Alpha-gal IgE Research Articles

Isolated Gastrointestinal Alpha-gal Meat Allergy Is a Cause for Gastrointestinal Distress Without Anaphylaxis

Isolated Gastrointestinal Alpha-gal Meat Allergy Is a Cause for Gastrointestinal Distress Without Anaphylaxis

S3011 Recurring Gastrointestinal Symptoms as a Novel Presentation of Alpha-Gal Allergy

INTRODUCTION: Galactose-alpha-1,3-galactose (alpha-gal) allergy is a delayed allergy after ingestion of mammalian meat such as beef, pork, or lamb. In the literature, symptoms range from urticaria to anaphylaxis with concomitant gastrointestinal manifestations. There are no case reports of adults with abdominal pain as the sole symptom of this allergy. This case delineates a novel presentation of the alpha-gal allergy with a patient with only gastrointestinal symptoms. CASE DESCRIPTION/METHODS: A 46 year old male with a past medical history of hypothyroidism, gastroesophageal reflux disease, hypertriglyceridemia, seasonal allergies and asthma presented with abdominal pain. His first episode occurred two years ago after the ingestion of prime rib, at which time he developed abdominal pain, nausea, and vomiting. Subsequently, he noticed abdominal pain after eating any red meat. Each abdominal pain episode was stabbing in quality and generally lasted two hours. Additional history revealed tick-exposure prior to the first episode of symptoms. Workup confirmed an allergy to beef with an elevated beef alpha-gal IgE of 0.71 kU/L (reference range, <0.35 kU/L). IgE levels were within normal range for pork and lamb. After eliminating all mammalian meat from the diet, the patient’s symptoms resolved. DISCUSSION: The first alpha-gal allergy to mammalian meat was documented in 2006 and it is still not fully understood. It is proposed that remnant alpha-gal from previous mammalian blood meals are transmitted to humans through the saliva of Amblyomma americanum (lone star tick), which is endemic to the southwest region of the United States. After ingestion of mammalian meat containing alpha-gal, the alpha-gal, found in glycolipids, is packaged into chylomicrons. It is released into the thoracic duct and IgE is deployed. It is suspected that this prolonged pathway is why symptoms do not manifest until 3 to 8 hours after ingestion. It is crucial to obtain a good clinical history and recognize that recurrent abdominal pain, nausea or vomiting may be the only presentation especially given that the current mean time to diagnosis is 7.1 years. Diagnosis is made with blood work assessing IgE levels to beef, pork, and lamb. Elevation of IgE titers to only one mammalian meat is required for diagnosis. Given the risk of anaphylaxis, prescription of an epinephrine pen and elimination of mammalian meat is the only treatment.

On the cause and consequences of IgE to galactose-α-1,3-galactose: A report from the National Institute of Allergy and Infectious Diseases Workshop on Understanding IgE-Mediated Mammalian Meat Allergy

The mammalian meat allergy known as the "α-Gal syndrome" relates to IgE specific for galactose-α-1,3-galactose (α-Gal), an oligosaccharide that is present in cells and tissues of nonprimate mammals. The recognition of delayed reactions to food derived from mammals in patients with IgE to α-Gal and also the association with tick bites have been increasing worldwide. In 2018, the National Institute of Allergy and Infectious Diseases, Division of Allergy, Immunology and Transplantation, sponsored a workshop on this emerging tick-related disease. International experts from the fields of tick biology, allergy, immunology, infectious disease, and dermatology discussed the current state of our understanding of this emerging medical condition. The participants provided suggestions for specific research priorities and for the development of resources to advance our knowledge of the mechanisms, diagnosis, management, and prevention of this allergic disease. This publication is a summary of the workshop and the panel's recommendations are presented herein.

