Indacaterol is an inhaled, long-acting β(2)-agonist providing 24-h bronchodilation with once-daily dosing in patients with COPD.
Subjects with moderate to severe COPD who completed a 26-week, ...randomized, double-blind study were eligible for enrollment in an extension, during which treatment with double-blind indacaterol, 150 or 300 μg once daily, or placebo was continued for a further 26 weeks. The primary objective was to evaluate the long-term safety of indacaterol. Efficacy end points included trough (24 h postdose) FEV(1) at 52 weeks, exacerbations, and health status (St. George Respiratory Questionnaire SGRQ).
Four hundred fifteen subjects participated in the extension. Adverse events, mostly mild or moderate, occurred in 76%, 77%, and 68% of subjects receiving indacaterol, 150 μg; indacaterol, 300 μg; and placebo, respectively. Serious adverse events occurred in 10.4%, 12.3%, and 10.5%, respectively. Indacaterol had no clinically significant effects on ECG findings (corrected QT interval) or on serum potassium or plasma glucose levels. Indacaterol increased trough FEV(1) relative to placebo throughout the study (difference of ≥ 170 mL at week 52). No tolerance to its bronchodilator effect was detected. Indacaterol treatment was accompanied by significant reductions in COPD exacerbations (rate ratios compared with placebo, 0.62-0.64; P < .05) and as-needed albuterol use (1.2-1.4 puffs/d decrease, P < .001 compared with placebo). Health status improved with indacaterol treatment, with decreases from baseline in mean total SGRQ score generally > 4 units.
During 1 year of treatment, indacaterol was well tolerated and provided significant and well-maintained bronchodilation that was accompanied by improved clinical outcomes.
ClinicalTrials.gov; No.: NCT00677807; URL: www.clinicaltrials.gov.
Significant heterogeneity of clinical presentation and disease progression exists within chronic obstructive pulmonary disease (COPD). Although FEV(1) inadequately describes this heterogeneity, a ...clear alternative has not emerged. The goal of phenotyping is to identify patient groups with unique prognostic or therapeutic characteristics, but significant variation and confusion surrounds use of the term "phenotype" in COPD. Phenotype classically refers to any observable characteristic of an organism, and up until now, multiple disease characteristics have been termed COPD phenotypes. We, however, propose the following variation on this definition: "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death)." This more focused definition allows for classification of patients into distinct prognostic and therapeutic subgroups for both clinical and research purposes. Ideally, individuals sharing a unique phenotype would also ultimately be determined to have a similar underlying biologic or physiologic mechanism(s) to guide the development of therapy where possible. It follows that any proposed phenotype, whether defined by symptoms, radiography, physiology, or cellular or molecular fingerprint will require an iterative validation process in which "candidate" phenotypes are identified before their relevance to clinical outcome is determined. Although this schema represents an ideal construct, we acknowledge any phenotype may be etiologically heterogeneous and that any one individual may manifest multiple phenotypes. We have much yet to learn, but establishing a common language for future research will facilitate our understanding and management of the complexity implicit to this disease.
For unclear reasons, obese children with asthma have higher morbidity and reduced response to inhaled corticosteroids.
To assess whether childhood obesity is associated with airway dysanapsis (an ...incongruence between the growth of the lungs and the airways) and whether dysanapsis is associated with asthma morbidity.
We examined the relationship between obesity and dysanapsis in six cohorts of children with and without asthma, as well as the relationship between dysanapsis and clinical outcomes in children with asthma. Adjusted odds ratios (ORs) were calculated for each cohort and in a combined analysis of all cohorts; longitudinal analyses were also performed for cohorts with available data. Hazard ratios (HRs) for clinical outcomes were calculated for children with asthma in the Childhood Asthma Management Program.
Being overweight or obese was associated with dysanapsis in both the cross-sectional (OR, 1.95; 95% confidence interval CI, 1.62-2.35 for overweight/obese compared with normal weight children) and the longitudinal (OR, 4.31; 95% CI, 2.99-6.22 for children who were overweight/obese at all visits compared with normal weight children) analyses. Dysanapsis was associated with greater lung volumes (FVC, vital capacity, and total lung capacity) and lesser flows (FEV
and forced expiratory flow, midexpiratory phase), and with indicators of ventilation inhomogeneity and anisotropic lung and airway growth. Among overweight/obese children with asthma, dysanapsis was associated with severe disease exacerbations (HR, 1.95; 95% CI, 1.38-2.75) and use of systemic steroids (HR, 3.22; 95% CI, 2.02-5.14).
Obesity is associated with airway dysanapsis in children. Dysanapsis is associated with increased morbidity among obese children with asthma and may partly explain their reduced response to inhaled corticosteroids.
