Introduction
Alpha-Gal syndrome (AGS) is a rare and unusual immune-mediated condition characterized by a delayed hypersensitivity reaction to oligosaccharide galactose-α-1,3-galactose (α-Gal). The allergen is found mainly in mammalian meat (beef, lamb, pork) and animal products. The disease is also referred to as red meat allergy [1]. Although this molecule is present in most mammals, it is absent in humans and some primates due to the inactivation of the gene encoding the glycosylation enzyme α1–3galactosyltransferase (α1–3GT) [2]. The development of AGS is associated with tick bites, in which the allergen has been identified in the tick’s digestive tract and saliva. The oligosaccharide enters the human body and induces the production of specific IgE antibodies against α-Gal [3]. Symptoms typically appear 3–6 h after consuming allergen-containing products. This delay is characteristic of this syndrome and distinguishes it from other food allergies. The clinical presentation of AGS varies, making it often difficult to establish a diagnosis. Patients most commonly present with gastrointestinal symptoms, which include abdominal pain, nausea, diarrhoea, and vomiting. Symptoms may also include itching, hives, intestinal cramps, and, in some patients, coughing, chills, or chest tightness. Recurrent anaphylactic reactions are also characteristic [1]. Increased awareness among physicians of the existence of AGS may allow for more effective diagnosis and care of patients with this syndrome.
This paper presents the case report of a 45-year-old patient with non-specific symptoms of AGS and variable asthma control, followed by a current literature review addressing clinical aspects of AGS management.
Case report
A 45-year-old man from central Poland, residing in an urban area, had a long-standing history of asthma and chronic rhinitis. Twenty-five years ago, he visited the allergy clinic due to a dry cough that had persisted for over a year. In addition, he reported persistent year-round nasal congestion, especially in the left nostril. In 2000, the patient was diagnosed with asthma and perennial rhinitis. Repeated spirometry over several years showed no signs of airway obstruction. Post-bronchodilator reversibility tests were negative. Despite treatment, the patient’s asthma symptoms worsened in 2017, with periodic cough and shortness of breath that did not consistently respond to standard doses of inhaled bronchodilators. Several times, the patient required short courses of systemic glucocorticosteroids (GCS). Treatment was changed to a combination of salmeterol and fluticasone, with salbutamol administered as needed. Subsequent spirometry tests, performed at different times of the year (to assess the seasonality of symptoms), showed normal ventilatory lung function. The patient’s asthma was characterized by variable control, requiring periodic increases in the on-demand inhaled salbutamol and the use of short-term oral systemic GCS. Currently, he was prescribed beclomethasone 100 µg with formoterol 6 µg (two doses, twice a day), intranasal fluticasone 100 µg into each nostril once daily, and inhaled salbutamol 100 µg as needed. Oral montelukast was also administered. The patient underwent multiple otolaryngology consultations. A computed tomography scan of the sinuses revealed a slight right-sided deviation of the nasal septum with swelling of the nasal turbinates. The rhinomanometry test was symmetrical. Otoscopic examination revealed no abnormalities. Over the years, the patient’s quality of life deteriorated due to nasal symptoms. The patient was treated intranasally with mometasone furoate, which was later replaced with a combination of azelastine hydrochloride and fluticasone propionate.
Furthermore, laboratory tests ruled out immune deficiencies and endocrine diseases. Diagnostic assessment for autoimmune conditions was also negative.
Family history of allergic diseases is negative; the patient denies use of stimulants.
In laboratory allergy tests, no specific IgE levels above 0.35 kU/l were found for tree allergens, cat dander, cow’s milk, casein, cat allergen components (Fel d1, Fel d 2, Fel d 4, Fel d 7), beef, pork, chicken, turkey, ragweed, timothy grass, mugwort, house dust mites and European cockroaches. A panel for domestic inhalant allergens, including animal allergens, was also performed and yielded negative results. The total IgE remained in the range of 63.5–67.5 kU/l. In skin prick tests (SPT) for inhalant allergens, a 6 mm diameter wheal was found only for tree extracts.
