Carla M. Davis

PedsQL eosinophilic esophagitis module: feasibility, reliability, and validity.

Objective: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory condition with a paucity of information on health-related quality of life (HRQOL). The objective of the study was to report on the measurement properties of the PedsQL EoE Module. Methods: The PedsQL EoE Module was completed in a multisite study by 196 pediatric patients with EoE and 262 parents of patients with EoE. Results: The PedsQL EoE Module scales evidenced excellent feasibility (0.6%–3.1% missing), excellent group comparison reliability across total scale scores (patient &agr; 0.93; parent proxy &agr; 0.94), good reliability for the 7 individual scales (patient &agr; 0.75–0.87; parent proxy &agr; 0.81–0.92), excellent test–retest reliability (patient intraclass correlation coefficient 0.88; parent intraclass correlation coefficient 0.82), demonstrated no floor effects and low ceiling effects, and demonstrated a high percentage of scaling success for most scales. Intercorrelations with the PedsQL Generic Core Scales were in the medium (0.30) to large (0.50) range. PedsQL EoE Module scores were worse among patients with active histologic disease (≥5 eos/hpf) compared with those in remission (patient self-report: 63.3 vs 69.9 [P < 0.05]; parent proxy report: 65.1 vs 72.3 [P < 0.01]), and those treated with dietary restrictions compared with those with no restrictions (patient self-report: 61.6 vs 74.3 [P < 0.01]; parent proxy report: 65.5 vs 74.7 [P < 0.01]). Conclusions: The results demonstrate excellent measurement properties of the PedsQL EoE Module. Patients with active histologic disease and those treated with dietary restrictions demonstrated worse PedsQL scores. The PedsQL EoE Module may be used in the evaluation of pediatric EoE disease-specific HRQOL in clinical research and practice.

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole‐exome screening methods to detect disease‐causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole‐exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome‐tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD‐causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high‐throughput genomic approach enabled detection of disease‐related variants in unexpected genes; permitted detection of low‐grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

International consensus guidelines for the diagnosis and management of food protein-induced enterocolitis syndrome: Executive summary-Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology.

&NA; Food protein–induced enterocolitis (FPIES) is a non‐IgE cell‐ mediated food allergy that can be severe and lead to shock. Despite the potential seriousness of reactions, awareness of FPIES is low; high‐quality studies providing insight into the pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. This consensus document is the result of work done by an international workgroup convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. These are the first international evidence‐based guidelines to improve the diagnosis and management of patients with FPIES. Research on prevalence, pathophysiology, diagnostic markers, and future treatments is necessary to improve the care of patients with FPIES. These guidelines will be updated periodically as more evidence becomes available.

Outcomes of patients with severe combined immunodeficiency treated with hematopoietic stem cell transplantation with and without preconditioning

BACKGROUND The effect of pretransplantation conditioning on the long-term outcomes of patients receiving hematopoietic stem cell transplantation for severe combined immunodeficiency (SCID) has not been completely determined. OBJECTIVE We sought to assess the outcomes of 23 mostly conditioned patients with SCID and compare their outcomes with those of 25 previously reported nonconditioned patients with SCID who underwent transplantation. METHODS In the present study we reviewed the medical records of these 23 consecutive, mostly conditioned patients with SCID who underwent transplantation between 1998 and 2007. RESULTS Eighteen patients (median age at transplantation, 10 months; range, 0.8-108 months) received haploidentical mismatched related donor, matched unrelated donor, or mismatched unrelated donor transplants, 17 of whom received pretransplantation conditioning (with 1 not conditioned); 13 (72%) patients engrafted with donor cells and survive at a median of 3.8 years (range, 1.8-9.8 year); 5 (38%) of 13 patients require intravenous immunoglobulin; and 6 of 6 age-eligible children attend school. Of 5 recipients (median age at transplantation, 7 months; range, 2-23 months) of matched related donor transplants, all 5 engrafted and survive at a median of 7.5 years (range, 1.5-9.5 year), 1 recipient requires intravenous immunoglobulin, and 3 of 3 age-eligible children attend school. Gene mutations were known in 16 cases: mutation in the common gamma chain of the IL-2 receptor (IL2RG) in 7 patients, mutation in the alpha chain of the IL-7 receptor (IL7RA) in 4 patients, mutation in the recombinase-activating gene (RAG1) in 2 patients, adenosine deaminase deficiency (ADA) in 2 patients, and adenylate kinase 2 (AK2) in 1 patient. Early outcomes and quality of life of the previous nonconditioned versus the present conditioned cohorts were not statistically different, but longer-term follow-up is necessary for confirmation. CONCLUSIONS Hematopoietic stem cell transplantation in patients with SCID results in engraftment, long-term survival, and a good quality of life for the majority of patients with or without pretransplantation conditioning.

Diagnosis and management of HIV drug hypersensitivity

Drug hypersensitivity reactions are an important cause of morbidity in HIV-infected patients who take complex medication regimens. Correct diagnosis and management of these reactions are essential in the clinical care of HIV disease. Trimethoprim-sulfamethoxazole, abacavir, nevirapine, atazanavir, and enfuvirtide can all cause hypersensitivity rashes. In this review, we discuss the evidence for immunologic mechanisms of hypersensitivity reactions to HIV medications, the clinical characteristics of these reactions, and guidelines that currently exist for their identification and management.