A CASE OF CHRONIC URTICARIA AND ANGIOEDEMA WITH FALSE-POSITIVE ALPHA-GAL IGE

Introduction Sensitization to galactose-alpha-1,3-galactose (alpha-gal) has been linked with delayed urticaria, angioedema and anaphylaxis to mammalian meat. We report chronic urticaria and angioedema (CUA) in a patient with false-positive alpha-gal and mammalian meat IgE. Case Description Patient is an 18-year-old male with urticaria and angioedema referred to our clinic for evaluation of positive IgE to alpha-gal and mammalian meat. He first developed urticaria/angioedema at 14 years of age. It was treated with H1, H2 blockers and completely resolved in 2 months. After being asymptomatic for 3 years, his symptoms recurred. No triggers were noted, including no dietary changes and worsening in symptoms upon meat or dairy ingestion. Laboratory evaluation was remarkable for positive IgE for alpha-gal (3.76 kU/L), beef (2.01 kU/L), lamb/mutton (0.77 kU/L) and pork (1 kU/L). Treatment with fexofenadine, cetirizine and famotidine was initiated and patient was referred to our clinic for further evaluation. We recommended a 2-week trial of red meat elimination diet, which didn't result in symptom improvement. Hives/angioedema didn't worsen after reintroduction of red meat. Montelukast was added to his medications, resulting in 70% improvement in symptoms. Discussion High rate of false-positive IgE to food allergens is well established. To our knowledge this is the first report of false positive alpha-gal IgE in CUA, misdiagnosed as allergy to mammalian meat. This case demonstrates the importance of a comprehensive history in CUA along with careful selection and evaluation of relevant laboratory tests. Sensitization to galactose-alpha-1,3-galactose (alpha-gal) has been linked with delayed urticaria, angioedema and anaphylaxis to mammalian meat. We report chronic urticaria and angioedema (CUA) in a patient with false-positive alpha-gal and mammalian meat IgE. Patient is an 18-year-old male with urticaria and angioedema referred to our clinic for evaluation of positive IgE to alpha-gal and mammalian meat. He first developed urticaria/angioedema at 14 years of age. It was treated with H1, H2 blockers and completely resolved in 2 months. After being asymptomatic for 3 years, his symptoms recurred. No triggers were noted, including no dietary changes and worsening in symptoms upon meat or dairy ingestion. Laboratory evaluation was remarkable for positive IgE for alpha-gal (3.76 kU/L), beef (2.01 kU/L), lamb/mutton (0.77 kU/L) and pork (1 kU/L). Treatment with fexofenadine, cetirizine and famotidine was initiated and patient was referred to our clinic for further evaluation. We recommended a 2-week trial of red meat elimination diet, which didn't result in symptom improvement. Hives/angioedema didn't worsen after reintroduction of red meat. Montelukast was added to his medications, resulting in 70% improvement in symptoms. High rate of false-positive IgE to food allergens is well established. To our knowledge this is the first report of false positive alpha-gal IgE in CUA, misdiagnosed as allergy to mammalian meat. This case demonstrates the importance of a comprehensive history in CUA along with careful selection and evaluation of relevant laboratory tests.

RESOLUTION OF GALACTOSE ALPHA 1-3 GALACTOSE (ALPHA-GAL) ANAPHYLAXIS AFTER TICK AND HOOVED MEAT AVOIDANCE

Introduction Anaphylatic reactions to Alpha-Gal carbohydrate epitope commonly present in meat of hooved animals and are recognized as an important cause of delayed anaphylaxis. Tick bites appear to be a necessary cofactor in developing sensitization to Alpha-Gal. Case Description Our patient is a 53-year-old female living in Oklahoma who presented to the clinic in 2011 with a two-year history of pruritis, hives, throat tightness, and facial swelling. Symptoms occurred at night after consuming corn or potato chips which had previously been tolerated. Prior to presentation, she had labs drawn which showed elevated counts to pork and beef. It was discovered that six hours after consuming meat she had these episodes and reported having tick bites from her dogs. Percutaneous tests with allergenic extracts showed minimal activity to fresh beef and lamb. Alpha-gal specific IgE was elevated at 65.8 kU/L and she was advised to avoid all meat products except poultry and fish. At four-month follow-up, she continued to avoid pork and beef without further events and had no new tick bites. She had her dogs and home treated for ticks and moved to a new house. At six years after presentation, she reintroduced small amounts of well cooked meat products without problems. Alpha-Gal specific IgE was 0.47 kU/L and continued to decline despite continued meat consumption. Discussion This case implies that, at least in this patient, both tick bites and meat exposure are necessary to maintain sensitization. Reintroducing the meat alone without tick exposure did not result in re-sensitization.

Predictive values of alpha-gal IgE levels and alpha-gal IgE: Total IgE ratio and oral food challenge-proven meat allergy in a population with a high prevalence of reported red meat allergy.