The patient was hospitalized twice due to acute headaches, and organic damage to the central nervous system was ruled out. In 2017, he was hospitalized due to chest pain; however, no diagnosis of a cardiac condition was established. Another hospitalization due to chest pain occurred in September 2024. He began to experience shortness of breath, chest pain of a pressing nature, palpitations, and headache. The symptoms varied in severity. In addition, on the day of hospital admission, he experienced weakness in his lower limbs and diarrhoea. The patient reported that he had eaten a Chinese meal the day before. Cardiological causes of the symptoms were ruled out. The allergological evaluation was expanded. The presence of specific IgE against red meat α-Gal was found at a level of 6.99 kU/l (ImmunoCAP®, Phadia, Sweden). The patient additionally reported that he had frequently visited forested areas, where he had been bitten by ticks several times (the exact number of tick bites was unknown). All aspects of AGS, including possible triggers and recommended food avoidance, were discussed with the patient, and emergency medications were prescribed. In the following months, he denied having been exposed to ticks. In January 2025, the patient developed urticaria several hours after eating a beef and pork kebab. After taking bilastine, the symptoms subsided. Another IgE assessment for α-Gal was performed, which showed its level at 1.59 kU/l (ImmunoCAP®, Phadia, Sweden). The patient is currently continuing anti-asthmatic treatment with stable control.
Discussion
Epidemiology and aetiology
AGS was first described in 2008 in patients treated with cetuximab, a chimeric mouse–human monoclonal antibody against the epidermal growth factor receptor (EGFR), where a relationship between the administration of the drug and red meat allergy was observed [4]. It was observed that IgE antibodies against cetuximab were specific for galactose-α-1,3-galactose, which is found in the Fab portion of the cetuximab heavy chain. In Poland, the first case was described in 2021 by a group of doctors from the Jagiellonian University Medical College in a patient with recurrent anaphylaxis after consuming red meat [5].
The presented case is one of the first cases described in Poland, and to the best of our knowledge, it is the first case described in central Poland at the time of writing this article (December 2025) [6, 7]. Medicines may represent a significant source of exposure to the α-Gal epitope, and their use can lead to both immediate and delayed hypersensitivity reactions, including severe anaphylaxis. The highest risk is associated with parenterally administered mammalian-derived preparations that contain large amounts of α-Gal or strongly activate the immune system. The best documented ones include cetuximab, gelatin colloid fluids, bioprosthetic valves, and high doses of heparin [8]. With cetuximab, reactions can be severe, often occurring after the first administration [8, 9]. There is also a correlation between higher doses of cetuximab and greater immunisation and production of anti-α-Gal IgE [10]. Another factor for AGS is tick bites – Amblyomma americanum (USA), Ixodes holocyclus (Australia), and Ixodes ricinus (Europe) [11]. A cohort study conducted by Ching et al. involved 3,000 US soldiers stationed in areas where the Amblyomma americanum tick is found, to assess the frequency of IgE seroconversion against α-Gal and to determine the risk factors for developing AGS [12]. During more than 3 years of observation, antibodies appeared in 4.9% of participants in whom they were initially absent. Sensitisation developed more frequently in Caucasians and in those who had spent longer periods of time in areas where the tick is observed. A review by Johnson et al. described the progressive expansion of the Amblyomma americanum tick in the north-eastern United States [13]. The authors report an increase in the number of patients with AGS. In another study supporting the link between the growing tick population in the north-eastern United States and increased detection of IgE antibodies against α-Gal, 3,000 soldiers were re-examined. α-Gal IgE was detected in 6% of them. A detailed analysis showed that the geographical distribution of soldiers with positive results coincided with the areas where the Amblyomma americanum tick is found [14]. In Poland, a link was observed between Ixodes ricinus ticks, a species found in Europe, and the production of α-Gal IgE [15].
