Jessica H. Savage

The natural history of soy allergy

BACKGROUND Soy allergy is very common, affecting approximately 0.4% of children. It is generally thought that the majority of children with soy allergy develop tolerance in early childhood; however, this has not been examined in a large cohort with soy allergy. OBJECTIVE We sought to describe the natural history of soy allergy and identify predictors of oral tolerance/outgrowing soy allergy. METHODS The records of patients with soy allergy seen in a tertiary referral clinic were reviewed. Data collected included soy allergy-related symptoms, history of other food allergies and atopic diseases, soy-specific IgE levels, peanut-specific IgE levels, and food challenge results. RESULTS One hundred thirty-three patients were studied (96 male and 37 female patients). Eighty-five (64%) had asthma, 95 (71%) had allergic rhinitis, and 108 (85%) had atopic dermatitis. Eighty-eight percent had concomitant peanut allergy. The median age at the initial visit was 1 year (range, 2 months to 17.5 years); the median duration of follow-up was 5 years (range, 1-19 years). Kaplan-Meier analysis predicted resolution of soy allergy in 25% by age 4 years, 45% by age 6 years, and 69% by age 10 years. By age 6 years, 59% of children with a peak soy IgE level of less than 5 kU/L, 53% of children with a peak s-IgE level of 5 to 9.9 kU/L, 45% of children with a peak s-IgE level of 10 to 49.9 kU/L, and 18% of children with a peak s-IgE level of greater than 50 kU/L had outgrown soy allergy (P < .01 for trend). CONCLUSIONS In this referral population approximately 50% of children with soy allergy outgrew their allergy by age 7 years. Absolute soy IgE levels were useful predictors of outgrowing soy allergy.

Food Allergy: Epidemiology and Natural History

The prevalence of food allergy is rising for unclear reasons, with prevalence estimates in the developed world approaching 10%. Knowledge regarding the natural course of food allergies is important because it can aid the clinician in diagnosing food allergies and in determining when to consider evaluation for food allergy resolution. Many food allergies with onset in early childhood are outgrown later in childhood, although a minority of food allergy persists into adolescence and even adulthood. More research is needed to improve food allergy diagnosis, treatment, and prevention.

Temporal trends and racial/ethnic disparity in self-reported pediatric food allergy in the United States

BACKGROUND The prevalence of food allergy is thought to be increasing, but data from the United States have not been systematically synthesized. OBJECTIVE To summarize the data on prevalence of food allergy in the US pediatric population and to estimate the effects of time, race/ethnicity, and method of assessing food allergy on the estimated prevalence. METHODS Embase, MEDLINE, bibliographies of identified reports, and data from publically available data sets were searched. Studies were limited to those in English with data from the general pediatric US population. Study synthesis was performed by meta-analysis and meta-regression to estimate the effect of study- and participant-level covariates. Meta-regression was limited to nationally representative surveys conducted by the Centers for Disease Control and Prevention. RESULTS A total of 10,090 publications were identified, from which 27 different survey administrations, representing 452,237 children, were identified, covering the period of 1988 to 2011. Because of heterogeneity among surveys in the estimated food allergy prevalence, a summary estimate of food allergy prevalence was not possible. Meta-regression was performed using 20 of these surveys. Temporal trends were pronounced, with an estimated increased prevalence of self-reported food allergy of 1.2 percentage points per decade (95% confidence interval [CI], 0.7-1.6). The increase per decade varied by race/ethnicity: 2.1% among non-Hispanic blacks (95% CI, 1.5%-2.7%), 1.2% among Hispanics (95% CI, 0.7%-1.7%), and 1.0% among non-Hispanic whites (95% CI, 0.4%-1.6%). CONCLUSION Self-report of food allergy among US children has sharply increased in the past 2 decades. The increase has been greatest among non-Hispanic black children, a disparity that needs to be investigated.

Potential mechanisms for the association between fall birth and food allergy

Season of birth has been reported as a risk factor for food allergy, but the mechanisms by which it acts are unknown.

Scratching the surface of allergic transfusion reactions.

Allergic transfusion reactions (ATRs) are a spectrum of hypersensitivity reactions that are the most common adverse reaction to platelets and plasma, occurring in up to 2% of transfusions. Despite the ubiquity of these reactions, little is known about their mechanism. In a small subset of severe reactions, specific antibody has been implicated as causal, although this mechanism does not explain all ATRs. Evidence suggests that donor, product, and recipient factors are involved, and it is possible that many ATRs are multifactorial. Further understanding of the mechanisms of ATRs is necessary so that rationally designed and cost‐effective prevention measures can be developed.