Presentation of atopic disease in a large cohort of pediatric liver transplant recipients

Shroff P, Mehta RS, Chinen J, Karpen SJ, Davis CM. Presentation of atopic disease in a large cohort of pediatric liver transplant recipients.

Utility of Component-Resolved Diagnostics in Food Allergy

Allergen component-resolved diagnostic testing (CRD) is a new methodology in clinical food allergy diagnosis, improving the ability to identify specific clinical phenotypes. Instead of relying on the crude allergen extracts used in standard allergy diagnostics, CRD utilizes purified or recombinant allergens for identification of specific molecules causing sensitization or allergy. This method is able to determine risk of the severity of allergic reactions in specific cases, like soy, peanut, and hazelnut allergy. The severity of allergic reaction can be predicted in peanut allergy with Ara h 2, and clinically relevant disease in pollen-allergic patients can be identified. However, age and geographic differences affect CRD results and it should always be utilized in the context of a clinical history. In the future, clinical phenotypes may be differentiated with larger prospective studies utilizing food challenges.

Food allergy in patients with primary immunodeficiency diseases: Prevalence within the US Immunodeficiency Network (USIDNET)

To the Editor: Primary immunodeficiency diseases (PIDDs) are congenital disorders caused by inherent defects in the immune system that typically present with recurrent or severe infections but can also involve autoimmune disease, lymphoproliferation, or allergy.1 Allergic diseases are an important expression of misdirected immunity, and certain PIDDs are frequently associated with atopy. Selective IgA deficiency (SIgAD) has been associated with asthma, allergic rhinitis, atopic dermatitis (AD), and food allergy (FA).2-4 AD/eczema with an increased IgE level is often associated with hyper-IgE syndrome (HIES), Omenn syndrome, immune dysregulation–polyendrocrinopathy–enteropathy–X-linked syndrome, and Comel-Netherton syndrome, whereas 80% to 100% of patients with Wiskott-Aldrich syndrome (WAS) present with AD-like skin problems4,5 and many have evidence of food reactivity. However, there are no definitive data in the United States on the overall prevalence of food allergies as a specific expression of clinically relevant atopy in patients with PIDDs. We present the first broad consideration of the prevalence of FA in patients with PIDDs using the US Immunodeficiency Network (USIDNET). The USIDNET is a research consortium established to advance scientific research in PIDDs.6 A query of 2923 patients with PIDDs registered in the USIDNET was performed to determine the responses to fields in the core registry form relevant to “allergic reactions to food” and “AD/eczema,” which were then cross-referenced to diagnosis. AD/eczema was included in the query as another manifestation of atopy. Of 2923 patients registered, 2263 provided responses to the relevant fields (allergic reactions to food and AD/eczema). There were 14 diagnoses associated with FA, AD, or both (Table I). Surprisingly, in aggregate, the prevalence of both FA and AD in patients with PIDDs (FA, 1.8%; AD, 6%) was lower than that in the general population (FA, 2.5%; AD, 10.7%; Fig 1).7,8 This stands in contrast to experience in other countries, such as Kuwait, where 19% of patients with PIDDs have FA.4 Currently, there are no other prevalence data available for FA and AD in the United States, and the USIDNET experience potentially distinguishes American patients from those in other countries or reflects the experience of those centers and clinics in the United States contributing data to the USIDNET. FIG. 1 Prevalence of FA and AD among patients with PIDDs compared with the general population. TABLE I Prevalence of FA and AD among patients with PIDDs Despite there not being an overall increased prevalence, FA was more commonly reported in patients with specific PIDDs when compared with what would be expected in the general population. This included patients with CD40 ligand deficiency (7.7%), primary hypogammaglobulinemia (7.1%), and HIES (6.3%). There was also an increased prevalence in patients with combined immunodeficiency (CID; 33.3%) and SIgAD (25%), but there were very few of these patients in the registry. Reported reactions include anaphylaxis, angioedema, asthma, bronchospasm, dermatitis, unspecified gastrointestinal reactions, and urticaria, with the most frequent being anaphylaxis (20%). Seventeen of the 40 patients with FA did not have a specified type of allergic reaction. Meanwhile, AD was most commonly reported in patients with nuclear factor κB essential modulator deficiency (62.5%), WAS (41.5%), CID (33.3%), selective IgM deficiency (33.3%), and HIES (25%). PIDDs that were associated with both FA and AD included common variable immunodeficiency (CVID), CID, and HIES. Despite the low numbers of patients, FA was found in 25% of those with SIgAD, which is similar to the findings (30%) of Aghamohammadi et al9 in a prospective cohort of Iranian patients with SIgAD and self-reported FA. In another prospective study children with SIgAD had an increased risk of parentally reported food hypersensitivity at 4 years of age.2 Because the majority of patients with SIgAD have substitution of secretory IgA with secretory IgM, it is not known whether they have adequate mucosal protection. This might allow food antigens to pass more efficiently through the gastrointestinal mucosa and predispose patients with SIgAD to FA. On the other hand, AD was not present in patients with SIgAD at the time of our query. It is possible that patients with SIgAD have a higher incidence of pure IgE-mediated rather than mixed or non–IgE-mediated manifestations of disease. The reports on AD in patients around the world with SIgAD are conflicting. In the Iranian cohort AD was present in 52% of patients with SIgAD,9 whereas it was found in only 2.3% of Brazilian patients with SIgAD.2 This discrepancy might be due to differing physician algorithms for AD diagnosis. In another study from Sweden by Janzi et al,2 parentally reported eczema was not associated with SIgAD. Other diagnoses associated with FA-related disease were more prevalent than in the general presentation, such as CD40 ligand deficiency, hypogammaglobulinemia, HIES, WAS, and CVID. HIES and WAS are associated with increased IgE levels and increased sensitization to specific food antigens. However, a limitation in this query is that genetic diagnosis of HIES was not further characterized, thus allowing for inclusion of patients with increased IgE levels for reasons other than signal transducer and activator of transcription 3, dedicator of cytokinesis 8, or tyrosine kinase 2, some of which might be purely atopic in nature. These molecularly defined PIDDs, except for primary hypogammaglobulinemia, are definitively associated with the substantially altered or defective T-cell immunity necessary for oral tolerance. This deficient immune regulation can lead to a skewed response, resulting in atopic disease. The high prevalence of FA in patients with primary hypogammaglobulinemia might suggest a concomitant T-cell dysfunction in these cases. Importantly, the number of patients with FA, AD, or both registered in the USIDNET at the time of the query was small, and this might underrepresent PIDDs associated with atopy. The overall lower prevalence of FA in patients with PIDDs might also be underestimated because 55% of patients had severe combined immunodeficiency, X-linked agammaglobulinemia, or CVID. A follow-up study should be undertaken in the future. Another limitation of the study is that it is based on a physician report questionnaire form; hence FA and AD rates could be overestimated. Moreover, there was a limitation in the core registry form for further description of reactions to food and AD/eczema. Manifestations of atopy, such as FA and AD, occurring early in life might be a presenting feature before diagnosis of a PIDD4,5 and, if associated with recurrent infections, should warrant clinicians to pursue an immunologic evaluation. Early diagnosis of PIDDs might have a potential benefit of better outcome. Although the prevalence of both FA and AD in patients with PIDDs is lower than in the general population, there should be a lower threshold for suspecting FA in patients with certain PIDDs.

