ENT and Allergy

A Health-Economic Analysis of Alpha-Gal Screening in the Asymptomatic Patient to Prevent Fatal Anaphylaxis.

Sensitization to galactose-α-1,3-galactose (alpha-gal) can present with variable signs and symptoms. Although sensitization may be asymptomatic in a large proportion of individuals, in some it may present as alpha-gal syndrome (AGS) with risks for potentially fatal anaphylaxis if not managed appropriately. We conducted a health-economic evaluation of population screening to decrease the risk of fatal anaphylaxis from asymptomatic unrecognized alpha-gal sensitization. Markov models evaluated patients with asymptomatic sensitization comparing outcomes in patients identified to have sensitization through screening with those who did not undergo screening. Those with detected alpha-gal sIgE received prescriptions for self-administered epinephrine and were assumed to have a 10-fold decrease in the risk of anaphylaxis fatality. The model incorporated the associated disutility of food allergy diagnosis and allergic reactions, as well as costs of screening, emergency department evaluations, and hospitalizations. Probabilities and costs were derived from the medical literature. Population-level microsimulation evaluated 1% of the US population with outcomes considered over a 5-year treatment course. In the population microsimulation (n = 3,431,477 per arm), costs were greater in the population receiving screening ($2,683,565,074 [standard deviation, SD, $2150] vs $1,711,493,170 [SD $1976]) with lower quality-adjusted life years (QALYs) in the screened population (15,355,262 QALYs [SD 0.35] vs 15,795,107 [SD 0.27]). A no-screening approach was associated with $972,071,904 in savings, while improving health quality by 439,845 QALYs. Extrapolated to the entire US population, not screening (compared with screening) would result in savings that could exceed $90 billion and preserve over 40 million QALYs during the 5-year horizon. Screening could be cost-effective if the annual anaphylaxis risk exceeded 50% for high-risk populations in whom identification of sensitization decreased the frequency of anaphylaxis. General screening of asymptomatic populations to prevent fatal AGS would be a low-value practice, though in patients at very high risk for severe anaphylaxis, screening could be considered.

Alpha-Gal Syndrome in a Pediatric Patient From Northeast Florida.

Alpha-gal syndrome (AGS) is a rare, tick-borne condition that is characterized by a delayed hypersensitivity reaction to galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in mammalian meat products. AGS is increasingly recognized in adults; however, cases often remain underreported or misdiagnosed in children. We report on a 10-year-old male in Northeast Florida presenting with gastrointestinal symptoms, urticaria, and oropharyngeal itching. These symptoms developed hours after consuming a cheeseburger. His medical history revealed multiple previous Lone Star tick bites. After an alpha-gal IgE panel was performed, the elevated specific IgE levels, in addition to the patient's prior history of tick bites, led to a diagnosis of AGS. The patient was prescribed avoidance of mammalian meat and an epinephrine auto-injector. There is a growing need for correct symptom recognition in pediatric cases, and improved clinical recognition may facilitate earlier diagnosis in pediatric patients. Florida's warm climate and abundant wooded and marshy areas support tick activity. Unlike typical IgE-presenting allergens, AGS reactions may occur hours after ingestion, leading to cases remaining underreported or misdiagnosed. Repeated exposures can lead to more severe symptoms, emphasizing the need for early diagnosis. With very limited surveillance, the true prevalence and incidence of AGS in Florida are unknown due to underreporting, and this case report sheds light on the clinical presentation of a pediatric AGS case in Northeast Florida.

Alpha-Gal Syndrome and Aortic Valve Replacement.

Alpha-gal syndrome (AGS) is an IgE-mediated hypersensitivity response to galactose-alpha-1,3-galactose (alpha-gal), an oligosaccharide present in beef and pork. This complicates bioprosthetic heart valve selection, as both bovine and porcine valves contain alpha-gal, posing risks of allergic reaction and potentially accelerated structural valve degeneration. A 78-year-old man with AGS and severe symptomatic aortic stenosis underwent transcatheter aortic valve replacement with a porcine-derived Evolut FX 29-mm valve following multidisciplinary evaluation. Preoperative allergist-guided prophylaxis, including IgE risk stratification, antihistamines, and corticosteroids, enabled successful implantation without complications. Bioprosthetic valves may pose unique risks for individuals sensitized to alpha-gal, where an alpha-gal IgE to total IgE ratio ≤5% is a proposed threshold in which patients can be rechallenged with animal products. This case highlights the successful management of a slightly higher ratio. The interplay between AGS, bioprosthetic valve selection, and structural valve durability necessitates an individualized approach to mitigate the hypersensitivity risks.

