Michelle L. Sever

Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy

BACKGROUND The prevalence of peanut allergy among children in Western countries has doubled in the past 10 years, and peanut allergy is becoming apparent in Africa and Asia. We evaluated strategies of peanut consumption and avoidance to determine which strategy is most effective in preventing the development of peanut allergy in infants at high risk for the allergy. METHODS We randomly assigned 640 infants with severe eczema, egg allergy, or both to consume or avoid peanuts until 60 months of age. Participants, who were at least 4 months but younger than 11 months of age at randomization, were assigned to separate study cohorts on the basis of preexisting sensitivity to peanut extract, which was determined with the use of a skin-prick test--one consisting of participants with no measurable wheal after testing and the other consisting of those with a wheal measuring 1 to 4 mm in diameter. The primary outcome, which was assessed independently in each cohort, was the proportion of participants with peanut allergy at 60 months of age. RESULTS Among the 530 infants in the intention-to-treat population who initially had negative results on the skin-prick test, the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001). Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P=0.004). There was no significant between-group difference in the incidence of serious adverse events. Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titers of peanut-specific IgE antibody. A larger wheal on the skin-prick test and a lower ratio of peanut-specific IgG4:IgE were associated with peanut allergy. CONCLUSIONS The early introduction of peanuts significantly decreased the frequency of the development of peanut allergy among children at high risk for this allergy and modulated immune responses to peanuts. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00329784.).

Effect of Avoidance on Peanut Allergy after Early Peanut Consumption

BACKGROUND In a randomized trial, the early introduction of peanuts in infants at high risk for allergy was shown to prevent peanut allergy. In this follow-up study, we investigated whether the rate of peanut allergy remained low after 12 months of peanut avoidance among participants who had consumed peanuts during the primary trial (peanut-consumption group), as compared with those who had avoided peanuts (peanut-avoidance group). METHODS At the end of the primary trial, we instructed all the participants to avoid peanuts for 12 months. The primary outcome was the percentage of participants with peanut allergy at the end of the 12-month period, when the participants were 72 months of age. RESULTS We enrolled 556 of 628 eligible participants (88.5%) from the primary trial; 550 participants (98.9%) had complete primary-outcome data. The rate of adherence to avoidance in the follow-up study was high (90.4% in the peanut-avoidance group and 69.3% in the peanut-consumption group). Peanut allergy at 72 months was significantly more prevalent among participants in the peanut-avoidance group than among those in the peanut-consumption group (18.6% [52 of 280 participants] vs. 4.8% [13 of 270], P<0.001). Three new cases of allergy developed in each group, but after 12 months of avoidance there was no significant increase in the prevalence of allergy among participants in the consumption group (3.6% [10 of 274 participants] at 60 months and 4.8% [13 of 270] at 72 months, P=0.25). Fewer participants in the peanut-consumption group than in the peanut-avoidance group had high levels of Ara h2 (a component of peanut protein)-specific IgE and peanut-specific IgE; in addition, participants in the peanut-consumption group continued to have a higher level of peanut-specific IgG4 and a higher peanut-specific IgG4:IgE ratio. CONCLUSIONS Among children at high risk for allergy in whom peanuts had been introduced in the first year of life and continued until 5 years of age, a 12-month period of peanut avoidance was not associated with an increase in the prevalence of peanut allergy. Longer-term effects are not known. (Funded by the National Institute of Allergy and Infectious Diseases and others; LEAP-On ClinicalTrials.gov number, NCT01366846.).

Indoor allergens in school and day care environments

Most studies that have examined exposure to indoor allergens have focused on home environments. However, allergen exposures can be encountered in environments other than the home. For example, many children spend a large part of their time in schools and day care facilities. Over the past 2 decades, a large number of studies have been conducted in school and day care environments. However, the role of indoor exposures in allergy and asthma development or morbidity in these settings is not well characterized. The purpose of this review is to evaluate the importance of indoor allergen exposures in school and day care settings. We summarize the key findings from recent scientific literature, describe exposure characteristics, discuss the role of these exposures in relation to asthma and allergy symptoms, and provide information on the effectiveness of published interventions.

