Alpha-gal syndrome

To the Editor: Meat is an important source of protein and could be roughly classified into red and white meat. White meat, which encompasses poultry, seafood such as fish and shrimp, and reptiles, etc., is characterized by its pale color when uncooked. Red meat is basically mammalian meat, including domestic animal meats, such as pork, beef, lamb, and wild animal meat in certain regions, such as kangaroos, seals, and whales. Uncooked mammalian meat appears red due to the presence of myoglobin in skeletal muscles. The clinical presentations of mammalian meat allergy comprise two types of allergic reactions, immediate-type and delayed-type, although both are mediated by immunoglobulin E (IgE). The immediate-type hypersensitivity manifests as allergic symptoms occurring shortly after ingestion of red meat and is primarily triggered by serum albumin and immunoglobulin which are the major allergenic components. This is the classic pattern of food allergy. The delayed-type hypersensitivity is characterized by delayed onset of allergic symptoms 2–6 h after red meat ingestion and is mediated by oligosaccharide α-gal-specific IgE which is a recently discoveried pattern of food allergy.1 Unlike most allergic diseases, the allergen of delayed-type red meat allergy, α-gal, is not protein but rather oligosaccharide. In nature, α-gal epitope (Galα1-3Galβ1-4Glc NAC-R) is abundantly expressed on glycoconjugates of protein-linked glycan chains in non-primate mammals, prosimians, and "New World monkeys", but not expressed in "Old World monkeys", apes, or humans. The β-galactose α-1,3-galactosyltransferase (referred to as glycosyltransferase UDP-Gal, α-1,3-GT, or α-1,3-glycosidic bond transferase) was inactivated by deletion mutations during evolution, which prevented the formation of α-1,3-glycosidic bonds. Alpha-gal could be found in various foods of mammalian origin, not only in skeletal muscle but also in visceral organs, fascia, smooth muscle, dairy products, and other products. Additionally, α-gal can be present in gelatin, which is processed and produced from connective tissues such as mammalian bone and fascia, as well as in biological drugs and vaccines containing mammalian α-gal.1–3 Currently, sensitization of α-gal and clinical manifestation of allergic reaction to α-gal is denoted as alpha-gal syndrome (AGS). Platts Mills' research revealed that patients with red meat allergy had a fairly high incidence of α-gal-specific IgE positivity, and the distribution of red meat allergy or higher α-gal-specific IgE coincided with that of the spectrum of Rocky Mountain spotted fever (RMSF) and Amblyomma americanum activity. A prospective study was performed revealing that after being bitten by ticks, total IgE and specific IgE antibodies to α-gal increased proportionally in three individuals.1 The first case of red meat allergy in China was reported at the Annual Meeting of the Chinese Allergy Association in 2011. A female developed anaphylaxis at midnight, 5 h after ingesting pork. The intradermal test of pork, beef, and lamb was positive. The ticks on her dog were identified as Haemaphysalis longicornis.2 Specific IgE to α-gal was strongly positive (>100 kU/L), specific IgE to dog, cat, milk, pork, beef, and lamb was also positive. Western blotting was performed and confirmed the specific binding of mammal meat extract and viscera (liver, kidney, etc.) with the patient's serum. In recent years, we have published more AGS cases, including red meat allergy case series research and vaccine-induced anaphylaxis.3,4 It is hypothesized that α-gal in the digestive tract of ticks and salivary glands originates from non-primate mammals that were previously bitten. As soon as α-gal-bearing ticks attack immune-susceptible humans, α-gal is injected into the victims and stimulates the victims' immune system to produce α-gal-specific IgE antibodies. Compared to delayed-type red meat allergy due to tick bites in Europe and the United States, a case series study of red meat allergy in China has shown that most of the patients with AGS had not noticed tick bites, and some of them denied having been bitten by ticks or insects even after careful questioning.1,3 This may be related the relatively moderate or gentle tick bite pattern in Northeast Asia (identified as Haemaphysalis longicornis in both China and Japan), which differs from that of previous studies in Europe and the United States. These ticks inject a variety of biologically active substances into the host simultaneously to facilitate its blood-sucking, encompassing not only proteins that anchor the mouthparts to the host's skin but also enzymes and vasodilators, alongside a specialized cocktail of anti-coagulants to prevent blood clotting, anesthetics to reduce the likelihood of detection by minimizing sensation at the bite site, immunosuppressants to inhibit local immune responses, and anti-inflammatory agents to decrease inflammation, all of which contribute to the stealth of the tick by ensuring that the bite remains undetected due to the absence of significant local pain or itching.This poses difficulties for the awareness of both victims and medical workers. It is recommended that if AGS is suspected, medical workers should evaluate not only patients' atopy constitution but also their risk of tick exposure carefully, such as residential region (suburban, rural, pasture, or forested areas); outdoor hobbies (hiking, fishing, etc., during tick active seasons such as spring to autumn); exposure of domestic or wild mammals (dog, pig, cattle, horse, deer, etc.).1 Cetuximab was the first medication discovered to be associated with α-gal. Some patients experienced anaphylaxis during or soon after their first cetuximab injection. Subsequent research indicated that the mechanism by which cetuximab causes anaphylaxis may be related to the presence of specific IgE antibodies in patients against the oligosaccharide α-gal epitope at the 88th amino acid on Fab portion of the heavy chain of cetuximab. And these patients were sensitized to