Definition and classification of hereditary angioedema.

Hereditary angioedema (HAE) is defined as a rare genetic disease with recurrent episodes of localized bradykinin-mediated swelling of the deep tissues of the skin, respiratory, and gastrointestinal tracts that can be life threatening. Classification of HAE has evolved over time with our further understanding of clinical phenotypes, underlying causes, and available testing. In most cases, HAE is caused by a deficiency of C1-esterase inhibitor (C1-INH) on the Serpin Family G Member 1 (SERPING1) gene, either through decreased amounts of C1-INH protein (C1-INH-HAE, type 1) or decreased function of C1-INH (C1-INH-HAE, type 2). HAE with normal C1-INH levels and function are divided into unknown cause or into non-C1-INH-HAE forms, which include known mutational defects in factor XII (called FXII-HAE in the Hereditary Angioedema International Working Group consensus), angiopoietin-1, plasminogen, and kininogen 1 genes. It is possible that, after an initial workup, a patient without a family history of HAE could be classified with an acquired form of angioedema (nonhereditary) that may later prove to be HAE due to a de-novo SERPING1 mutation. Because there are forms of nonhistaminergic (H1-antihistamine unresponsive) angioedema that appear clinically very similar to HAE, it is essential that the patient undergoes a thorough clinical history and diagnostic evaluation to ensure that he or she is properly diagnosed and classified.

An Overview of Seminal Plasma Hypersensitivity and Approach to Treatment.

Seminal plasma hypersensitivity (SPH) presents with localized vaginal and/or systemic allergic symptoms on exposure to protein components of seminal plasma. Although the true incidence is unclear, it is a likely underdiagnosed but an important cause of vulvovaginitis and dyspareunia that affects women across the entire globe. Systemic SPH is likely elicited by an IgE-mediated reaction to seminal plasma proteins other than spermatozoa. Localized reactions are likely mediated by a non-IgE immunologic mechanism. The diagnosis of both conditions is made clinically. Clinical presentation typically involves local vaginal discomfort and/or systemic symptoms including urticaria, angioedema, wheezing, dyspnea, gastrointestinal symptoms, or frank anaphylaxis. In roughly half of cases of localized SPH, reactions occur after first-time intercourse. Use of a condom prevents reactions, which aids confirming a diagnosis. In addition to a detailed history, skin prick and/or serologic testing may assist in making the diagnosis. Both local and systemic SPH are managed by the use of barrier contraception or intravaginal graded desensitization. Although SPH has not been shown to directly cause infertility, it may make conception challenging due to the discomfort or systemic symptoms caused by unprotected vaginal intercourse. Data indicate that women with localized reactions have variable fertility outcomes, although the majority are able to have resolution of symptoms after desensitization and have normal term pregnancies. This review provides a step-by-step approach for evaluating and treating women with localized or systemic SPH.

KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies.

The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.

Oral immunotherapy for multiple foods in a pediatric allergy clinic setting.

BACKGROUND: The increasing incidence of pediatric food allergy results in significant health care burden and family stress. Oral immunotherapy (OIT) can induce tolerance to peanut, milk, and egg. OIT for other foods, particularly multiple foods simultaneously, has not been thoroughly studied. OBJECTIVE: To summarize our experience with OIT for multiple foods in a pediatric allergy clinic setting. METHODS: Medical records were reviewed for patients undergoing OIT for multiple foods. Methods and outcomes of OIT were summarized. Outcomes were analyzed for correlation with baseline food allergen skin prick tests (SPTs) and specific IgE (sIgE) test results. RESULTS: Forty-five patients aged 1.5 to 18 years undertook OIT for up to 12 foods, including peanut, tree nuts, seeds, legumes, and egg. At the time of review, 35 patients were receiving daily maintenance dosing, 4 had completed OIT and were continuing to eat their foods 3 times weekly, and 6 had stopped OIT because of anxiety, inconvenience, or allergy symptoms. A total of 49% of patients had reactions during the up-dosing process, mostly oral itching (33%), perioral hives (40%), and abdominal pain (35%). There was no correlation of baseline skin prick test (SPT) and sIgE test results with reaction threshold for baseline food challenge, lowest dose causing reactions during up-dosing, or time to reach maintenance. Higher baseline sIgE level but not baseline SPT result was associated with an increased number of allergic reactions during OIT. Baseline SPT correlated with stopping OIT. CONCLUSION: A similar approach to that used for peanut OIT can be taken for nonpeanut foods and for multiple foods simultaneously. High baseline allergy test results are not a contraindication to OIT.

Understanding differences in allergen immunotherapy products and practices in North America and Europe.

