Laura M. Gober

Common variants at 5q22 associate with pediatric eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the accumulation of eosinophils in the esophagus. We report association of EoE with variants at chromosome 5q22 encompassing TSLP and WDR36 (rs3806932, combined P = 3.19 × 10−9). TSLP is overexpressed in esophageal biopsies from individuals with EoE compared with unaffected individuals, whereas WDR36 expression is unaltered between the two groups. These data implicate the 5q22 locus in the pathogenesis of EoE and identify TSLP as the most likely candidate gene in the region.

Evidence of in vivo basophil activation in chronic idiopathic urticaria

Background Approximately 40% of chronic idiopathic urticaria (CIU) subjects have autoantibodies to either FcɛRIα or IgE. The effect of such autoantibodies on circulating basophil activation status is unknown.

Invariant natural killer T cells from children with versus without food allergy exhibit differential responsiveness to milk-derived sphingomyelin.

BACKGROUND A key immunologic feature of food allergy (FA) is the presence of a T(h)2-type cytokine bias. Ligation of the invariant natural killer T cell (iNKT) T-cell receptor (TCR) by sphingolipids presented via the CD1d molecule leads to copious secretion of T(h)2-type cytokines. Major food allergens (eg, milk, egg) are the richest dietary source of sphingolipids (food-derived sphingolipids [food-SLs]). Nonetheless, the role of iNKTs in FA is unknown. OBJECTIVE To investigate the role of iNKTs in FA and to assess whether food-SL-CD1d complexes can engage the iNKT-TCR and induce iNKT functions. METHODS PBMCs from 15 children with cows milk allergy (MA), 12 children tolerant to cows milk but with allergy to egg, and 13 healthy controls were incubated with α-galactosylceramide (αGal), cows milk-sphingomyelin, or hens egg-ceramide. iNKTs were quantified, and their cytokine production and proliferation were assessed. Human CD1d tetramers loaded with milk-sphingomyelin or egg-ceramide were used to determine food-SL binding to the iNKT-TCR. RESULTS Milk-sphingomyelin, but not egg-ceramide, can engage the iNKT-TCR and induce iNKT proliferation and T(h)2-type cytokine secretion. Children with FA, especially those with MA, had significantly fewer peripheral blood iNKTs and their iNKTs exhibited a greater T(h)2 response to αGal and milk-sphingomyelin than iNKTs of healthy controls. CONCLUSION iNKTs from children with FA, especially those with MA, are reduced in number and exhibit a T(h)2 bias in response to αGal and milk-sphingomyelin. These data suggest a potential role for iNKTs in FA.

Immediate Type I Hypersensitivity Response Implicated in Worsening Injection Site Reactions to Adalimumab

BACKGROUND Tumor necrosis factor (TNF) inhibitors such as adalimumab, etanercept, and infliximab play an increasingly important role in the management of a variety of chronic inflammatory disorders. With their increasing use, a wide spectrum of dermatological adverse effects, including injection site reactions and the development of dermatitis, have been recognized. Previous studies have implicated the role of the delayed-type hypersensitivity reaction in mediation of injection site reactions to etanercept. To our knowledge, there have been no published studies on immunologic mechanism of injection site reactions to adalimumab to date. OBSERVATIONS We describe 2 patients with a history of worsening injection site reactions to adalimumab. Findings from skin testing in both patients were suggestive of an immediate type I hypersensitivity reaction to adalimumab. A histamine release assay performed on peripheral blood leukocytes from both patients demonstrated significant histamine release on exposure to adalimumab. Furthermore, passive transfer of serum from one of the allergic patients to basophils from a nonatopic, healthy donor sensitized those cells to release significant amounts of histamine with exposure to adalimumab. Conclusion This study demonstrates that an IgE-mediated immediate type I hypersensitivity reaction plays a role in the mediation of worsening injection site reactions in some patients receiving adalimumab.

Basophil histamine release activity and disease severity in chronic idiopathic urticaria.

BACKGROUND Altered basophil degranulation phenotypes are found in patients with chronic idiopathic urticaria (CIU). OBJECTIVE To evaluate CIU disease severity in relation to basophil histamine release (HR) characteristics. METHODS Patients with CIU were recruited from allergy and dermatology clinics. Patients with recent use of systemic corticosteroids or immunosuppressants were excluded. Patients completed disease severity surveys and had blood basophils isolated and stimulated for HR using polyclonal goat anti-human IgE and N-formyl-met-leu-phe. The HR was measured using automated fluorometry. Multivariate linear regression analyses were used to investigate relationships between HR data and CIU disease measures. RESULTS Fifty patients completed surveys, of which 34 were further categorized into 2 subgroups based on basophil HR response to anti-IgE stimulation: responders (> or = 10% HR) and nonresponders (< 10% HR). Responders and nonresponders reported similar use of oral corticosteroids, work absences, and quality-of-life impairment but differed in their patterns of medications used for CIU. Basophil responders had a trend of higher use of the emergency department for CIU management. Multivariate regression revealed that patients with the basophil responder phenotype experienced significantly higher current itch scores (P = .02) compared with nonresponders. CONCLUSIONS Quality-of-life impairment is similar in CIU basophil subsets. Patients with CIU with a basophil responder phenotype report longer disease duration, a higher frequency of emergency department use, and significantly higher itch severity.

