Precision medicine in asthma: the role of bronchial thermoplasty.

PURPOSE OF REVIEW: The inflammatory makeup of severe asthma is heterogeneous. Identification of the predominant cellular endotype via biomarkers can aid in the selection of more advanced therapies. This review is clinically focused on how to use these biomarkers to help select between biologic agents and/or bronchial thermoplasty. RECENT FINDINGS: Several Th2 biomarkers exist for the detection of eosinophilic disease; however, the best biomarker for clinical practice is debatable depending upon local resources. Currently, there are three federal drug agency-approved biologic agents (omalizumab, mepolizumab and reslizumab) to treat severe asthma with frequent exacerbations despite standard medical therapy. Several others are either in clinical trials or in the development phase for the treatment of eosinophilic asthma. To date, agents targeting neutrophilic inflammation have been largely unsuccessful. Bronchial thermoplasty has emerged as an option for the treatment of severe asthma. SUMMARY: The appropriate selection of patients through the use of eosinophilic biomarkers has led to significant reductions in exacerbations with the use of mAb therapy. Bronchial thermoplasty has also shown reductions in asthma exacerbations and improved quality of life; however, it is unclear which patients may respond best to this intervention.

Factors Related to Biologic Adherence and Outcomes Among Moderate-to-Severe Asthma Patients.

BACKGROUND: Adherence barriers to asthma biologics may not be uniform across administration settings for patients with moderate-to-severe asthma. OBJECTIVE: To examine differences in asthma biologic adherence and associated factors, as well as association with a 1-year all-cause emergency department (ED) visit, across administration settings. METHODS: A retrospective study of biologic naïve moderate-to-severe asthma patients with initial biologic therapy between January 1, 2016, and April 30, 2020, in the Optum Clinformatics Data Mart was performed. Three administration settings were identified: Clinic-only (outpatient office/infusion center), Home (self-administration), and Hybrid setting (mixture of clinic and self-administration). Asthma biologic adherence was the proportion of observed over expected biologic dose administrations received within 6 months from initial therapy. Factors associated with adherence were identified by administration setting, using Poisson regression analyses. A relationship between a 1-year all-cause ED visit and adherence was assessed for each administration setting using Cox regression analyses. RESULTS: The study cohort was 3932 patients. Biologics adherence was 0.75 [0.5, 1] in Clinic setting, the most common administration setting, and 0.83 [0.5, 1] in both Home and Hybrid settings. Specialist access was consistently associated with better biologic adherence, whereas Black race, Hispanic ethnicity, lower education, Medicare only insurance, and higher patient out-of-pocket cost were associated with worse biologic adherence in some settings. In the Hybrid setting, hazard for a 1-year all-cause ED visit decreased with biologic adherence. CONCLUSIONS: Asthma biologic adherence varied by administration setting. Efforts to improve asthma biologic adherence should consider promoting self-administration when beneficial, improving prior specialist access, and targeting patients with higher risk of suboptimal adherence particularly Black and Hispanic patients.

Development and Evaluation of a Small Airway Disease Index Derived From Modeling the Late-Expiratory Flattening of the Flow-Volume Loop.

