Delayed anaphylaxis to alpha-gal, an oligosaccharide in mammalian meat.

IgE-mediated hypersensitivity refers to immune reactions that can be rapidly progressing and, in the case of anaphylaxis, are occasionally fatal. To that end, identification of the associated allergen is important for facilitating both education and allergen avoidance that are essential to long-term risk reduction. As the number of known exposures associated with anaphylaxis is limited, discovery of novel causative agents is crucial to evaluation and management of patients with idiopathic anaphylaxis. Within the last 10 years several apparently separate observations were recognized to be related, all of which resulted from the development of antibodies to a carbohydrate moiety on proteins. Interestingly, the exposure differed from airborne allergens but was nevertheless capable of producing anaphylactic and hypersensitivity reactions. Our recent work has identified these responses as being due to a novel IgE antibody directed against a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose ("alpha-gal"). This review will present the historical summary of the identification of cetuximab hypersensitivity due to alpha-gal IgE and discuss the non-primate mammalian meat food allergy as well as current goals and directions of our research programs.

Dietary elimination therapy is an effective option for adults with eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is an immune-mediated disorder. Food elimination is an established treatment for children, but data in adults are limited. We aimed to determine the response of adults with EoE to dietary therapy. METHODS: This was a retrospective cohort study using the University of North Carolina EoE database from 2006 to 2012. Subjects were age 18 and older, had EoE by consensus guidelines, and had undergone dietary therapy either with a targeted elimination diet or a 6-food elimination diet (SFED). Outcomes were symptomatic, endoscopic, and histologic improvement. Demographic, endoscopic, symptomatic, and laboratory predictors of response to dietary therapy were assessed. RESULTS: Of 31 adults who underwent dietary therapy (mean age, 36 y; 48% male; 90% white; mean baseline eosinophil count, 78 eos/hpf), 22 had a targeted elimination diet and 9 had SFED. Symptoms improved in 71% (68% in targeted, 78% in SFED), and endoscopic appearance improved in 54% (53% in targeted, 56% in SFED). After dietary therapy, the mean eosinophil count decreased to 43 eos/hpf (P = .009). Eleven subjects (39%) responded with fewer than 15 eos/hpf (32% in targeted and 56% in SFED; P = .41). No clinical, endoscopic, or histologic factors predicted response to dietary therapy. Of the 11 responders, 9 underwent food re-introduction to identify trigger(s), and 4 (44%) reacted to dairy, 4 (44%) reacted to eggs, 2 (22%) reacted to wheat, 1 (11%) reacted to shellfish, 1 (11%) reacted to legumes, and 1 (11%) reacted to nuts. CONCLUSIONS: Dietary elimination is a successful treatment modality for adults with EoE. Further research should emphasize which factors can predict effective dietary therapy.

Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation.

OBJECTIVES: The chemokine receptors CCR2 and CX3CR1 are important in the development of coronary artery disease. The purpose of this study is to analyze the effect of a novel CCR2 inhibitor in conjunction with CX3CR1 deletion on vascular inflammation. METHODS: The novel CCR2 antagonist MRL-677 was characterized using an in vivo model of monocyte migration. To determine the relative roles of CCR2 and CX3CR1 in vascular remodeling, normal or CX3CR1 deficient mice were treated with MRL-677. After 14 days, the level of intimal hyperplasia in the artery was visualized by paraffin sectioning and histology of the hind limbs. RESULTS: MRL-677 is a CCR2 antagonist that is effective in blocking macrophage trafficking in a peritoneal thioglycollate model. Intimal hyperplasia resulting from vascular injury was also assessed in mice. Based on the whole-blood potency of MRL-677, sufficient drug levels were maintained for the entire 14 day experimental period to afford good coverage of mCCR2 with MRL-677. Blocking CCR2 with MRL-677 resulted in a 56% decrease in the vascular injury response (n = 9, p < 0.05) in normal animals. Mice in which both CCR2 and CX3CR1 pathways were targeted (CX3CR1 KO mice given MRL-677) had an 88% decrease in the injury response (n = 6, p = 0.009). CONCLUSION: In this study we have shown that blocking CCR2 with a low molecular weight antagonist ameliorates the inflammatory response to vascular injury. The protective effect of CCR2 blockade is increased in the presence of CX3CR1 deficiency suggesting that CX3CR1 and CCR2 have non-redundant functions in the progression of vascular inflammation.

Quantitative Sensory Testing, Antihistamines, and Beta-Blockers for Management of Persistent Breast Pain: A Case Series.

BACKGROUND: It is not uncommon for mothers to have persistent pain with breastfeeding beyond the first few weeks after birth. Persistent pain can be multifactorial, with neuropathic pain maintained by central sensitization being one dimension. Our knowledge in delineating categories of persistent pain is simple and not very sophisticated. METHODS: We have developed and tested a Lactation Quantitative Sensory Test (L-QST) to quantify the neuropathic component of persistent breastfeeding pain. We present three case reports of neuropathic breastfeeding pain and treatment, and we discuss the potential role of histamine and catecholamines in persistent breastfeeding-associated pain. CONCLUSIONS: The L-QST can be a useful tool to quantify neuropathic pain. Further studies are needed to test inter-observer reliability and reproducibility of this tool. Antihistamines can be considered for treating persistent pain in breastfeeding women with a history of allergy or atopy, and beta-blockers may be helpful in women with multiple pain disorders.

Diagnosis of Life-Threatening Alpha-Gal Food Allergy Appears to Be Patient Driven.

OBJECTIVE: Patients exhibiting life-threatening symptoms associated with the alpha-gal food allergy (delayed urticaria or anaphylaxis due to mammalian meat) are frequently undiagnosed, causing unnecessary emergency department (ED) and health care visits, and extensive pain and suffering. This study aimed to determine the path to diagnosis experienced by alpha-gal patients. METHODS: Semistructured interviews were conducted from March to June 2016 with a chronological systematic sample of approximately 10% of patients diagnosed with alpha-gal and treated by the University of North Carolina Allergy and Immunology Clinic (n = 28). Main outcome measures included average length of time between first symptoms' appearance and diagnosis, number and type of health care encounters en route to diagnosis, and typical symptom severity. RESULTS: Six interviewees (21%) were diagnosed within a year of experiencing symptoms, of the remaining 22, mean time to diagnosis was 7.1 years. In over 100 medical encounters (including 28 ED visits and 2 urgent care) the correct diagnosis or effective diagnosing referral occurred less than 10% of the time. Seventy-one percent (20/28) described their first symptoms as severe. More patients found the allergist specializing in this condition on their own (n = 12; 43%) than those who were formally diagnosed or received referrals (n = 10; 36%) through the health care system. CONCLUSIONS: The medical community is challenged to stay abreast of emerging and newly uncovered illnesses through traditional medical literature communication channels. Presently, patients more often discover a diagnosis of alpha-gal allergy by using information resources on their own than by presenting to the ED with anaphylaxis.

De-novo onset of eosinophilic esophagitis after large volume allergen exposures.

Eosinophilic esophagitis (EoE) is a chronic immune-mediated condition believed to have an allergic component, but the timing of the initial allergen triggers that cause the disease is poorly understood. While the clinical presentation of EoE is often of longstanding symptoms, in animal models, acute exposure to an allergen challenge successfully produces EoE. In this report, we present three cases of individuals who developed esophageal eosinophilia and EoE shortly after a clearly identified exposure to aeroallergens. These cases highlight the allergic etiology of EoE, and provide a link from humans to the previously described experimental mechanisms.