Arnon Elizur

Airway Inflammation in Cystic Fibrosis

Patients with cystic fibrosis (CF) experience declining pulmonary function related to chronic airway inflammation, which results from epithelial and immune cell secretion of proinflammatory mediators that promote neutrophil influx into the airways. This inflammatory response may be disproportionate to the inciting infectious stimulus, resulting in an overly exuberant influx of neutrophils. The neutrophils release proteases, including neutrophil elastase, that eventually overwhelm the antiprotease capacity of the lung and cleave structural proteins, leading to bronchiectasis. This deleterious inflammatory process in patients with CF has become a potential therapeutic target, though the development of effective antiinflammatory therapies has been limited by the lack of sensitive outcome measures. Historically, indirect measures of lung disease, such as spirometry, have been used to assess the effect of antiinflammatory drugs. BAL remains the primary method of interrogating the inflammatory status of the airway, but the procedure is invasive and may eventually be supplanted by induced sputum. Anatomic imaging with high-resolution CT scanning is used clinically, but has unknown utility, and functional imaging, using positron emission tomography, appears promising but is still investigational. Despite the paucity of outcome measures, clinical trials of antiinflammatory agents, including corticosteroids and ibuprofen, have demonstrated benefits, though their use has been limited by adverse effects. Azithromycin is increasingly used as an immunomodulatory agent, although its mechanism of action remains unclear. Strategies for modulating the airway inflammation in patients with CF are currently under development and may offer new therapeutic options for these patients.

Airway inflammation in cystic fibrosis: molecular mechanisms and clinical implications

Airway epithelial cells and immune cells participate in the inflammatory process responsible for much of the pathology found in the lung of patients with cystic fibrosis (CF). Intense bronchial neutrophilic inflammation and release of proteases and oxygen radicals perpetuate the vicious cycle and progressively damage the airways. In vitro studies suggest that CF transmembrane conductance regulator (CFTR)-deficient airway epithelial cells display signalling abnormalities and aberrant intracellular processes which lead to transcription of inflammatory mediators. Several transcription factors, especially nuclear factor-κB, are activated. In addition, the accumulation of abnormally processed CFTR in the endoplasmic reticulum results in unfolded protein responses that trigger ‘cell stress’ and apoptosis leading to dysregulation of the epithelial cells and innate immune function in the lung, resulting in exaggerated and ineffective airway inflammation. Measuring airway inflammation is crucial for initiating treatment and monitoring its effect. No inflammatory biomarker predictive for the clinical course of CF lung disease is currently known, although neutrophil elastase seems to correlate with lung function decline. CF animal models mimicking human lung disease may provide an important insight into the pathogenesis of lung inflammation in CF and identify new therapeutic targets.

Natural Course and Risk Factors for Persistence of IgE-Mediated Cow's Milk Allergy

OBJECTIVE To describe the natural course of IgE-mediated cows milk allergy (IgE-CMA) and to determine risk factors for its persistence in a population-based cohort. STUDY DESIGN In a prospective cohort study, 54 infants with IgE-CMA were identified from a population of 13 019 children followed from birth. Diagnosis of IgE-CMA was based on history, skin prick test (SPT), and an oral food challenge (OFC) when indicated. Allergic infants were followed for 48-60 months. Families were contacted by telephone every 6 months and asked about recent exposures to milk. OFC was repeated to evaluate for recovery. Clinical characteristics, SPT, and OFC outcomes were compared between infants with persistent IgE-CMA and infants who recovered. RESULTS Thirty-one infants (57.4%) recovered from IgE-CMA during the study period. Most infants (70.9%) recovered within the first 2 years. Risk factors for persistence on multivariate analysis included a reaction to <10 mL of milk on OFC (or on first exposure as estimated by the guardian, if OFC was not performed) (P = .01), a larger wheal size on SPT (P = .014), and age of ≤30 days at time of first reaction (P = .05). CONCLUSIONS Resolution occurs in most infants with IgE-CMA. Infants reacting to <10 mL of milk or in the first month of life, and those with a larger wheal size on SPT, are at increased risk for persistence.

Oral Immunotherapy for Peanut Allergy: Multipractice Experience With Epinephrine-treated Reactions

BACKGROUND Peanut allergy creates the risk of life-threatening anaphylaxis that can disrupt psychosocial development and family life. The avoidance management strategy often fails to prevent anaphylaxis and may contribute to social dysfunction. Peanut oral immunotherapy may address these problems, but there are safety concerns regarding implementation in clinical practice. OBJECTIVE The purpose of this report is to communicate observations about the frequency of epinephrine-treated reactions during peanut oral immunotherapy in 5 different allergy/immunology practices. METHODS Retrospective chart review of peanut oral immunotherapy performed in 5 clinical allergy practices. RESULTS A total of 352 treated patients received 240,351 doses of peanut, peanut butter, or peanut flour, and experienced 95 reactions that were treated with epinephrine. Only 3 patients received 2 doses of epinephrine, and no patient required more intensive treatment. A total of 298 patients achieved the target maintenance dose for a success rate of 85%. CONCLUSION Peanut oral immunotherapy carries a risk of systemic reactions. In the context of oral immunotherapy, those reactions were recognized and treated promptly. Peanut oral immunotherapy may be a suitable therapy for patients managed by qualified allergists/immunologists.