Food allergy endotypes revisited.

In the last century, food allergy has become recognized as an increasingly prevalent and heterogeneous condition. Advances in biomedical technology have revealed complex genetic, environmental, immune, and metabolic pathways underlying the pathogenesis of food-allergic disorders. These findings permit classification of distinct food allergy endotypes with unique pathophysiologic features. In this review, we suggest that these endotypes of food-allergic disorders should be defined on the basis of (1) whether or not the allergic antibody IgE plays an essential role in disease pathogenesis, (2) the molecular features of the allergen (protein vs carbohydrate), and (3) the molecular markers associated with prognosis, severity, or clinical presentation. Beyond these broad categories, additional subtypes with unique mechanistic characteristics are discussed.

Characterization of alpha-gal syndrome and sensitization on Eastern Long Island.

Delayed anaphylaxis due to Alpha-gal allergy: A modified desensitization protocol with red meat in an adult patient.

Alpha-gal allergy is the sensitization to Alpha-gal present in saliva when a tick bites and the development of an IgE-mediated reaction to Alpha-gal also present in red meat by cross-reactivity. In contrast to other food allergies, symptoms occur as late as 2-6 hours after a meal. Prick to prick testing with nonmammalian meat in combination with cooked mammalian meat is recommended for diagnosis. However, the main diagnostic test is Alpha-gal sIgE> 0.1 IU/mL. The primary recommendation in patients with Alpha-gal syndrome is to prevent new tick bites and avoid all mammalian meats. Since most of the dishes in our country's food culture contain red meat, elimination diet may adversely affect patients quality of life. In the management of these patients, the option of desensitization with red meat can be considered by evaluating the benefit-risk ratio together with the patient. Our patient with a history of tick bites and a reaction pattern ranging from urticaria to anaphylaxis two hours after meat consumption was evaluated for Alpha gal allergy. The patient was found to be positive by prick-to-prick with cooked red meat. In addition, the high level of Alpha-gal specific IgE (27.3 Ku/L) confirmed the Alpha-gal allergy, and the decision to apply desensitization with red meat was taken. There are only two literatures on this subject, one of which includes two adult cases and the other a single pediatric case. Since a reaction developed in the fifth step of the 27-step desensitization scheme (Ünal et al.), which we took as a reference, which led to a dose increase of more than 100 times, we modified the protocol by using an intermediate steps. We repeated the prick-to-prick test with red meat after desensitization in our case who successfully completed the modified desensitization protocol. Observation of more than half reduction in test edema diameter concretely supports the success of our modified desensitization protocol.

Glycolipid-mediated basophil activation in alpha-gal allergy.

Alpha-gal-containing glycolipids activate basophils sensitized with plasma from alpha-gal allergic subjects in an IgE-dependent manner suggesting a role for glycolipid in the effector phase of IgE-mediated food allergy.

Intraoperative anaphylaxis to gelatin-based hemostatic agents: a case report.

Surgiflo Haemostatic Matrix is an absorbable gelatin matrix hemostatic material that has been widely used in various surgical operations to assist hemostasis. Nonetheless, as biologically active agents (contains porcine gelatin), there is potential for allergic reactions to these products. Here, we report the case of a 71-year-old man who had intraoperative anaphylaxis with cardiovascular events to gelatin associated with the use of a topical hemostatic agent (Surgiflo). The patient reported a history of red meat allergy and tick bites during his allergological examination after anaphylaxis. He also had high levels of specific IgE antibodies towards alpha-gal. Special consideration should be given before administering bovine- or porcine-derived gelatin products during surgery to patients with animal-related allergies, such as alpha-gal or gelatin allergy and an atopic background.

A novel Australian tick () inducing mammalian meat allergy after tick bite.

