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For patients with moderate-to-severe persistent allergic asthma, omalizumab is approved for subcutaneous administration according to a recommended dosing table based on weight and total immunoglobulin E (IgE) level. The aim of this analysis was to assess asthma outcomes including quality of life in patients with allergic asthma initiated on omalizumab in the PROSPERO trial; patients were stratified by where their IgE and body weight fell on the approved dosing table. Patient groups were defined as Inside Dosing Table: patients whose IgE and weight fell within the approved dosing table (n = 506); Insufficient Data to Recommend a Dose: patients who fell into the section of the approved dosing table where not enough clinical data were available to make dosing recommendations (n = 72); and Outside Dosing Table: patients who fell outside the approved dosing table due to baseline IgE and/or weight (n = 209). Overall, asthma and quality of life outcomes were improved after omalizumab initiation for both patients who fall within the recommended dosing table or those who fall outside the recommended dosing table. Our results suggest that omalizumab treatment may be effective in a wide range of patients with moderate-to-severe allergic asthma. ClinicalTrials.gov identifier NCT01922037., Competing Interests: Declaration of competing interest NMC: consultant and/or speaker bureau member for Amgen, ARS Pharmaceuticals Inc., AstraZeneca, Blueprint Medicines, Bryn Pharma, Genentech Inc., GlaxoSmithKline, Hikma Pharmaceuticals, Incyte, Novartis, Regeneron, and Sanofi; speaker bureau member for Incyte; consultant for ARS Pharmaceuticals Inc., Bryn Pharma, Genentech, Inc., Hikma Pharmaceuticals, and Novartis Pharmaceuticals Corporation. ML: institution received research grant support on her behalf from Sanofi; received honoraria for serving as a consultant for AstraZeneca. CTJH: former employee of Genentech, Inc. LAM, AS, JWS, BLT: employees of Genentech, Inc.; stockholders of Roche. NAH: received honoraria for serving as advisor or consultant for Amgen, AstraZeneca, Genentech, Inc., GlaxoSmithKline, Novartis Pharmaceuticals Corporation, Regeneron, Sanofi, and Teva. Institution received research grant support on his behalf from AstraZeneca, Genentech, Inc., GlaxoSmithKline, Novartis, Sanofi, and Teva. TBC: consultant and speaker bureau member for Genentech, Inc.; consultant for Novartis Pharmaceuticals Corporation; chief medical advisor for Food Allergy Research & Education., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fractional exhaled nitric oxide (FeNO) has potential as a prognostic biomarker in asthma, but its prognostic value among other recognised indicators is unclear. We assessed the added prognostic value of baseline FeNO to blood eosinophil count and prior severe asthma exacerbations for subsequent exacerbations., Methods: In this post-hoc analysis of the 52-week, double-blind, phase 3 LIBERTY ASTHMA QUEST study, we identified 620 patients with moderate-to-severe asthma who were randomly assigned to placebo; had uncontrolled asthma with inhaled glucocorticoids plus up to two controllers; one or more exacerbations in the previous year; FEV 1 percent predicted 40-80%; FEV 1 reversibility of 12% or higher and 200 mL; Asthma Control Questionnaire (ACQ-5) score of 1·5 or higher; and complete data on baseline type 2 biomarkers (FeNO, eosinophils, and total IgE) with no baseline minimum requirement. Annualised severe exacerbation rate was assessed by baseline FeNO (<25 ppb, ≥25 to <50 ppb, ≥50 ppb; negative binomial model) and cross-classified by baseline blood eosinophils (<150 cells per μL, ≥150 to <300 cells per μL, ≥300 cells per μL) and prior exacerbations (one, two or more), all adjusted for baseline ACQ-5, postbronchodilator FEV 1 , and other clinical characteristics. Post-hoc analyses were done in the intention-to-treat population. The