Clinical predictors for favorable outcomes in an oral immunotherapy program for IgE-mediated cow's milk allergy

BACKGROUND Avoidance strategies in patients with cows milk allergy occasionally fail to protect these patients from inadvertent exposures, leading to life-threatening reactions. OBJECTIVE To assess the safety and efficacy of milk oral immunotherapy as an alternative therapeutic strategy. METHODS Patients (n = 280, >4 years old) with IgE-mediated cows milk allergy were enrolled into a milk oral immunotherapy program at a single hospital center. High-risk patients were not excluded. The treatment protocol consisted of 3 rounds of oral induction performed every 4 weeks. On day 1, a patients reaction threshold was determined. On days 2 and 3, a tolerated starting dose below the threshold was confirmed. Day 4 mimicked the home treatment, which continued until the next induction. RESULTS The median initial starting dose was 52.5 mg of cows milk protein. Excluding those whose treatment failed in the first week (n = 5) or are still undergoing treatment (n = 15), 61.5% (160 of 260 patients) achieved 7,200 mg and 85.4% of patients were consuming at least 180 mg of milk protein. Reactions at home requiring the use of injectable epinephrine occurred in 15.7% of patients (44 of 280) and in 0.075% (58 of 77,098) of doses administered. Predictors for achieving a full dose in multivariate analysis included a starting dose higher than 30 mg of milk protein (odds ratio 4.6, P < .001), not requiring epinephrine during induction (odds ratio 5.2, P < .001) or home treatment (odds ratio 2.6, P = .037), and the lack of nonanaphylactic type symptoms (odds ratio 15.6, P < .001). CONCLUSION Milk oral immunotherapy, carried out in a highly controlled setting, is successful in protecting the overwhelming majority of patients from accidental exposures to cows milk protein.

Efficacy of baked milk oral immunotherapy in baked milk-reactive allergic patients

BACKGROUND Patients with IgE-mediated cows milk allergy who are nonreactive to baked milk (BM) can be desensitized with BM to promote tolerance to unheated milk (UM). OBJECTIVE We sought to test whether patients who are BM reactive can progress in BM oral immunotherapy (OIT) and become desensitized to UM as well. METHODS Fifteen patients (>4 years) who previously failed to complete our milk OIT program were enrolled into the BM OIT protocol. A dose of BM (180 °C for 30 minutes) which was less than the eliciting dose was increased 50% monthly while under medical supervision until the primary outcome dose of 1.3 g/d BM protein was achieved. Basophil reactivity and milk protein-specific IgE binding were analyzed at the first round of BM OIT therapy (T0) and at 12 months of BM treatment. RESULTS In terms of the primary outcome, only 3 (21%) of 14 patients tolerated the 1.3 g/d BM dose. Although some patients initially progressed in BM OIT, 8 of 11 failed because of IgE-mediated reactions. Three did not complete the program because of non-IgE-mediated factors. An increase in challenge threshold to UM was noted in patients continuing until 12 months (P = .003), including those among whom reactions precluded continuation in the program. Patients (n = 3) who successfully reached maintenance had decreased milk-specific IgE reactivity. Furthermore, the mean difference at T0 between induced HM and UM percentages of CD203c expression was significantly lower in patients who successfully completed BM OIT than in those who did not (-11% vs 4.4%, P = .0002), which is consistent with their decreased clinical reactivity to BM. CONCLUSIONS Although use of hypoallergenic BM in OIT is a promising therapy, care must be taken before its administration in BM-reactive patients because of the risk for anaphylaxis and only limited increase in challenge threshold attained.

Cow's milk associated rectal bleeding: a population based prospective study

Isolated rectal bleeding in infants is often attributed to the consumption of cows milk. However, the prevalence of this condition has not been described, and its preferred diagnostic methods and management are controversial.

Clinical and laboratory 2-year outcome of oral immunotherapy in patients with cow's milk allergy.

Studies examining the long‐term effect of oral immunotherapy in food‐allergic patients are limited. We investigated cows milk‐allergic patients, >6 months after the completion of oral immunotherapy (n = 197). Questionnaires, skin prick tests, and basophil activation assays were performed. Of the 195 patients contacted, 180 (92.3%) were consuming milk protein regularly. Half experienced adverse reactions, mostly mild. Thirteen patients (6.7%) required injectable epinephrine. Higher reaction rate after immunotherapy was associated with more anaphylactic episodes before treatment and a lower starting dose (OR = 2.1, P = 0.035 and OR = 2.3, P = 0.035, respectively). Reaction rate in patients who were 6–15 months, 15–30 months, or >30 months post‐treatment decreased from 0.28/month to 0.21/month to 0.15/month, respectively (P < 0.01). Milk‐induced %CD63 and %CD203c expression was significantly lower in patients >24 months vs in patients <24 months post‐treatment (P = 0.038 and P = 0.047, respectively). In conclusion, many patients experience mild adverse reactions after completing oral immunotherapy and some require injectable epinephrine. Progressive desensitization, both clinically and in basophil reactivity, occurs over time.

Patient quality of life following induction of oral immunotherapy for food allergy

Patient quality of life improves following successful completion of oral immunotherapy (OIT), but the process itself might have undesirable effects. We aimed to evaluate patient quality of life following OIT initial induction.

Pediatric asthma admissions: Chronic severity and acute exacerbations

Factors resulting in intensive care unit (ICU) admissions for asthma exacerbations remain largely unclear. We compared ICU and general pediatric ward admissions for asthma exacerbations. Charts of 56 (2- to 18-year-old) patients admitted consecutively to the ICU during a 1-year period for asthma exacerbations were compared with charts of 56 age-, sex-, race-, and era-matched patients admitted to a general pediatric ward. Few patients in both groups received oral steroids before admission. Children with different chronic asthma severities had comparable severities of acute exacerbation. In conclusion, acute asthma exacerbations dissociate in severity from chronic asthma and are under-treated with systemic corticosteroids.