Tick-induced mammalian meat allergy has become an emergent allergy world-wide after van Nunen et al. first described the association between tick bites and the development of mammalian meat allergy in 2007. Cases of mammalian meat allergy have now been reported on all 6 continents where humans are bitten by ticks, in 17 countries - Australia, United States of America (USA), Europe (France, Spain, Germany, Belgium, Switzerland, Sweden, United Kingdom, Italy, and Norway), Asia (Korea and Japan), Central America (Panama), South America (Brazil), and Africa (South Africa and Ivory Coast). To date, in each of these countries, bites from only a single tick species have been linked to the development of mammalian meat allergy: (Australia), (USA), (Europe), and (Panama) are confirmed as culprits, and (Japan and Korea), (Brazil), (Ivory Coast), and (Japan) suspected of provoking mammalian meat allergy after tick bite. Other tick species remain to be formally identified (South Africa). Identification of tick species associated with development of mammalian meat allergy is crucial to the uptake of public health measures to prevent tick bites from culprit tick species, for both individuals living in these tick-endemic areas and those who choose to visit these regions. We report a tick associated with the enhancement of mammalian meat anaphylaxis after tick bite which is novel for both Australia and the world and establishes () as a second tick species associated with mammalian meat allergy in Australia.

IgE to the Mammalian Oligosaccharide Galactose-α-1,3-Galactose Is Associated With Increased Atheroma Volume and Plaques With Unstable Characteristics-Brief Report.

Emerging evidence suggests a link between coronary artery disease and type 2 immunity. We sought to test the hypothesis that IgE sensitization to the mammalian oligosaccharide galactose-α-1,3-galactose (α-Gal)-the target allergen of delayed anaphylaxis to red meat-is associated with coronary artery disease. Total IgE and specific IgE to α-Gal were assayed on sera from 118 subjects who presented for cardiac catheterization and underwent intravascular ultrasound. IgE to α-Gal was detected in 26%, and atheroma burden was higher in sensitized subjects (=0.02). Because α-Gal sensitization relates to an environmental exposure that could be a risk factor for early-onset coronary artery disease (ie, tick bites), we age stratified the cohort. In subjects ≤65 years of age, the strength of the association with atheroma burden was stronger (<0.001), and plaques in the sensitized group had less stable features based on intravascular ultrasound. To address the specificity of the association with IgE to α-Gal, IgE to inhalants and peanut were assayed and were not associated with coronary artery disease. Total IgE and α-Gal-specific IgE were strongly associated with each other, but the strength of the relationship with atheroma burden was stronger for α-Gal-specific IgE. This association was significant when adjusted for sex, diabetes mellitus, hypertension, statin use, and total IgE (regression coefficient, 12.2; SE, 5.2; =0.02). Increased atheroma burden and plaques with more unstable features were associated with IgE to α-Gal-an effect most pronounced in subjects ≤65 years of age. IgE sensitization to α-Gal may represent a novel, and potentially modifiable, risk factor for coronary atherosclerosis.

Accurate assessment of alpha-gal syndrome using cetuximab and bovine thyroglobulin-specific IgE.

IgE against galactose-α-1,3-galactose (α-Gal) causes alpha-gal syndrome. Bovine thyroglobulin (BTG) and cetuximab share this epitope. We aimed to determine the utility of specific IgE (sIgE) against cetuximab as compared to BTG for diagnosing alpha-gal syndrome. Twelve patients with alpha-gal syndrome, 11 patients with immediate beef or pork allergy, 18 asymptomatic individuals with meat sensitization, and 10 non-atopic subjects were enrolled. We checked the levels of sIgE against BTG and cetuximab using the streptavidin CAP assay. Additionally, IgE reactivity to BTG and cetuximab was assessed by immunoblotting. All alpha-gal syndrome patients had a high concentration of sIgE against BTG, and cetuximab. In contrast to alpha-gal syndrome, patients with immediate allergic reactions to meat consumption and those with asymptomatic sensitization had significantly lower concentration of BTG and cetuximab sIgE, and a high prevalence of sIgE against bovine or porcine serum albumin. Although the concentration of sIgE against alpha-gal was lower in individuals with asymptomatic sensitization, IgE immunoblotting showed the presence of sIgE against α-Gal in this group. Differentiation of alpha-gal syndrome from patients with immediate allergy to meat consumption or asymptomatic sensitization requires quantification of cetuximab- or BTG-induced sIgE via detection of IgE for α-gal.

Red meat allergy induced by tick bites: A Norwegian case report.

Food allergies, especially delayed hypersensitivity reactions, are often challenging for both patients and clinicians. Here, we report the case of a 64-year-old man who had allergic reactions six hours after eating a meal containing red meat. He reported that he had several tick bites in months before the reaction. High serum specific IgE levels of alpha-gal confirmed the diagnosis of alpha-gal allergic reaction with delayed onset after red meat ingestion caused by tick bite.

Food allergy to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal): four case reports and a review.