LIBERTY ASTHMA QUEST STUDY is registered on ClinicalTrials.gov, NCT02414854, and is complete., Findings: Patients with baseline FeNO of 50 ppb or higher (n=144) had a 1·54-times higher exacerbation rate than patients with FeNO of less than 25 ppb (n=291; relative risk 1·54 [95% CI 1·11-2·14]; p=0·0097). Patients with baseline FeNO of 25 to <50 ppb (n=185) had a 1·33-times higher exacerbation rate than patients with FeNO of less than 25 ppb (1·33 [0·99-1·78]; p=0·0572). Patients with baseline FeNO of 25 ppb or higher, a blood eosinophil count of 150 cells per μL or higher, and two or more prior exacerbations (n=157) had an exacerbation rate 3·62-times higher than patients with FeNO of less than 25 ppb, a blood eosinophil count of less than 150 cells per μL, and one prior exacerbation (n=116; 3·62 [1·67-7·81]; p=0·0011)., Interpretation: In uncontrolled, moderate-to-severe asthma, higher baseline FeNO levels were associated with greater risk of severe asthma exacerbations, particularly in combination with elevated eosinophil count and prior exacerbations, supporting the added value of FeNO as a prognostic biomarker. Further research is needed to confirm FeNO as an independent predictor for asthma exacerbations., Funding: Sanofi and Regeneron Pharmaceuticals., Competing Interests: Declaration of interests WWB declares consultant fees from AstraZeneca, Genentech, GlaxoSmithKline (GSK), Novartis, Regeneron Pharmaceuticals, and Sanofi, and is on the data safety monitoring board (DSMB) for Boston Scientific. SEW reports involvement in industry trials for AstraZeneca, Boehringer Ingelheim, GSK, Novartis, and Sanofi. TBC declares research support provided by American Lung Association, Genentech, Novartis, Patient-Centered Outcomes Research Institute, and Sanofi; was a consultant for AstraZeneca, Boehringer Ingelheim, Genentech, Novartis, and Regeneron Pharmaceuticals; was part of the speaker bureau for Genentech; and is on the DSMB for Novartis. JMF reports being an advisory board member for and receiving personal fees from American Lung Association, Boehringer Ingelheim, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Teva; received peer-review funding from AllerGen NCE, BC Lung Association, and Canadian Institutes of Health Research; had research funding paid directly to the University of British Columbia from AstraZeneca, Boehringer Ingelheim, GSK, Novartis, and Sanofi; and received speaker fees or honoraria from AstraZeneca, Boehringer Ingelheim, GSK, and Novartis. MSR, ND, NP, and PJR are employees of Sanofi. NMHG is a former employee and shareholder of Regeneron Pharmaceuticals. YD and SH are employees and shareholders of Regeneron Pharmaceuticals. TOR was a prior employee of Sanofi. IDP reports receiving speaker fees from Aerocrine, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Regeneron Pharmaceuticals, Sanofi, and Teva; received payments for organisation of educational events from AstraZeneca, GSK, Sanofi, Regeneron Pharmaceuticals, and Teva; received consultant fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Circassia, Dey Pharma, Genentech, GSK, Knopp Biosciences, Merck, Merck Sharp & Dohme, Napp Pharmaceuticals, Novartis, Regeneron Pharmaceuticals, RespiVert, Sanofi, Schering-Plough, and Teva; received international scientific meeting sponsorship from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Napp Pharmaceuticals, Regeneron Pharmaceuticals, Sanofi, and Teva; and reports a research grant from Chiesi., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Asthma prevalence, morbidity, and mortality disproportionately impact African American/Black (AA/B) and Hispanic/Latinx (H/L) communities. Adherence to daily inhaled corticosteroid (ICS), recommended by asthma guidelines in all but the mildest cases of asthma, is generally poor. As-needed ICS has shown promise as a patient-empowering asthma management strategy, but it has not been rigorously studied in AA/B or H/L