Asthma outcomes: Pulmonary physiology

doi:10.1016/j.jaci.2011.12.986

Journal of Allergy and Clinical Immunology

Volume 129, Issue 3, Supplement, March 2012, Pages S65-S87

https://doi.org/10.1016/j.jaci.2011.12.986 Get rights and content

Background

Outcomes of pulmonary physiology have a central place in asthma clinical research.

Objective

At the request of National Institutes of Health (NIH) institutes and other federal agencies, an expert group was convened to provide recommendations on the use of pulmonary function measures as asthma outcomes that should be assessed in a standardized fashion in future asthma clinical trials and studies to allow for cross-study comparisons.

Methods

Our subcommittee conducted a comprehensive search of PubMed to identify studies that focused on the validation of various airway response tests used in asthma clinical research. The subcommittee classified the instruments as core (to be required in future studies), supplemental (to be used according to study aims and in a standardized fashion), or emerging (requiring validation and standardization). This work was discussed at an NIH-organized workshop in March 2010 and finalized in September 2011.

Results

A list of pulmonary physiology outcomes that applies to both adults and children older than 6 years was created. These outcomes were then categorized into core, supplemental, and emerging. Spirometric outcomes (FEV₁, forced vital capacity, and FEV₁/forced vital capacity ratio) are proposed as core outcomes for study population characterization, for observational studies, and for prospective clinical trials. Bronchodilator reversibility and prebronchodilator and postbronchodilator FEV₁ also are core outcomes for study population characterization and observational studies.

Conclusions

The subcommittee considers pulmonary physiology outcomes of central importance in asthma and proposes spirometric outcomes as core outcomes for all future NIH-initiated asthma clinical research.

Section snippets

Summary

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Spirometry is a highly standardized test that can be performed reproducibly in both children and adults.
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Spirometry is a useful measure of severity of airflow limitation in asthma and is predictive of clinical outcomes.
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Normal values for spirometry are well established for healthy populations in the United States.

Definition and methodology for measurement

Spirometry measures maximal expiratory flow and exhaled volume during a forced expiratory vital capacity maneuver. The test is widely available and is highly standardized in terms of

Summary

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Bronchodilator reversibility is a measure of the magnitude of airway smooth muscle relaxation.
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Bronchodilator reversibility is diminished in patients with well-controlled asthma, as well as those with predominant inflammatory narrowing or remodeling of the airways, so it is not a good measure of asthma severity or response to therapy.
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The recommended method for measurement of bronchodilator reversibility is 4 inhalations of albuterol followed by spirometry in 15 minutes.

Definition and methodology for measurement

Bronchodilator

Summary

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PEF is a measure of maximum instantaneous expiratory flow and is used as an indicator of airway caliber in asthma.
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PEF can be self-administered on a daily basis and results recorded manually or electronically to obtain day-to-day or within-day variability.
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PEF is not useful for distinguishing restrictive from obstructive ventilatory defects.

Definition and methodology for measurement

The PEF is defined as the highest instantaneous expiratory flow achieved during a maximal forced expiratory maneuver starting at TLC. Because the PEF is

Airway responsiveness

This section describes 4 tests of airway responsiveness: (1) methacholine inhalation challenge, (2) exercise challenge, (3) isocapnic hyperventilation challenge, and (4) mannitol inhalation challenge.

Summary

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Lung volume testing by either body plethysmography or dilutional gas methods is used to measure elevated RV caused by peripheral airway closure, an indirect measure of airway smooth muscle tone and airway geometry.
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The test is safe and noninvasive, but the need for specialized equipment and skilled testing personnel limits its utility in large-scale clinical studies.

Definition and methodology for measurement

By assessing lung volumes or their combinations (capacities), one can measure the physical size and mechanical properties of the

Summary

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Measurement of airway resistance (R_aw) is a direct indicator of airway caliber; increased resistance is dominated by narrowing of central airways.
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R_aw is a useful measure of airway constriction or relaxation in response to experimental interventions but has limited value as a clinical outcome measure.
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R_aw is measured with several different techniques, which vary considerably in complexity and expense.

Definition and methodology for measurement

The measurement of R_aw and its reciprocal, airway conductance, is most commonly achieved with the

Summary

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Forced oscillation technique (FOT) measures the pressure-flow characteristics of the airways over a range of frequencies that define the impedance spectrum of the lung.
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The measurement has the advantage that it can be done during quiet breathing by untrained subjects at repeated intervals.
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At present, there are no widely recognized, standardized, clinically meaningful outcome measures derived from FOT, but it is an area of active investigation.

Definition and methodology for measurement

FOT is used to measure respiratory impedance by

Summary

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Peripheral airway resistance (Rp) is measured with a wedged bronchoscope and is considered to measure the resistance in small peripheral airways and collateral channels.
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The utility of Rp as a baseline measure or clinical outcome measure is not established.
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The applicability of the test is limited by the requirement for a semi-invasive procedure that has limited application in patients with severe or symptomatic asthma.

Definition and methodology for measurement

Rp is defined as the pressure measured by a pressure transducer at the tip of

Summary

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PV curves of the lung are used to study the static mechanical characteristics of the lung, specifically compliance and maximum elastic recoil pressure.
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The applicability of PV curves is limited by the special equipment required for measurement, as well as the requirement to insert an esophageal balloon; there is also limited information on the clinical utility of the measurements.