Until recently, food allergies to mammalian meats have been considered to be very rare. The observation that patients not previously exposed to the monoclonal chimeric antibody cetuximab suffered from severe anaphylaxis upon first exposure, led to the identification of galactose-alpha-1,3-galactose as a new relevant carbohydrate allergen. These patients later often suffered from anaphylactic reactions to red meat. Epidemiological data indicated that bites by the tick Amblyomma americanum in the USA, later also by Ixodes species in other continents, resulted in sensitisation to alpha-gal. On the other hand, in African patients with parasitic disorders, a high prevalence of anti-alpha-gal IgE, without clinical relevance, has been reported. In our four cases, one patient with a late onset of meat allergy had a history of a tick bite. The other three patients had symptoms from childhood or at a juvenile age. This indicates that in some patients, other ways of sensitisation may also take place. However, in patients without atopy, tick bite-induced IgE to alpha-gal may be more relevant. Diagnosis is based on a history of delayed onset of anaphylaxis. Skin tests with commercially available meat test solutions are often equivocal or negative; skin tests with raw meat and particularly pork kidney are more sensitive. Determination of specific IgE to alpha-gal is commercially available. The highest sensitivity is observed with skin and basophil activation tests with cetuximab which is, however, limited by its high costs.

Anaphylactic Reactions to Novel Foods: Case Report of a Child With Severe Crocodile Meat Allergy.

Availability of "exotic" foods is steadily increasing. In this report, we describe the first case of anaphylaxis to crocodile meat. The patient was a 13-year-old boy with severe immunoglobulin E-mediated allergy to chicken meat. When tasting crocodile meat for the first time, he developed an anaphylactic reaction. Cross-reactivity between chicken and crocodile meat was suspected to have triggered this reaction. Basophil activation and immunoglobulin E testing confirmed the boy's allergic reaction to crocodile meat proteins. Molecular analysis identified a crocodile α-parvalbumin, with extensive sequence homology to chicken α-parvalbumin, as the main cross-reactive allergen. We conclude that crocodile meat can be a potent food allergen and patients with allergy to chicken meat should be advised to avoid intake of meat from crocodile species. Both foods and people travel around the world and accessibility to exotic foods is steadily growing. As a result, novel allergic cross-reactivities are likely to become a challenge in the management of food allergy and, as our report illustrates, cross-reactivity has to be considered even between foods that might not intuitively be perceived as related.

Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment.

This review focuses on advances and updates in the epidemiology, pathogenesis, diagnosis, and treatment of food allergy over the past 3 years since our last comprehensive review. On the basis of numerous studies, food allergy likely affects nearly 5% of adults and 8% of children, with growing evidence of an increase in prevalence. Potentially rectifiable risk factors include vitamin D insufficiency, unhealthful dietary fat, obesity, increased hygiene, and the timing of exposure to foods, but genetics and other lifestyle issues play a role as well. Interesting clinical insights into pathogenesis include discoveries regarding gene-environment interactions and an increasing understanding of the role of nonoral sensitizing exposures causing food allergy, such as delayed allergic reactions to carbohydrate moieties in mammalian meats caused by sensitization from homologous substances transferred during tick bites. Component-resolved diagnosis is being rapidly incorporated into clinical use, and sophisticated diagnostic tests that indicate severity and prognosis are on the horizon. Current management relies heavily on avoidance and emergency preparedness, and recent studies, guidelines, and resources provide insight into improving the safety and well-being of patients and their families. Incorporation of extensively heated (heat-denatured) forms of milk and egg into the diets of children who tolerate these foods, rather than strict avoidance, represents a significant shift in clinical approach. Recommendations about the prevention of food allergy and atopic disease through diet have changed radically, with rescinding of many recommendations about extensive and prolonged allergen avoidance. Numerous therapies have reached clinical trials, with some showing promise to dramatically alter treatment. Ongoing studies will elucidate improved prevention, diagnosis, and treatment.

Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1,3-galactose.

