Study Warns on Alpha-Gal Syndrome and Blood Transfusions

In areas with high prevalence of tick-induced alpha-gal syndrome (AGS), patients with blood type O appeared to be at significantly increased risk for allergic transfusion reactions to B or AB blood units, according to a retrospective cohort study.

In regions with high prevalence of AGS in the U.S., people with type O blood who received B or AB platelet or plasma units were nearly four times more likely to have an allergic transfusion reaction versus those who received O units (overall risk ratio [RR] 3.93, 95% CI 2.96-5.21, P<0.001), reported Richard Kaufman, MD, of the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and colleagues in JAMA Internal Medicine.

Notably, type O patients living in AGS low-prevalence regions did not have a significantly increased risk of allergic transfusion reactions when they received B or AB blood units (RR 1.06, 95% CI 0.88-1.29, P=0.53).

“This cohort study provides provocative epidemiologic evidence consistent with TRAGS [transfusion-related alpha-gal syndrome] representing a newly recognized risk to recipients of blood transfusions,” Kaufman and colleagues wrote.

“We anticipate that this will change transfusion practices in the U.S., at least in AGS high-prevalence regions,” said Kaufman in a press release.

Group B or AB plasma or platelet units may be given to patients with blood type O in bleeding emergencies or to avoid wasting B or AB units.

AGS is a food allergy transmitted to humans by tick bites. The critical antigen in AGS is galactose-α-1,3-galactose (alpha-gal), a carbohydrate expressed by most mammals but not humans. Patients with AGS usually develop allergic reactions 2 to 6 hours after eating meat from mammals, with presentations ranging from mild urticaria and gastrointestinal symptoms to rare cases of fatal anaphylaxis. The lone star tick is primarily responsible for AGS cases in the U.S., and it is prevalent throughout the Northeast, Southeast, and Midwest.

“The changing climate and ensuing greater proliferation of ticks is leading to illnesses and symptoms we had not seen before, and we continue to learn about them in real time,” said co-author Nancy Dunbar, MD, also of the Dartmouth Hitchcock Medical Center, in the press release. “AGS is a particularly fascinating and challenging tickborne disease as it causes this life-threatening allergy the patient did not have before, and now we know the risk is even greater for AGS patients who are type O.”

The structure of alpha-gal is very similar to the group B antigen on human red blood cells, platelets, and epithelium, which leads alpha-gal antibodies to cross-react with B antigen.

The study offers the strongest evidence yet that TRAGS exists, noted Marie Hollenhorst, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues in an accompanying editorial.

However, “it is important to understand that the number of allergic reactions attributed to alpha-gal syndrome is currently vanishingly small and the added absolute risk to transfusion recipients who live in high-prevalence AGS regions is negligible,” they wrote.

Among the international study’s 558,823 transfusions, allergic transfusion reactions were reported in only 1,744 cases — a rate of 0.3%.

“Physicians should be aware of TRAGS as a potential newly identified allergic transfusion reaction,” they acknowledged, but a stronger causal argument linking alpha-gal immunoglobulin E antibodies to TRAGS might have been made if the study’s transfusion recipients had been tested for the telltale antibody.

For patients with type O blood, prior allergic reactions to transfusions, and positive test results for alpha-gal immunoglobulin E antibodies, “it would be reasonable to avoid future transfusion of plasma or platelet products from group B or AB donors,” they noted.

For this study, Kaufman and team included 40 sites in the U.S., Australia, France, Germany, and Japan in the Biomedical Excellence for Safer Transfusion Collaborative study. In the U.S., nine sites were considered high-prevalence and 15 were considered low-prevalence.

In subgroup analyses among patients with blood type O receiving B units, the risk ratio for moderate to severe allergic transfusion reactions was 9.14 (95% CI 5.39-15.52, P<0.001) in the AGS high-prevalence cluster sites compared with 2.15 (95% CI 1.34-3.47, P=0.002) in the AGS low-prevalence cluster sites.

Giving type A units to type O patients in AGS high-prevalence regions was not linked to a significantly greater risk of allergic reactions compared with type O units (RR 1.60, 95% CI 0.89-2.89, P=0.12).

Type O patients at sites outside the U.S. were five times less likely than U.S. patients to receive type B or AB units, and did not have the same risks from B or AB units as their U.S. counterparts. At one high-prevalence site in Japan, type O patients who received B or AB units actually had a significantly lower risk of allergic reactions (RR 0.33, 95% CI 0.13-0.85, P=0.02).

Study limitations included the possibility that geographic factors not related to AGS could explain the findings. In addition, testing patients for alpha-gal antibodies wasn’t feasible, and patients’ history of AGS wasn’t known.