The metabolomics of asthma control: a promising link between genetics and disease

Short‐acting β agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking β agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative “omics” approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC‐MS), using plasma samples from 20 individuals with asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome‐wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over‐representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites—monoHETE_0863 and sphingosine‐1‐phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine‐related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control.

Atopic predisposition of recipients in allergic transfusion reactions to apheresis platelets

BACKGROUND: The biologic mechanisms of allergic transfusion reactions (ATRs) are largely unknown. We sought to compare the atopic predisposition of platelet (PLT) recipients who experienced an ATR to nonreactive control recipients.

Evaluation of Ara h2 IgE thresholds in the diagnosis of peanut allergy in a clinical population.

TO THE EDITOR: Component resolved specific IgE testing for peanut allergy has recently received much attention as a means of more accurately identifying patients with peanut allergy than the routine use of peanut extract–specific IgE serology or skin testing. Among the peanut component proteins, IgE antibodies to Ara h2, and to a much lesser extent Ara h1, Ara h3, Ara h6, and Ara h9, have been identified as the major driver of clinically relevant allergy.1–9 Because sensitization to Ara h2 is found in 40% to 90% of patients with clinical peanut allergy,1–8,10 some investigators have proposed using specific IgE to Ara h2 serology as a way to reduce the need for oral food challenges.11 Various IgE anti-Ara h2 cut points have been proposed to predict clinically relevant peanut allergy. Codreanu et al,2 for instance, suggested a threshold of 0.23 kUA/L Ara h2 for identifying peanut allergic subjects and further suggest that “The DBPCFC [double-blind placebo-controlled food challenge] should no longer be considered a mandatory diagnostic procedure, but will remain a useful test for defining the eliciting dose for patients who are candidates for oral immunotherapy.” 2(p225) Nicolaou and Custovic10 similarly proposed 0.35 kUA/L as a threshold. In their study, this threshold exhibited a 100% diagnostic sensitivity. However, it still remains unclear whether these thresholds should be used to suggest home introduction of peanuts to patients (if they fall below the threshold) or whether they should be used in place of a food challenge (if they rise above the threshold). Nor is it clear how accurate either of these applications will be in a general clinical population. Here, we apply a variety of cutoff values for IgE anti-Ara h2 to a pediatric allergy clinic to determine whether using component-resolved diagnostics for peanut would result in decreased need for food challenge. Subjects who had diagnostic peanut oral challenges at the Pediatric Allergy Clinic between 2003 and 2010, had stored serum available within 2 years of their challenge, and were sensitized to peanut were identified retrospectively. Samples were obtained from banked excess serum originally drawn for clinical purposes. Human subjects’ approval was given by the Johns Hopkins Institutional Review Board. Because this was a retrospective study, informed consent was waived by the Institutional Review Board. Peanut food challenges were open. The cumulative maximum food challenge dose was 5 g of peanut protein for children younger than 5 years and 8 g otherwise (equivalent to ~17 and 27 peanuts, respectively). The form of peanuts depended on patient preference and other allergies, but the form was most commonly peanut butter or peanut candies. Food challenges were done for diagnostic purposes, and they were stopped when clear clinical symptoms developed, including symptoms in the following systems: skin (hives, full body flushing), upper respiratory (sneezing, significant rhinorrhea), lower respiratory (wheezing, cough), gastrointestinal (significant persistent abdominal pain, vomiting), and cardiovascular (hypotension, loss of consciousness). Although the threshold varied according to clinical circumstances, most often oral challenges were done when the peanut-specific IgE was <2 kUA/L in patients with a clear history of reaction and <5 kUA/L in patients without a clear history. IgE antibody specific for peanut extract and for the individual peanut components (Ara h1, h2, h3, h8, and h9) were quantified in kUA/L by the ImmunoCAP-250 (Thermo Fisher Scientific, Waltham, Mass). Each serum sample was additionally analyzed in the ImmunoSorbent Allergen bioChip assay (ISAC103; Thermo Fisher Scientific).3 Semiquantitative IgE antibody results were reported in ISAC Standardized Units (ISUs), with <0.3 ISU being considered negative. The available ISAC peanut allergen specificities examined for this report included Ara h1, Ara h2, Ara h3, and Ara h8. Diagnostic sensitivity and specificity and positive and negative