Melanie M. Makhija

Omalizumab facilitates rapid oral desensitization for peanut allergy

Background: Peanut oral immunotherapy is a promising approach to peanut allergy, but reactions are frequent, and some patients cannot be desensitized. The anti‐IgE medication omalizumab (Xolair; Genentech, South San Francisco, Calif) might allow more rapid peanut updosing and decrease reactions. Objective: We sought to evaluate whether omalizumab facilitated rapid peanut desensitization in highly allergic patients. Methods: Thirty‐seven subjects were randomized to omalizumab (n = 29) or placebo (n = 8). After 12 weeks of treatment, subjects underwent a rapid 1‐day desensitization of up to 250 mg of peanut protein, followed by weekly increases up to 2000 mg. Omalizumab was then discontinued, and subjects continued on 2000 mg of peanut protein. Subjects underwent an open challenge to 4000 mg of peanut protein 12 weeks after stopping study drug. If tolerated, subjects continued on 4000 mg of peanut protein daily. Results: The median peanut dose tolerated on the initial desensitization day was 250 mg for omalizumab‐treated subjects versus 22.5 mg for placebo‐treated subject. Subsequently, 23 (79%) of 29 subjects randomized to omalizumab tolerated 2000 mg of peanut protein 6 weeks after stopping omalizumab versus 1 (12%) of 8 receiving placebo (P < .01). Twenty‐three subjects receiving omalizumab versus 1 subject receiving placebo passed the 4000‐mg food challenge. Overall reaction rates were not significantly lower in omalizumab‐treated versus placebo‐treated subjects (odds ratio, 0.57; P = .15), although omalizumab‐treated subjects were exposed to much higher peanut doses. Conclusion: Omalizumab allows subjects with peanut allergy to be rapidly desensitized over as little as 8 weeks of peanut oral immunotherapy. In the majority of subjects, this desensitization is sustained after omalizumab is discontinued. Additional studies will help clarify which patients would benefit most from this approach.

The nasal methylome and childhood atopic asthma

Background: Given the strong environmental influence on both epigenetic marks and allergic asthma in children, the epigenetic alterations in respiratory epithelia might provide insight into allergic asthma. Objective: We sought to identify DNA methylation and gene expression changes associated with childhood allergic persistent asthma. Methods: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma (n = 36) versus healthy control subjects (n = 36). Results were validated in an independent population of asthmatic children (n = 30) by using a shared healthy control population (n = 36) and in an independent population of white adult atopic asthmatic patients (n = 12) and control subjects (n = 12). Results: We identified 186 genes with significant methylation changes, differentially methylated regions or differentially methylated probes, after adjustment for age, sex, race/ethnicity, batch effects, inflation, and multiple comparisons. Genes differentially methylated included those with established roles in asthma and atopy and genes related to extracellular matrix, immunity, cell adhesion, epigenetic regulation, and airflow obstruction. The methylation changes were substantial (median, 9.5%; range, 2.6% to 29.5%). Hypomethylated and hypermethylated genes were associated with increased and decreased gene expression, respectively (P < 2.8 × 10−6 for differentially methylated regions and P < 7.8 × 10−10 for differentially methylated probes). Quantitative analysis in 53 differentially expressed genes demonstrated that 32 (60%) have significant methylation‐expression relationships within 5 kb of the gene. Ten loci selected based on the relevance to asthma, magnitude of methylation change, and methylation‐expression relationships were validated in an independent cohort of children with atopic asthma. Sixty‐seven of 186 genes also have significant asthma‐associated methylation changes in nasal epithelia of adult white asthmatic patients. Conclusions: Epigenetic marks in respiratory epithelia are associated with allergic asthma and gene expression changes in inner‐city children.

Coronin-1A: Immune Deficiency in Humans and Mice

Since the discovery of coronins in 1991 significant research has been carried out to understand their molecular structure and cellular mechanisms of the action. While a number of binding partners have been discovered, the precise mechanisms of action of Coronin-1A are still being elucidated, both in vitro and in vivo. The role of Coronin-1A in the development and function of the immune system is irrefutable, in both humans and mice, and deficiency of Coronin-1A results in CID. Although some immunological manifestations of Coronin-1A deficiency differed between the patients described so far, absence of Coronin-1A affected the T cell compartment in all patients. B cell numbers were lower than normal and antibody responses were impaired. Variable NK cell defects associated with absent Coronin-1A to date will require detailed analysis of further patients. HCT was curative for patients with Coronin-1A deficiency when the disease was diagnosed early, before onset of irreversible complications arising from infections and EBV associated malignancy. With new evidence about the potential of anti-Coronin-1A monoclonal antibodies to treat B cell malignancies and T cell-mediated auto-inflammatory diseases, Coronin-1A can now be said to be involved in the overall regulation of the immune system, and inappropriate expression can lead to either immune deficiency or autoimmunity.