Pathophysiological mechanism
The pathophysiological mechanisms of AGS have not been fully elucidated, but recent publications confirm the link between tick bites and immunisation and the onset of antibody production against α-Gal, which in turn triggers an allergy to red meat. This relationship has only been described in certain tick species. Observation of patients suggests that tolerance to the antigen is initially preserved, but multiple bites cause the existing tolerance to break down and trigger symptoms of the disease [11]. Evidence suggests that tick saliva plays a key role in the development of immune responses. It consists of a mixture of enzymatically and immunomodulatory active substances, making it easier for ticks to feed on humans. It has been shown that saliva contains high concentrations of prostaglandin E2 (PGE2), reduces the production of pro-inflammatory cytokines (IL-12, TNF-α, IL-1β), and increases the production of anti-inflammatory mediators (IL-10, TGF-β) [16]. Several mechanisms have been proposed in the literature to explain how tick bites can induce α-Gal sensitisation. These concepts focus primarily on the content of tick saliva and its effect on the host’s immune response. The first proposed concept assumes that the α-Gal antigen is present in tick saliva. Under laboratory conditions, during Amblyomma americanum infestation, a gradual transformation of the N-glycan profile occurs in its salivary glands. As the duration of blood feeding increases, so does the amount of glycan structures, including those containing the key epitope galactose α-1,3-galactose (α-Gal), which are introduced into the human body and are a potential source of stimulation of the host’s immune response. It has been suggested that the accumulation of α-Gal epitopes during successive bites leads to human sensitisation [17]. Another proposed mechanism involves α-Gal antigen in tick saliva, which is presented to antigen-presenting cells and B lymphocytes. Another possible mechanism is based on the possibility that prostaglandin E2 in tick saliva induces a class switch in B lymphocytes producing anti-α-Gal IgE from pre-existing mature B lymphocyte clones producing anti-α-Gal IgM and/or IgG antibodies [18]. Interestingly, the carbohydrate structure of the α-Gal molecule is similar to that of the blood group B antigen. Studies show that blood groups B and AB are rare among AGS patients [19, 20]. It has been shown that these individuals have significantly lower levels of anti-α-Gal IgE in their blood. The B antigen on erythrocytes may stimulate tolerance to α-Gal [21].
Clinical presentation
AGS is a relatively new food allergy phenotype. A study involving 128 people with AGS indicates characteristic features in the patient’s clinical profile. In most cases, the patient is middle-aged. After consuming meat or meat products, allergy symptoms develop, mostly after 2 h of eating. The most common symptoms were urticaria (90%), gastrointestinal symptoms (74%), and angioedema (62%). Anaphylaxis (mainly in the form of cardiovascular symptoms) occurred in individuals with increased antibody titres, and coexisting atopy increases the risk of respiratory anaphylaxis symptoms such as shortness of breath, wheezing, coughing, and bronchospasm [22]. This observation is also relevant to the present case with long-term asthma with a variable course. The duration and frequency of tick exposure remain unknown and so do whether and how this could have affected the course of his asthma. The relationship between atopic diseases and AGS requires further investigation. Additionally, on two occasions, symptoms were more delayed than typically reported in the literature. The co-occurrence of other allergies was assessed by Kiewiet et al. in a group of 138 patients with a confirmed positive IgE anti-α-Gal profile. Symptoms of anaphylaxis were reported by 47.8% of patients. The most commonly identified allergies were to food allergens (33%), followed by grass and tree pollen allergens (33%) and pets (27%). Molecular analysis showed that positive results for cat (75%) and dog (85%) skin extracts rarely corresponded to sensitisation to the actual allergenic molecules, Fel d 1 and Can f 1/Can f 5 (21.7% and 10.1%, respectively). Only sensitisation to lactoferrin correlated with an increased risk of anaphylaxis, which may suggest the presence of α-Gal in lactoferrin [23]. Idiopathic anaphylaxis in individuals who have not yet been diagnosed may be a significant clinical symptom. In a study by Carter et al., anti-α-Gal IgE antibody levels were examined in 70 individuals with idiopathic anaphylaxis, in which the following symptoms predominated: urticaria, angioedema, tachycardia, and gastrointestinal complaints. IgE antibodies against α-Gal were detected in six individuals (9%). When treatment was administered by eliminating red meat from the diet, no further anaphylaxis was observed. The researchers emphasise the importance of routine testing for anti-α-Gal antibodies in patients with idiopathic anaphylaxis, as this may be the first symptom of AGS [24]. In another study, Binder et al. analysed 100 patients. The clinical presentation varied from urticaria to severe anaphylaxis, which was observed in 75% of patients. Similarly, symptoms usually occurred 2–6 h after consuming products containing α-Gal. The most common symptoms were skin and mucosal symptoms (87%), with urticaria being the most frequent, followed by gastrointestinal symptoms (66%), most commonly nausea, vomiting, and abdominal pain. Pork and beef were the most common triggers of anaphylaxis symptoms. Especially severe gastrointestinal symptoms were observed in patients who also reacted to dairy products, while patients who tolerated dairy products more often had isolated skin symptoms, which may indicate a different clinical phenotype. Patients who tolerated dairy products had a higher ratio of IgE α-Gal to total IgE, suggesting possible differences in the immune response between these groups [25].