Eosinophilic Esophagitis: Clinical Presentation in Children

Eosinophilic esophagitis (EoE) is increasing in western nations. Symptoms in infants and young children include feeding difficulties, failure to thrive, and gastroesophageal reflux. School-aged children may present with vomiting, abdominal pain, and regurgitation; adolescents and adults with dysphagia and food impaction. Delayed diagnosis increases risk of stricture formation. Children with untreated EoE have tissue changes resembling airway remodeling. Endoscopy does not always correlate. Management centers on food elimination. Approaches include skin prick and patch testing, removal of foods, or an amino acid formula diet. Long-term elimination diets can produce nutritional deficiencies and have poor adherence.

Oral viscous budesonide can be successfully delivered through a variety of vehicles to treat eosinophilic esophagitis in children

Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized by eosinophilic infiltration of the esophagus. Symptoms vary, with infants and young children typically presenting with feeding difficulties or failure to thrive, older children presenting with abdominal pain or vomiting, and adolescents and adults presenting with dysphagia or food impaction. Diagnosis must be confirmed on esophagogastroduodenal endoscopy, with esophageal biopsy showing at least 15 eosinophils (eos)/hpf. Gastroesophageal reflux disease and proton pump inhibitoreresponsive esophageal eosinophilia must be excluded with high-dose proton pump inhibitor therapy. The main treatments currently available for EoE are dietary therapy and corticosteroids. Systemic corticosteroids are reserved for emergency cases such as severe dysphagia or stricture and weight loss, whereas swallowed topical corticosteroids comprise the main pharmacologic therapy for EoE. One option is oral viscous budesonide (OVB), created typically by mixing liquid budesonide (Pulmicort Respule) intended for nebulized administration with sucralose (Splenda) to create a slurry consistency. Some patients, however, are wary of using artificial sweeteners such as Splenda. A recent study compared the use of Splenda and Neocate Nutra, a hypoallergenic food powder, as the vehicle for delivering OVB and found that they were similarly effective. We report the various vehicles that have been used by patients with EoE at the Children’s Hospital of Philadelphia. The study protocol was approved by the Institutional Review Board of the Children’s Hospital of Philadelphia. We reviewed the electronic medical records of all patients with EoE treated with OVB during a 5.5-year period between November 2008 and May 2014. Charts were reviewed for demographic data, the vehicle used to mix budesonide, and esophageal biopsy data. Active EoE was defined as a peak esophageal eosinophil count of 15 eos/hpf or more. We compared the peak esophageal eosinophil count on the biopsies performed immediately before and after the initiation of OVB. All follow-up biopsies were performed at least 6 weeks after initiation. Some patients did not respond by the first biopsy following OVB initiation but did show response on a subsequent biopsy after the dose of OVB was increased. For these patients, we used the peak eosinophil count from the biopsy showing response. Patients were considered responsive if peak eosinophil count improved from 15 eos/hpf or more to less than 15 eos/hpf. The starting dose of OVB was determined by a standardized dosing schedule based on the patient’s weight: 0.5 mg daily for less than 20 kg, 1 mg daily for 20 to 40 kg, and 2 mg daily for more than 40 kg. Seventy patients were treated with OVB during the time period studied. Three patients were excluded because the vehicle used to mix budesonide could not be confirmed. Six patients were excluded because they were started on OVB during a time of inactive EoE (<15 eos/hpf) because of unavailability of previous therapy or desire to switch from dietary therapy. Of the 61 remaining patients, 49 were male (80%). Ages ranged from 1 to 17 years (median, 8 years) at the time of OVB initiation. The various vehicles with associated budesonide doses used by all 61 patients are presented in Table I. The most frequently used vehicle was Splenda (N 1⁄4 30 [49%]). Twenty-seven of the 30 patients using Splenda responded (90%), demonstrating improvement in their peak eosinophil count to less than 15 eos/ hpf. The 3 patients without response did have decreased peak eosinophil counts but not less than 15 eos/hpf. The mean peak eosinophil count for all 30 patients using Splenda decreased from 56.5 eos/hpf to 3.9 eos/hpf after the initiation of OVB. Following Splenda, applesauce (N 1⁄4 19) and honey (N 1⁄4 7) were the next most commonly used vehicles. Fifteen of the 19 patients using applesauce responded (79%). Of the 4 patients without response, 1 patient did ultimately respond when switched to honey. The mean peak eosinophil count for all patients using applesauce decreased from 56.3 eos/hpf to 9.8 eos/ hpf after the initiation of OVB. Six of the 7 patients started on OVB using honey responded (86%). The patient without response had documented poor compliance. The mean peak eosinophil count for all patients using honey decreased from 53.7 eos/hpf to 8.6 eos/hpf after the initiation of OVB. The following vehicles were also used, by 1 patient each: hot cocoa mix, pear sauce, xanthan gum, and rice cereal. One patient used a compounded formulation of OVB prepared by a compounding pharmacy. The patient using rice cereal did show some improvement from more than 100 eos/hpf to 40 eos/hpf but not to less than 15 eos/hpf. The patients using hot cocoa mix, pear sauce, xanthan gum, and a compounded formulation all responded. The specific peak eosinophil counts for each of these patients are presented in Table I. In summary, we report success using various vehicles to deliver OVB to treat EoE in children. Similar to previous findings, we show that there are promising alternatives to Splenda. Although Splenda remains the standard and is highly successful, most of the patients using applesauce and honey have also been effectively treated with OVB. In addition, individual patients using hot cocoa mix, pear sauce, xanthan gum, and a compounded formulation have responded to OVB.