patients or in a real-world setting. Design and Aim The PeRson EmPowered Asthma RElief (PREPARE) Study is a randomized, open-label, pragmatic study which aims to assess whether a patient-guided, reliever-triggered ICS strategy called PARTICS (Patient-Activated Reliever-Triggered Inhaled CorticoSteroid) can improve asthma outcomes in AA/B and H/L adult patient populations. In designing and implementing the study, the PREPARE research team has relied heavily on advice from AA/B and H/L Patient Partners and other stakeholders. Methods PREPARE is enrolling 1200 adult participants (600 AA/Bs, 600H/Ls) with asthma. Participants are randomized to PARTICS + Usual Care (intervention) versus Usual Care (control). Following a single in-person enrollment visit, participants complete monthly questionnaires for 15 months. The primary endpoint is annualized asthma exacerbation rate. Secondary endpoints include asthma control; preference-based quality of life; and days lost from work, school, or usual activities. Discussion The PREPARE study features a pragmatic design allowing for the real-world assessment of a patient-centered, reliever-triggered ICS strategy in AA/B and H/L patients. Outcomes of this study have the potential to offer powerful evidence supporting PARTICS as an effective asthma management strategy in patient populations that suffer disproportionately from asthma morbidity and mortality., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite currently available therapies and detailed treatment guidelines, many patients with asthma remain symptomatic. Tiotropium delivered by the soft mist inhaler Respimat®, as add-on therapy to medium-dose inhaled corticosteroids (ICS), has been shown to improve lung function and asthma control in patients with symptomatic moderate asthma., Objective: To determine whether the efficacy of tiotropium Respimat® in asthma differs by patients' study baseline characteristics., Methods: Two replicate Phase III, randomized, double-blind, placebo-controlled, parallel-group studies (MezzoTinA-asthma®; NCT01172808 and NCT01172821) of once-daily tiotropium Respimat 5 μg and 2.5 μg add-on to ICS were conducted in patients with symptomatic asthma despite treatment with medium-dose ICS with or without additional controllers. Subgroup analyses of peak forced expiratory volume in 1 s (FEV 1 ), trough FEV 1 , risk of severe asthma exacerbation and Asthma Control Questionnaire responder rate were performed to determine whether results were influenced by patients' baseline characteristics., Results: In this analysis, 523 patients received placebo while 517 and 519 patients received the 5 μg and 2.5 μg dose of tiotropium Respimat, respectively. The magnitude of the improvements in lung function and asthma control, as well as the reduced risk of severe exacerbation with both doses of tiotropium Respimat versus placebo, was independent of a broad range of baseline characteristics., Conclusions: Once-daily tiotropium Respimat as add-on to ICS is a beneficial treatment option for patients with asthma who remain symptomatic despite at least medium-dose ICS, regardless of baseline characteristics., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: In patients with severe asthma, tiotropium improves lung function and exacerbation risk when added to high-dose inhaled corticosteroids plus long-acting β2 agonists. We aimed to assess the safety and efficacy of tiotropium in patients with moderate asthma who were symptomatic despite treatment with medium-dose inhaled corticosteroids., Methods: We did two 24-week, replicate, randomised, double-blind, placebo-controlled, parallel-group, active-comparator trials at 233 sites in 14 countries. Eligible patients were aged 18-75 years with symptomatic asthma and a pre-bronchodilator forced expiratory volume in 1 s (FEV1) of 60-90% predicted despite use of medium-dose inhaled corticosteroids, and had never smoked or were ex-smokers for 1 year