Can we predict fall asthma exacerbations? Validation of the seasonal asthma exacerbation index

Background: A Seasonal Asthma Exacerbation Predictive Index (saEPI) was previously reported based on 2 prior National Institute of Allergy and Infectious Diseases Inner City Asthma Consortium trials. Objective: This study sought to validate the saEPI in a separate trial designed to prevent fall exacerbations with omalizumab therapy. Methods: The saEPI and its components were analyzed to characterize those who had an asthma exacerbation during the Preventative Omalizumab or Step‐Up Therapy for Fall Exacerbations (PROSE) study. We characterized those inner‐city children with and without asthma exacerbations in the fall period treated with guidelines‐based therapy (GBT) in the absence and presence of omalizumab. Results: A higher saEPI was associated with an exacerbation in both the GBT alone (P < .001; area under the curve, 0.76) and the GBT + omalizumab group (P < .01; area under the curve, 0.65). In the GBT group, younger age at recruitment, higher total IgE, higher blood eosinophil percentage and number, and higher treatment step were associated with those who had an exacerbation compared with those who did not. In the GBT + omalizumab group, younger age at recruitment, increased eosinophil number, recent exacerbation, and higher treatment step were also associated with those who had an exacerbation. The saEPI was associated with a high negative predictive value in both groups. Conclusions: An exacerbation in children treated with GBT with or without omalizumab was associated with a higher saEPI along with higher markers of allergic inflammation, treatment step, and a recent exacerbation. Those that exacerbated on omalizumab had similar features with the exception of some markers of allergic sensitization, indicating a need to develop better markers to predict poor response to omalizumab therapy and alternative treatment strategies for children with these risk factors. The saEPI was able to reliably predict those children unlikely to have an asthma exacerbation in both groups.

Chapter 31: Common in vitro tests for allergy and immunology.

Allergen-specific IgE antibody is the most commonly ordered in vitro test in the practice of allergy and is used to diagnose type I hypersensitivity reactions to foods or reactivity to aeroallergens in patients with relative contraindications to skin-prick testing such as dermatographism. The Phadebas radioallergosorbent test (RAST; Pharmacia, Uppsala, Sweden) was the first assay reported for the detection of the allergen-specific IgE antibody. In a RAST, antigen (allergen) is bound to a solid phase, such as a paper disk, and then incubated with human serum. A buffer wash removes unbound serum proteins, and radiolabeled anti-human IgE is added to detect bound IgE, if present. The results are reported in arbitrary units of IgE per milliliter of serum. The term RAST was originally a brand name but it is now often used colloquially (and incorrectly) to describe any in vitro assay for allergen-specific IgE. Total serum IgE can be measured and is helpful in determining atopic presentations such as in allergic bronchopulmonary aspergillosis or in patients with persistent asthma who are candidates for monoclonal anti-IgE antibody therapy with, omalizumab. In patients with recurrent bacterial infections of the sinopulmonary tract, the basic humoral immune system testing includes measuring quantitative immunoglobulins (IgG, IgA, and IgM) and comparing them to age-matched normal ranges. Most clinical laboratories use nephelometry to measure immunoglobulin levels quantitatively. Nephelometry detects either the rate or the end point of soluble immune complex formation (the IgG in sera complexes with an anti-IgG antibody forming a classic immunoprecipitation reaction) by monitoring the scatter of transmitted light. The most common method for the screening of cellular immunodeficiency involved the measurement of the absolute and relative representation of the major lymphocyte subsets, T-cells, T-helper cells, T-cytotoxic cells, B-cells and NK-cells.

Increased Resting Energy Expenditure is Associated with Failure to Thrive in Infants with Severe Combined Immunodeficiency

OBJECTIVES To measure resting energy expenditure (REE) and determine whether increased REE (hypermetabolism) is associated with failure to thrive (FTT) in patients with severe combined immunodeficiency (SCID) at diagnosis. STUDY DESIGN REE was measured in 26 patients with SCID in a single transplant center. Predicted REE was determined with World Health Organization standards. Measured REE >110% of predicted REE was classified as hypermetabolism. Other data collected included FTT status, infections, genotype, phenotype, and the feeding methods used. RESULTS Fifteen of 26 patients (57.7%) had FTT, and 18 of 26 patients (69.2%) were hypermetabolic. Hypermetabolism occured in 14 of 15 patients (93%) with FTT, and only 4 of 11 patients (36%) without FTT had hypermetabolism (P = .003). There was a significant difference between the measured REE (71.75 ± 16.6 kcal/kg) and the predicted REE (52.85 ± 2.8 kcal/kg; P < .0001). Eleven of 17 patients (65%) required nasogastric feeding, parenteral nutrition, or both to meet their energy needs. CONCLUSIONS Hypermetabolism is common in patients with SCID and may contribute to the development of FTT. The hypermetabolism in these patients may necessitate intensive nutrition support.

