Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations.

In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease.

This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work.

The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available.

Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed.

The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.

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Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)

Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma

Asthma is a serious health problem throughout the world During the past two decades, many scientific advances have improved our understanding of asthma and ability to manage and control it effectively However, recommendations for asthma care need to be adapted to local conditions, resources and services Since it was formed in 1993, the Global Initiative for Asthma, a network of individuals, organisations and public health officials, has played a leading role in disseminating information about the care of patients with asthma based on a process of continuous review of published scientific investigations A comprehensive workshop report entitled "A Global Strategy for Asthma Management and Prevention", first published in 1995, has been widely adopted, translated and reproduced, and forms the basis for many national guidelines The 2006 report contains important new themes First, it asserts that "it is reasonable to expect that in most patients with asthma, control of the disease can and should be achieved and maintained," and recommends a change in approach to asthma management, with asthma control, rather than asthma severity, being the focus of treatment decisions The importance of the patient-care giver partnership and guided self-management, along with setting goals for treatment, are also emphasised

https://erj.ersjournals.com/content/erj/31/1/143.full.pdf

Global strategy for asthma management and prevention: GINA executive summary.

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

Although asthma has been considered as a single disease for years, recent studies have increasingly focused on its heterogeneity. The characterization of this heterogeneity has promoted the concept that asthma consists of multiple phenotypes or consistent groupings of characteristics. Asthma phenotypes were initially focused on combinations of clinical characteristics, but they are now evolving to link biology to phenotype, often through a statistically based process. Ongoing studies of large-scale, molecularly and genetically focused and extensively clinically characterized cohorts of asthma should enhance our ability to molecularly understand these phenotypes and lead to more targeted and personalized approaches to asthma therapy.

/pdf/asthma-phenotypes-the-evolution-from-clinical-to-molecular-1a6ydbpfb2.pdf

Asthma phenotypes: the evolution from clinical to molecular approaches

Background: A recombinant humanized anti-IgE mAb, omalizumab, forms complexes with free IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in the treatment of asthma. Objective: The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid–dependent asthma. Methods: In this phase III, double-blinded, placebo-controlled trial, 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period. Results: Omalizumab treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase (0.28 vs 0.54 [ P = .006] and 14.6% vs 23.3% [ P = .009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [ P = .003] and 21.3% vs 32.3% [ P = .004], respectively). Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo (median 75% vs 50% [ P P Conclusion: The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use. (J Allergy Clin Immunol 2001;108:184-90.)

Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma.

Background: A recombinant humanized anti-IgE mAb, omalizumab, forms complexes with free IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in the treatment of asthma. Objective: The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid‐dependent asthma. Methods: In this phase III, double-blinded, placebo-controlled trial, 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period. Results: Omalizumab treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase (0.28 vs 0.54 [P = .006] and 14.6% vs 23.3% [P = .009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P = .003] and 21.3% vs 32.3% [P = .004], respectively). Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo (median 75% vs 50% [P < .001]), and beclomethasone dipropionate discontinuation was more likely with omalizumab (39.6% vs 19.1% [P < .001]). Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue β-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to that of placebo. Conclusion: The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use. (J Allergy Clin Immunol 2001;108:184-90.)

https://www.jacionline.org/article/S0091-6749(01)65945-1/pdf

Allergy, rhinitis, other respiratory diseases Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma

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

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

ContextSeasonal allergic rhinitis is a common IgE-mediated disorder that produces
troublesome symptoms. A recombinant humanized monoclonal anti-IgE antibody
(omalizumab) forms complexes with free IgE, blocking its interaction with
mast cells and basophils and lowering free IgE levels in the circulation.ObjectiveTo assess the efficacy and safety of omalizumab for prophylaxis of symptoms
in patients with seasonal allergic rhinitis.DesignRandomized, double-blind, dose-ranging, placebo-controlled trial conducted
from July 25 through November 21, 1997.SettingTwenty-five outpatient centers throughout the United States.PatientsFive hundred thirty-six patients aged 12 to 75 years with at least a
2-year history of moderate to severe ragweed-induced seasonal allergic rhinitis
and a baseline IgE level between 30 and 700 IU/mL.InterventionsPatients were randomly assigned to receive omalizumab, 50 mg (n = 137),
150 mg (n = 134), or 300 mg (n = 129), or placebo (n = 136) subcutaneously
just prior to ragweed season and repeated during the pollen season every 3
weeks in patients with baseline IgE levels of 151 to 700 IU/mL (4 total treatments)
and every 4 weeks in patients with baseline IgE levels of 30 to 150 IU/mL
(3 total treatments).Main Outcome MeasuresSelf-assessed daily nasal symptom severity scores (range, 0-3), rescue
antihistamine use, and rhinitis-specific quality of life during the 12 weeks
from the start of treatment.ResultsNasal symptom severity scores were significantly lower in patients who
received 300 mg of omalizumab than in those who received placebo (least squares
means, 0.75 vs 0.98, respectively; P = .002). A significant
association was observed between IgE reduction and nasal symptoms and rescue
antihistamine use. Rhinitis-specific quality of life scores were consistently
better in patients who received 300 mg of omalizumab than in those who received
lower dosages or placebo and did not decline during peak season. The frequency
of adverse events was not significantly different among the omalizumab and
placebo groups.ConclusionOmalizumab decreased serum free IgE levels and provided clinical benefit
in a dose-dependent fashion in patients with seasonal allergic rhinitis.

https://jamanetwork.com/journals/jama/articlepdf/194477/joc01099.pdf

Margaret McAlary

Papers

Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma.

Allergy, rhinitis, other respiratory diseases Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma

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

Effect of Omalizumab on symptoms of seasonal allergic rhinitis: A randomized controlled trial

Effect of Omalizumab on Symptoms of Seasonal Allergic Rhinitis