The Toll-like receptor 5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens

Allergic asthma is a complex disease characterized by eosinophilic pulmonary inflammation, mucus production and reversible airway obstruction. Exposure to indoor allergens is a risk factor for asthma, but this disease is also associated with high household levels of total and particularly Gram-negative bacteria. The ability of bacterial products to act as adjuvants suggests they might promote asthma by priming allergic sensitization to inhaled allergens. In support of this idea, house dust extracts (HDEs) can activate antigen-presenting dendritic cells (DCs) in vitro and promote allergic sensitization to inhaled innocuous proteins in vivo. It is unknown which microbial products provide most of the adjuvant activity in HDEs. A screen for adjuvant activity of microbial products revealed that the bacterial protein flagellin (FLA) stimulated strong allergic airway responses to an innocuous inhaled protein, ovalbumin (OVA). Moreover, Toll-like receptor 5 (TLR5), the mammalian receptor for FLA, was required for priming strong allergic responses to natural indoor allergens present in HDEs. In addition, individuals with asthma have higher serum levels of FLA-specific antibodies as compared to nonasthmatic individuals. Together, these findings suggest that household FLA promotes the development of allergic asthma by TLR5-dependent priming of allergic responses to indoor allergens.

Feasibility of Using Subject-Collected Dust Samples in Epidemiologic and Clinical Studies of Indoor Allergens

Studies of indoor allergen exposures are often limited by the cost and logistics of sending technicians to homes to collect dust. In this study we evaluated the feasibility of having subjects collect their own dust samples. The objectives were to compare allergen concentrations between subject- and technician-collected samples and to examine the sample return rate. Using a dust collection device and written instructions provided to them by mail, 102 subjects collected a combined dust sample from a bed and bedroom floor. Later the same day, a technician collected a side-by-side sample. Dust samples were weighed and analyzed for the cat allergen Fel d 1 and the dust mite allergen Der p 1. Fifty additional subjects who were enrolled by telephone were mailed dust collection packages and asked to return a dust sample and questionnaire by mail. A technician did not visit their homes. Correlations between subject- and technician-collected samples were strong for concentrations of Fel d 1 (r = 0.88) and Der p 1 (r = 0.87). With allergen concentrations dichotomized at lower limits of detection and clinically relevant thresholds, agreements between methodologies ranged from 91 to 98%. Although dust weights were correlated (r = 0.48, p < 0.001), subjects collected lighter samples. Among the group of 50 subjects, 46 returned a dust sample and completed questionnaire. The median number of days to receive a sample was 15. With some limitations, subject-collected dust sampling appears to be a valid and practical option for epidemiologic and clinical studies that report allergen concentration as a measure of exposure.

Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis: The GRASS Randomized Clinical Trial