Purpose
Limited data exist on the correlation between higher flow rates of high-flow nasal cannula (HFNC) and its physiologic effects in patients with acute hypoxemic respiratory failure (AHRF). We ...assessed the effects of HFNC delivered at increasing flow rate on inspiratory effort, work of breathing, minute ventilation, lung volumes, dynamic compliance and oxygenation in AHRF patients.
Methods
A prospective randomized cross-over study was performed in non-intubated patients with patients AHRF and a PaO
2
/FiO
2
(arterial partial pressure of oxygen/fraction of inspired oxygen) ratio of ≤300 mmHg. A standard non-occlusive facial mask and HFNC at different flow rates (30, 45 and 60 l/min) were randomly applied, while maintaining constant FiO
2
(20 min/step). At the end of each phase, we measured arterial blood gases, inspiratory effort, based on swings in esophageal pressure (ΔPes) and on the esophageal pressure–time product (PTP
Pes
), and lung volume, by electrical impedance tomography.
Results
Seventeen patients with AHRF were enrolled in the study. At increasing flow rate, HFNC reduced ΔPes (
p
< 0.001) and PTP
Pes
(
p
< 0.001), while end-expiratory lung volume (ΔEELV), tidal volume to ΔPes ratio (
V
T
/ΔPes, which corresponds to dynamic lung compliance) and oxygenation improved (
p
< 0.01 for all factors). Higher HFNC flow rate also progressively reduced minute ventilation (
p
< 0.05) without any change in arterial CO
2
tension (
p
= 0.909). The decrease in ΔPes, PTP
Pes
and minute ventilation at increasing flow rates was better described by exponential fitting, while ΔEELV,
V
T
/ΔPes and oxygenation improved linearly.
Conclusions
In this cohort of patients with AHRF, an increasing HFNC flow rate progressively decreased inspiratory effort and improved lung aeration, dynamic compliance and oxygenation. Most of the effect on inspiratory workload and CO
2
clearance was already obtained at the lowest flow rate.
In addition to affecting the oxygen supply to the brain, pulmonary function is a marker of multiple insults throughout life (including smoking, illness, and socioeconomic deprivation). In this ...meta-analysis of existing longitudinal studies, the hypothesis that lower pulmonary function and respiratory illness are linked to an elevated risk of dementia was tested.
A systematic review was conducted of longitudinal studies using PubMed until April 1, 2019, and, where possible, results were pooled in random effects meta-analyses.
Ten studies relating pulmonary function to later dementia risk and 11 studies of respiratory illness and dementia (including one that assessed both factors) were identified. The lowest quartile of FEV
compared with the highest was associated with a 1.4-fold (hazard ratio HR, 1.46; 95% CI, 0.77-2.75) increased dementia risk (N
= 62,209; two studies). A decrease of 1 SD in FEV
was associated with a 28% increase in dementia risk (HR, 1.28; 95% CI, 1.03-1.60; N
= 67,505; six studies). Respiratory illness was also associated with increased dementia risk to a similar degree (pooled HR, 1.54; 95% CI, 1.30-1.81; N
= 288,641; 11 studies).
Individuals with poor pulmonary function experience an increased risk of dementia. The extent to which the association between poor pulmonary function and dementia is causal remains unclear and requires examination.
The evolution of airway obstruction into late adolescence of extremely preterm (gestational age <28 weeks) or extremely low-birthweight (birth weight <1000 g) survivors in the era after surfactant ...was introduced is unclear.
To compare changes in spirometry from 8 to 18 years of age of a geographical cohort of preterm survivors with normal birth weight controls, and to determine higher risk groups within the preterm cohort.
Of 297 extremely preterm/low-birthweight survivors born in 1991-1992 in the state of Victoria, Australia, 81% and 70% had spirometry at 8 and 18 years of age, respectively. Corresponding rates among 260 normal birth weight controls were 80% and 58%, respectively. Data were analysed using linear mixed models.
The preterm group had substantial impairments in airflow at both ages compared with controls (eg, mean differences in z-score for FEV
; 8 years -1.02, 95% CI -1.21 to -0.82; 18 years -0.92, 95% CI -1.14 to -0.71). The preterm group had a greater increase in small airway obstruction between 8 and 18 years compared with controls. Within the preterm group, those who had bronchopulmonary dysplasia in the newborn period and those who were smokers at 18 years had airway obstruction that increased over time compared with those who did not.
Preterm survivors born in the surfactant era had significant impairments in airflow through childhood into late adolescence that increased over time compared with controls. At-risk preterm participants include those who had bronchopulmonary dysplasia, and smokers at 18 years.