A Case of Exuberant Candidal Onychomycosis in a Child With Hyper IgE Syndrome

An 8-year-old girl with recurrent oral thrush as an infant and toddler, multiple diaper yeast infections, recurrent ear infections that required multiple ear-tube placements, a long history of mild atopic dermatitis, and at least 7 Staphylococcus aureus abscesses on the extremities presented with new-onset thickening of the thumbnail that had failed therapy with 40% urea cream (Figure 1). Of note, she had no history of bronchopulmonary infections. Periodic acidSchiff stained sections of a nail-plate clipping revealed yeast

Intermittent Therapy for Flare Prevention and Long-term Disease Control in Stabilized Atopic Dermatitis: A Randomized Comparison of 3-Times-Weekly Applications of Tacrolimus Ointment Versus Vehicle

Breneman D, Fleisher AB, Abramovitis A, et al. J Am Acad Dermatol . 2008;58(6):990–999 PURPOSE OF THE STUDY. To examine the usefulness of regular intermittent therapy instead of treating flares for the approach of atopic dermatitis (AD). STUDY POPULATION. A total of 383 patients were randomly assigned to the stabilization phase, and 288 patients were controlled on tacrolimus ointment. There were 68 children (aged 2–16 years) and 57 adults (>16 years) in the tacrolimus arm and 37 children and 35 adults in the vehicle arm. Eighty-five percent had moderate AD, and 15% had severe AD. METHODS. Adult and pediatric patients with moderate-to-severe AD who were clear of disease after up to 16 weeks of treatment with tacrolimus ointment were randomly assigned in a double-blind fashion to 3-times-weekly treatment with either tacrolimus ointment (0.03% or 0.1%) or vehicle for 40 weeks. The primary end point was the number of flare-free treatment days. Relapses were treated with open-labeled tacrolimus. RESULTS. There were 288 patients who entered the randomization phase. The largest reasons for not finishing the stabilization phase were voluntary patient withdrawal for 95 patients and loss to follow-up for 55 patients. Only 16 (4.2%) patients were withdrawn for lack of efficacy. A total of 125 patients were randomly assigned to tacrolimus, and 72 patients were assigned to vehicle. The mean number of flare-free treatment days was 177 for the tacrolimus group and 134 for the vehicle group ( P = .003). Median time to first relapse was 169 days for the tacrolimus group and 43 for the vehicle group ( P = .037). CONCLUSIONS. Maintenance therapy with tacrolimus ointment was associated with significantly more flare-free days compared with vehicle and a significantly longer time until first disease relapse. REVIEWER COMMENTS. This article examined the possibility of proactive treatment of AD instead of reacting to flares. The principle is similar to the use of maintenance medication for asthma. Similar results were seen with topical fluticasone propionate (Berth-Jones J, Damstra RJ, Golsch S, et al. BMJ . 2003;326[7403]:1367). One significant limitation is that the study only included patients who responded to topical tacrolimus. The question now is whether it can be generalized to all patients with AD or patients not controlled with daily topical therapies.

Food Protein-Induced Enterocolitis Syndrome Food Challenges: Experience from a Large Referral Center

BACKGROUND Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that is diagnosed based on clinical findings, but can be confirmed with oral food challenge (OFC). OFC is more often performed to assess the development of tolerance. Most studies describing OFCs in FPIES are limited in size. OBJECTIVE We sought to describe our experience with OFCs using our FPIES protocol. Patients were given one-third of serving size with a 4-hour observation period, followed by home titration to full dose. METHODS We conducted a retrospective chart review of patients who underwent OFC via the FPIES protocol from 2014 to 2017. Data regarding the history of reaction, age at the time of challenge, and reactions during challenge or with home introduction were collected. RESULTS A total of 169 OFCs were completed under the FPIES protocol, in 119 patients to 19 different foods. Thirty challenges (18%) were positive, with 17 challenges (10%) during initial challenge and 13 (7.7%) during home dosing. Most reactions during initial challenge required intravenous fluids (IVF), but hypotension was uncommon. One hundred thirty-nine (82%) OFCs were negative with home introduction, indicating tolerance to the challenged foods. The mean age of passing a challenge to milk, soy, and grain was earlier than that of other solid foods. CONCLUSIONS Our data suggest that our FPIES OFC protocol is safe. Early administration of IVF may prevent the development of hypotension. It is difficult to stratify the risk of severe or delayed reaction based on patient characteristics, and more data are needed to identify those appropriate for home introduction.