or more with 10 pack-years or less. Patients were randomly assigned (1:1:1:1), with computer-generated pseudorandom numbers, to receive once-daily tiotropium 5 μg or 2·5 μg, twice-daily salmeterol 50 μg, or placebo, while maintaining inhaled corticosteroids. Patients and study investigators were masked to treatment allocation. Prespecified co-primary endpoints, assessed at week 24 in the full analysis set, were peak FEV1 response, measured within the first 3 h after evening dosing; trough FEV1 response; and responder rate assessed according to the seven-question Asthma Control Questionnaire (ACQ-7). These studies are registered with ClinicalTrials.gov, numbers NCT01172808 and NCT01172821., Findings: Between Aug 24, 2010, and Nov 13, 2012, we randomly assigned 2103 patients to the tiotropium 5 μg group (n=519), the tiotropium 2·5 μg group (n=520), the salmeterol group (n=541), or the placebo group (n=523); 1972 (94%) patients completed the study. Peak and trough FEV1 responses were significantly greater with tiotropium and salmeterol than with placebo and were similar in both studies. With pooled data, difference versus placebo in peak FEV1 was 185 mL (95% CI 146-223) in the tiotropium 5 μg group, 223 mL (185-262) in the tiotropium 2·5 μg group, and 196 mL (158-234) in the salmeterol group (all p<0·0001); difference in trough FEV1 was 146 mL (95% CI 105-188), 180 mL (138-221), and 114 mL (73-155; all p<0·0001), respectively. There were more ACQ-7 responders in the tiotropium 5 μg (OR 1·32, 95% CI 1·02-1·71; p=0·035) and 2·5 μg (1·33, 1·03-1·72; p=0·031) groups, and the salmeterol group (1·46, 1·13-1·89; p=0·0039), than in the placebo group. 48 (2%) of 2100 patients had serious adverse events (tiotropium 5 μg n=11, tiotropium 2·5 μg n=12, salmeterol n=11, placebo n=14)., Interpretation: Once-daily tiotropium add-on to medium-dose inhaled corticosteroids reduces airflow obstruction and improves asthma control in patients with moderate symptomatic asthma. Patterns of response with both tiotropium doses were similar to those of salmeterol, and all active compounds had good safety and tolerability. Tiotropium is a safe and effective bronchodilator, and an alternative to salmeterol in this patient population., Funding: Boehringer Ingelheim., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Since Noon first described allergen immunotherapy a century ago the basic premise of subcutaneous injections (SCIT) of relevant aeroallergens to induce clinical tolerance has remained true [1]. Indeed, allergen immunotherapy did not change dramatically over the first 75 years, but over the past 25 years there have been a number of important advancements leading to newer approaches and novel formulations. Here we review the top 50 articles published in the past 2 years on allergens, environmental control, and immunotherapy for asthma and allergic rhinitis and the use of immunomodulators in allergic disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A possible link between allergic rhinitis (AR) and allergic asthma has long been a subject of debate. Surveys report that up to 78% of asthma patients have AR and 38% of patients with AR have asthma. Evidence points to a causal or coincidental relation between these upper and lower airway diseases. Various agents used to manage one entity have shown benefit in treating the other. The 2001 Allergic Rhinitis and Its Impact on Asthma guidelines call for patients with either condition to be assessed for the other. Medical therapy for AR or asthma should be chosen with awareness of the probable coexistence of these diseases. We present the case for and against the united airway theory proposed to explain the association between these diseases. The roles of various therapies for dually afflicted patients are evaluated, including topical corticosteroids, antihistamines, leukotriene modifiers, anti-immunoglobulin E monoclonal antibody, theophylline, and immunotherapy.

