Respiratory System Dynamics.

While static mechanical forces govern resting lung volumes, dynamic forces determine tidal breathing, airflow, and changes in airflow and lung volume during normal and abnormal breathing. This section will examine the mechanisms, measurement methodology, and interpretation of the dynamic changes in airflow and lung volume that occur in health and disease. We will first examine how the total work of breathing can be described by the parameters of the equation of motion, which determine the pressure required to move air into and out of the lung. This will include a detailed description of airflow characteristics and airway resistance. Next, we will review the changes in pressure and flow that determine maximal forced inspiration and expiration, which result in the maximal flow-volume loop and the clinically important forced expired volume in 1 second. We will also assess the mechanisms and interpretation of bronchodilator responsiveness, dynamic hyperinflation, and airways hyperresponsiveness.

Inhaled anti-TSLP antibody fragment, ecleralimab, blocks responses to allergen in mild asthma.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a key upstream regulator driving allergic inflammatory responses. We evaluated the efficacy and safety of ecleralimab, a potent inhaled neutralising antibody fragment against human TSLP, using allergen inhalation challenge (AIC) in subjects with mild atopic asthma. METHODS: This was a 12-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre allergen bronchoprovocation study conducted at 10 centres across Canada and Germany. Subjects aged 18-60 years with stable mild atopic asthma were randomised (1:1) to receive 4 mg once-daily inhaled ecleralimab or placebo. Primary end-points were the allergen-induced change in forced expiratory volume in 1 s (FEV1) during the late asthmatic response (LAR) measured by area under the curve (AUC3-7h) and maximum percentage decrease (LAR%) on day 84, and the safety of ecleralimab. Allergen-induced early asthmatic response (EAR), sputum eosinophils and fractional exhaled nitric oxide (F ENO) were secondary and exploratory end-points. RESULTS: 28 subjects were randomised to ecleralimab (n=15) or placebo (n=13). On day 84, ecleralimab significantly attenuated LAR AUC3-7h by 64% (p=0.008), LAR% by 48% (p=0.029), and allergen-induced sputum eosinophils by 64% at 7 h (p=0.011) and by 52% at 24 h (p=0.047) post-challenge. Ecleralimab also numerically reduced EAR AUC0-2h (p=0.097) and EAR% (p=0.105). F ENO levels were significantly reduced from baseline throughout the study (p<0.05), except at 24 h post-allergen (day 43 and day 85). Overall, ecleralimab was safe and well tolerated. CONCLUSION: Ecleralimab significantly attenuated allergen-induced bronchoconstriction and airway inflammation, and was safe in subjects with mild atopic asthma.

Sounding the alarmins-The role of alarmin cytokines in asthma.

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date, there is no evidence that IL-25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL-25, IL-33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.

Effect of daily dosing with tiotropium against methacholine induced bronchoconstriction in asthmatics.

INTRODUCTION: Loss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta2-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist ipratropium bromide have reported no tolerance after regular use against inhaled methacholine. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on methacholine induced bronchoconstriction in a population of mild asthmatics. METHODS: We performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 µg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge. RESULTS: The average doubling dose increase in methacholine PD20 following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD20 was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p < 0.001). CONCLUSION: LAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta2-agonist bronchodilators.

Muscarinic Receptor Antagonism and Allergen Induced Airway Responses in Allergic Asthma: A Scoping Review.