The long-term respiratory sequelae of infants born extremely preterm (EP) and now graduating from neonatal intensive care remains uncertain.
To assess the degree of respiratory morbidity and ...functional impairment at 11 years in children born EP (i.e., at or less than 25 completed weeks of gestation) in relation to neonatal determinants and current clinical status.
Pre- and postbronchodilator spirometry were undertaken at school in children born EP and classroom control subjects. Physical examination and respiratory health questionnaires were completed. Multivariable regression was used to estimate the predictive power of potential determinants of lung function.
Spirometry was obtained in 182 of 219 children born EP (129 with prior bronchopulmonary dysplasia BPD) and 161 of 169 classmates, matched for age, sex, and ethnic group. Children born EP had significantly more chest deformities and respiratory symptoms than classmates, with twice as many (25 vs. 13%; P < 0.01) having a current diagnosis of asthma. Baseline spirometry was significantly reduced (P < 0.001) and bronchodilator responsiveness was increased in those born EP, the changes being most marked in those with prior BPD. EP birth, BPD, current symptoms, and treatment with beta-agonists are each associated independently with lung function z-scores (adjusted for age, sex, and height) at 11 years. Fifty-six percent of children born EP had abnormal baseline spirometry and 27% had a positive bronchodilator response, but less than half of those with impaired lung function were receiving any medication.
After extremely preterm birth, impaired lung function and increased respiratory morbidity persist into middle childhood, especially among those with BPD. Many of these children may not be receiving appropriate treatment.
More infants with bronchopulmonary dysplasia (BPD) now survive to adulthood, but little is known regarding persisting respiratory impairment. We report respiratory symptoms, lung function and ...health-related quality of life (HRQoL) in adult BPD survivors compared with preterm (non-BPD) and full-term controls. Respiratory symptoms (European Community Respiratory Health Survey) and HRQoL (EuroQol (EQ)-5D) were measured in 72 adult BPD survivors (mean ± sd study age 24.1 ± 4.0 years; mean ± sd gestational age 27.1 ± 2.1 weeks; and mean ± sd birth weight 955 ± 256 g) cared for in the regional neonatal intensive care unit, Royal Maternity Hospital, Belfast, UK (between 1978 and 1993). These were compared with 57 non-BPD controls (mean ± sd study age 25.3 ± 4.0 years; mean ± sd gestational age 31.0 ± 2.5 weeks; and mean ± sd birth weight 1238 ± 222 g) and 78 full-term controls (mean ± sd study age 25.7 ± 3.8 years; mean ± sd gestational age 39.7 ± 1.4 weeks; and mean ± sd birth weight 3514 ± 456 g) cared for at the same hospital. Spirometry was performed on 56 BPD, 40 non-BPD and 55 full-term participants. BPD subjects were twice as likely to report wheeze and three times more likely to use asthma medication than controls. BPD adults had significantly lower forced expiratory volume in 1 s and forced expiratory flow at 25-75% of forced vital capacity than both the preterm non-BPD and full-term controls (all p<0.01). Mean EQ-5D was 6 points lower in BPD adults compared to full-term controls (p<0.05). BPD survivors have significant respiratory and quality of life impairment persisting into adulthood.
Mechanistic target of rapamycin inhibitors reduce loss of lung function in lymphangioleiomyomatosis (LAM), although their benefit varies between individuals. We examined lung function response and ...side effects to rapamycin in a national cohort.
Subjects were receiving rapamycin for progressive lung disease. Clinical evaluation, detailed phenotyping, serial lung function, rapamycin and safety monitoring were performed according to a clinical protocol. Lung function change, measured as FEV
slope (ΔFEV
), was reported for those treated for 1 year or longer.
Rapamycin was associated with improved ΔFEV
in 21 individuals where pretreatment data were available (p<0.0001). In 47 treated for a mean duration of 35.8 months, mean ΔFEV
was +11 (SD 75) mL/year, although it varied from +254 to -148 mL/year. The quartile with the highest positive ΔFEV
had greater pretreatment FEV
(p=0.02) and shorter disease durations (p=0.02) than the lowest quartile. Serum rapamycin level was positively associated with side effects (p=0.02) but not ΔFEV
over 1 year. Within the first month of therapy, apthous ulcers, nausea and diarrhoea were associated with higher rapamycin levels. Acne, oedema and menstrual irregularities tended to increase over the first year of therapy. At the end of observation, the prevalence of side effects was 5% or less.
Rapamycin reduces lung function loss in LAM, although in some, ΔFEV
continues to fall at an accelerated rate. Poor response to rapamycin was associated with lower pretreatment lung function and longer disease duration but not serum level. Early intervention with low-dose rapamycin may preserve lung function and reduce side effects.
PDF