Excessive decrease in the flow of the late expiratory portion of a flow volume loop (FVL) or "flattening", reflects small airway dysfunction. The assessment of the flattening is currently determined by visual inspection by the pulmonary function test (PFT) interpreters and is highly variable. In this study, we developed an objective measure to quantify the flattening. We downloaded 172 PFT reports in PDF format from the electronic medical records and digitized and extracted the expiratory portion of the FVL. We located point A (the point of the peak expiratory flow), point B (the point corresponding to 75% of the expiratory vital capacity), and point C (the end of the expiratory portion of the FVL intersecting with the x-axis). We did a linear fitting to the A-B segment and the B-C segment. We calculated: 1) the AB-BC angle (∠ABC), 2) BC-x-axis angle (∠BCX), and 3) the log ratio of the BC slope over the vertical distance between point A and x-axis [log (BC/A-x)]. We asked an expert pulmonologist to assess the FVLs and separated the 172 PFTs into the flattening and the non-flattening groups. We defined the cutoff value as the mean minus one standard deviation using data from the non-flattening group. ∠ABC had the best concordance rate of 80.2% with a cutoff value of 149.7°. We then asked eight pulmonologists to evaluate the flattening with and without ∠ABC in another 168 PFTs. The Fleiss' kappa was 0.320 (lower and upper confidence intervals [CIs]: 0.293 and 0.348 respectively) without ∠ABC and increased to 0.522 (lower and upper CIs: 0.494 and 0.550) with ∠ABC. There were 147 CT scans performed within 6 months of the 172 PFTs. Twenty-six of 55 PFTs (47.3%) with ∠ABC <149.7° had CT scans showing small airway disease patterns while 44 of 92 PFTs (47.8%) with ∠ABC ≥149.7° had no CT evidence of small airway disease. We concluded that ∠ABC improved the inter-rater agreement on the presence of the late expiratory flattening in FVL. It could be a useful addition to the assessment of small airway disease in the PFT interpretation algorithm and reporting.

Therapeutic Inertia in Prescribing Biologics for Patients with Moderate-to-Severe Asthma: Workshop Summary.

Moderate-to-severe asthma represents about a quarter of the nearly 10% of Americans diagnosed with asthma. Many patients with moderate-to-severe asthma have uncontrolled symptoms that lead to exacerbations requiring oral corticosteroids. There are many factors contributing to poor asthma control, including poor adherence to prescribed therapies, the under-prescribing of biologics and therapeutic inertia. We convened an eight-member panel from fields of primary care, pulmonology, immunology, health services and clinical research, behavioral science and pharmaceutical medical affairs, with the goal of identifying contributing factors and solutions to therapeutic inertia with asthma biologics. We used the Capability, Opportunity, and Motivation (COM-B) model to classify patient and provider behavior towards therapeutic inertia. The model incorporates existing behavior theories and is driven by the interaction of capability, opportunity, and motivation. We used a Delphi method to identify and develop six primary solutions: 1) integration of patient-centered outcomes into asthma management practice; 2) provider education about asthma treatment; 3) moderate-to-severe asthma care delivery redesign; 4) harmonized, evidence-based protocol for the management of moderate-to-severe asthma; 5) designated coordinator approach for optimal asthma management; and 6) a case coordination digital support tool. Integration of patient-centered outcomes into asthma management practice and provider education were identified as having the highest potential to impact therapeutic and clinical inertia. The COM-B model is effective in identifying improvement within therapeutic inertia targeting the capabilities, opportunities, and motivations of patients, providers, and payer systems.

Active trafficking of alpha 1 antitrypsin across the lung endothelium.

The homeostatic lung protective effects of alpha-1 antitrypsin (A1AT) may require the transport of circulating proteinase inhibitor across an intact lung endothelial barrier. We hypothesized that uninjured pulmonary endothelial cells transport A1AT to lung epithelial cells. Purified human A1AT was rapidly taken up by confluent primary rat pulmonary endothelial cell monolayers, was secreted extracellularly, both apically and basolaterally, and was taken up by adjacent rat lung epithelial cells co-cultured on polarized transwells. Similarly, polarized primary human lung epithelial cells took up basolaterally-, but not apically-supplied A1AT, followed by apical secretion. Evidence of A1AT transcytosis across lung microcirculation was confirmed in vivo by two-photon intravital microscopy in mice. Time-lapse confocal microscopy indicated that A1AT co-localized with Golgi in the endothelium whilst inhibition of the classical secretory pathway with tunicamycin significantly increased intracellular retention of A1AT. However, inhibition of Golgi secretion promoted non-classical A1AT secretion, associated with microparticle release. Polymerized A1AT or A1AT supplied to endothelial cells exposed to soluble cigarette smoke extract had decreased transcytosis. These results suggest previously unappreciated pathways of A1AT bidirectional uptake and secretion from lung endothelial cells towards the alveolar epithelium and airspaces. A1AT trafficking may determine its functional bioavailablity in the lung, which could be impaired in individuals exposed to smoking or in those with A1AT deficiency.