European Respiratory Society/American Thoracic Society technical statement: standardisation of the measurement of lung volumes, 2023 update.

This document updates the 2005 European Respiratory Society (ERS) and American Thoracic Society (ATS) technical standard for the measurement of lung volumes. The 2005 document integrated the recommendations of an ATS/ERS task force with those from an earlier National Heart, Lung, and Blood Institute workshop that led to the publication of background papers between 1995 and 1999 and a consensus workshop report with more in-depth descriptions and discussion. Advancements in hardware and software, new research and emerging approaches have necessitated an update to the 2005 technical standard to guide laboratory directors, physiologists, operators, pulmonologists and manufacturers. Key updates include standardisation of linked spirometry, new equipment quality control and validation recommendations, generalisation of the multiple breath washout concept beyond nitrogen, a new acceptability and grading system with addition of example tracings, and a brief review of imaging and other new techniques to measure lung volumes. Future directions and key research questions are also noted.

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.

Spirometry screening for airway obstruction in asymptomatic smokers.

BACKGROUND: Screening spirometry might help identify patients with chronic obstructive pulmonary disease (COPD) at an earlier stage. In this study, we evaluated the prevalence of airway obstruction in a cohort of asymptomatic smokers who underwent spirometry as part of a routine health maintenance examination. METHODS: The study cohort consisted of a consecutive sample of 386 asymptomatic smokers (≥5 pack-years) without a history of COPD or asthma, who completed spirometry testing as part of a routine health maintenance examination. RESULTS: Overall, 9 study subjects (2.3%, 95% confidence interval: 1.1-4.4%) had evidence of airway obstruction on spirometry. Univariate and multiple regression analyses showed that the risk of airway obstruction was not significantly associated with age, sex, race, smoking history or past history of respiratory symptoms. DISCUSSION: Spirometry screening of asymptomatic smokers may help detect a small number of patients with airway obstruction who are at high risk for COPD.

Persistence of multiple illnesses in World Trade Center rescue and recovery workers: a cohort study.

BACKGROUND: More than 50,000 people participated in the rescue and recovery work that followed the Sept 11, 2001 (9/11) attacks on the World Trade Center (WTC). Multiple health problems in these workers were reported in the early years after the disaster. We report incidence and prevalence rates of physical and mental health disorders during the 9 years since the attacks, examine their associations with occupational exposures, and quantify physical and mental health comorbidities. METHODS: In this longitudinal study of a large cohort of WTC rescue and recovery workers, we gathered data from 27,449 participants in the WTC Screening, Monitoring, and Treatment Program. The study population included police officers, firefighters, construction workers, and municipal workers. We used the Kaplan-Meier procedure to estimate cumulative and annual incidence of physical disorders (asthma, sinusitis, and gastro-oesophageal reflux disease), mental health disorders (depression, post-traumatic stress disorder [PTSD], and panic disorder), and spirometric abnormalities. Incidence rates were assessed also by level of exposure (days worked at the WTC site and exposure to the dust cloud). FINDINGS: 9-year cumulative incidence of asthma was 27·6% (number at risk: 7027), sinusitis 42·3% (5870), and gastro-oesophageal reflux disease 39·3% (5650). In police officers, cumulative incidence of depression was 7·0% (number at risk: 3648), PTSD 9·3% (3761), and panic disorder 8·4% (3780). In other rescue and recovery workers, cumulative incidence of depression was 27·5% (number at risk: 4200), PTSD 31·9% (4342), and panic disorder 21·2% (4953). 9-year cumulative incidence for spirometric abnormalities was 41·8% (number at risk: 5769); three-quarters of these abnormalities were low forced vital capacity. Incidence of most disorders was highest in workers with greatest WTC exposure. Extensive comorbidity was reported within and between physical and mental health disorders. INTERPRETATION: 9 years after the 9/11 WTC attacks, rescue and recovery workers continue to have a substantial burden of physical and mental health problems. These findings emphasise the need for continued monitoring and treatment of the WTC rescue and recovery population. FUNDING: Centers for Disease Control and Prevention and National Institute for Occupational Safety and Health.

Aging and Susceptibility to Pulmonary Disease.