Importance Sublingual immunotherapy and subcutaneous immunotherapy are effective in seasonal allergic rhinitis. Three years of continuous treatment with subcutaneous immunotherapy and sublingual immunotherapy has been shown to improve symptoms for at least 2 years following discontinuation of treatment. Objective To assess whether 2 years of treatment with grass pollen sublingual immunotherapy, compared with placebo, provides improved nasal response to allergen challenge at 3-year follow-up. Design, Setting, and Participants A randomized double-blind, placebo-controlled, 3–parallel-group study performed in a single academic center, Imperial College London, of adult patients with moderate to severe seasonal allergic rhinitis (interfering with usual daily activities or sleep). First enrollment was March 2011, last follow-up was February 2015. Interventions Thirty-six participants received 2 years of sublingual immunotherapy (daily tablets containing 15 µg of major allergen Phleum p 5 and monthly placebo injections), 36 received subcutaneous immunotherapy (monthly injections containing 20 µg of Phleum p 5 and daily placebo tablets) and 34 received matched double-placebo. Nasal allergen challenge was performed before treatment, at 1 and 2 years of treatment, and at 3 years (1 year after treatment discontinuation). Main Outcomes and Measures Total nasal symptom scores (TNSS; range; 0 [best] to 12 [worst]) were recorded between 0 and 10 hours after challenge. The minimum clinically important difference for change in TNSS within an individual is 1.08. The primary outcome was TNSS comparing sublingual immunotherapy vs placebo at year 3. Subcutaneous immunotherapy was included as a positive control. The study was not powered to compare sublingual immunotherapy with subcutaneous immunotherapy. Results Among 106 randomized participants (mean age, 33.5 years; 34 women [32.1%]), 92 completed the study at 3 years. In the intent-to-treat population, mean TNSS score for the sublingual immunotherapy group was 6.36 (95% CI, 5.76 to 6.96) at pretreatment and 4.73 (95% CI, 3.97 to 5.48) at 3 years, and for the placebo group, the score was 6.06 (95% CI, 5.23 to 6.88) at pretreatment and 4.81 (95% CI, 3.97 to 5.65) at 3 years. The between-group difference (adjusted for baseline) was −0.18 (95% CI, −1.25 to 0.90; [P = .75]). Conclusions and Relevance Among patients with moderate to severe seasonal allergic rhinitis, 2 years of sublingual grass pollen immunotherapy was not significantly different from placebo in improving the nasal response to allergen challenge at 3-year follow-up. Trial Registration clinicaltrials.gov Identifier: NCT01335139; EudraCT Number: 2010-023536-16

A Multi-Center Ring Trial of Allergen Analysis using Fluorescent Multiplex Array Technology

BACKGROUND Consistent performance of allergen assays is essential to ensure reproducibility of exposure assessments for investigations of asthma and occupational allergic disease. This study evaluated intra- and inter-laboratory reproducibility of a fluorescent multiplex array, which simultaneously measures eight indoor allergens in a single reaction well. METHODS A multi-center study was performed in nine laboratories in the US and Europe to determine the inter-laboratory variability of an 8-plex array for dust mite, cat, dog, rat, mouse and cockroach allergens. Aliquots of 151 dust extract samples were sent to participating centers and analyzed by each laboratory on three separate occasions. Agreement within and between laboratories was calculated by the concordance correlation coefficient (CCC). RESULTS Results were obtained for over 32,000 individual allergen measurements. Levels covered a wide range for all allergens from below the lower limit of detection (LLOD = 0.1-9.8 ng/ml) to higher than 6800 ng/ml for all allergens except Mus m 1, which was up to 1700 ng/ml. Results were reproducible within as well as between laboratories. Within laboratories, 94% of CCC were ≥ 0.90, and 80% of intra-laboratory results fell within a 10% coefficient of variance (CV%). Results between laboratories also showed highly significant positive correlations for all allergens (~0.95, p<0.001). Overall means of results were comparable, and inter-laboratory CV% for all allergens except Rat n 1 ranged between 17.6% and 26.6%. CONCLUSION The data indicate that performance criteria for fluorescent multiplex array technology are reproducible within and between laboratories. Multiplex technology provides standardized and consistent allergen measurements that will streamline environmental exposure assessments in allergic disease.

Comparison of enzyme immunoassay-based assays for environmental Alternaria alternata.

BACKGROUND Alternaria alternata-derived allergenic materials are causes of human disease. Several immunoassays exist to quantify these materials. OBJECTIVE To compare methods for evaluating Alternaria content. METHODS Four methods, including 1 monoclonal antibody (MAb)-based assay specific for recombinant Alt a 1, 1 MAb-based assay for chromatographically purified Alt a 1, 1 polyclonal antibody (PAb)-based assay for chromatographically purified Alt a 1, and 1 PAb-based assay for whole Alternaria extract, were evaluated. Environmental samples collected as part of the National Survey of Lead and Allergens in Housing were examined. Alternaria spore counts were determined in dust by observation. RESULTS The MAb-based assay for recombinant Alt a 1 detected Alternaria in few samples (25%); the PAb-based assay for whole Alternaria proteins detected antigen in 97% of the samples. The PAb- and MAb-based assays for purified Alt a 1 detected antigen in 100% of the samples. There was a significant positive correlation between the 2 assays directed against purified Alt a 1. There was a positive correlation between the PAb-based assay for whole Alternaria and the PAb-based assay for Alt a 1. Nearly all the dust samples contained Alternaria spores, and there was a strong positive correlation between counts and all assays. CONCLUSION Because of the multifaceted nature of Alternaria, the disparities between methods for quantifying Alternaria, the cross-reactivity between fungal allergens, and the documented genetic promiscuity of this fungus, enzyme immunoassays using PAbs against a range of Alternaria proteins will probably produce the most reliable estimation of overall Alternaria exposure in house dust.

