Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

/pdf/international-ers-ats-guidelines-on-definition-evaluation-sedelwbk4v.pdf

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in number and frequency of use since the introduction of the first recombinant protein therapeutic--human insulin--25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacological action.

Protein therapeutics: a summary and pharmacological classification

These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American Col- lege of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology. The American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology have jointly accepted responsibility for establishing ''Allergen immunotherapy: A practice parameter third update.'' This is a complete and com- prehensive document at the current time. The medical environ- ment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individ- ual, including those who served on the Joint Task Force, is authorizedtoprovideanofficial AAAAIorACAAIinterpretation ofthesepracticeparameters.Anyrequestforinformationaboutor an interpretation of these practice parameters by the AAAAI or the ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion. A current list of published practice parameters of the Joint Task Force on Practice ParametersforAllergyandImmunologycanbefoundinTableE1 in this article's Online Repository at www.jacionline.org. Disclosure ofpotentialconflictofinterest:L.Coxisaconsultant forGenentech/Novartis, Hollister-Stier, and Stallergenes; is a speaker for Novartis; has received research support from Stallergenes; is on the Board of Directors for the American Board of Allergy and Immunology; and is on the US Food and Drug Administration (FDA)'s Allergenic Product Advisory Committee. H. Nelson is a consultant for Merck and Planet Biopharmaceuticals, is a Data and Safety Monitoring Board member of DBV Technologies, and has received research support from ALK-AbellM. Nelson has re- ceivedresearchsupportfromtheDepartmentofDefense,isaspeakerfortheAmerican College of Allergy, Asthma & Immunology (ACAAI), and is a member of the FDA's AdvisoryCommitteeonAllergicProducts.R.Weberisonthespeakers'bureauforAs- traZeneca and Genentech, has received research support from Novartis and Glaxo- SmithKline, and is Committee Chair of the ACAAI. D. I. Bernstein is a consultant and on the advisory board for ALK America, is on the advisory board for Merck, and has received research support from Merck and Schering-Plough. J. Blessing- Moore is a speaker for Merck-Schering/AstraZeneca, Novartis, TEVA, and Meda Alcon and has received research support from Meda. D. A. Khan is a speaker for As- traZeneca and Merck, has received research support from the Vanberg Family Foun- dation and the Sellars Family Foundation, is Conjoint Board Review Chair for the ACAAI,andisapastpresidentoftheTexasAllergy,AsthmaandImmunologySociety. D. M. Lang is a speaker and consultant for GlaxoSmithKline; is a speaker for Astra- Zeneca, Merck, TEVA, Sanofi-Aventis, and Genentech/Novartis; and has received re- search support from Genentech/Novartis. R. A. Nicklas is a fellow for the ACAAI. J. Oppenheimer is a consultant and has provided lectures for AstraZeneca, Merck, and GlaxoSmithKline; and has received research support from AstraZeneca, Merck, Glax- oSmithKline, and Genentech. J. M. Portnoy is a speaker for Phadia, Merck, and CSL Behring; hasreceived researchsupportfromtheUSDepartment ofHousingandUrban Development;andisa board memberof theACAAI board of regents.S.L. Spector has received research support from Genentech, GlaxoSmithKline, Schering-Plough, Aventis, Novartis, Pharmaxis, Boehringer Ingelheim, AstraZeneca, Johnson & John- son, Xyzal, Alcon, Centocor, Sepracor, UCB, Amgen, Capnia, and IVAX. S. Tilles isaspeakerforAlcon; isontheadvisoryboard forALK,Ista,Merck,andStallergenes; has received research support from Alcon, Amgen, Amphastar, Astellas, Boehringer Ingelheim,Ception,Genentech,Icagen, MAP Pharma, MEDA, Merck, Novartis, Rox- ane, and Sepracor; is Associate Editor of Allergy Watchand Annals of Allergy; and is a task force member for the Joint Task Force for Practice Parameters. D. Wallace is a speaker and advisor for Alcon, is a speaker for Merck and Sanofi-Aventis, and is President-Elect of the ACAAI. The rest of the authors have declared that they have no conflict of interest.

