The effect of inhaled extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide on distal and central airway indices, assessed using Functional Respiratory Imaging in COPD (DARWiIN).

BACKGROUND: This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function. METHODS: Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siVaw) and resistance (siRaw) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siVaw and siRaw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siVaw and siRaw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV1) and COPD Assessment Test (CAT) were also assessed. RESULTS: There were no significant changes in pre-dose siVaw or siRaw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siRaw in the distal airways (- 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siVaw and siRaw (siVaw: 39.8% and 62.6%; siRaw: - 51.1% and - 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siVaw: 77.9%; siRaw: - 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV1 was 62.2 mL (p = 0.0690), and in CAT total score was - 3.30 (p < 0.0001). CONCLUSIONS: In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021.

BMI but not central obesity predisposes to airway closure during bronchoconstriction.

BACKGROUND AND OBJECTIVE: Obesity produces restrictive effects on lung function. We previously reported that obese patients with asthma exhibit a propensity towards small airway closure during methacholine challenge which improved with weight loss. We hypothesized that increased abdominal adiposity, a key contributor to the restrictive effects of obesity on the lung, mediates this response. This study investigates the effect of body mass index (BMI) versus waist circumference (WC) on spirometric lung function, sensitivity to airway narrowing and closure, and airway closure during bronchoconstriction in patients with asthma. METHODS: Participants underwent spirometry and methacholine challenge. Sensitivity to airway closure and narrowing was assessed from the dose-response slopes of the forced vital capacity (FVC) and the ratio of forced expiratory volume in 1 s (FEV1 ) to FVC, respectively. Airway closure during bronchoconstriction (closing index) was computed as the percent reduction in FVC divided by the percent reduction in FEV1 at maximal bronchoconstriction. RESULTS: A total of 116 asthmatic patients (56 obese) underwent methacholine challenge. Spirometric lung function was inversely related to WC (P < 0.05), rather than BMI. Closing index increased significantly during bronchoconstriction in obese patients and was related to increasing BMI (P = 0.01), but not to WC. Sensitivity to airway closure and narrowing was not associated with BMI or WC. CONCLUSION: Although WC is associated with restrictive effects on baseline lung function, increased BMI, rather than WC, predisposes to airway closure during bronchoconstriction. These findings suggest that obesity predisposes to airway closure during bronchoconstriction through mechanisms other than simple mass loading.

Is aging a "comorbidity" of asthma?

The aging population is growing at an unparalleled rate. Asthma is common in the elderly (age over 65 years) and can be more severe with little chance for remission. Asthma in older individuals is often under-diagnosed, misdiagnosed and frequently under-treated. Concomitant medical and psychosocial conditions are more prevalent in the elderly and can obfuscate the presentation of asthma and make it more difficult to assess and manage. While these comorbidities are important in understanding elderly asthma, aging itself can be considered a "comorbidity" since it impacts structural and functional changes in the lung. Structural changes of the aging lung may worsen physiologic function in asthma. The immune system also changes with age, with increased vulnerability to pathogens and differences in airway inflammation, leading to variability in how asthma manifests and responds to treatment. The fact that aging can influence the severity and presentation of asthma along with its diagnosis and management is important for the treating physician to understand. This article will discuss the multitude of factors that justify considering aging as a comorbidity of asthma.

Inhaled steroids reduce pain and sVCAM levels in individuals with sickle cell disease: A triple-blind, randomized trial.

Clinical and preclinical data demonstrate that altered pulmonary physiology (including increased inflammation, increased blood flow, airway resistance, and hyper-reactivity) is an intrinsic component of Sickle Cell Disease (SCD) and may contribute to excess SCD morbidity and mortality. Inhaled corticosteroids (ICS), a safe and effective therapy for pulmonary inflammation in asthma, may ameliorate the altered pulmonary physiologic milieu in SCD. With this single-center, longitudinal, randomized, triple-blind, placebo controlled trial we studied the efficacy and feasibility of ICS in 54 nonasthmatic individuals with SCD. Participants received once daily mometasone furoate 220 mcg dry powder inhalation or placebo for 16 weeks. The primary outcome was feasibility (the number who complete the trial divided by the total number enrolled) with prespecified efficacy outcomes including daily pain score over time (patient reported) and change in soluble vascular cell adhesion molecule (sVCAM) levels between entry and 8-weeks. For the primary outcome of feasibility, the result was 96% (52 of 54, 95% CI 87%-99%) for the intent-to-treat analysis and 83% (45 of 54, 95% CI 71%-91%) for the per-protocol analysis. The adjusted treatment effect of mometasone was a reduction in daily pain score of 1.42 points (95%CI 0.61-2.21, P = 0.001). Mometasone was associated with a reduction in sVCAM levels of 526.94 ng/mL more than placebo (95% CI 50.66-1003.23, P = 0.03). These results support further study of ICS in SCD including multicenter trials and longer durations of treatment. www.clinicaltrials.gov (NCT02061202).

