusions: Xe MRI captures sustained ventilation improvements after ETI initiation. Xe MRI metrics may provide a suitable endpoint for future interventional trials, particularly for people with CF with mild lung disease.

Rationale: Oscillometry is a feasible and safe method to measure pulmonary function in children with asthma exacerbations in the emergency department (ED), but its utility to measure respiratory impedance as an objective marker of response to initial acute asthma treatments is unknown. Objectives: We sought to determine the associations between respiratory impedance-derived metrics and asthma exacerbation severity and treatment response in the pediatric ED. Methods: We conducted a prospective study of children, ages 4-18 years, who presented to a tertiary-care pediatric ED for asthma exacerbations. Respiratory system impedance was measured with oscillometry before and after initial treatment with inhaled bronchodilators and systemic corticosteroids. Regression models estimated the associations between respiratory impedance-derived metrics (low-frequency resistance, R7, a measure of total airway obstruction; frequency dependence of resistance, R7-19, a measure of peripheral airway resistance; and reactance area, AX, a measure of lung tissue stiffness and variability in ventilation), vital signs, and clinical outcomes. Receiver operating characteristic analyses were used to quantify the ability of respiratory impedance-derived metrics and vital signs to discriminate outcomes. Results: Of 177 participants, 144 (81%) completed a valid initial oscillometry assessment. Forty-seven percent had moderate or severe exacerbations, and 61% met the treatment response definition. Frequency dependence of resistance (R7-19: adjusted odds ratio [aOR], 1.39; 95% confidence interval [CI] = 1.08-1.83) and area of reactance (AX: aOR, 1.28; 95% CI = 1.05-1.58), were associated with higher odds of moderate or severe exacerbation. Greater initial R7-19 was associated with decreased odds of treatment response (aOR, 0.75; 95% CI = 0.57-0.98). A combination of impedance-derived metrics and vital signs best differentiated exacerbation severity (area under the curve [AUC] = 0.73), treatment response (AUC = 0.69), and hospitalization (AUC = 0.78). Conclusions: Respiratory impedance-derived metrics (R7, R7-19, and AX), in combination with vital signs, can guide ED clinical decisions and improve outcomes for children with asthma exacerbations.

Rationale: Data on the effect of gabapentinoids on patients with chronic obstructive pulmonary disease (COPD) are sparse, although the U.S. Food and Drug Administration has issued a safety warning for these medications, particularly in individuals with respiratory risk factors. Objectives: To investigate whether gabapentinoid use is associated with increased COPD exacerbations requiring systemic corticosteroids. Methods: Using a nationwide administrative claims database, we conducted a retrospective cohort study using an active-comparator new-user design. We identified patients with COPD and neuropathic or chronic pain who initiated gabapentinoid treatment between 2015 and 2022. Two active-comparator new-user cohorts were created: one with tricyclic antidepressants and the other with serotonin-noradrenaline reuptake inhibitors. Patient backgrounds were balanced using overlapping propensity score weighting. Results: The primary outcome was the initial occurrence of COPD exacerbations requiring systemic corticosteroids. Hazard ratios (HRs) associated with gabapentinoids were assessed using a weighted Cox proportional hazards model. In the tricyclic antidepressant cohort (37,098 patients), gabapentinoids were associated with a higher incidence of the primary outcome (67.8 vs. 46.7 per 100 person-years; HR, 1.21 [95% confidence interval, 1.03-1.42]). In the serotonin-noradrenaline reuptake inhibitor cohort (48,480 patients), gabapentinoids were also linked to a higher incidence of the primary outcome (68.8 vs. 51.4 per 100 person-years; HR, 1.18 [95% confidence interval, 1.10-1.28]). Conclusions: Gabapentinoids may increase the risk of COPD exacerbations compared with other central nervous system-active medications at the same treatment stage for neuropathic or chronic pain, suggesting that their use should be limited to clearly beneficial cases.