Disparate reports exist on the eosinophil chemotactic capacity of interleukin-8 (IL-8). We hypothesized that the difference is due to the methods used to purify eosinophils. We therefore compared the eosinophilotactic capacity of IL-8 on human cells isolated by Percoll (positive selection) vs. magnetic cell separation system (MACS) (negative selection). Discontinuous Percoll gradients were preceded by dextran and Ficoll-Paque steps, and followed by gelatin wash and red blood cell (RBC) lysis. MACS isolation included: Percoll 1.090 g/ml layering and RBC lysis; incubation with CD16 antibody conjugated to magnetic beads (to bind neutrophils); and isolation of eluate from column positioned in magnet. Percoll isolated eosinophils migrated to IL-8 in a dose-responsive fashion. Although MACS isolation provided a greater number and higher purity of eosinophils, these eosinophils did not migrate to IL-8. Neither dextran sedimentation, Ficoll-Paque and Percoll prior to, nor Percoll discontinuous gradients subsequent to, MACS isolation reversed the negative chemotactic response. Moreover, Percoll-isolated eosinophils further purified with CD16 MicroBeads no longer chemotactically responded to IL-8. This inhibition was not due to change in eosinophil purity, a loss of eosinophil adhesion molecules or activation markers, the presence of a soluble neutrophil or eosinophil inhibitor or the effect of the magnet. Thus, the technique used to isolate eosinophils clearly affects the chemotactic responsiveness of this cell to IL-8. Since several in vivo studies suggest that IL-8 is an eosinophil chemoattractant, Percoll isolation of these cells might be more appropriate for studies involving eosinophil chemotactic responses to IL-8.

The measurement of histamine in samples obtained from human lung is important in determining the roles of histamine and mast cells in normal and disease states. We, therefore, compared different assays for the measurement of histamine in human lung samples. Both a single isotope enzymatic assay and a radioimmunoassay (RIA) were capable of accurately measuring the low concentrations of histamine (0.05-2.0 ng/ml) normally found in bronchoalveolar lavage fluid. The RIA was also able to measure histamine levels up to 1500 ng/ml in human lung tissue samples. Moreover, the RIA measurement of high levels of histamine in lung samples compared favorably to an automated spectrofluorometric method. Unlike either the single isotope enzymatic assay or the automated spectrofluorometric assay which have effective capabilities at less than and greater than 2 ng/ml, respectively, the RIA can accurately measure histamine levels from 0.05 to 1500 ng/ml. Since the RIA is easier to perform, less costly, and has a wider range of effectiveness, this assay should prove valuable in assessing histamine levels from a variety of human lung samples, thereby, providing an avenue to elucidate the roles of histamine and mast cells in lung functions.

Quinuclidinyl benzilate, a muscarinic antagonist, has previously been used in its tritiated form ([3H]-QNB) to study the lung muscarinic receptor. We investigated whether a newer iodinated form of QNB ([125I]-QNB) of higher specific activity would be an appropriate ligand to study the human peripheral lung muscarinic receptor. Both the tritiated and iodinated ligands bound specifically to human lung at 23 degrees C. At 37 degrees C the specific binding of [3H]-QNB increased slightly, but no specific binding of [125I]-QNB was found. The data from multiple equilibrium binding experiments covering a wide range of radiolabeled QNB concentrations were combined and analyzed using the computer modeling program, LIGAND. The tritiated QNB identified a single affinity human lung binding site with a Kd of 46 +/- 9 pM and a receptor concentration of 34 +/- 3 fmol/mg protein. The iodinated QNB identified a single higher affinity human lung binding site (Kd = 0.27 +/- 0.32 pM) of much smaller quantity (0.62 +/- 0.06 fmol/mg protein). Competition studies comparing the binding of unlabeled QNB relative to labeled QNB indicated that unlabeled QNB had the same Kd as that measured for [3H]-QNB, but a 5 log greater Kd than that measured for [125I]-QNB. Other muscarinic receptor agonists and antagonists competed with [3H]-QNB, but not [125I]-QNB for binding to muscarinic receptors with the expected magnitude and rank order of potency. We conclude that of the 2 radiolabeled forms of QNB available, only the tritiated form should be used to study the human peripheral lung muscarinic receptor.

In order to obtain mononuclear cells from peripheral human blood for the study of cell surface receptors, it was necessary to effectively eliminate contaminating platelets. The usual Hypaque-Ficoll isolation procedures were found to produce mononuclear cells contaminated with 10-1000 platelets per mononuclear cell (by phase microscopy). Multiple slow speed centrifugations reduced the contamination to 5-10 platelets per mononuclear cell. However, centrifugation of EDTA-anticoagulated blood through Hypaque (D20(20) 1.060) at 400 X g for 5 min at 22 degrees C followed by the usual Hypaque-Ficoll gradient reduced platelet contamination to less than 1 platelet per 2 mononuclear cells. Thus, a rapid and simple gradient procedure is capable of significantly reducing platelet contamination of mononuclear cell preparations and should facilitate the analysis of mononuclear cell receptors and functions.