Asthma phenotypes and endotypes: a personalized approach to treatment.

PURPOSE OF REVIEW: Asthma is quite common and is better described as a syndrome with a heterogeneous presentation than as a single disease. Although most individuals can be effectively managed using a guideline-directed approach to care, those with the most severe illness may benefit from a more targeted therapy. The review describes our current understanding of how asthma phenotypes (observable characteristics) and endotypes (specific biologic mechanisms) can be employed to gain insight into asthma pathobiology and personalized therapy. RECENT FINDINGS: Our understanding of the heterogeneity of asthma is increasing. The concept of asthma phenotype has become more complex, incorporating both clinical and biologic features. Several asthma endotypes (e.g., allergic bronchopulmonary mycosis, aspirin-exacerbated respiratory disease, severe late-onset hypereosinophilic asthma, etc.) have been proposed, but further research is needed to delineate specific mechanisms underlying asthma pathogenesis. Several biologic therapies targeting certain phenotypes are in development and are expected to broaden our armamentarium for treatment of severe asthma. SUMMARY: Asthma is a heterogeneous condition with diverse characteristics and biologic mechanisms. Severe asthma is associated with significant morbidity and even mortality and represents a major unmet need. Stratification of asthma subtypes into phenotypes and endotypes should move the field forward in terms of more effective and personalized treatment.

"Sarcoid like" granulomatous pulmonary disease in World Trade Center disaster responders.

BACKGROUND: More than 20,000 responders have been examined through the World Trade Center (WTC) Medical Monitoring and Treatment Program since September 11, 2001. Studies on WTC firefighters have shown elevated rates of sarcoidosis. The main objective of this study was to report the incidence of "sarcoid like" granulomatous pulmonary disease in other WTC responders. METHODS: Cases of sarcoid like granulomatous pulmonary disease were identified by: patient self-report, physician report and ICD-9 codes. Each case was evaluated by three pulmonologists using the ACCESS criteria and only "definite" cases are reported. RESULTS: Thirty-eight patients were classified as "definite" cases. Six-year incidence was 192/100,000. The peak annual incidence of 54 per 100,000 person-years occurred between 9/11/2003 and 9/11/2004. Incidence in black responders was nearly double that of white responders. Low FVC was the most common spirometric abnormality. CONCLUSIONS: Sarcoid like granulomatous pulmonary disease is present among the WTC responders. While the incidence is lower than that reported among firefighters, it is higher than expected.

Forced expiratory time: a composite of airway narrowing and airway closure.

Forced expiratory time (FET) is a spirometrically derived variable thought to reflect lung function, but its physiological basis remains poorly understood. We developed a mathematical theory of FET assuming a linear forced expiratory flow-volume profile that terminates when expiratory flow falls below a defined detection threshold. FET is predicted to correlate negatively with both FEV1 and FVC if variations in the rate of lung emptying (relative to normal) among individuals in a population exceed variations in the amount of lung emptying. We retrospectively determined FET pre- and postmethacholine challenge in 1,241 patients (818 had normal lung function, 137 were obstructed, and 229 were restricted) and examined its relationships to spirometric and demographic variables in both hyperresponsive and normoresponsive individuals. Mean FET was 9.6 ± 2.2 s in the normal group, 12.3 ± 3.0 s in those with obstruction, and 8.8 ± 1.9 s in those with restriction. FET was inversely related to FEV1/FVC in all groups, negatively related to FEV1 in the obstructed patients, and positively related to FVC in both the normal and restricted patients. There was no relationship with methacholine responsiveness. Overall, our theory of the relationship between FET to the spirometric indices is supported by these findings and potentially explains how FET is affected by sex, age, smoking status, and possibly body mass index.NEW & NOTEWORTHY Forced expiratory time (FET) has long been felt to reflect important physiological information about lung function but exactly how has never been clear. Here, we use a model analysis to assess the contributions of airway narrowing versus airway closure to FET in a population of individuals and find support for the theory that FET correlates positively with FEV1 if the amounts of lung emptying over a forced expiration vary from predicted values more than variations in the rates of lung emptying, whereas the correlation is negative in the opposite case.