The clinical presentation of inflammatory bowel disease may be similar to red meat allergy syndrome, so gastroenterologists must be careful not to miss AGS. The study by Muratore et al. presented two examples of patients with inflammatory bowel disease (IBD) – one with Crohn’s disease and the other with ulcerative colitis. The patients reported recurrent nausea and vomiting, as well as diarrhoea occurring several hours after consuming red meat. After testing, elevated levels of α-Gal-specific IgE antibodies were found, which led to the implementation of an elimination diet and, in the first case, the avoidance of AGS-related medical products, resulting in the resolution of symptoms [26]. The most intriguing symptoms in our patient were those related to the circulatory system during the first reaction. This highlights the need to identify potential biomarkers of this reaction that could be detected as quickly as possible.
Children may also be among patients with AGS [27]. In this population, symptoms are also misinterpreted, as in the case of a 7-year-old boy who was initially suspected of having chronic spontaneous urticaria due to initial difficulties in identifying the causative factor [28]. In a study by Wilson et al., 35 children and 226 adults were analysed who had confirmed specific IgE against α-Gal (≥ 0.35 IU/ml). The clinical and immunological profile of the children was largely similar to that observed in adults. Most children reported late symptoms typical of AGS, appearing several hours after a meal. The most common symptoms were urticaria and gastrointestinal complaints, which were reported by about two-thirds of paediatric patients. This percentage was almost identical to that in adults, suggesting similar clinical reactivity regardless of age [29].
The risk of allergic symptoms in patients with AGS varies significantly depending on the type of food consumed. Offal, especially pork and beef kidneys, has the highest allergenic potential, as it has the highest α-Gal epitope content and the strongest ability to activate basophils and mast cells. Red meat was characterised by a high degree of potential to cause allergic symptoms. It was noted that meat from wild animals is more allergenic than meat from farm animals. Among all the products tested, milk had the lowest allergenicity [30].
Diagnostics
In AGS, consumption of red meat often leads to delayed anaphylaxis, which significantly hinders early detection of the disease due to the unclear triggering factor of anaphylaxis. This is likely because α-Gal is associated with lipids, which are slowly absorbed in the form of chylomicrons. The appearance of these structures in the blood enables cross-linking of IgE on mast cells and basophils, which initiates degranulation and clinical symptoms [31]. In addition, meat is characterised by a long digestive and intestinal passage process. Therefore, several hours after ingestion, allergens may penetrate the intestinal mucosa and cause an allergic reaction [32].
Diagnosis is primarily based on medical history, interpretation of symptoms, α-Gal IgE testing, BAT, and oral provocation testing. Standard skin tests (SPT) for meat extracts are characterised by low sensitivity and often give negative or inconclusive results, prompting the search for new products, such as the promising results of SPT with cetuximab [33].
The most important diagnostic element in AGS is a thorough patient history. Initially, the patient may not associate their symptoms with meat consumption, which poses a diagnostic challenge [1, 11]. The detection of specific IgE against α-Gal plays a key role in the diagnosis of red meat allergy, with a positive result considered to be above the diagnostic threshold of 0.35 kU/l. However, lowering the threshold to 0.1 kU/l is being considered because a low cut-off concentration is characterised by high sensitivity and specificity. The data collected indicate that a diagnostic threshold of 0.1 kU/l may be a useful tool in the diagnosis of AGS, particularly in the context of ruling out the disease [34].