Minimally important differences and risk levels for the Composite Asthma Severity Index

To the Editor: The Composite Asthma Severity Index (CASI) is a comprehensive severity scale combining multiple facets of asthma severity: impairment, risk, and treatment. The CASI score, which was developed as a research tool for intervention studies, ranges from 0 to 20 points, with higher scores indicating higher levels of severity, and includes 5 domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. This report expands on the introduction of the CASI score in Wildfire et al by determining risk levels, the minimally important difference (MID), and the suggested effect size for the score. Information about CASI, including study forms and an online calculator, is available at www.asthmaseverity.org. This report uses data from the Asthma Phenotypes in the Inner City (APIC) study to describe the relationship between CASI and the global clinician assessment of severity, establish cutoff points of the CASI score discriminating low versus medium or high asthma severity, and provide preliminary estimates of the MID and a treatment effect for the CASI. Data from the Inner City Anti-IgE Therapy for Asthma Study (ICATA), a double-blind randomized clinical trial evaluating the impact of the addition of omalizumab to guidelines-based therapy, are used to evaluate the MID and effect size developed. The MID, which is defined as the smallest difference in a measure that is considered clinically meaningful, can vary depending on the context. The MID presented in this report refers to an individual’s change over time. In addition, we present the difference between 2 populations as the minimal important effect size, which serves as a benchmark for a treatment effect in a study. The APIC study was an observational study designed to identify determinants of asthma severity. During the APIC study, children aged 6 to 17 years, with a wide range of asthma severity, received standardized guidelines-directed asthma treatment for 1 year. At screening and the final visit, the CASI score was calculated and the children were assigned numeric (0-100) and categorical (‘‘low,’’ ‘‘medium,’’ or ‘‘high’’) global severity assessments by study clinicians. We examined the relationships between CASI and the numeric (0-100) clinician assessment at screening to establish CASI risk levels and an MID for CASI. Traditional measures of risk and impairment, such as clinical and lung functionmeasures, were not appropriate ‘‘criterion standards’’ for the CASI because it contains elements of both. The mean CASI score at screening was 4.8 6 3.22; the maximum possible CASI score is 20. There was a strong relationship between CASI and the numeric (0-100) clinician assessment of severity (r 5 0.65; 95% CI, 0.60-0.69), indicating that any increase in CASI translates to an increase in clinician estimate of asthma severity. The categorical clinician assessment rated 294 participants (41%) as ‘‘low’’ severity, 309 (43%) as ‘‘medium’’ severity, and 113 (16%) as ‘‘high’’ severity at the screening visit. To establish CASI risk levels, we examined the relationship betweenCASI and the clinician categorical assessment of severity using receiver operator curve analysis. Of the 294 low severity participants, 75%hadCASI scores of 3 or lower, and aCASI score of 3 was found to be optimal to discriminate a low severity rating from a medium or high severity rating (area under the curve 5 0.86; Fig 1, A). The same optimal cutoff point of 3 was identified using data available for 557 participants from the final visit (data not shown). Similar receiver operator curves were created to discriminate between participants with medium and high categorical clinician assessments, but based on area under the curve, no recommended cutoff point was identified. In addition, as a continuous score, the CASI is shown to have a high correlation with asthma severity, and increases in CASI values both above and below the established cutoff point of 3 are associated with significant increases in severity (correlation with clinician assessment for CASI score 0-3 5 0.37; 95% CI, 0.27-0.46; CASI score from 3 to 20 5 0.47; 95% CI, 0.40-0.54; Fig 1, B). TheMID forCASI is informedby its design.CASI scores in each of the 5 domains were alignedwith theNational AsthmaEducation and Prevention Program Expert Panel Report asthma guidelines. As a result, a 1-point change in CASI score corresponds to either a 1-point increase in the participant’s asthma control level (for day symptoms/albuterol use, night symptoms/albuterol use, and lung functionmeasure) or a change inmedication (inhaled corticosteroids for the controller treatment domain and prednisone for the exacerbation domain). Therefore, a 1-point difference in any domain constitutes a change that could be considered clinically significant, serving as a lower bound for theMID. To further define the MID, anchor-based analysis, a methodology for estimating the MIDon the basis of a clinical referencemeasure,was performed by categorizing the numeric clinician rating of severity into 10-point intervals (Table I). Mean differences in CASI scores were calculated between adjacent anchor categories and yielded an MID of 0.9 with Hedges g statistic of 0.36 (0.2 5 small effect, 0.5 5 medium effect, and 0.8 5 large effect). The validity of 0.9 change was evaluated using data from the ICATA study, where 52% (98 of 189) of the participants in the treatment arm demonstrated a CASI score decrease of 0.9 points between randomization and the end of the study, compared with only 40% (69 of 172) of participants in the placebo arm (x P 5 .03). Because changes in CASI occur in no less than a 1-point increment, we rounded this value to propose an MID of 1 CASI point. To determine the minimal important effect size, which is not limited to whole numbers as it represents the average of a population of individuals, a statistical simulation was performed using APIC data by creating a simulated placebo group and an active treatment group (n5 250 for each). The simulation yielded a mean difference of 0.49 CASI points between 2 treatment arms (95% CI, 0.01-0.99). In the ICATA study, participants in the treatment arm showed a significant improvement in CASI over participants in the placebo arm (0.67 points improvement, P<.001). Additional details regarding this result, includingmethodology and estimates based on several population sizes, are available as an online supplement at https://github.com/RhoInc/ CASI_MID. More research in high-risk populations, to include larger numbers of participants, is needed to discriminate between the mediumand high-risk levels of asthma severity using the CASI score. In addition, further research is needed to determinewhether