PURPOSE: The purpose of this scoping review was to identify existing clinical and basic science knowledge surrounding the effect of muscarinic receptor antagonism on allergen-induced airway responses to inform future clinical research in this area. METHODS: Multiple advanced searches were performed using the National Library of Medicine PubMed search engine. Each search began with two terms; for example, "atropine and asthma" or "tiotropium and airway inflammation". Results were then further refined to include terms such as "allergen" or "ovalbumin (OVA)". Abstracts of refined searches were reviewed for relevance to allergic asthma and allergen-induced airway responses including the early and late asthmatic responses, airway inflammation and tissue remodelling. There was no restriction regarding publication date. Reference lists of selected papers were also reviewed for relevant publications. RESULTS: Nine human clinical trial publications and fourteen animal model publications were identified. In humans, single dose atropine (n=4), ipratropium (n=4) or oxitropium (n=1) administered pre-challenge produced equivocal effects on allergen-induced early asthmatic responses as reported but favored inhibition in eight of nine studies after re-analyses. Animal model investigations (n=14) showed mostly favorable results, especially with respect to airway inflammation and tissue remodelling, although two studies were negative, and one study showed a worsening in allergen induced airway inflammation following muscarinic receptor antagonism. CONCLUSION: Existing human and animal model data suggest muscarinic receptor antagonism may be beneficial in preventing allergen induced airway responses in those with allergic asthma. Additional human research utilizing current standardized methodologies is required.

International consensus on lung function testing during the COVID-19 pandemic and beyond.

Coronavirus disease 2019 (COVID-19) has negatively affected the delivery of respiratory diagnostic services across the world due to the potential risk of disease transmission during lung function testing. Community prevalence, reoccurrence of COVID-19 surges and the emergence of different variants of SARS-CoV-2 have impeded attempts to restore services. Finding consensus on how to deliver safe lung function services for both patients attending and for staff performing the tests are of paramount importance. This international statement presents the consensus opinion of 23 experts in the field of lung function and respiratory physiology balanced with evidence from the reviewed literature. It describes a robust roadmap for restoration and continuity of lung function testing services during the COVID-19 pandemic and beyond. Important strategies presented in this consensus statement relate to the patient journey when attending for lung function tests. We discuss appointment preparation, operational and environmental issues, testing room requirements including mitigation strategies for transmission risk, requirement for improved ventilation, maintaining physical distance and use of personal protection equipment. We also provide consensus opinion on precautions relating to specific tests, filters, management of special patient groups and alternative options to testing in hospitals. The pandemic has highlighted how vulnerable lung function services are and forces us to re-think how long-term mitigation strategies can protect our services during this and any possible future pandemic. This statement aspires to address the safety concerns that exist and provide strategies to make lung function tests and the testing environment safer when tests are required.

Allergen provocation tests in respiratory research: building on 50†years of experience.

The allergen provocation test is an established model of allergic airway diseases, including asthma and allergic rhinitis, allowing the study of allergen-induced changes in respiratory physiology and inflammatory mechanisms in sensitised individuals as well as their associations. In the upper airways, allergen challenge is focused on the clinical and pathophysiological sequelae of the early allergic response, and is applied both as a diagnostic tool and in research settings. In contrast, bronchial allergen challenge has almost exclusively served as a research tool in specialised research settings with a focus on the late asthmatic response and the underlying type 2 inflammation. The allergen-induced late asthmatic response is also characterised by prolonged airway narrowing, increased nonspecific airway hyperresponsiveness and features of airway remodelling including the small airways, and hence allows the study of several key mechanisms and features of asthma. In line with these characteristics, allergen challenge has served as a valued tool to study the cross-talk of the upper and lower airways and in proof-of-mechanism studies of drug development. In recent years, several new insights into respiratory phenotypes and endotypes including the involvement of the upper and small airways, innovative biomarker sampling methods and detection techniques, refined lung function testing as well as targeted treatment options further shaped the applicability of the allergen provocation test in precision medicine. These topics, along with descriptions of subject populations and safety, in line with the updated Global Initiative for Asthma 2021 document, will be addressed in this review.

Atopy risk among school-aged children in relation to early exposures to a farm environment: A systematic review.