Allergen immunotherapy (AIT) is thought to be clinically effective and safe in treating allergic rhinitis, asthma, and stinging insect allergy in Europe and North America. However, there are intercontinental differences in AIT therapeutic products in terms of their application and regulation. In North America unmodified standardized and nonstandardized aqueous aeroallergen extracts are approved and used almost exclusively for subcutaneous immunotherapy, whereas more product options are available in Europe, including adsorbed allergens, chemically modified allergens, or both. Both liquid extracts and tablets are approved for sublingual immunotherapy in Europe. Nevertheless, within the European Union, there are major differences in AIT products approved and used in individual countries. There are major differences in the clinical approach to subcutaneous immunotherapy in polysensitized patients; in the United States mixed extracts containing multiple aeroallergens are used, whereas European allergists preferably administer separate injections of single allergen sources or homologous groups deemed to be clinically relevant. Moreover, the regulatory approach differs between the European Union and United States. In contrast to the United States, where common allergen standards exist based on biologic activity, no common standards exist in Europe. In terms of development of new investigational products, the United States has followed the European example for phase II and III studies; no formal US Food and Drug Administration guidance has been issued.

Transnasal Endoscopy in Unsedated Children With Eosinophilic Esophagitis Using Virtual Reality Video Goggles.

BACKGROUND & AIMS: Evaluation and treatment of children with eosinophilic esophagitis (EoE) requires serial endoscopic, visual, and histologic assessment by sedated esophagogastroduodenoscopy (EGD). Unsedated transnasal endoscopy (TNE) was reported to be successful in a pilot study of children. We evaluated video goggle and virtual reality-based unsedated TNE in children with EoE, collecting data on rates of completion, adverse events, and adequacy of visual and histologic findings. METHODS: We performed a retrospective study of 190 children and young adults (age, 3-22 y) who underwent video goggle or virtual reality-based unsedated TNE from January 2015 through February 2018. We analyzed data on patient demographics, procedure completion, endoscope type, adverse events, visual and histologic findings, estimated costs, and duration in the facility. Esophageal biopsies from the first 173 subjects who underwent TNE were compared with those from previous EGD evaluations. RESULTS: During 300 attempts, 294 TNEs were performed (98% rate of success). Fifty-four patients (age, 6-18 y) underwent multiple TNEs for dietary or medical management of EoE. There were no significant adverse events. Visual and histologic findings were adequate for assessment of EoE. TNE reduced costs by 53.4% compared with EGD (TNE $4393.00 vs EGD $9444.33). TNE was used increasingly from 2015 through 2017, comprising 31.8% of endoscopies performed for EoE. The total time spent in the clinic (front desk check-in to check-out) in 2018 was 71 minutes. CONCLUSIONS: In a retrospective study of 190 children and young adults (age, 3-22 y) who underwent video goggle or virtual reality-based unsedated TNE, TNE was safe and effective and reduced costs of EoE monitoring. Advantages of TNE include reduced risk and cost associated with anesthesia as well as decreased in-office time, which is of particular relevance for patients with EoE, who require serial EGDs.

How to prevent food allergy during infancy: what has changed since 2013?

PURPOSE OF REVIEW: The purpose of this review is to summarize recent studies and emerging consensus guidelines regarding food allergy prevention in infants of the past 5 years. RECENT FINDINGS: Prior to 2013, the general consensus regarding prevention of food allergy in infants was to recommend delayed introduction or complete avoidance of commonly allergenic foods, such as milk, egg and peanut. However, in the past 5 years, several landmark studies have been conducted, particularly with peanut. The results of these studies have led to a paradigm shift from recommending delayed introduction to early introduction and frequent feeding of highly allergenic foods such as peanut, with hopes of achieving primary and secondary prevention of food allergy in infants. SUMMARY: Recent clinical trials have demonstrated that early introduction and frequent feeding, rather than delayed introduction or complete avoidance, of commonly allergenic foods plays a critical role in preventing food allergy in infants. More studies are required to risk-stratify infants by personal and family atopic history to tailor guidelines for groups with inherently different risks. The universal acceptance of the guidelines and their application outcome are still to be determined.

Magnetic resonance imaging indicates decreased choroidal and retinal blood flow in the DBA/2J mouse model of glaucoma.

PURPOSE: This study tests the hypothesis that reduced retinal and choroidal blood flow (BF) occur in the DBA/2J mouse model of glaucoma. METHODS: Quantitative BF magnetic resonance imaging (MRI) with a resolution of 42 × 42 × 400 µm was performed on DBA/2J mice at 4, 6, and 9 months of age and C57BL/6 age-matched controls under isoflurane anesthesia. BF MRI images were acquired with echo-planar imaging using an arterial spin labeling technique and a custom-made eye coil at 7 Tesla. Automated profile analysis was performed to average layer-specific BF along the length of the retina and choroid. In separate experiments, servo-null micropressure measurements of iliac arterial pressure were performed in old mice of both strains. RESULTS: Choroidal BF was lower in DBA/2J mice than in age-matched C57BL/6 control mice at 4, 6, and 9 months of age (P < 0.01 for all age-matched groups). Retinal BF was lower in DBA/2J mice than in C57BL/6 mice at the 9-month time point (P < 0.01). Mean arterial pressure was not significantly different in aged C57BL/6 mice compared with aged DBA/2J mice. CONCLUSIONS: The reduced ocular blood flow in DBA/2J mice compared with C57BL/6 control mice suggests that ischemia or hypoxia should be considered as a possible contributing factor in the optic neuropathy in the DBA/2J mouse model of glaucoma.