Severe meat allergy with anaphylaxis may be caused by sensitization to alpha-gal. Levels of alpha-gal sensitization that correlate with high risk of meat allergy are currently unknown. We have identified an area with a high prevalence of reported red meat allergy which offered the opportunity to evaluate the diagnostic value of IgE antibody tests. To determine levels of alpha-gal IgE and alpha-gal:total IgE ratio in a large cohort of subjects with challenge-proven meat allergy compared with control subjects from the same environment, we conducted fieldwork assessing 131 participants who reported adverse reactions to meat, and 26 control subjects, by questionnaires, IgE sensitization to alpha-gal and oral food challenge to beef sausage. Eighty-four participants were diagnosed with alpha-gal allergy. Alpha-gal IgE ranged between 0.7 and 344.5kU/L. Alpha-gal:total IgE ratio ranged from 0.1% to 67.6%. Logistic regression analysis showed both alpha-gal IgE and alpha-gal:total IgE ratio strongly correlated with meat allergy, with AUC of 0.95. The values giving the best correct classification were IgE of 2.00kU/L and ratio of 0.75%. The value above which there is a 95% probability of meat allergy is IgE>5.5kU/L and ratio of 2.12%. Alpha-gal allergy in a population with a high prevalence of reported red meat allergy showed a more rapid onset of symptoms than previously described and a high prevalence of isolated subjective gastrointestinal manifestations. Cutoff values are described for levels of sensitization to alpha-gal IgE and alpha-gal:total IgE ratio that are highly likely to result in clinically significant meat allergy.

A Case of Unexplained Shock Following Steak Consumption

SESSION TITLE: Fellow Case Report Slide: Pulmonary Critical Care Disorders: Think Twice SESSION TYPE: Affiliate Case Report Slide PRESENTED ON: Sunday, October 23, 2016 at 10:45 AM - 12:00 PM INTRODUCTION: Delayed anaphylaxis following red meat consumption is a novel phenomenon in the Southwestern United States. This presentation will illustrate a case of IgE mediated activity against the galactose-α-1,3-galactose (alpha-gal) epitope. This carbohydrate determinant is common in humans and isotope switching to alpha-gal IgE occurs following ectoparasite exposure. First described in 2009, early case reports led to identification of the Amblyomma americanum, or lone star tick, as the sensitizing exposure. We present the first reported case of anaphylaxis in New Hampshire from red meat consumption following alpha-gal sensitization. CASE PRESENTATION: Our patient is a 69 year old male who presented with an anaphylactic reaction. He has no known allergies or co-morbidities. A history revealed consumption of steak 6 hours before symptom onset of generalized urticaria, angioedema and dyspnea. Treatment included anti-histamines, steroids, and epinephrine. It was later divulged he sustained a tick bite 5 weeks prior to this admission. Further work-up identified a total IgE of 129 kU/L and an elevated alpha-gal IgE of 10 kU/L (normal ≤0.34 kU/L). His history and serologic testing allowed us to confirm a diagnosis of delayed anaphylaxis due to a red meat allergy. He made a full recovery, and received follow-up in our Allergy clinic and counseling on red meat avoidance. DISCUSSION: IgE sensitization to the oligosaccharide alpha-gal following exposure to the lone star tick is described largely in the southeastern United States. After red meat ingestion, a delayed anaphylactic reaction may occur. The diagnosis should be suspected when caring for the patient with anaphylaxis of unclear etiology, and is confirmed using an IgE specific immunoassay. Treatment in the acute setting is supportive, and long term care includes avoidance of mammalian meats and prevention of further tick exposure. CONCLUSIONS: This case demonstrates a vector-associated sensitivity leading to delayed anaphylaxis following consumption of mammalian meat. It is the first documneted occurrence in our state, supporting the described geographic spread of the lone start tick. Practitioners should maintain this condition on their differential as it becomes increasingly recognized in non-endemic regions. Reference #1: Commins, Scott P., et al. “Delayed Anaphylaxis to Alpha-gal, an Oligosaccharide in Mammalian Meat.” Allergology International 65.1 (2016): 16-20. DISCLOSURE: The following authors have nothing to disclose: Elliot Backer, James Carroll No Product/Research Disclosure Information