BACKGROUND AND OBJECTIVES: Childhood atopy is a complex condition with both a genetic and an environmental component. This systematic review will explore the current understanding of the importance of early life exposures to a farm in the development of atopy measured by objective markers of skin prick testing, and specific IgE measurements in school age children. METHODS: A systematic review was performed. RESULTS: Among 7285 references identified, 14 studies met the inclusion criteria (13 cross-sectional studies and 1 case-control study). The results were fairly consistent in that early farm-related exposures can protect children from becoming atopic at school age. In general, there was heterogeneity in the assessment of outcomes and exposures. CONCLUSIONS: Early-life farm exposures are associated with a protective effect on childhood atopy as assessed by objective markers. Future work should focus on understanding specific farm exposures that may important in these associations between atopy and farm exposures in children.

Assessment Of Ratio Of Peak Expiratory Flow Rate To Vital Capacity For Identifying Pulmonary Fibrosis.

BACKGROUND: Pulmonary fibrosis (PF) is associated with reduction in vital capacity (VC) and increase in expiratory flow rates, including peak expiratory flow (PEF). Full pulmonary function testing and computed tomography chest scans are limited resources in some geographic areas and a simple and sensitive screening test would be of value. We hypothesized that increase in the ratio of % predicted PEF over % predicted VC (%PEF/%VC), from spirometry alone might be sensitive to screen for pulmonary fibrosis. METHODS: The %PEF/%VC from 1,000 consecutive spirometric flow volume curves was nearly normally distributed: 7.5% (approximately 1.5 standard deviations) had a ratio ≥ 1.4. We evaluated the sensitivity and specificity of this cut point for a diagnosis of PF in a retrospective chart review of 391 patients with good quality spirometry and respirologists' confirmed diagnoses. RESULTS: Of the 391 patients analyzed, 98 had PF, 79 were normal, 70 had a combined obstructive and restrictive processes, 57 had obstructive lung disease, 61 had extra-parenchymal restriction and 26 had non-fibrotic interstitial lung disease. A %PEF/%VC ≥ 1.4 was only 54.1% sensitive in predicting PF, however it had a specificity of 94.9%. There was a 95.1% specificity for ruling in intra-parenchymal opposed to extra-parenchymal restriction. CONCLUSION: A %PEF/%VC ≥ 1.4 was not sensitive enough to screen for PF but did demonstrate high specificity and thus may be helpful in identifying intraparenchymal restriction.

Direct and indirect bronchoprovocation tests in dose-response studies of inhaled corticosteroids: Past, present, and future directions.

Inhaled corticosteroids (ICS) are a mainstay of treatment in eosinophilic asthma. Many studies have explored the dose-response effect of different formulations of ICS through direct or indirect bronchoprovocation testing. Such studies are important for investigating efficacy and identifying the relative potency between formulations. However, lack of consistency in methods and designs has hindered the comparability of study findings. This review discusses current knowledge of the dose-response, or lack thereof, of different formulations of ICS through direct and indirect bronchoprovocation testing. The strengths and weaknesses of past studies inform recommendations for future methodological considerations in this field, such as utilizing a randomized double-blind crossover design, enrolling participants likely to respond to ICS therapy, and carefully selecting treatment durations and washout periods to assess incremental improvement in airway hyperresponsiveness while reducing the likelihood of a carryover effect.

Comparison of methacholine and mannitol challenges: importance of method of methacholine inhalation.