/pdf/allergen-immunotherapy-a-practice-parameter-third-update-1itlwly1yo.pdf

Allergen immunotherapy: A practice parameter third update

IgE plays an important role in allergic asthma. We hypothesized that reducing IgE in the airway mucosa would reduce airway inflammation. Forty-five patients with mild to moderate persistent asthma with sputum eosinophilia of 2% or more were treated with humanized monoclonal antibody against IgE (omalizumab) (n = 22) or placebo (n = 23) for 16 weeks. Outcomes included inflammatory cells in induced sputum and bronchial biopsies, and methacholine responsiveness. Treatment with omalizumab resulted in marked reduction of serum IgE and a reduction of IgE+ cells in the airway mucosa. The mean percentage sputum eosinophil count decreased significantly (p < 0.001) from 6.6 to 1.7% in the omalizumab group, a reduction significantly (p = 0.05) greater than with placebo (8.5 to 7.0%). This was associated with a significant reduction in tissue eosinophils; cells positive for the high-affinity Fc receptor for IgE; CD3+, CD4+, and CD8+ T lymphocytes; B lymphocytes; and cells staining for interleukin-4, but not with improvement in airway hyperresponsiveness to methacholine. This study shows antiinflammatory effects of omalizumab treatment and provides clues for mechanisms whereby omalizumab reduces asthma exacerbations and other asthma outcomes in more severe asthma. The lack of effect of omalizumab on methacholine responsiveness suggests that IgE or eosinophils may not be causally linked to airway hyperresponsiveness to methacholine in mild to moderate asthma.

https://www.atsjournals.org/doi/pdf/10.1164/rccm.200312-1651OC

Effects of Treatment with Anti-immunoglobulin E Antibody Omalizumab on Airway Inflammation in Allergic Asthma

Asthma is the leading chronic disease among children in most industrialized countries. However, the evidence base on specific aspects of pediatric asthma, including therapeutic strategies, is limited and no recent international guidelines have focused exclusively on pediatric asthma. As a result, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams to find a consensus to serve as a guideline for clinical practice in Europe as well as in North America. This consensus report recommends strategies that include pharmacological treatment, allergen and trigger avoidance and asthma education. The report is part of the PRACTALL initiative, which is endorsed by both academies.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1398-9995.2007.01586.x

Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report

Background and Objective. There seems to be a strong causal relationship between allergy and the origins of asthma. Susceptibility to both is determined by a combination of genetics and environment acting through a complex network of cytokines. Nearly 90% of affected children have positive skin tests indicating the presence of specific immunoglobulin E (IgE), with sensitivity to house dust mite, Alternaria, cockroach, cat, and dog most closely linked to the disease. Greater exposure to house dust mite during infancy leads to earlier onset of wheezing, and elevated serum IgE levels correlate with the appearance of asthma symptoms. Specific IgE binds to high-affinity (FceRI) receptors on mast cells and basophils. The IgE-mediated reactions that follow exposure of sensitized mast cells to an allergen are designated early- and late-phase asthmatic responses (EAR and LAR). EAR is characterized by release of histamine and other preformed mediators within 1 hour of allergen exposure. It is often followed by LAR, an infiltration of the airways by inflammatory cells associated with an episode of more prolonged, and usually more severe airflow obstruction, 4 to 8 hours after antigen exposure. Chronic airway symptoms result from persistent LAR caused by continuous allergen exposure. IgE antibodies are capable of passive transfer of both EAR and LAR sensitivity. IgE-mediated mast cell activation contributes to chronic tissue eosinophilia and airway remodeling, with permanent loss in pulmonary function. Omalizumab (rhuMAb-E25) is a recombinant, humanized, monoclonal anti-IgE antibody of mouse origin developed for the treatment of IgE-mediated diseases. Omalizumab binds to free IgE at the same site as the high-affinity receptor. Although it attaches to free IgE, it does not bind to IgA, IgG, or cell-bound IgE. It therefore does not induce cross-linking of cell-bound IgE, which would lead to the release of allergic mediators. It has been reported to decrease serum IgE levels in a dose-dependent manner, inhibit EAR and LAR, and cause a down-regulation of FceRI receptors on basophils. Omalizumab has been reported to be safe and effective in improving asthma control and reducing the requirement for oral and inhaled corticosteroids. This double-blind, randomized, placebo-controlled study evaluated the safety, steroid-sparing effects, and impact on disease exacerbations of omalizumab in the treatment of childhood asthma. Methods. Participants were 334 males and premenarchal females aged 6 to 12 years, with moderate to severe allergic asthma requiring treatment with inhaled corticosteroids. During a run-in phase, all children were switched to equivalent doses of beclomethasone dipropionate (BDP), and the dose was adjusted to assure maintenance of asthma control achieved with previous corticosteroid treatment. Children were randomized to subcutaneously administered placebo (N = 109) or omalizumab (N = 225) at a dose based on body weight and initial serum IgE (0.016 mg/kg/IgE [IU/mL] per 4 weeks). BDP dose (initial range 168–420 μg/d) was kept stable for 16 weeks (stable-steroid phase), reduced over 8 weeks to the minimum effective dose (steroid-reduction phase), and maintained constant for the final 4 weeks. Results. More participants in the omalizumab group decreased their BDP dose, and their reduction was greater than that of the placebo group (median reduction 100% vs 66.7%). BDP was withdrawn completely in 55% of the omalizumab group versus 39% of the placebo group. The incidence and the frequency of asthma exacerbations requiring treatment with doubling of BDP dose or systemic corticosteroids were lower in the omalizumab group. The treatment differences were statistically significant during the steroid-reduction phase, during which fewer participants in the omalizumab group had asthma exacerbation episodes (18.2% vs 38.5%), and the mean number of episodes per patient was smaller than with placebo (0.42 vs 2.72). Five asthma exacerbations requiring hospitalization all occurred in the placebo group. Participants9 and investigators9 global evaluations of treatment effectiveness were more favorable for omalizumab than placebo. Investigators rated effectiveness excellent for 31.5% of the omalizumab group versus 16.3% of the placebo group and good for 44.7% of the omalizumab group versus 32.7% of the placebo group. There was little change in asthma symptom scores or spirometry measurements during either the stable-steroid or steroid dose-reduction phase, with minimal differences between the treatment groups. The requirement for rescue medication in the omalizumab group during both the stable-steroid and steroid dose-reduction phases was consistently lower than at baseline. At week 28, the median number of puffs of rescue medication taken daily was 0 in the omalizumab group and 0.46 in the placebo group. The change from baseline was significant in favor of omalizumab. Over the entire treatment period, patients in the omalizumab group missed a mean of 0.65 school days, compared with a mean of 1.21 days in the placebo group. The mean number of unscheduled medical contacts attributable to asthma-related medical problems was significantly smaller in the omalizumab group than in the placebo group throughout the treatment period (0.15 vs 5.35). Median reduction in serum free IgE was 95% to 99% among omalizumab patients. Median free IgE ranged from 133 to 790 IU/mL at baseline and was in the range of 6 to 9 IU/mL during the treatment period. The dosing scheme used in the trial therefore effectively reduced serum IgE in patients with initial concentrations as high as 1300 IU/mL. There was no reduction in free IgE in the placebo group. Omalizumab treatment was well tolerated. There were no serious treatment-related adverse events. The frequency and types of all adverse events were similar in the omalizumab and placebo groups. The majority of adverse events were mild to moderate in severity. No adverse events suggestive of serum sickness or immune complex formation were observed. Study-drug–related adverse events occurred more frequently in the omalizumab group than in the placebo group (6.2% vs 0.9%). Urticaria was reported in 9 omalizumab patients (4%) compared with 1 (0.9%) placebo patient and was mild or moderate in nearly all cases. Conclusion. Treatment with omalizumab is safe in children with asthma. It reduces the requirement for inhaled corticosteroids while protecting against disease exacerbation.

https://pediatrics.aappublications.org/content/pediatrics/108/2/e36.full.pdf

Stephen Pollard

Papers

Treatment of Childhood Asthma With Anti-Immunoglobulin E Antibody (Omalizumab)