Using mass cytometry to identify novel B cell subsets in red meat allergy

Abstract Previous studies have identified a novel food allergy driven by IgE antibodies specific for galactose-α-1,3-galactose (alpha-gal), an oligosaccharide found in red meat. While it is known that B cells play an important role in allergy as the producers of IgE antibodies that drive the allergic response, little is known about the phenotype of these B cells. The number of markers used to identify the major human B cell subsets by flow cytometry has been limited to common B cell proteins and thus precludes high dimensional immune phenotyping of B cell subsets, including unique phenotypes present in allergic individuals. We have addressed this problem by using mass cytometry (CyTOF), which enables the simultaneous analysis of up to 40 markers in a single staining panel. Here we analyzed the expression of 23 cell surface markers in PBMCs from 19 alpha-gal-allergic patients and 20 non-allergic controls by CyTOF. Additionally, we combined our CyTOF data with clinical endpoints to identify markers that may correlate with allergic disease. Our data reveals substantial heterogeneity within major B cells subsets on an individual level. Furthermore, our analysis identifies a number of markers that vary significantly in their expression in allergic versus non-allergic B cells and correlate with serum alpha-gal IgE titers. We hypothesize that B cells with this phenotype play an important role in mediating alpha-gal allergy. These findings demonstrate the power of using CyTOF and analytical tools to extract a hierarchy from high dimensional cytometry data in an unsupervised manner to identify known B cell subsets as well as to find novel B cell populations that differ between alpha-gal allergic and non-allergic individuals.

A Case of Idiopathic Systemic Capillary Leak Syndrome: Masquerader of Anaphylaxis – an Emblematic Case from a Cohort of 21 Patients

S A T U R D A Y Mike Tankersley, MD, FAAAAI, Alan DeJarnatt, MD, Ross DeJarnatt; University of Tennessee Health Sciences Center, Allergy and Asthma Care. RATIONALE: Galactose-alpha-1,3-galactose hypersensitivity (alphagal) is a recently reported condition associated with the production of specific IgE to this oligosaccharide found in mammalian meat. A registry was maintained of alpha-gal patients to more fully understand this condition in our patient population. METHODS: A retrospective chart review of a single-site Allergy practice in Tennessee was conducted of the clinic’s alpha-gal registry of patients seen from 2010-2015. RESULTS: There were 38 patients diagnosed with alpha-gal hypersensitivity over a five-year period (2010-2015). Patient characteristics included: mean age at diagnosis 50.7 years (range 14-74 years), 44.7% were male (17/38), mean alpha-gal IgE 29.7 kU/L (range 1.1-97.3; two patients excluded from mean with levels >100). Four patients had followup alpha-gal levels which had all decreased: patient 1 (6.2 to 1.9 kU/L after 42 months), patient 2 (23.2 to 8.7 kU/L after 42 months), patient 3 (82.3 to 58.7 kU/L after 34 months) and patient 4 (95.2 to 1.3 kU/L after 48 months). Signs and symptoms included cutaneous pruritus, urticaria, angioedema, hoarseness, dyspnea, nausea, vomiting, diarrhea, lightheadedness, hypotension, and syncope. Culprit foods included beef, pork, venison, cow’smilk, and lamb. Time between onset of signs and symptoms to diagnosis was 1 month-15 years. Time between ingestion and signs/ symptoms was 1-6 hours. CONCLUSIONS: Alpha-gal hypersensitivity is not an uncommon food hypersensitivity as demonstrated by the 38 patients diagnosed in this single-site clinic in Tennessee over a 5-year period. All medical care providers should maintain a high index of suspicion of this condition in patients presenting with anaphylaxis in the absence of an immediate allergen association.

Quantitative Binding Assay for Measuring Specific IgG Antibodies to Alpha-Gal Using the Neoglycoprotein Gal-α-1,3-Gal-β-1,4-Glcnac-Human Serum Albumin

Tick bites are known to induce IgE production to alpha-gal. Elevated alpha-gal IgG1 compared to natural alpha-gal IgG2 production has been reported in alpha-gal IgE+ subjects. We here report further investigation of the relationship between alpha-gal IgG and both reactions to red meat and exposure to ticks. Methods: IgG from serum was absorbed onto recombinant Protein G-Sepharose and incubated with radiolabeled allergen. The radioactivity of bound allergen was measured using a gamma counter. A control curve was generated in parallel to assign unitage. Additional testing of serum immunoglobulins was performed via ImmunoCAP and nephelometry. Results: Alpha-gal IgG was measured in a Northern Sweden cohort and in subjects presenting to allergy clinics in Virginia with delayed reactions to red meat. Alpha-gal IgG was significantly higher in alpha-gal IgE+ subjects versus alpha-gal IgE- subjects, and longitudinal serology in several alpha-gal IgE+ subjects demonstrates parallel alpha-gal IgE and IgG response trends. Among the alpha-gal IgE+ subjects, alpha-gal IgG was higher in those with alpha-gal IgE:total IgE ratios >25%, but was not related to reported severity to red meat. Compared to the alpha-gal IgE- subjects in Virginia, alpha-gal IgG was lower in the group from Northern Sweden, where alpha-gal IgE-mediated hypersensitivity is absent and ticks are rare. Conclusions: Alpha-gal IgG is strongly related to alpha-gal IgE and is significantly lower in prevalence and titer in subjects without tick exposure. The absence of a relationship between alpha-gal IgG and severity of reactions to red meat suggests that the alpha-gal syndrome may not be a suitable candidate for conventional immunotherapy.