Rationale: In children with adenotonsillar hypertrophy, there is substantial variation in pediatric obstructive sleep apnea (pOSA) severity, which may be driven by differences in pathophysiological traits (endotypes), including pharyngeal collapsibility, dilator muscle compensation, arousal threshold, and chemoreflex loop gain. Objectives: To determine if pathophysiological traits for pOSA vary with participant characteristics, correlate with pOSA severity, and change after adenotonsillectomy. Methods: Traits estimation, requiring adequate nasal pressure data quality, was performed during sleep (primary analysis in rapid eye movement [REM]) from baseline polysomnography (N = 1,117; age 6.9 ± 1.5 yr; body mass index standardized using age- and sex-specific z-score [BMI-z] 0.89 ± 1.23; total apnea-hypopnea index [AHI], 5.1 ± 9.1 events/h; REM AHI, 11.0 ± 20.1 events/h) and postintervention polysomnography (N = 360; adenotonsillectomy or watchful waiting). Associations of each endotype (per standard deviation [SD]) with AHI and with patient characteristics (race/ethnicity, age, sex, and BMI-z) were characterized using multivariable regression. The effects of adenotonsillectomy on AHI and endotypes were also examined. Results: The sample comprised 52% females and children from diverse racial and ethnic backgrounds and geographic sites. Higher REM AHI was observed in Black (7.81 ± 1.01, β_adjusted ± standard error of the mean, events/h) and Asian (9.37 ± 3.35) compared with White children; these differences were accompanied by greater collapsibility (0.30 ± 0.09 per SD) in Black children and decreased compensation (-0.99 ± 0.20) in Asian children. Notably, sex and BMI-z were not associated with any endotype. Higher REM AHI was associated with greater collapsibility (13.64 ± 1.73 events/h/SD) and reduced compensation (-4.22 ± 0.98) but not increased loop gain. Increased collapsibility and reduced compensation partially explained higher REM AHI in Black as well as Asian and Indigenous children. Reduced AHI with adenotonsillectomy was accompanied by improved collapsibility in REM (Δ = 16.88% ± 1.94%). Conclusions: Increased collapsibility and reduced compensation contribute to higher REM AHI levels in children and may explain an elevated pOSA severity in REM in Black and Asian children. Clinical trial registered with www.clinicaltrials.gov (NCT00560859).

Rationale: Inflammation is central to chronic obstructive pulmonary disease (COPD) pathogenesis but incompletely represented in COPD prognostic models. The neutrophil-to-lymphocyte ratio (NLR) is a readily available inflammatory biomarker. Objectives: To explore the associations of NLR with smoking status, clinical features of COPD, and future adverse outcomes. Methods: We analyzed NLR calculated from the complete blood count of participants who currently or formerly smoked (n = 2,624) and tobacco-naive control subjects (n = 187) in the SPIROMICS multicenter observational cohort study. We assessed the stability of NLR at 6 weeks and 1 year, the association with select blood biomarkers, and the impact of smoking on NLR and cell counts. We stratified participants by NLR quartiles to compare cross-sectional clinical features at enrollment, prospectively observed exacerbations at 1 year, and mortality during longitudinal follow up. Results: Higher NLR quartiles were broadly associated with more severe clinical features of COPD. NLR values were repeatable at 6 weeks (intraclass correlation coefficient, 0.74) and 1 year (intraclass correlation coefficient, 0.62). The impact of smoking on NLR varied with the severity of airflow limitation, mediated by an interaction between smoking, forced expiratory volume in 1 second percent predicted, and neutrophil counts but not lymphocyte counts. The highest NLR quartile (>3.11) was associated with an increased risk of exacerbation over 1 year (adjusted odds ratio, 1.51; 95% confidence interval, 1.18, 1.92) and increased risk of mortality (adjusted hazard ratio, 1.41; 95% confidence interval, 1.20, 1.66) compared with quartiles 1-3. Conclusions: Elevated NLR in stable COPD is a widely available biomarker associated with increased risk for exacerbation and death. The impact of cigarette smoking on NLR varies with disease severity.

Electrical impedance tomography (EIT) is a radiation-free, noninvasive method of measuring the regional behavior of the lung that may be particularly suited to neonatal medicine. It is used more and more commonly in neonatology, particularly in the research setting. To harmonize efforts in terms of scientific and clinical use of this novel technology, we summarize the current knowledge on EIT use in both term and preterm infants and delineate potential future perspectives in this state-of-the-art article. We describe the current use in research and practice in neonatal medicine, including the following areas: 1) the cardiopulmonary transition immediately after birth; 2) changes in airway management, including the use of different interfaces, endotracheal intubation, extubation to noninvasive respiratory support and (endotracheal) suctioning; 3) surfactant administration; 4) different body positions; 5) different modes of invasive and noninvasive respiratory support; 6) evaluation of acute pulmonary pathologies; 7) the predictive value of using EIT in neonatology; and 8) the assessment of pulmonary perfusion. In summary, EIT is a very valuable research tool in neonatal medicine, where it allows us to understand physiological principles and pathogenesis of disease more deeply. It may also be useful for selected clinical situations in neonatology, including major acute lung pathologies, because it allows accurate and noninvasive assessment of intrapulmonary volume changes in neonates. However, there are still some barriers to widespread implementation in clinical practice.