Monday, December 7, 2015
Oral immunotherapy (OIT) has shown overall benefit in desensitizing many patients with persistent IgE-mediated food allergy. Still, the treatment is not without adverse reactions. In a large OIT milk treatment program conducted in Israel, approximately 15% of patients were unable to follow it to completion because of IgE-mediated reactions. Some patients with allergy to unheated milk or egg tolerate such foods when they are heated, as heating likely induces conformational changes to a number of the epitopes responsible for IgE binding.
Goldberg et al present a study of 14 children who failed unheated- or unbaked-milk OIT who received OIT with baked milk testing the hypothesis that this might result in desensitization to to unheated milk as well (J Allergy Clin Immunol 2015; 136(6): 1601-1606). Only three of the children tolerated the primary outcome dose of 1.3 g of baked milk protein, and eight out of the other 11 experienced IgE-mediated reactions, including two patients with anaphylactic episodes requiring intramuscular epinephrine. The three children who reached the 1.3 g baked milk dose were able to tolerate up to 900 mg of unheated milk at the end of the study, and all patients remaining in the program through 12 months demonstrated an increase in tolerance to unheated milk The authors also provide evidence that a basophil activation test, comparing patient reactivity to heated or unheated milk, could prospectively distinguish between patients succeeding or failing to complete the program.
Friday, December 4, 2015
Randomized controlled trial of primary prevention of atopy using house dust mite oral immunotherapy in early childhood
The epidemic proportion of atopic diseases in the last 30 years has resulted in major health and economic effects. Atopy is believed to be due to a genetic propensity to produce IgE antibodies in response to an allergen; such propensity is due to an imbalance between various lymphocyte subsets,TH1, TH2 and T regulatory (Treg) cells in particular. In the absence of early intervention, children born with atopic diathesis are likely to develop allergic disease. Zolkipli et al. report the results of a house dust mite allergy prevention study conducted in infants (J Allergy Clin Immunol 2015; 136(6): 1541-1547).
Overcoming maturation deficiencies in the developing immune system and countering TH2 bias requires a very early strong and adequate immune stimulation. In the first 18 months of life, the gut is the primary site of Treg cells stimulation in response to antigens, suggesting oral exposure is likely the most effective in inducing tolerance. The authors hypothesized that exposure to a ubiquitous allergen, such as house dust mite (HDM), would result in both HDM-allergen-specific and a more generalized desensitization effect preventing the atopic march. One hundred eleven infants less than one year of age who had two or more first-degree relatives with allergic disease received an oral administration of HDM extract twice daily for 12 months.
The authors found that HDM-allergen extract induced a significant reduction in sensitization to any common allergen as compared to placebo. There was, interestingly, no significant difference in the cumulative proportion of infants who developed HDM-specific sensitization between the active and placebo groups, nor did HDM-allergen extract impact the number who developed eczema, wheeze, or food allergy. The intervention was well-tolerated, with no differences between the two groups in relevant adverse events.
This early proof-of-concept study points to a feasible, safe, and effective preventive measure. High-dose HDM-allergen extract appears to exert a prophylactic effect on the development of atopy, as defined by skin prick test response to any common allergen. Preventive reduction in allergen sensitization in early childhood may translate into a reduction of asthma, eczema, rhinoconjunctivitis, and food allergy as children at risk for these diseases grow up.
Chronic rhinosinusitis affects approximately 10% of the adult population in industrialized countries. Its effects range from pain in patients with chronic rhinosinusitis without nasal polyps (CRSsNP) to nasal obstruction and comorbid asthma in those suffering from chronic rhinosinusitis with nasal polyps (CRSwNP). Current therapy approaches, such as pharmacotherapy and endoscopic surgery, focus on these two phenotypes. They have not, however, proved effective regarding long-term control of symptoms or risk of recurrence for many patients with severe polyp disease. Bachert et al. discuss the current shift in treatment focus from phenotype to endotype and the related innovative therapies on the horizon (J Allergy Clin Immunol 2015; 136(6): 1431-1440).
A clinical phenotype groups patients with similar clinically observable characteristics. Various pathomechanisms underlie a given phenotype. Understanding and characterizing disease via a shared and unique pathomechanism creates an endotype, opening novel targets for therapeutic intervention. Patients with severe CRSwNP, associated with disease recurrence and comorbid asthma, show TH2-biased inflammation and IgE formation. This has led to proof of concept studies using interventions such as Omalizumab, Reslizumab, Mepolizumab, and Dupilumab to target the associated TH2 cytokines. None of these has been registered yet for the indication of nasal polyposis, and it is unclear if one has advantages over the others.
For patients with severe CRSwNP, topical glucocorticosteroids are usually not effective. The permanent application of oral corticosteroids would lead to health deterioration, and repeated surgeries are not a feasible option. While biologics pose problems that remain to be solved, including the necessity of regular systemic application with the risk of side effects and the high financial cost, they offer a direction that is nonetheless promising. Approaches including silencing techniques, or the blocking of transcription factor GATA-3, and the local application of apathogenic bacteria to produce therapeutically effective proteins are currently under investigation as well.
In spite of optimal guidelines-based asthma treatment many children and adolescents with asthma continue to experience exacerbations. Asthma exacerbations have serious consequences, from increased morbidity to disease progression. While exacerbations can occur at any time to any patient, children with advanced disease, greater degrees of atopy, or who have experienced a recent exacerbation appear most susceptible to further exacerbation, and the time of year in which it is most likely to occur is in the autumn.
Previous Inner-City Asthma Consortium (ICAC) studies demonstrated higher daily doses of inhaled corticosteroids (ICSs) or the addition of omalizumab to year-round treatment reduced exacerbation frequency. Continuous treatment with either, however, risks side effects and incurs financial cost. Teach et al. have examined a seasonal, preventive approach, finding the addition of omalizumab four to six weeks prior to the start of school to ongoing guidelines-based management significantly reduces autumn exacerbation occurrence (J Allergy Clin Immunol 2015; 136(6): 1476-1485).
The authors compared the effects of preseasonal treatment with either omalizumab, an ICS boost or placebo in inner-city asthmatic children aged 6 to 17 years who had experienced one or more exacerbations in the 19 months prior. Patients completed a four- to nine-month run-in phase following study enrollment, during which they received guidelines-based care intended to achieve asthma control. Four to six weeks before the start of the school year and the autumn season, they initiated omalizumab, ICS boost, or placebo which continued through the first 90 days of each child’s school year.
The rate of exacerbations in autumn among the children who had received either omalizumab was significantly lower than among the children who had received a placebo. Among the children who had experienced an exacerbation during the run-in phase, omalizumab proved significantly more effective in preventing an exacerbation than ICS boost or placebo with a greater than 80% protection rate. Adverse events across all groups were rare and similar.
Such a seasonal approach in treatment adjustment represents a first-time report of a novel strategy, indeed suggesting a paradigm shift, in confronting the “September epidemic” of asthma. Those who have experienced a recent exacerbation respond better to Omalizumab.