Alpha-Gal IgE Sensitization in the United States; Surveillance Update

S A T U R D A Y 114 Alpha-Gal IgE Sensitization in the United States; Surveillance Update Michelle L. Altrich, PhD, Sharlene P. Blum, Shannon M. Foster; Viracor-IBT Laboratories, Lee’s Summitt, MO, Viracor-IBT Laboratories. RATIONALE: Galactose-alpha-1,3-galactose (alpha-gal), is a crossreactive carbohydrate moiety found in red meats such as beef, pork and lamb and is associated with a delayed IgE response. A link to lone star tick bites was established by researchers at the University of Virginia and although the mechanism of sensitization is not clearly elucidated, it remains the primary suspect. METHODS: A retrospective review of national laboratory data was conducted for alpha-gal IgE testing performed in 2012 and 2013, utilizing data with de-identified patient health information only when the source location could be identified. This data was mapped according to 6 geographical regions and compared to the July 2011 CDC published map of lone star tick populations. RESULTS: For the total data set, 37% displayed positive results for alphagal IgE. In the subset of samples that could be tied to a source location, the positive rate declined to 33%. The regions with the highest prevalence of positive samples continue to overlap with the location of the lone star tick with a positive rate as high as 46% in TN andAR. In other non-lone star tick regions the positive rates varied from 8% to 17%. CONCLUSIONS: The overall positive rate of samples tested in 20122013 decreased compared to 2009-2011, and the total number of tests increased, suggesting there is more screening of patients potentially exposed to the lone star tick. The overall regional prevalence rates continue to support the hypothesis that lone star tick bites trigger the development of the alpha gal allergy.

Ectoparasite Induced Elevations of alpha-gal Specific IgE are Associated with Increased Total Serum IgE and Cat Sensitization but not with Asthma

Ectoparasite Induced Elevations of alpha-gal Specific IgE are Associated with Increased Total Serum IgE and Cat Sensitization but not with Asthma

Anti-Gal Titers in Healthy Adults and Inflammatory Bowel Disease Patients

Introduction ALPHA-GAL is a glycoconjugate present on cell membranes of mammals and bacteria but not humans who display anti-Gal antibodies (AB) in high titers provoked by the commensal gut flora. In the present study, we sought to determine the longitudinal course of alpha-Gal specific AB titers of all isotypes over 8 weeks among healthy adult subjects. Furthermore, we hypothesized that inflammatory bowel disease (IBD) patients display increased anti-Gal titers. Materials and methods We drew serum from healthy probands ( n = 20) weekly for 8 weeks and obtained plasma samples of from patients suffering from Crohn's disease ( n = 20) and ulcerative colitis ( n = 20). We measured anti-Gal ABs of all isotypes and total immunoglobulin (Ig) content using an enzyme-linked immunosorbent assay technique. For statistical evaluation of the longitudinal titers, we calculated confidence intervals for the slopes of a random intercept model, comparing variances between and within the probands. For group comparisons, we performed paired student t-tests and Pearson correlations. Results Alpha-Gal specific IgG, IgM, IgD, and IgA titers remained unvaried within a narrow range upon longitudinal observation. Most probands did not display alpha-Gal specific IgE ABs. Crohn's disease patients showed highly increased alpha-Gal-specific IgA titers compared with control subjects ( P < .01). Conclusion Apart from IgE, alpha-Gal-specific ABs of all isotypes remained constant over longer time periods in healthy subjects. Thus, significant titer changes actually represent increased antigen exposure and a specific anti-alpha-Gal response. Crohn's disease patients display increased anti-Gal IgA titers compared with healthy controls, which reflects a chronically impaired mucosal gut barrier in this patient cohort.