An observational pilot study screening blood products from research donors for Alpha-Gal Sensitization.

Clinical Center

Investigators

Abstract

Tick bites from species such as the lone star tick (Amblyomma Americanum) endemic to the southeastern United States and other regions expose individuals to an oligosaccharide not found in humans, galactose-alpha-1,3-galactose (alpha-Gal). A spectrum of disorders may result from IgE-mediated hypersensitivity reactions to exposure to alpha-Gal, alpha-Gal syndrome (AGS). AGS is characterized by new, delayed onset allergy to meat (e.g., beef, pork, lamb, venison, rabbit, or other products made from mammalian organs or lard), cow’s milk, or gelatins usually presenting 2-6 hours after consuming the product. Allergic symptoms may include unexplained hives, swelling, or other new allergic reactions and may induce severe, life-threatening anaphylaxis. A history of allergic hypersensitivity reactions may or may not be present; reportedly, serum IgE level is not necessarily predictive of symptoms or severity of reactions. The diagnosis of AGS requires demonstration of new, acquired allergy to meat or meat-derived products, diagnostic testing for the alpha-Gal specific IgE (sIgE), and exclusion of other causes of disease. AGS is not a nationally notifiable condition, but voluntary public health case reporting shows that thousands of people may be affected. Sensitization to alpha-Gal in the US may be rising: From 2010-2018, more than 34,000 persons in the United States were diagnosed with AGS. From January 1, 2017-December 31, 2022, 295,400 individuals in the US were tested for sIgE via major commercial laboratories, with 48.2% test positivity. The true prevalence of AGS may be higher than these estimates and is expected to rise as clinicians learn to recognize this condition Though the pathophysiology of this condition is not well understood, multiple risk factors may put people at risk to develop AGS. Tick bites are the best known risk factor for IgE to develop against alpha-Gal. Other risk factors include male sex, rural residence, and time outdoors. A possible association of AGS with ABO blood group has been observed: People with group A or O blood may have higher odds of developing AGS compared to the general population and to people with group B. Drugs, vaccines, and other medications with stabilizers have been found to contain alpha-Gal or other alpha-glycans. Yet sIgE, while harmful in people with AGS, may be protective against some infectious diseases. Two examples are 1) self-tolerance to antigen B observed in the immune response to alpha-Gal in malaria and tuberculosis, and 2) high amounts of sIgE in asymptomatic COVID-19 patients. Volunteer blood donors are not screened for this allergy or prohibited from donating blood. With this population, it is possible to measure the prevalence of alpha-Gal sensitization, similar to previous NIH Clinical Center Department of Transfusion Medicine (NIH/CC/DTM) studies of transmission of transfusion-transmitted infections (TTIs). The NIH/CC/DTM Blood Bank, which collects blood donations to supply blood to patients at the NIH CC, is an ideal site to screen blood product donors for alpha-Gal sensitization, with a large base of repeat, longtime donors where transfusion services have reported potential cases of AGS. We are initiating an IRB-approved observational pilot study to screen donors of whole blood, platelets, and other research products for serum IgE (sIgE) as a potential laboratory marker of alpha-Gal sensitization. The study will involve laboratory testing and data analysis of sIgE test positivity, without any clinical diagnosis. Since NIH/CC/DTM Laboratories currently lacks in-house sIgE testing capabilities, the initial phase will focus on: 1. Evaluating the specificity and sensitivity of several commercially available immunoassays (e.g., ELISA). 2. Assessing the feasibility and validity of the Basophil Activation Test (BAT). 3. Assessing the feasibility and validity of the Mast Cell Activation Test (MAT). In the second phase, all specimens will be sent to an external reference laboratory for confirmation using the FDA-approved ImmunoCAP Specific IgE fluorescent enzyme immunoassay (Thermo Fisher), to validate results obtained from in-house testing. Serological testing will be performed on approximately 300 biospecimens of human serum provided by approximately 180 NIH Clinical Center blood product research donors to determine sIgE levels among these donors from the year 2007 (when alpha-Gal syndrome was first described) to the present to calculate the point and period seroprevalence of alpha-Gal sensitization as measured by sIgE levels. All biospecimens exist at the time of this submission, having been obtained from blood donors enrolled in research blood product programs of the NIH/CC/DTM who fully consented to the use of their donations for secondary research such as this study. The study results on the prevalence of alpha-Gal sensitization in NIH/CC/DTM blood product research donors will help DTM investigators to consider undertaking a larger, prospective study to enroll blood product research donors to better understand the natural history of AGS.