BACKGROUND: Direct inhalation challenges (e.g. methacholine) are stated to be more sensitive and less specific for a diagnosis of asthma than are indirect challenges (e.g. exercise, non-isotonic aerosols, mannitol, etc.). However, data surrounding comparative sensitivity and specificity for methacholine compared to mannitol challenges are conflicting. When methacholine is inhaled by deep total lung capacity (TLC) inhalations, deep inhalation inhibition of bronchoconstriction leads to a marked loss of diagnostic sensitivity when compared to tidal breathing (TB) inhalation methods. We hypothesized that deep inhalation methacholine methods with resulting bronchoprotection may be the explanation for conflicting sensitivity/specificity data. METHODS: We reviewed 27 studies in which methacholine and mannitol challenges were performed in largely the same individuals. Methacholine was inhaled by dosimeter TLC methods in 13 studies and by tidal breathing in 14 studies. We compared the rates of positive methacholine (stratified by inhalation method) and mannitol challenges in both asthmatics and non-asthmatics. RESULTS: When methacholine was inhaled by TLC inhalations the prevalence of positive tests in asthmatics, 60.2% (548/910), was similar to mannitol, 58.9% (537/912). By contrast, when methacholine was inhaled by tidal breathing the prevalence of positive tests in asthmatics 83.1% (343/413) was more than double that of mannitol, 41.5% (146/351). In non-asthmatics, the two methacholine methods resulted in positive tests in 18.8% (142/756) and 16.2% (27/166) by TLC and TB inhalations respectively. This compares to an overall 8.3% (n = 76) positive rate for mannitol in 913 non-asthmatics. CONCLUSION: These data support the hypothesis that the conflicting data comparing methacholine and mannitol sensitivity and specificity are due to the method of methacholine inhalation. Tidal breathing methacholine methods have a substantially greater sensitivity for a diagnosis of asthma than either TLC dosimeter methacholine challenge methods or mannitol challenge. Methacholine challenges should be performed by tidal breathing as per recent guideline recommendations. Methacholine (more sensitive) and mannitol (more specific) will thus have complementary diagnostic features.

Respiratory Duty Cycles in Individuals With and Without Airway Hyperresponsiveness.

BACKGROUND: The respiratory duty cycle (Ti/Ttot) can influence bronchoprovocation test results and nebulized drug delivery. The Ti/Ttot has not yet been examined in individuals with airway hyperresponsiveness (AHR) in typical bronchoprovocation test conditions. This study investigated the mean Ti/Ttot in participants with and without AHR and whether the Ti/Ttot changes with increasing bronchoconstriction. METHODS: Fifteen participants with AHR and fifteen participants without AHR completed this randomized crossover study. An ultrasonic spirometer was used for continuous measurement of the Ti/Ttot as participants inhaled room air or aerosolized solution. Each participant completed two methacholine challenges, one using a continuous-output vibrating mesh nebulizer/ultrasonic spirometer and one with the nebulizer only. Prior to each methacholine challenge, participants inhaled room air and aerosolized saline through the nebulizer/spirometer setup to record baseline Ti/Ttot data. RESULTS: The mean Ti/Ttot findings [95% CIs] during room air inhalation were 0.392 [0.378-0.406] and 0.447 [0.426-0.468] in participants with and without AHR, respectively (P < .001). The mean Ti/Ttot during saline inhalation were 0.389 [0.373-0.405] and 0.424 [0.398-0.450] in participants with and without AHR (P = .040). The Ti/Ttot showed a nonsignificant downward trend with progressive methacholine-induced bronchoconstriction. CONCLUSIONS: The mean Ti/Ttot in participants with AHR closely resembles the assumed Ti/Ttot of 0.40 recommended for standard use when calculating methacholine challenge results. Since the Ti/Ttot did not change significantly over the course of a methacholine challenge, the same Ti/Ttot can be used to calculate the dose of methacholine inhaled, regardless of the level of bronchoconstriction. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03505489; URL: www.clinicaltrials.gov.

The effect of deep inhalation on mannitol responsiveness.

