129Xe MRI Ventilation Defects in Asthma: What is the Upper Limit of Normal and Minimal Clinically Important Difference?

RATIONALE AND OBJECTIVES: The minimal clinically important difference (MCID) and upper limit of normal (ULN) for MRI ventilation defect percent (VDP) were previously reported for hyperpolarized 3He gas MRI. Hyperpolarized 129Xe VDP is more sensitive to airway dysfunction than 3He, therefore the objective of this study was to determine the ULN and MCID for 129Xe MRI VDP in healthy and asthma participants. MATERIALS AND METHODS: We retrospectively evaluated healthy and asthma participants who underwent spirometry and 129XeMRI on a single visit; participants with asthma completed the asthma control questionnaire (ACQ-7). The MCID was estimated using distribution- (smallest detectable difference [SDD]) and anchor-based (ACQ-7) methods. Two observers measured VDP (semiautomated k-means-cluster segmentation algorithm) in 10 participants with asthma, five-times each in random order, to determine SDD. The ULN was estimated based on the 95% confidence interval of the relationships between VDP and age. RESULTS: Mean VDP was 1.6 ± 1.2% for healthy (n = 27) and 13.7 ± 12.9% for asthma participants (n = 55). ACQ-7 and VDP were correlated (r = .37, p = .006; VDP = 3.5·ACQ + 4.9). The anchor-based MCID was 1.75% while the mean SDD and distribution-based MCID was 2.25%. VDP was correlated with age for healthy participants (p = .56, p =.003; VDP = .04·Age-.01). The ULN for all healthy participants was 2.0%. By age tertiles, the ULN was 1.3% ages 18-39 years, 2.5% for 40-59 years and 3.8% for 60-79 years. CONCLUSION: The 129Xe MRI VDP MCID was estimated in participants with asthma; the ULN was estimated in healthy participants across a range of ages, both of which provide a way to interpret VDP measurements in clinical investigations.

CT Mucus Score and 129Xe MRI Ventilation Defects After 2.5 Years' Anti-IL-5Rα in Eosinophilic Asthma.

BACKGROUND: We previously showed in patients with poorly controlled eosinophilic asthma that a single dose of benralizumab resulted in significantly improved Asthma Control Questionnaire (ACQ-6) score and 129Xe MRI ventilation defect percent (VDP) 28 days postinjection, and 129Xe MRI VDP and CT airway mucus occlusions were shown to independently predict this early ACQ-6 response to benralizumab. RESEARCH QUESTION: Do early VDP responses at 28 days persist, and do FEV1, fractional exhaled nitric oxide, and mucus plug score improve during a 2.5 year treatment period? STUDY DESIGN AND METHODS: Participants with poorly controlled eosinophilic asthma completed spirometry, ACQ-6, and MRI, 28 days, 1 year, and 2.5 years after initiation of treatment with benralizumab; chest CT was acquired at enrollment and 2.5 years later. RESULTS: Of 29 participants evaluated at 28 days post-benralizumab, 16 participants returned for follow-up while on therapy at 1 year, and 13 participants were evaluable while on therapy at 2.5 years post-benralizumab initiation. As compared with 28 days post-benralizumab, ACQ-6 score (2.0 ± 1.4) significantly improved after 1 year (0.5 ± 0.6, P = .02; 95% CI, 0.1-1.1) and 2.5 years (0.5 ± 0.5, P = .03; 95% CI, 0.1-1.1). The mean VDP change at 2.5 years (-4% ± 3%) was greater than the minimal clinically important difference, but not significantly different from VDP measured 28 days post-benralizumab. Mucus score (3 ± 4) was significantly improved at 2.5 years (1 ± 1, P = .03; 95% CI, 0.3-5.5). In six of eight participants with previous occlusions, mucus plugs vanished or substantially diminished 2.5 years later. VDP (P < .001) and mucus score (P < .001) measured at baseline, but not fractional exhaled nitric oxide or FEV1, independently predicted ACQ-6 score after 2.5 years. INTERPRETATION: In poorly controlled eosinophilic asthma, early MRI VDP responses at 28 days post-benralizumab persisted 2.5 years later, alongside significantly improved mucus scores and asthma control.

Airway autoimmunity, asthma exacerbations, and response to biologics.