Studies have demonstrated that increased amounts of histamine in the airways of asthmatic patients are associated with increased airway reactivity. However, using routine bronchoalveolar lavage (BAL), histamine can be detected in only a portion of asthmatic subjects and a minority of control populations. To obtain relevant mediators from the airways in higher concentrations by avoiding the dilution inherent with a standard BAL, a technique was developed to lavage isolated airway segments of the human lung that employed a double-lumen bronchoscope and a balloon-tipped catheter. Lavage fluid obtained by this method yielded significantly higher concentrations of histamine than that obtained with routine BAL (asthmatic subjects, 2,403 +/- 633 pg/ml vs 188 +/- 42 pg/ml; rhinitis subjects, 533 +/- 187 pg/ml vs 113 +/- 53 pg/ml; normal subjects, 174 +/- 63 pg/ml vs 11 +/- 11 pg/ml). Similar findings were also noted for prostaglandin D2 (PGD2). Segmental airway lavage also resulted in higher lavage fluid concentrations of LTB, than routine BAL. Segmental airway lavage should help in studying the relationship of mast cell degranulation to airways reactivity in both asthmatic and other study populations.

In order to study rabbit mononuclear cell surface receptors, it was necessary to develop a procedure to isolate mononuclear cell preparations that are free of significant contamination by other cell types, especially platelets. Centrifugation of dextran-sedimented, anti-coagulated whole blood through Hypaque (density 1.060) at 600 X g for 5 min at 22 degrees C eliminated greater than 93% of starting platelets. A second 5-min Hypaque centrifugation of Hypaque-Ficoll-isolated mononuclear cells (MNC) (approximately 80% lymphocytes) at 450 X g for 5 min at 22 degrees C reduced platelet contamination to less than one platelet per three MNC, and resulted in the overall removal of greater than 99.5% of starting platelets. These relatively pure MNC which were isolated in less than 2 hr were identified as having beta-adrenergic receptors by radioligand binding techniques using [125I]iodohydroxybenzylpindolol [( 125I]IHYP). Binding of [125I]IHYP to intact rabbit MNC was a saturable, stereospecific, and rapid process with a dissociation constant (KD) of 0.53 +/- 0.18 nM and a binding capacity of 3,461 +/- 235 sites/cell.

To determine the amount of histamine in BAL fluid in subjects with RA and to ascertain if elevated histamine levels were associated with parameters of active pulmonary disease, we measured BAL fluid histamine levels in 31 subjects with RA and 36 normal subjects. The subjects with RA had a significantly greater mean BAL histamine level than the normal subjects, (313 +/- 154 pg/ml vs 18 +/- 8 pg/ml; p less than 0.05). When the subjects with RA were divided into three groups based on chest radiograms (1 = normal; 2 = pleural disease only; 3 = interstitial or nodular disease), we found that subjects in group 3 had significantly lower values for TLC and D. Subjects in group 3 also had higher percentages of BAL neutrophils and eosinophils and higher BAL histamine levels (group 1, 115 +/- 52 pg/ml; group 2, 30 +/- 30 pg/ml; and group 3, 1,182 +/- 709 pg of histamine per milliliter). Moreover, BAL histamine levels were negatively correlated with TLC (r = -0.46; p = 0.01) and FVC (r = -0.45; p = 0.01) and positively correlated with BAL neutrophils (r = 0.6; p = 0.0003) and BAL eosinophils (r = 0.89; p = 0.0001). These data suggest that the BAL histamine level may be a useful marker to determine the activity of pulmonary disease in RA.