Carbohydrate-specific IgE antibodies present on nonprimate mammalian proteins were incriminated recently in delayed meat anaphylaxis. The aim of this study was to explore whether anaphylaxis to mammalian kidney is also associated with galactose-α-1,3-galactose (αGal)-specific IgE. Fourteen patients with anaphylaxis to pork or beef kidney underwent prick tests to meat and kidney. Some patients also underwent skin tests to Erbitux(®) (cetuximab). IgE antibodies to αGal, swine urine proteins, beef and pork meat, serum albumin proteins, cat, and rFel d 1 were measured by ImmunoCAP(®). The αGal levels were estimated in meats and kidney by ELISA inhibition assay. Cross-reactivity between αGal and pork kidney was studied with the ImmunoCAP(®) inhibition assay. Among the 14 patients, 12 presented with anaphylactic shock. Reactions occurred within 2 h from exposure in 67% of patients. Associated risk factors were observed in 10 cases, and alcohol was the main cofactor. Three patients underwent an oral challenge to pork kidney, and anaphylaxis occurred after ingestion of small quantities (1-2 g). Prick tests to kidney were positive in 54% of patients. All tested patients showed positive skin tests to Erbitux(®). All patients tested positive for IgE to αGal, with levels ranging from 0.4 to 294 kU/l. IgE binding to αGal was inhibited by raw pork kidney extract (mean, 77%; range, 55-87%), which showed a high amount of αGal determinants. Pork or beef kidney anaphylaxis is related to αGal IgE. Its peculiar severity could be due to an elevated content of αGal epitopes in kidney.

Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2009.

This review highlights some of the research advances in anaphylaxis and hypersensitivity reactions to foods, drugs, and insects, as well as advances in allergic skin disease that were reported in the Journal in 2009. Among key epidemiologic observations, several westernized countries report that more than 1% of children have peanut allergy, and there is some evidence that environmental exposure to peanut is a risk factor. The role of regulatory T cells, complement, platelet-activating factor, and effector cells in the development and expression of food allergy were explored in several murine models and human studies. Delayed anaphylaxis to mammalian meats appears to be related to IgE binding to the carbohydrate moiety galactose-alpha-1,3-galactose, which also has implications for hypersensitivity to murine mAb therapeutics containing this oligosaccharide. Oral immunotherapy studies continue to show promise for the treatment of food allergy, but determining whether the treatment causes tolerance (cure) or temporary desensitization remains to be explored. Increased baseline serum tryptase levels might inform the risk of venom anaphylaxis and might indicate a risk for mast cell disorders in persons who have experienced such episodes. Reduced structural and immune barrier function contribute to local and systemic allergen sensitization in patients with atopic dermatitis, as well as increased propensity of skin infections in these patients. The use of increased doses of nonsedating antihistamines and potential usefulness of omalizumab for chronic urticaria was highlighted. These exciting advances reported in the Journal can improve patient care today and provide insights on how we can improve the diagnosis and treatment of these allergic diseases in the future.

Asthma and allergic diseases in schoolchildren: third cross-sectional survey in the same primary school in Ankara, Turkey.

We investigated prevalence and determinants of asthma and allergic diseases in a cross-sectional survey of schoolchildren aged 6-14 in 2002. This was the third of a series of cross-sectional surveys, conducted in 1992 and 1997, in the same school in Ankara, Turkey. Questionnaire including information on house characteristics, dietary habits, past and current exposures and diseases were distributed to 1064 children (523 boys, 541 girls) and filled by the parents at home. Percentage of children having a pet was significantly higher (1992: 7.9, 1997: 22.9, 2002: 21), but that of passive smoking was significantly lower (1992: 74, 1997: 64, 2002: 64.1) in 1997 and 2002 when compared with 1992. Current prevalence percentage of asthma (1992: 8.3, 1997: 9.8, 2002: 6.4), wheeze (1992: 11.9, 1997: 13.3, 2002: 6.4), hay fever (1992: 15.4, 1997: 14.1, 2002: 7.2), and eczema (1992: 4, 1997: 4.3, 2002: 1.8) were significantly lower in 2002 compared with 1992. Multiple logistic regression analysis model for current wheeze included ingestion of cow's milk (no regular ingestion: reference, ORs and 95% CIs, <1 glass/day: 0.5, 0.3-1.0; at least 1 glass/day: 0.3, 0.2-0.7), ingestion of red meat (2.2, 1.2-3.8), and currently holding a dog (6.1, 1.6-23.4). Multiple logistic regression analysis model for current hay fever included ingestion of red meat (1.8, 1.1-2.9) and father's education (none of the parents finished secondary school: reference, secondary school to university: 0.5, 0.2-1.0). Our findings suggested that current prevalence of asthma and allergic diseases decreased among schoolchildren in Ankara, in the last 10 yr, and ingestion of milk and red meat could have a role in the occurrence of asthma and hay fever. Detailed assessment of dietary habits is required to test this hypothesis.