red meat and some of them had experienced delayed-type anaphylaxis after ingestion of red meat before cetuximab allergy.1 Gelatin is a complex combination of proteins and peptides produced through partial hydrolysis of collagen extracted from the skin, bone, or connective tissue of bovine or porcine animals or fish. It is widely utilized as a food ingredient or additive, substitute for infusion colloidal plasma, and stabilizer in vaccines. Alpha-gal was detected in gelatin of mammal origin. Most patients allergic to red meat were sensitized to gelatin, and yet only a subset of gelatin allergy patients was clinically allergic to red meat.4 Cases of allergy or anaphylaxis to gelatin-containing food, vaccines, and plasma substitutes have been reported. The duration of onset depends on the route by which gelatin was introduced. The fastest onset is caused by exposure to a hemostatic sponge containing gelatin when filling a wound during intraoperative hemostasis, which usually manifests 5 min after exposure, followed by intravenous infusion of gelatin as a colloidal capacity supplement. For suppositories containing gelatin, allergic reactions may occur half an hour afterward, slightly longer than after intravenous preparations. Allergy symptoms caused by gelatin in vaccines usually occur 0.5–1 h after vaccine injection. Gelatin in vaccines for measles, mumps, and rubella (MMR), chickenpox, encephalitis, rubella, and influenza virus has been documented to cause allergies, with MMR being the most prevalent.4 We reported anaphylaxis caused by gelatin components in chickenpox and hepatitis A vaccines. The specific IgE of α-gal, gelatin, cow's milk, pork, mutton, beef, cat dander, and dog dander was positive in the patients yet they did not manifest immediate-type or delayed-type red meat allergy,4 which was consistent with previous studies. The absence of red meat allergy history is not a guarantee of safety from gelatin allergy. Evaluation of specific IgE antibodies to α-gal is recommended in patients with a high risk of anaphylaxis. Human blood type was associated with the prevalence of red meat allergy under an equivalent exposure density of tick bites. Individuals of types A or O are more likely to produce anti-α-gal-specific IgE antibodies following tick bites, whereas individuals of types B and AB are more likely to develop tolerance to α-gal antigens and are therefore less susceptible to red meat allergy and AGS. In our clinical investigation, most of the patients with a history of red meat allergy were non-B blood types (A or O), which was consistent with previous researches. Human ABO blood group substances, expressed on the membrane of erythrocytes, are primarily oligosaccharides. Human type B substances are formed by a combination of α-gal and fucose residue, similar to that of α-gal structure in non-primate mammals, thus the immune systems are prone to immune tolerance rather than sensitized to α-gal exposure. Red meat allergy usually manifests as a delayed pattern, i.e., allergic symptoms typically begin 2–6 h after meat consumption, which is different from traditional IgE-mediated food allergy. However, some patients reported a shorter delay, which was typically associated with alcohol consumption, high α-gal content in food, and exercise after a meal. It is currently believed that the delayed symptoms of red meat allergy are related to the digestion, absorption, and transfer of related glycoproteins and/or glycolipids. Compared to proteins, lipids are digested through a distinct, slower mechanism. Since lipids are digested and absorbed more slowly than proteins, the combination of α-gal and lipids may induce delayed reactions in patients with α-gal allergies. Diagnosis of red meat allergy is based on the delayed onset of allergic symptoms or anaphylaxis after intake of red meat, and proven sensitization to red meat (skin test and/or serum IgE) and α-gal specific IgE ≥0.35 kU/L (ImmunoCap) as well. The absence of tick bites does not exclude AGS because tick bites may be easily ignored. Currently, diagnosis of red meat allergy is difficult and challenging, partly due to the delay of symptoms. It is recommended to conduct a red meat skin prick test as a primary screening, but the sensitivity of skin prick tests to red meat extracts is rather low. The sensitivity of intradermal tests is higher than that of skin prick tests, but commercial intradermal reagents for red meat are not available in many countries, including China. Detection of α-gal specific IgE is crucial to the diagnosis of AGS. We detected α-gal specific IgE in patients with clinically confirmed red meat allergies, all of whom were positive for α-gal. Basophil activation tests based on cluster of differentiation (CD) 63 expression can also be considered. Sensitization to dog or cat dander may serve as collateral evidence of red meat allergy or AGS since all of our patients tested positive for dog and/or cat dander. Based on our experience, the semiquantitative allergen panels currently available in China exhibit rather poor accuracy in detecting red meat allergy. AGS is an unusual clinical syndrome and a latent fatal disease characterized by α-gal sensitization and may manifest as delayed food allergy or anaphylaxis after consuming mammalian meat. If exposed to medications, vaccines, or medical instruments containing α-gal through oral, injection, transplantation, or surgical routes, sensitized individuals are at risk of developing urticaria, anaphylaxis, or even death. Tick bites are regarded as an important sensitization pathway, particularly in populations with blood groups A or O (non-B type). Currently, the pathogenesis of AGS is not completely understood. Further research on the pathogenesis of AGS will provide a deeper understanding of the pathogenesis, diagnosis, and treatment of infection, allergic diseases, and even tumors.5 Funding This work was supported by grants from the National High Level Hospital Clinical Research Funding (Nos. 2022-PUMCH-B-088 and 2022-PUMCH-B-032). Conflicts of interest None.