predictive values were computed with exact binomial confidence intervals for the defined thresholds by comparing individual component-specific IgE levels as measured by ImmunoCAP and ISAC with peanut food challenge outcome. All calculations were performed with STATA/SE 11.0 (Stata Corp, College Station, Tex). Sixty patients were included in this analysis, including 26 with a history of acute peanut reaction and 34 with a positive test but no previous history of reaction. With peanut food challenge, 26 reacted and 35 did not. One patient initially failed a peanut challenge at age 4.8 years and then later passed at 7.2 years and had sera available from both times (peanut specific IgE of 1.5 kUA/L at first challenge and 0.8 kUA/L at second challenge). The mean age at the time of challenge was 7 years (range, 3–19 years) and occurred at a mean of 5 months after the serum was obtained. Generally, the peanut extract–specific IgE for both groups was relatively low (Table I). TABLE I Subject characteristics Ara h2 was the most commonly recognized peanut component by IgE antibody in sera from patients who failed peanut food challenges, with a diagnostic sensitivity among this population (when sensitization was defined as ≥60.1 kUA/L) of 96% and diagnostic specificity of 54% (Table II). In contrast, IgE anti-Ara h1, -Ara h3, -Ara h8, and -Ara h9 antibodies were insensitive predictors of failed peanut oral food challenge (sensitivity: Ara h1, 23%; Ara h3, 24%; Ara h8, 12%; and Ara h9, 12%) but showed moderate specificity (Ara h1, 80%; Ara h3, 74%; and Ara h9, 82%). The exception was Ara h8, which at a cutoff of 0.1 kUA/L displayed a poor specificity (56%). In fact, if subjects had detectable anti-Ara h8 IgE, they were more likely to pass a peanut food challenge than if they did not (P = .01); however, 3 subjects with positive anti-Ara h8 IgE did fail the challenge (11% of those positive). The sensitivity, specificity, positive predictive value, negative predictive value, and percent misclassified, defined as the total percentage labeled as either allergic or nonallergic in error, for various cutoffs of Ara h2–specific IgE are listed in Table II, including diagnostic sensitivity to Ara h2 as defined by ISAC. A high rate of misclassification was observed for all IgE anti-Ara h2 cutoff levels tested: 26% were misclassified at 0.23 kUA/L, 21% at 0.35 kUA/L, 36% at 2 kUA/L, and 21% at 0.3 ISU with ISAC (Table II). Among those with anti-Ara h2 IgE below 0.35 kUA/L who reacted to the food challenge, none had lower respiratory or cardiovascular symptoms or required epinephrine. However, 2 patients (10%) with anti-Ara h2 IgE below 2 kUA/L had lower respiratory symptoms and 5 (25%) required epinephrine. TABLE II Diagnostic characteristics of various thresholds for Ara h2–specific IgE Previous studies have shown that IgE antibody to peanut components in general, and Ara h2 in particular, correlate well with symptomatic peanut allergy.1,2,7,8,10 Less well explored is how peanut component diagnostics perform in the patient population that an allergist will commonly encounter. Here, we used IgE anti-Ara h2 cutoffs that others had previously suggested were accurate in predicting food allergy and found a high rate of misclassification for all cutoffs evaluated. Although the predictive ability is clearly improved over a crude peanut specific IgE, the use of IgE anti-Ara h2 values above these cutoffs as a replacement for food challenge will still result in many patients being classified as peanut allergic who are not truly allergic. Conversely, if patients with levels below these cutoffs are considered nonallergic and advised to consume peanut at home, some patients will react. A limitation to these data is that in some patients a fairly significant interval passed between serum acquisition and food challenge, but this is likely representative of clinical practice. Ultimately, our data underscore the notion that even with more tailored tests of antigen-specific IgE, we are still left with the problem that sensitization does not equal clinical disease. Whether any type of specific IgE testing will match the highly predictive qualities that we have come to expect of diagnostic testing in modern medicine remains an open question. For the present time, we are not yet at a stage where laboratory-based tests can substitute for clinical history and oral food challenge.

Allergic agonists in apheresis platelet products are associated with allergic transfusion reactions.

BACKGROUND: The mechanisms that underlie allergic transfusion reactions (ATRs) are not well characterized, but likely involve recipient, donor, and product factors. To assess product factors associated with ATRs, we investigated candidate mediators in apheresis platelet (PLT) products associated with ATRs and controls.

A prospective microbiome-wide association study of food sensitization and food allergy in early childhood

Alterations in the intestinal microbiome are prospectively associated with the development of asthma; less is known regarding the role of microbiome alterations in food allergy development.