An analysis of IgE and IgG antibodies specific for α-Gal was performed in patients with delayed allergy to red meat. It was found that IgE and IgG specific for α-Gal in these patients most often recognise bovine gamma globulin (BGG). The IgG subclass profile in patients was clearly different from that in individuals without red meat allergy. Patients showed elevated levels of α-Gal-specific IgG1 and IgG3, while individuals without allergies showed higher concentrations of IgG4 (the comparison group consisted of individuals with birch pollen allergy associated with apples). This suggests an uncommon nature of the immune response in the context of food allergies [35].
In recent years, the basophil activation test (BAT) has been found to be a useful tool for differentiating between fully symptomatic AGS and the asymptomatic presence of IgE antibodies against α-Gal in patients before the first application of cetuximab. In patients with clinical symptoms, BAT reveals clearly increased basophil activation. Additionally, the degree of basophil activation positively correlates with the severity of symptoms [36].
Despite its high sensitivity and specificity, BAT is not widely available in clinical practice. For this reason, when the results of immunological tests and medical history do not allow for a clear confirmation of AGS, the gold standard remains an oral provocation test, preferably with cooked pork kidney [37].
Treatment
Targeted treatment is difficult. The basic non-medical approach is to eliminate the consumption of products containing oligosaccharide galactose-α-1,3-galactose, especially mammalian meat, including beef, pork, lamb, offal, and game. Most patients tolerate dairy products, although in some patients, symptoms persist despite the elimination of red meat, in which case dairy products should also be eliminated from the diet. It is also important to pay attention to numerous hidden sources of mammalian ingredients, such as pork casings in poultry sausages, fats added to dishes, and gelatin in sweets [31]. Particular attention should also be paid to possible factors contributing to the reaction, such as alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and physical exertion [31, 38]. A key element is also the prevention of further tick bites by wearing appropriate clothing and using repellents, as well as the rapid removal of ticks, as observational data indicate that the concentration of specific IgE antibodies against α-Gal may gradually decrease in patients with AGS as long as they avoid further tick bites. A retrospective analysis of 67 patients showed that in individuals who did not report exposure to ticks, α-Gal-IgE and tIgE levels decreased significantly over time. The opposite trend was observed in patients exposed to tick bites – in the majority (62%), there was an increase in α-Gal IgE concentration, and tIgE was not reduced [39]. Patients who avoid bites for a long time (1–2 years) often regain their ability to tolerate meat [40]. The key and fundamental method of effective treatment of the disease is patient education. Patients at increased risk should be educated on reading food labels, recognising hidden sources of allergens, and receive clear instructions on what to do in the event of an allergic reaction [40].
The main pharmacological treatment used is oral antihistamines. Oral cromoglycate solution or short-term oral GCS therapy may be considered [41]. Regarding our patient, the symptoms of urticaria after eating subsided after taking bilastine and did not require stronger medication. However, due to the severity of the previous symptoms and the co-occurrence of asthma, the patient was prescribed adrenaline. One of the promising treatment options for AGS is oral immunotherapy (OIT). In a study of 20 patients with confirmed red meat allergy, 12 underwent desensitisation in two protocols (early and delayed). The rest formed a control group. All desensitised patients achieved tolerance to meat. During a five-year follow-up, the concentration of α-Gal IgE gradually decreased in most of them, while it remained stable in the control group. In only a few patients, tick bites again caused symptoms and an increase in IgE levels, which proved the efficacy and safety of the therapy [42]. Another promising treatment for AGS is anti-IgE monoclonal antibodies (omalizumab) [40]. It was observed that combining it with OIT increases the efficacy and safety of OIT [40].
Conclusions
This case, supplemented by a review of the current literature, highlights the diagnostic challenges associated with this recently described allergy. Low awareness among physicians and patients about the existence contributes to difficulties in linking atypical symptoms with prior tick exposure. The potential occurrence of AGS should also be considered when evaluating adverse drug reactions. This case highlights that many questions remain unresolved with regard to the diagnostic and therapeutic approach to AGS. Considering this, further research into AGS is warranted to provide more insights, particularly into its epidemiology and clinical management. Additionally, AGS may be considered as a possible cause of otherwise unexplained respiratory discomfort; however, its association with asthma remains uncertain and warrants further study.