Four-year calibration stability of the EasyOne portable spirometer.

BACKGROUND: Clinical practice guidelines recommend daily spirometer calibration checks and weekly linearity checks. The long-term stability of the volume and flow accuracy of a specific model of spirometer should be carefully characterized before modification of the frequency of calibration checks is considered for that model of spirometer. METHODS: The EasyOne ultrasonic flow-sensing spirometer was chosen for use by the clinical centers at the 2002 inception of the World Trade Center Worker and Volunteer Medical Screening Program. The screening program quality-control procedure required that the expiratory and inspiratory volume accuracy of each spirometer be checked every day of testing, and the flow accuracy (linearity) checked every week. The calibration check results were transferred to a central database for summary. RESULTS: Over 5,000 calibration-check results (4,109 single-speed and 1,189 three-speed) were accumulated from a total of 34 spirometers during the period February 2003 through March 2007. The mean single-speed calibration errors (and 5th-95th percentiles) were -2 mL (-80 to 70 mL) for exhalation and -10 mL (-80 to 60 mL) for inhalation. 98% of the exhalation and 97% of the inhalation calibration checks were accurate within 3.0%. There was no evidence of significant non-linearity according to the results of the 3-speed calibration checks (mean errors of -3, -5, and -6 mL at each speed). CONCLUSIONS: The EasyOne retained inhalation and exhalation volume accuracy of better than 3% for at least 4 years. Routine multiple-speed volume calibration checks may not be necessary with the EasyOne. The acceptability and repeatability of patient efforts should be the primary focus of quality-assurance programs with spirometers that have been demonstrated to remain accurate for long periods.

Quality of spirometry performed by 13,599 participants in the World Trade Center Worker and Volunteer Medical Screening Program.

OBJECTIVE: To determine the ability of spirometry technicians in the World Trade Center Worker and Volunteer Medical Screening Program to meet American Thoracic Society spirometry quality goals. METHODS: Spirometry technicians were trained centrally and performed spirometry sessions at 6 sites in the greater New York City area. We reviewed and graded the spirometry results for quality every month. RESULTS: About 80% (range 70-88%) of the spirometry sessions met the American Thoracic Society spirometry goals. In general, the spirometry technicians with the most experience were more successful in meeting the quality goals. Participant characteristics explained very little of the quality variability. CONCLUSIONS: The overall spirometry quality in this multicenter program was very good. Efforts to improve spirometry quality should focus on the performance of individual spirometry technicians.

The bronchoprotective effect of deep inspiration is flow rate dependent.

BACKGROUND AND STUDY OBJECTIVE: Deep inspiration (DI) protects against methacholine-induced bronchoconstriction in healthy subjects. We hypothesized that this bronchoprotective effect of DI depends upon the inspiratory flow rate. DESIGN: Prospective, controlled study. SETTING: Pulmonary function laboratory within a large tertiary medical center. PARTICIPANTS: Ten healthy nonsmokers without asthma or rhinitis. MEASUREMENTS: First, we performed a methacholine challenge in the absence of DI to determine the concentration sufficient to reduce FEV(1) by 20%. On two subsequent days, the challenge was repeated with the addition of either a fast or slow DI immediately before the threshold concentration of methacholine. We calculated the % reduction in FEV(1) and FVC from baseline. RESULTS: Mean % reduction in FEV(1) and FVC was significantly less with a fast DI than with no DI (20+/-3% vs. 34+/-4% for FEV(1), p=0.02; 12+/-3% vs. 23+/-3% for FVC, p=0.03); slow DIs did not significantly affect the methacholine-induced reduction in lung function. CONCLUSION: A fast DI is bronchoprotective while a slow DI is not. Elucidating the conditions that maximize or alternatively, eliminate bronchoprotection in healthy subjects may ultimately provide insight into the pathophysiology of asthma.

The Effects of Aging on Lung Structure and Function.

Growth of the segment of the population older than 65 years has led to intensified interest in understanding the biology of aging. This article is focused on age-related alterations in lung structure that produce predictable changes in physiologic function, both at rest and during exercise. Increased insight into the physiology of the healthy aging lung should ultimately lead to improved methods of lung function assessment in the elderly (defined as those older than 65 years) as well as better understanding of the manifestations and possibly even the treatment of geriatric lung disease.

An Official American Thoracic Society Workshop Report: Evaluation and Management of Asthma in the Elderly.