BACKGROUND: Mannitol inhalation testing is specific for asthmatics with eosinophilic airway inflammation, a factor that has been negatively correlated with the development of deep inhalation bronchoprotection. OBJECTIVE: To evaluate the effect of deep inhalations on responsiveness to inhaled mannitol in correlation with the degree of airway inflammation. METHODS: Twenty participants with stable asthma completed this randomized, crossover study. A screening visit assessed responsiveness to methacholine and airway inflammation through fractional exhaled nitric oxide (FeNO) measures and sputum induction. Participants next completed two mannitol challenges, one with deep inhalations (standard method) and one with inhalations to half of total lung capacity, and two methacholine challenges, one with tidal breathing (standard method) and one with deep inhalations. Only the inhalation technique for dose administration differed between repeat mannitol or methacholine challenges. RESULTS: Deep inhalations did not significantly influence the provocative dose of mannitol causing a 15% fall in forced expiratory volume in 1 second ((P = .73; n = 7) or the mannitol dose-response slope (P = .26; n = 20). Deep inhalations produced significant bronchoprotection against methacholine (P = .03; n = 20). FeNO levels were significantly correlated to sputum eosinophilia (P = .02; n = 15), responsiveness to deep inhalation methacholine (P = .005; n = 20), the dose-response slopes from deep inhalation mannitol (P = .01; n = 20), and the dose-response slope from non-deep inhalation mannitol (P = .005; n = 20). CONCLUSIONS AND CLINICAL RELEVANCE: Deep inhalations did not produce significant bronchoprotection against inhaled mannitol. This result is in agreement with past findings linking airway inflammation with loss of deep inhalation bronchoprotection. CLINICAL TRIAL REGISTRATION: This study was prospectively registered on clinicaltrials.gov (NCT03505489).

Use of a vibrating mesh nebulizer for allergen challenge.

BACKGROUND: Allergen inhalation tests are a valuable research tool. The allergen dose producing an early asthmatic response (EAR) can be predicted from methacholine responsiveness and allergen skin test endpoint (STE). The Wright® jet nebulizer, which is both inefficient and increasingly difficult to obtain, has been used historically. We assessed the Solo® vibrating mesh nebulizer as an alternative for allergen and methacholine challenges. METHODS: Eighteen mild atopic asthmatics completed the study. Doubling concentration allergen prick skin tests were performed to determine the STE in allergen units/mL. The Wright® protocol was used to measure the methacholine provocation dose causing a 20% forced expired volume in one second (FEV1) fall (PD20) (µg) and the allergen PD20 (units). The Solo® protocol (0.5 mL nebulized to completion, tidal breathing inhalation) was used to determine both methacholine PD20 and allergen PD20. The nebulizer order was randomized and separated by ≥ 2 weeks. RESULTS: All data were log transformed. The allergen PD20, predicted from the methacholine PD20 and the STE, was within 2 doubling doses of the PD20 measured with the Wright® and 2.64 doubling doses of that measured with Solo®. The Wright® allergen PD20 correlated with the Wright® methacholine PD20 (r = 0.74) and the STE (r = 0.78) and more strongly with the product of the two (Wright® methacholine PD20 × STE, r = 0.91, p < 0.00001). The Solo® allergen PD20 showed similar relationships with the Solo® methacholine PD20 (r = 0.61), the STE (r = 0.75) and the product of the two (Solo® methacholine PD20 × STE, r = 0.83, p < 0.00002). The Wright® and the Solo® methacholine geometric mean PD20s were not significantly different (49.3 and 54.5 µg respectively, p = 0.62). The Wright® allergen PD20 was slightly but significantly lower than the Solo® allergen PD20 (geometric means 6.7 and 10.5 units respectively, p = 0.003). CONCLUSION: The Solo® allergen PD20 showed the same relationship with methacholine responsiveness and STE as did the Wright®. The Solo® allergen PD20 was slightly but significantly higher than the Wright® allergen PD20. The Solo® vibrating mesh nebulizer was well tolerated and is an acceptable alternative for allergen challenge.Trial registration clinicaltrials.gov: NCT03491358.

Reversible bilateral phrenic nerve paralysis.

Bilateral phrenic nerve paralysis is a rare potentially life-threatening condition which is usually due to trauma (including surgery) or neurologic disease. We present a patient with apparent rapid onset bilateral phrenic nerve paralysis whose primary symptom was severe positional (supine) dyspnea with profound supine oxygen desaturation. Nerve conduction study abnormalities of the phrenic nerves and some left brachial plexus nerves suggested a diagnosis of ALS. He was treated with supportive night time ventilatory assistance (BiPAP) and over 4 years his condition recovered essentially completely. In retrospect the most likely diagnosis was a rare brachial plexopathy referred to as neuralgic amyotrophy.