Biologic therapies in asthma are indicated in severe disease, and they are directed against specific inflammatory modulators that contribute to pathogenesis and severity. Currently approved biologics target T2 cytokines (IgE, IL-5, IL-4/IL-13, and TLSP) and have demonstrated efficacy in clinical outcomes such as exacerbation rate and oral corticosteroid dose reductions, blood and airway eosinophil depletion, and lung function improvement. However, a proportion of these patients may show inadequate responses to biologics, with either initial lack of improvement or clinical and functional worsening after an optimal initial response. Exacerbations while on a biologic may be due to several reasons, including imprecise identification of the dominant effector pathway contributing to severity, additional inflammatory pathways that are not targeted by the biologic, inaccuracies of the biomarker used to guide therapy, inadequate dosing schedules, intercurrent airway infections, anti-drug neutralizing antibodies, and a novel phenomenon of autoimmune responses in the airways interfering with the effectiveness of the monoclonal antibodies. This review, illustrated using case scenarios, describes the underpinnings of airway autoimmune responses in driving exacerbations while patients are being treated with biologics, device a strategy to evaluate such exacerbations, an algorithm to switch between biologics, and perhaps to consider two biologics concurrently.

Iron in airway macrophages and infective exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Excess pulmonary iron has been implicated in the pathogenesis of lung disease, including asthma and COPD. An association between higher iron content in sputum macrophages and infective exacerbations of COPD has previously been demonstrated. OBJECTIVES: To assess the mechanisms of pulmonary macrophage iron sequestration, test the effect of macrophage iron-loading on cellular immune function, and prospectively determine if sputum hemosiderin index can predict infectious exacerbations of COPD. METHODS: Intra- and extracellular iron was measured in cell-line-derived and in freshly isolated sputum macrophages under various experimental conditions including treatment with exogenous IL-6 and hepcidin. Bacterial uptake and killing were compared in the presence or absence of iron-loading. A prospective cohort of COPD patients with defined sputum hemosiderin indices were monitored to determine the annual rate of severe infectious exacerbations. RESULTS: Gene expression studies suggest that airway macrophages have the requisite apparatus of the hepcidin-ferroportin axis. IL-6 and hepcidin play roles in pulmonary iron sequestration, though IL-6 appears to exert its effect via a hepcidin-independent mechanism. Iron-loaded macrophages had reduced uptake of COPD-relevant organisms and were associated with higher growth rates. Infectious exacerbations were predicted by sputum hemosiderin index (ß = 0.035, p = 0.035). CONCLUSIONS: We demonstrate in-vitro and population-level evidence that excess iron in pulmonary macrophages may contribute to recurrent airway infection in COPD. Specifically, IL-6-dependent iron sequestration by sputum macrophages may result in immune cell dysfunction and ultimately lead to increased frequency of infective exacerbation.

Underestimation of airway luminal eosinophilia by quantitative sputum cytometry.

RATIONALE: On Wright-stained sputum cytospins, eosinophil differential of ≥ 1.2% is considered abnormal, and ≥ 2.3% identifies an eosinophilic endotype. We hypothesized that failure to consider free eosinophil granules (FEG), and the re-emergence (unmasking) of eosinophilia due to various reasons underestimate the prevalence of the eosinophilic endotype. METHODS: This is a retrospective analysis of our Institutional Review Board-approved clinical sputum database. Of the 24,176 examinations of sputa from patients with various airway diseases, 17,693 were viable cell counts from 9570 patients (6604 on a single occasion, 2967 from multiple occasions). The prevalence of intact eosinophil % at 1.2 and 2.3% thresholds was first examined. Then, additional evidence of eosinophilia was assessed by semi-quantitative enumeration of FEGs. In those patients whose sputa were examined on multiple occasions (at the time of an exacerbation or after corticosteroid dose was reduced), re-emergence (unmasking) of eosinophilia was assessed . RESULTS: Using the threshold of eosinophilia ≥ 1.2%, 6289/17693 (35.6%) of sputa were classified as eosinophilic. This increased to 7850/17693 (44.4%) when the presence of FEGs was considered. Using the threshold of eosinophilia ≥ 2.3%, 4647/17693 (26.3%) of sputa were classified as eosinophilic. This increased to 5435/17693 (30.7%) when the presence of FEG were considered. Extrapolating from the prevalence of re-emergence observed in the 2967 patients who had sputa examined on multiple occasions to the whole sample, we estimated that eosinophilia at 1.2% threshold would be observed in at least 60% of the samples, and a clinically relevant eosinophilia at 2.3% threshold would be observed in at least 48.5% of the samples. CONCLUSIONS: Using a large sputum cytometry clinical database (17,693 viable cell counts), we demonstrate that a single time point intact cell count underestimates the prevalence of eosinophilia in a variety of airway diseases. The prevalence of eosinophilia increases from 35.6 to 60% (40% underestimation) at the 1.2% threshold, and from 26.3 to 48.5% (45% underestimation) at the 2.3% clinically relevant threshold, when free granules and a second examination are considered. This has important implications to identify the eosinophilic and Th2 high endotype both for clinical trials of anti-eosinophil therapies, and to select patients who may respond well to glucocorticosteroids and anti-IL5 therapies.

Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena.

BACKGROUND: In clinical trials, the two anti-interleukin (IL)-5 monoclonal antibodies (mAbs: mepolizumab and reslizumab) approved to treat severe eosinophilic asthma reduce exacerbations by ∼50-60%. OBJECTIVE: To observe response to anti-IL-5 mAbs in a real-life clinical setting, and to evaluate predictors of suboptimal response. METHODS: In four Canadian academic centres, predefined clinical end-points in 250 carefully characterised moderate-to-severe asthmatic patients were collected prospectively to assess response to the two anti-IL-5 mAbs. Suboptimal response was determined based on failure to reduce maintenance corticosteroid (MCS) or asthma symptoms scores (Asthma Control Questionnaire (ACQ)) or exacerbations, in addition to persistence of sputum/blood eosinophils. Worsening in suboptimal responders was assessed based on reduced lung function by 25% or increase in MCS/ACQ. A representative subset of 39 patients was evaluated for inflammatory mediators, autoantibodies and complement activation in sputum (by ELISA) and for immune-complex deposition by immunostaining formalin-fixed paraffin-embedded sputum plugs. RESULTS: Suboptimal responses were observed in 42.8% (107 out of 250) patients treated with either mepolizumab or reslizumab. Daily prednisone requirement, sinus disease and late-onset asthma diagnoses were the strongest predictors of suboptimal response. Asthma worsened in 13.6% (34 out of 250) of these patients. The majority (79%) of them were prednisone-dependent. Presence of sputum anti-eosinophil peroxidase immunoglobulin (Ig)G was a predictor of suboptimal response to an anti-IL-5 mAb. An increase in sputum C3c (marker of complement activation) and deposition of C1q-bound/IL-5-bound IgG were observed in the sputa of those patients who worsened on therapy, suggesting an underlying autoimmune-mediated pathology. CONCLUSION: A significant number of patients who meet currently approved indications for anti-IL5 mAbs show suboptimal response to them in real-life clinical practice, particularly if they are on high doses of prednisone. Monitoring blood eosinophil count is not helpful to identify these patients. The concern of worsening of symptoms associated with immune-complex mediated complement activation in a small proportion of these patients highlights the relevance of recognising airway autoimmune phenomena and this requires further evaluation.

Mechanisms and therapeutic strategies for non-T2 asthma.

Non-T2 asthma is traditionally defined as asthma without features of T2 asthma. The definition is arbitrary and is generally based on the presence of neutrophils in sputum, or the absence (or normal levels) of eosinophils or other T2 markers in sputum (paucigranulocytic), airway biopsies or in blood. This definition may be imprecise as we gain more knowledge from applying transcriptomics and proteomics to blood and airway samples. The prevalence of non-T2 asthma is also difficult to estimate as most studies are cross-sectional and influenced by concomitant treatment with glucocorticosteroids, and by the presence of recognized or unrecognized airway infections. No specific therapies have shown any clinical benefits in patients with asthma that is associated with a non-T2 inflammatory process. It remains to be seen if such an endotype truly exists and to identify treatments to target that endotype. Meanwhile, identifying intense airway neutrophilia as an indicator of airway infection and airway hyperresponsiveness as an indicator of smooth muscle dysfunction, and treating them appropriately, and not increasing glucocorticosteroids in patients who do not have obvious T2 inflammation, seem reasonable.

Reducing two-unit red cell transfusions on the oncology ward: a choosing wisely initiative.