114 A Multicenter Study Assessing the Clinical, Endoscopic and Histologic Response to Four Food Elimination Diet for the Treatment of Eosinophilic Esophagitis

G A A b st ra ct s calculated at baseline and at week 12. Proximal and distal esophageal scores, total scores (summation of proximal and distal), and subscores for individual component of EREFS (edema, rings, exudates, furrows, stricture) were prospectively recorded. Baseline and followup EREFS scores were compared, and post-treatment eosinophil counts and EREFS scores were correlated. Data analysis was performed on the intent-to-treat population. Results: A total of 93 subjects were randomized from 25 centers, and 87 were included in the final analysis. 97% of subjects had endoscopic features identified at baseline. The OBS (n= 49) and placebo (n=38) groups did not differ in baseline demographic and endoscopic characteristics. EREFS scores significantly improved after treatment in both proximal (3.4 to 1.5; p<0.0001) and distal esophagus (4.3 to 2.4; p<0.0001) with OBS but not placebo (proximal 3.3 to 3.4; distal 3.6 to 3.9). Features of edema, rings, exudates and furrows showed significant improvement with OBS but not placebo (Figure). Strictures did not significantly change following OBS or placebo although subjects with high grade strictures were excluded from trial entry. Proximal, distal and total EREFS correlated with peak eosinophil counts after treatment (R: 0.35, p<0.0001). Conclusions: (1) This is the first study to utilize a validated endoscopic scoring instrument in a randomized controlled trial of medical therapy for EoE. (2) Significant benefit was demonstrated in the inflammatory (edema, exudates, furrows), ring, and total EREFS scores. (3) Significant correlation was demonstrated between EREFS and peak eosinophil counts. (4) Endoscopic outcomes may be important endpoints of EoE clinical trials that complement symptom and histologic assessments. Written on behalf of the MPI-101-06 Investigators.

Patterns of allergen sensitization and self-reported allergic disease in parents of food allergic children

BACKGROUND Sensitization in adults has not been extensively studied. OBJECTIVE To investigate patterns of allergen sensitization in parents of food allergic children and to compare self-report of allergic disease with specific IgE (sIgE) measurements. METHODS A total of 1,252 mothers and 1,225 fathers of food allergic children answered standardized questionnaires about demographics, home environment, history of atopic diseases, and food allergy. Skin prick testing and sIgE serum tests were performed to 9 foods and 5 aeroallergens. RESULTS A total of 66.1% of parents were sensitized to either a food or aeroallergen. Mean sIgE levels were low for all foods tested. A total of 14.5% of mothers and 12.7% of fathers reported current food allergy. Only 28.4% had sensitization to their reported allergen. Fathers had significantly higher rates of sensitization to both foods and aeroallergens (P < .01) than mothers. Logistic regression evaluating predictors of self-reported food allergy revealed statistically significant positive associations in fathers with self-reported asthma, environmental allergy, and eczema. For mothers, significant positive associations were found with environmental allergy and having more than 1 food allergic child. CONCLUSION This cohort of parents of food allergic children found higher rates of sensitization to foods and aeroallergens compared with the general population. However, food sIgE levels were low and correlated poorly with self-reported food allergy. Sex differences in sensitization to foods and aeroallergens were seen.

Anaphylaxis to Food

This article provides a clinically focused review of food-induced anaphylaxis that includes epidemiology, risk factors, allergens, diagnosis, and management. Currently, there is no treatment for food allergy. Dietary avoidance and emergency preparedness are the cornerstones of management. Effective and safe therapies to reduce the risk of serious food-induced reactions are urgently needed, as are reliable biomarkers to predict severity.