Asthma in the elderly (>65 yr old) is common and associated with higher morbidity and mortality than asthma in younger patients. The poor outcomes in this group are due, in part, to underdiagnosis and undertreatment. There are a variety of factors related to aging itself that affect the presentation of asthma in the elderly and influence diagnosis and management. Structural changes in the aging lung superimposed on structural changes due to asthma itself can worsen the disease and physiologic function. Changes in the aging immune system influence the cellular composition and function in asthmatic airways. These processes and differences from younger individuals with asthma are not well understood. Phenotypes of asthma in the elderly have not been clearly delineated, but it is likely that age of onset and overlap with chronic obstructive pulmonary disease impact disease characteristics. Physiologic tests and biomarkers used to diagnose and follow asthma in the elderly are generally similar to testing in younger individuals; however, whether they should be modified in aging has not been established. Confounding influences, such as comorbidities (increasing the risk of polypharmacy), impaired cognition and motor skills, psychosocial effects of aging, and age-related adverse effects of medications, impact both diagnosis and treatment of asthma in the elderly. Future efforts to understand asthma in the elderly must include geriatric-specific methodology to diagnose, characterize, monitor, and treat their disease.

Nocturnal asthma: mechanisms and management.

Nocturnal asthma, defined as an exacerbation of asthma at night, is associated with increases in symptoms and need for medication, increased airway responsiveness and worsening of lung function. Nighttime worsening of asthma has been recognized since the 5th century A.D. and is believed to be quite common, affecting a majority of asthmatics. The mechanisms of nocturnal asthma are intimately related to circadian rhythms, which influence inflammatory cells and mediators, hormone levels and cholinergic tone. Patients with nocturnal asthma symptoms may have greater nighttime activation of inflammatory cells and mediators, lower levels of epinephrine and increased vagal tone. In addition, underlying differences in the glucocorticoid receptor and b- receptors in these patients may diminish their ability to respond to therapy. While sleep appears to play a role in the pathophysiology of nocturnal asthma, it is not essential to it. Selective timing of medication can increase its efficacy and reduce its toxicity. Available therapy includes inhaled and oral corticosteroids, sustained-release theophylline, long-acting b-agonists, leukotriene- modifying agents and anticholinergic medication. The definition, epidemiology, potential mechanisms and management of nocturnal asthma are discussed in this review.

Longitudinal assessment of spirometry in the World Trade Center medical monitoring program.

BACKGROUND: Multiple studies have demonstrated an initial high prevalence of spirometric abnormalities following World Trade Center (WTC) disaster exposure. We assessed prevalence of spirometric abnormalities and changes in spirometry between baseline and first follow-up evaluation in participants in the WTC Worker and Volunteer Medical Monitoring Program. We also determined the predictors of spirometric change between the two examinations. METHODS: Prebronchodilator and postbronchodilator spirometry, demographics, occupational history, smoking status, and respiratory symptoms and exposure onset were obtained at both examinations (about 3 years apart). RESULTS: At the second examination, 24.1% of individuals had abnormal spirometry findings. The predominant defect was a low FVC without obstruction (16.1%). Between examinations, the majority of individuals did not have a greater-than-expected decline in lung function. The mean declines in prebronchodilator FEV(1) and FVC were 13 mL/yr and 2 mL/yr, respectively (postbronchodilator results were similar and not reported). Significant predictors of greater average decline between examinations were lack of bronchodilator responsiveness at examination 1 and weight gain [corrected]. CONCLUSIONS: Elevated rates of spirometric abnormalities were present at both examinations, with reduced FVC most common. Although the majority had a normal decline in lung function, lack of bronchodilator response at examination 1 and weight gain were significantly associated with greater-than-normal lung function declines [corrected]. Due to the presence of spirometric abnormalities > 5 years after the disaster in many exposed individuals, longer-term monitoring of WTC responders is essential.

Effect of obesity on clinical presentation and response to treatment in asthma.

Obesity is a risk factor for being diagnosed with asthma, but there is conflicting evidence on whether obesity is a risk factor for lung function abnormalities characteristic of asthma. We studied a cohort of 488 subjects, 47% of whom were obese. Obese and non-obese subjects with asthma had similar airflow limitation and bronchodilator responsiveness, but obese participants had increased sleep disturbance and gastroesophageal reflux disease, higher cytokine levels, and a trend towards increased exacerbations when treated with theophylline. Obese and non-obese asthmatics have similar lung function abnormalities, but comorbidities and altered responses to medications may significantly affect asthma control in obese people.