Methodology for measurement and other considerations

Measurements of the PV characteristics of the lung are used in people with asthma to determine the cause of

Summary

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The diffusing capacity for carbon monoxide (Dlco) test measures the integrity and surface area of the alveolar-capillary membrane of the lung.
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The Dlco test may be elevated in asthma, but this is not a specific finding.
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The Dlco is most useful to rule out other lung diseases, such as emphysema or interstitial lung disease.

Methodology for measurement and other considerations

The single-breath Dlco test is measured according to well-validated guidelines² and is designed as a measure of gas transfer or alveolar-capillary integrity. The maneuver is

Summary

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The multiple-breath washout (MBW) is an emerging measure of homogeneity of ventilation distribution in the lungs.
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The test is limited by lack of standardization and lack of information on clinical associations of the several parameters that can be derived from this test.

Methodology for measurement and other considerations

MBW, which was initially developed to measure FRC, evaluates the elimination from the lung of nitrogen or nonresident inert gases, such as helium or sulphur hexafluoride. As airway disease progresses, heterogeneity of ventilation

Summary

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Wheeze and cough recorders are promising technologies for assessment of asthma symptoms in ambulatory patients or in patients who are too young to perform other lung function tests.
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There is limited information on the utility of these devices for asthma research.

Methodology for measurement and other considerations

Wheeze and cough recorders have been developed to objectively monitor the presence, frequency, and severity of these clinical manifestations of asthma.215, 216 They may be used for monitoring patients during sleep, at home or work, or

Summary

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Nasal airway resistance and acoustic rhinometry measure mechanical obstruction of the nose, which is a common finding in asthma.
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Lack of normal values and standardized methodology limit the usefulness of these measures at the present time.

Methodology for measurement and other considerations

The vast majority of people with asthma also suffer from some form of nasal disease, ranging from intermittent rhinitis to chronic rhinosinusitis. This indicates that asthma affects not only the lower airways but also the entire respiratory system. From this

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2023, Allergology International
Tezepelumab, a human monoclonal antibody, blocks the activity of thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study (NCT03347279), tezepelumab reduced exacerbations by 56% compared with placebo in adults and adolescents with severe, uncontrolled asthma. This analysis evaluated the efficacy and safety of tezepelumab in NAVIGATOR patients recruited in Japan.
NAVIGATOR was a phase 3, multicenter, randomized, double-blind, placebo-controlled study. Patients (12–80 years old) were randomized 1:1 to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. Endpoints assessed included: the annualized asthma exacerbation rate (AAER) over 52 weeks (primary endpoint) and the change from baseline to week 52 in pre-bronchodilator forced expiratory volume in 1 s (FEV₁) and Asthma Control Questionnaire (ACQ)-6 score. The safety of tezepelumab was also assessed.
Overall, 97 patients recruited in Japan were randomized (tezepelumab, n = 58; placebo, n = 39). The AAER over 52 weeks was 1.54 (95% confidence interval [CI]: 0.90, 2.64) with tezepelumab compared with 3.12 (95% CI: 1.82, 5.35) with placebo (rate ratio: 0.49 [95% CI: 0.25, 0.99]; 51% reduction). For tezepelumab and placebo, the least-squares mean (standard error) change from baseline to week 52 for pre-bronchodilator FEV₁ was 0.23 (0.06) L and 0.19 (0.07) L and the ACQ-6 score was −1.12 (0.15) and −0.97 (0.19), respectively. The frequency of adverse events was similar between treatment groups (tezepelumab, 86.2%; placebo, 87.2%).
Tezepelumab reduced exacerbations compared with placebo, and was well tolerated, in NAVIGATOR patients with severe, uncontrolled asthma recruited in Japan.

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: The Asthma Outcomes workshop was funded by contributions from the National Institute of Allergy and Infectious Diseases; the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; the Agency for Healthcare Research and Quality; and the Merck Childhood Asthma Network, as well as by a grant from the Robert Wood Johnson Foundation. Contributions from the National Heart, Lung, and Blood Institute; the National Institute of Allergy and Infectious Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Environmental Health Sciences; and the US Environmental Protection Agency funded the publication of this article and all other articles in this supplement.

: Disclosure of potential conflict of interest: R. S. Tepper has received research support from the NHLBI. R. S. Wise is a consultant for GlaxoSmithKline, AstraZeneca, Novartis, Boehringer-Ingelheim, Merck, and Sunovion; and has received research support from GlaxoSmithKline, Boehringer-Ingelheim, Merck, and Forest. R. Covar has received research support from the NHLBI. C. G. Irvin has received research support from the NIH and the American Lung Association. M. Kraft has received research support from GlaxoSmithKline, Merck, Asthmatx, Eumedics, Novartis, and Genentech. M. C. Liu has received research support from GlaxoSmithKline, MedImmune, Sanofi-Aventis, and Amgen. G. T. O'Connor is a consultant for Sunovion Inc and has received research support from Novartis. R. Sorkness has received research support from the NIH. The rest of the authors declare that they have no relevant conflicts of interest.

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