Background/context: Despite Choosing Wisely recommendations for single unit red blood cell transfusion orders, ~50% of orders on the oncology ward at London Health Sciences Centre (LHSC) were for two units. The oncology ward at LHSC is a 60 bed tertiary care unit. In mid 2016, LHSC was 18 months into its implementation of computerised provider order entry (CPOE). Aim/objectives: By December 2017, increase the proportion of one-unit red cell transfusion orders on the oncology ward from 50% to 80. Measures: Outcome: % one-unit red cell transfusion orders (aggregated monthly). Improvement/innovation/change ideas: Our initial theory was that unawareness of the guidelines (established in 2014) and subscription to the obsolete doctrine of two-unit transfusions were the primary behavioural drivers. Initial change ideas included an educational/awareness blitz including rounds presentations, memos and posters. Failure led us to revisit our hypothesis and carry out a real-time audit, where our team was notified on each two-unit transfusion. This revealed the true root cause: the overwhelming majority of two-unit transfusions could be traced back to standing orders that were entered on an admission order set. After provider engagement, we proceeded to remove all admission order sets containing two-unit transfusions. Impact/lessons learned/results: After order set removal, our one-unit transfusion rate rose to 86% and was sustained for 17 months. We learnt two primary lessons. First that CPOE and poor order set design combined to perpetuate poor ordering practices. Second that revisiting our hypothesis and engaging in thoughtful root cause analysis that included direct observation ultimately led to an effective, sustainable solution. Discussion/spread: Our study underscores the importance of executing root cause analysis on a microsystem level. We would expect the factors driving poor performance to be completely different on a service such as general internal medicine. Our study also highlights the potential pitfalls of CPOE and the importance of regular order set review to ensure adherence to current evidence.

Airway Eosinophilopoietic and Autoimmune Mechanisms of Eosinophilia in Severe Asthma.

Eosinophils are critical in asthma biology, contributing to symptoms, airflow obstruction, airway hyperresponsiveness, and remodeling. In severe asthma, in addition to local maturation in bone marrow, in situ eosinophilopoiesis plays a key role in the persistence of airway eosinophilia. Local milieu of structural, epithelial and inflammatory cells contribute by generating eosinophilopoietic cytokines in response to epithelial-derived alarmins. Another mechanism of persistent airway eosinophilia is glucocorticosteroid insensitivity, which is linked to recurrent airway infections and presence of local autoantibodies. Novel molecules are being developed to target specific immune pathways as potential steroid-sparing strategies.

Pulmonary 3He Magnetic Resonance Imaging Biomarkers of Regional Airspace Enlargement in Alpha-1 Antitrypsin Deficiency.

RATIONALE AND OBJECTIVES: Thoracic x-ray computed tomography (CT) and hyperpolarized 3He magnetic resonance imaging (MRI) provide quantitative measurements of airspace enlargement in patients with emphysema. For patients with panlobular emphysema due to alpha-1 antitrypsin deficiency (AATD), sensitive biomarkers of disease progression and response to therapy have been difficult to develop and exploit, especially those biomarkers that correlate with outcomes like quality of life. Here, our objective was to generate and compare CT and diffusion-weighted inhaled-gas MRI measurements of emphysema including apparent diffusion coefficient (ADC) and MRI-derived mean linear intercept (Lm) in patients with AATD, chronic obstructive pulmonary disease (COPD) ex-smokers, and elderly never-smokers. MATERIALS AND METHODS: We enrolled patients with AATD (n = 8; 57 ± 7 years), ex-smokers with COPD (n = 8; 77 ± 6 years), and a control group of never-smokers (n = 5; 64 ± 2 years) who underwent thoracic CT, MRI, spirometry, plethysmography, the St. George's Respiratory Questionnaire, and the 6-minute walk test during a single 2-hour visit. MRI-derived ADC, Lm, surface-to-volume ratio, and ventilation defect percent were generated for the apical, basal, and whole lung as was CT lung area ≤-950 Hounsfield units (RA950), low attenuating clusters, and airway count. RESULTS: In patients with AATD, there was a significantly different MRI-derived ADC (P = .03), Lm (P < .0001), and surface-to-volume ratio (P < .0001), but not diffusing capacity of carbon monoxide, residual volume or total lung capacity, or CT RA950 (P > .05) compared to COPD ex-smokers with a significantly different St. George's Respiratory Questionnaire. CONCLUSIONS: In this proof-of-concept demonstration, we evaluated CT and MRI lung emphysema measurements and observed significantly worse MRI biomarkers of emphysema in patients with AATD compared to patients with COPD, although CT RA950 and diffusing capacity of carbon monoxide were not significantly different, underscoring the sensitivity of MRI measurements of AATD emphysema.