Egg hypersensitivity in review.

Egg hypersensitivity is the second most common food allergy with a prevalence of up to 1.7% and the discovery of information about egg allergy is ongoing. This review aims to summarize the current understanding of the allergens involved, natural history, clinical presentation, diagnostic strategies, treatment options, egg-containing vaccine guidelines, and future therapies for health care providers in managing egg hypersensitivity. Recent clinically applicable articles are reviewed for the allergist as an update for the state of the art management of egg allergy. Approximately 70% of children will outgrow egg allergy by 16 years of age and children are able to tolerate well-cooked eggs sooner than uncooked eggs. Egg-specific IgE of >50 kIU(A)/L can be used as a predictor for persistent egg allergy. Double-blind placebo-controlled food challenges are still the gold standard for diagnosis. Oral immunotherapy trials still are not generalizable for routine clinical practice, but the influenza vaccine can be given to most egg-allergic patients. Allergists can now educate, diagnose, and manage egg-allergic patients with state-of-the-art information to improve patients quality of life as never before.

Changes in prevalence and characteristics of IgE-mediated food allergies in children referred to a tertiary care center in 2003 and 2008.

Although epidemiological trends in peanut allergy have been determined, there are limited data for changes in prevalence and clinical characteristics for other common food allergens. This study was performed to determine the trends in prevalence and clinical characteristics of physician-diagnosed pediatric food allergy (FA) at a large urban-based tertiary care center from 2003 to 2008. The electronic medical record system was searched to identify all unique patients with FA as a diagnosis for 2003 and 2008. Included patients had either a definite clinical reaction on ingestion and (1) a positive specific IgE or skin-prick test or (2) food-specific IgE of >90% specificity. Patients with allergies to cows milk, eggs, fish, peanuts, sesame, shellfish, soy, tree nuts, and wheat were included. The percentage of FA clinic patients increased from 3 to 8% over 5 years. The severity of initial reactions to food also increased from 2003 to 2008 (p < 0.05). Mean initial food-specific IgE decreased from 52 kU/L in 2003 to 40 kU/L in 2003 (p = 0.002). The age at diagnosis decreased from 2003 to 2008 for cows milk (2.64-1.36 years; p < 0.05) and fish (5.10-2.86 years; p < 0.05) allergies. Peanuts and shellfish were associated with anaphylaxis and severe symptoms in 2008. Clinical characteristics of food-allergic reactions in this large tertiary care center worsened in severity over 5 years and reactions were associated with a lower specific IgE at presentation for peanut and shellfish allergy. Clinical presentation of FA may change over time and this phenomenon warrants study to determine contributory factors.