Shaker M, Wang J, Chu D, Anagnostou A, Greenhawt M
The journal of allergy and clinical immunology. In practice •
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.
Jacobs JW, Kaufman RM, Schwartz JY, Hall E, Tahiri T, et al.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons •
Alpha-gal syndrome (AGS) is an IgE-mediated hypersensitivity to the oligosaccharide galactose-α-1,3-galactose, acquired through tick bites and increasingly recognized as a cause of allergic reactions to mammalian-derived medical products. Every major transplant modality creates distinct conditions under which sensitized patients may encounter alpha-gal, yet AGS knowledge has developed almost entirely outside the transplant literature. In conventional solid organ transplantation, risk arises primarily from perioperative exposures to porcine-derived heparin, gelatin-based hemostatic agents, and other mammalian-derived materials. In xenotransplantation, the well-characterized role of alpha-gal as the principal xenoantigen has driven development of glycoprotein alpha-galactosyltransferase 1-knockout swine, but the distinct IgE-mediated pathway that defines AGS has received little attention. Hematopoietic stem cell transplantation introduces questions about conditioning-related immune remodeling of preexisting IgE sensitization, rabbit antithymocyte globulin as an underrecognized alpha-gal exposure, and transfusion-related alpha-gal syndrome when group B or AB plasma-containing blood products are transfused to susceptible patients. Cellular therapy manufacturing workflows that use animal-derived ancillary materials represent a further theoretical exposure pathway. Importantly, detectable anti-alpha-gal IgE does not invariably predict clinical reactivity, and the most appropriate clinical approach is risk stratification rather than reflexive exclusion. Generating the evidence base to support such stratification will require collaboration across allergy, transplant, and transfusion medicine.
Malard L, Beuscart C, de Chaisemartin L, de la Taille V, Delettre F, et al.
Vox sanguinis •
Severe transfusion reactions to group B-incompatible platelets and plasma possibly related to the α-gal syndrome (AGS) have been recently described. AGS is a potentially severe Immunoglobulin E mediated allergy to mammalian meat and meat-derived products associated with tick bites. The involved allergen, galactose-α-1,3-galactose (α-gal), is antigenically similar to the blood group B antigen. To further assess a potential association between AGS and allergic transfusion reactions (ATRs), we comparatively assessed the frequency of ATRs after plasma or platelet concentrate (PC) transfusion in relation to the degree of ABO compatibility between the recipient and the involved blood component in France. In France, all transfusions are centrally recorded, and ATR reporting is mandatory. Frequencies of severe ATRs involving PC or plasma in relation to ABO group distributions were analysed between 1 January 2022 and 31 December 2024. Among 981,955 PC and 580,230 plasma evaluable transfusions, severe ATRs were significantly higher in group O recipients transfused with group B or AB platelets (relative risk [RR]: 5.06, 95% confidence interval [CI]: 3.27-7.83, p < 0.001) and plasma (RR: 2.15, 95% CI: 1.37-3.36, p < 0.001) while not in group A recipients of group B or AB platelets (RR: 0.95, 95% CI: 0.30-2.96) or plasma (RR: 0.92, 95% CI: 0.45-1.88), when compared to ATR rates in all other recipients of PC or plasma, respectively. In this national retrospective haemovigilance analysis, group B or AB PC or plasma transfused to group O recipients is associated with an increased risk of severe ATRs. Further studies will establish whether AGS is involved in this increased risk.
Alpha-gal syndrome (AGS) is caused by IgE antibodies against the alpha-gal oligosaccharide, which is structurally similar to the Group B antigen. Recent case reports of severe allergic transfusion reactions (ATRs) in Group O patients receiving Group B plasma and platelets raise the possibility of a new adverse event, herein called transfusion-related AGS (TRAGS). The primary goal of this study was to assess the frequency of Groups B and AB plasma and platelet transfusions to Group O patients. In this multi-site retrospective study, participating sites submitted the numbers of platelet and plasma transfusions administered during a 2-year period categorized by patient and product ABO group. Fourteen sites from 10 countries participated. Group O patients received Group AB for an average of 9.9% (range 2.8%-29.2%) of plasma transfusions and Group B for 3.2% (0%-12.8%). AB plasma transfusion to Group O patients represented 4.5% (0.9%-14.6%) of the total plasma transfused; Group B 1.4% (0%-5.1%). Group O patients received Group AB for an average of 1.5% (range 0%-5.9%) of platelet transfusions and Group B for 4.1% (0%-14.2%). AB platelet transfusion to Group O patients represented 0.6% (0%-2.7%) of the total platelets transfused; Group B platelets were 1.8% (0%-6.7%). Evidence supporting the possibility of a new adverse event, TRAGS, is accumulating. This study quantifies how often Group O patients may be exposed to Group B antigen in Group B or AB plasma and/or platelet transfusions, providing an estimate of the scope of potential risk for TRAGS.
Jones VM, Nakahara H, Choudhary SK, Dunbar NM, Szczepiorkowski ZM, et al.
Transfusion •
The bites of certain tick species can induce galactose-α-1,3-galactose (alpha-gal) IgE formation. Individuals with alpha-gal IgE can become allergic to meat, a condition termed alpha-gal syndrome. Alpha-gal is structurally related to B antigen. Recent case reports (Gilstad et al., 2023 and Miller et al., 2024) suggest that transfusing group B plasma or platelets to group O individuals with alpha-gal IgE can trigger severe allergic transfusion reactions. However, mechanistic evidence is lacking. A 76-year-old group O man undergoing heart surgery became profoundly hypotensive after receiving 50 mL of a group B platelet unit. He recovered with diphenhydramine treatment. We investigated potential causes of anaphylaxis (alpha-gal syndrome; IgA deficiency; protamine, and rocuronium allergies). The platelet unit and patient samples were analyzed by flow cytometry. Indirect basophil activation tests (iBATs) were performed on the patient's plasma. The patient's serum tryptase level spiked, consistent with anaphylaxis. His serum tested positive for alpha-gal IgE (1.49 kU/L). Flow cytometric analyses demonstrated that: (1) the transfused platelets expressed substantial B antigen, and (2) the patient's plasma contained IgE-recognizing alpha-gal and B antigen > A antigen. In iBATs, resting allogeneic basophils incubated with the patient's plasma showed equivalent (albeit weak) activation when stimulated with either alpha-gal or B antigen. We report a case of anaphylactic shock in an O patient transfused with a B platelet unit. The in vitro data suggest, but do not prove, that the reaction was mediated by recipient alpha-gal IgE. Further studies are needed to establish whether transfusion-related alpha-gal syndrome ("TRAGS") is a true clinical entity.