The lungs are continually subjected to noxious and inert substances, are immunologically active, and are in a constant state of damage and repair. This makes the pulmonary system particularly vulnerable to diseases of aging. Aging can be understood as random molecular damage that is unrepaired and accumulates over time, resulting in cellular defects and tissue dysfunction. The breakdown of cellular mechanisms, including stem cell exhaustion, genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, altered intercellular communication, and changes in the extracellular matrix is thought to advance the aging process itself. Chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and cancers illustrate a pathologic breakdown in these mechanisms beyond normal aging. The immune system becomes less effective with advancing age. There is a low-level state of chronic inflammation termed inflammaging which is thought to be driven by immunosenescence, the changes in the innate and adaptive immune systems with advancing age that lead to dysregulation and decreased effectiveness of the immune system. These processes of aging lead to expected changes in the form and function of the respiratory system, most notably a loss of lung elasticity, decrease in respiratory muscle strength, increase in ventilation-perfusion mismatching, and stiffening of the vasculature. The astute clinician is aware of these expected findings and does not often attribute dyspnea to aging alone. Maintaining a low threshold to investigate for comorbid disease and understanding how pulmonary disease presents differently in the elderly than in younger adults can improve clinical outcomes. © 2022 American Physiological Society. Compr Physiol 12:3509-3522, 2022.

"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.

Standardization of spirometry in assessment of responders following man-made disasters: World Trade Center worker and volunteer medical screening program.

BACKGROUND: Spirometry is the most commonly used pulmonary function test to screen individuals for suspected lung disease. It is also used for screening workers with exposures to agents associated with pulmonary diseases. Although the American Thoracic Society (ATS) provides guidelines for spirometers and spirometry techniques, many factors are not standardized, so that results from individual pulmonary function laboratories vary substantially. These differences can create substantial difficulties in using data pooled from multiple sites to understand health consequences of disasters that involve exposures to pulmonary toxins. This article describes the approach used to minimize these differences for a consortium of institutions who are providing medical monitoring examinations to World Trade Center (WTC) responders. The protocol improved upon the minimal ATS guidelines. METHODS: Spirometric measurements were obtained before and after use of a bronchodilator. A fourth-generation spirometer was chosen that exceeded ATS spirometer accuracy standards. The accuracy was verified at the beginning of each day of testing. Technologists who performed the spirometry tests were centrally trained and certified and received regular reports on their performance. Reference values and normal ranges were obtained from the National Health and Nutrition Examination Survey (NHANES III) data set. A standardized interpretation flowchart was followed to reduce misclassification rates for airway obstruction and restriction. Patients with spirometric abnormalities were referred for more extensive diagnostic testing. RESULTS: More than 12,000 spirometry tests were performed during the first examination. The 20 spirometers used at the 6 participating institutions maintained accuracy within 3% for more than 4 years. Overall, more than 80% of the test sessions met ATS quality goals. Spirometry abnormality rates exceeded those obtained for adults who participated in the NHANES III survey. CONCLUSIONS: The program allowed standardization of the performance and interpretation of spirometry results across multiple institutions. This facilitated reliable and rapid diagnosis of lung disease in the large number of WTC responders screened. We recommend this approach for postdisaster pulmonary evaluations in other settings.

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.

The World Trade Center disaster and the health of workers: five-year assessment of a unique medical screening program.

BACKGROUND: Approximately 40,000 rescue and recovery workers were exposed to caustic dust and toxic pollutants following the 11 September 2001 attacks on the World Trade Center (WTC). These workers included traditional first responders, such as firefighters and police, and a diverse population of construction, utility, and public sector workers. METHODS: To characterize WTCrelated health effects, the WTC Worker and Volunteer Medical Screening Program was established. This multicenter clinical program provides free standardized examinations to responders. Examinations include medical, mental health, and exposure assessment questionnaires; physical examinations; spirometry; and chest X rays. RESULTS: Of 9,442 responders examined between July 2002 and April 2004, 69% reported new or worsened respiratory symptoms while performing WTC work. Symptoms persisted to the time of examination in 59% of these workers. Among those who had been asymptomatic before September 11, 61% developed respiratory symptoms while performing WTC work. Twenty-eight percent had abnormal spirometry; forced vital capacity (FVC) was low in 21%; and obstruction was present in 5%. Among nonsmokers, 27% had abnormal spirometry compared with 13% in the general U.S. population. Prevalence of low FVC among nonsmokers was 5-fold greater than in the U.S. population (20% vs. 4%). Respiratory symptoms and spirometry abnormalities were significantly associated with early arrival at the site. CONCLUSION: WTC responders had exposure-related increases in respiratory symptoms and pulmonary function test abnormalities that persisted up to 2.5 years after the attacks. Longterm medical monitoring is required to track persistence of these abnormalities and identify late effects, including possible malignancies. Lessons learned should guide future responses to civil disasters.