Efficacy of an In-home Test Kit in Reducing Dust Mite Allergen Levels: Results of a Randomized Controlled Pilot Study

Abstract Background: Dust mite allergens can induce allergic sensitization and exacerbate asthma symptoms. Although dust mite reduction and control strategies exist, few asthmatics employ them. Objectives: We examined whether an in-home test kit, which quantifies dust mite allergen levels, resulted in behavioral changes in implementation and maintenance of mite reduction strategies and helped reduce allergen levels in homes of dust mite-sensitive children. Methods: We enrolled 60 households of children aged 5–15 with parent-reported dust mite allergy into a randomized controlled trial. Intervention homes (N = 30) received educational material about reducing dust mites and test kits at 1, 2, 5 and 8 months. Control homes (N = 30) received only educational material. At baseline, 6 and 12 months, study staff visited all homes, collected dust samples from three locations and obtained information about parents’ mite reduction behaviors by questionnaire. Allergen concentrations (Der f 2/Der p2) in dust were assessed by immunoassays. After adjusting for visit and location, allergen concentrations in intervention and control homes were compared using mixed effects model analysis. Results: In the intervention homes, allergen concentrations in the child’s bedroom and living room floors were significantly reduced over time compared to control homes. Although not all location-specific differences in allergen concentrations were statistically significant, combining data across locations, there was a differential reduction in allergen concentrations in the intervention group versus the control group (p = 0.02). Conclusion: The use of in-home test kits along with education may beneficially influence behaviors and attitudes toward dust mite reduction strategies and help reduce residential dust mite allergen levels.

Asthma severity, not asthma control, is worse in atopic compared with nonatopic adolescents with asthma

BACKGROUND The effects of atopic and nonatopic asthma phenotypes on asthma morbidity are unclear. Moreover, asthma morbidity in patients without atopy might be mediated by immunoglobulin E (IgE). OBJECTIVE To determine differences in morbidity in patients with asthma with and without atopy in a population of inner-city adolescents with asthma and to assess the impact of total IgE (tIgE) in this population. METHODS Data were obtained from 546 inner-city adolescents in the Asthma Control Evaluation study. A positive skin prick test reaction to 14 aeroallergens and specific IgE to 5 aeroallergens determined atopic status. High (≥75th percentile) and low (≤25th percentile) tIgE levels were categorized. Asthma control (Asthma Control Test) and asthma severity (Composite Asthma Severity Index [CASI]) were measured at multiple time points over 1 year. Fractional exhaled nitric oxide (FeNO) and measurements of morbidity also were collected. Multivariable and repeated measures analyses modeled the relation between atopic status and morbidity. RESULTS Baseline CASI scores increased 0.90 point (P < .05) and FeNO increased 0.85 natural logarithmic unit (P < .001) in participants with vs without atopy. Repeated measures analyses showed consistent results. Participants without atopy and increased tIgE had FeNO 0.73 natural log unit higher (P < .01) than low tIgE and a nonsignificant increase in CASI. The CASI score and FeNO levels were higher for high than for low tIgE in participants with atopy. CONCLUSION In this population, participants with atopic asthma had worse asthma severity and higher FeNO compared with those with nonatopic asthma, but no difference in control. In all participants, higher tIgE indicated worse severity and higher FeNO. In this population, asthma severity and FeNO might be mediated by IgE in the 2 asthma phenotypes.