Red meat allergy (alpha-gal syndrome): the link with tick bites and delayed reactions

Galactose-alpha-1,3-galactose is an oligosaccharide (a sugar) present in the proteins and lipids of most mammals, including cattle, pigs and sheep, but not in humans, so the human immune system can recognise it as foreign. This distinguishes alpha-gal from typical food allergens: it is not a protein but a carbohydrate. IgE antibodies to alpha-gal were first described in connection with immediate reactions to cetuximab, an anticancer drug, and then in connection with allergy to mammalian meat.

The exact mechanism by which a tick bite sensitises to a sugar is not fully explained; the authors of reviews speak of attempts to describe the immune mechanisms and of the possibility that this may shed light on type 2 immunity in general. The evidence that exposure to certain hard ticks causes sensitisation is multi-directional (clinical observations, serological studies, a mouse model), but it is not yet known why in some people bitten by ticks sensitisation arises and in others it does not. Additional factors, such as atopy, may modify the clinical picture, which we discuss below.

The delay is the most characteristic feature of the syndrome and the main reason for delayed diagnosis. The description of the first series of patients from Virginia remains a model example of this clinical picture.

Why does the reaction come after several hours? The explanation is not fully established, and we do not present any hypothesis here as fact. It is worth noting, however, that the 3-6 hour range comes from patients' histories, and in a controlled challenge the median time to symptoms can be shorter: in an analysis of 91 children and adults reacting to meat given under observation it was 90 minutes in people with isolated gastrointestinal symptoms and 120 minutes in those with systemic symptoms. The practical conclusion is independent of the mechanism: a dinner with meat and a reaction at night or some hours later may be linked, and the delay is variable.

The first descriptions of the syndrome came from the United States, where the main role is attributed to the tick species Amblyomma americanum. In Europe the sensitisation is linked to other species, and the evidence points to the castor bean tick (Ixodes ricinus), the same one that in Poland transmits Lyme disease and tick-borne encephalitis virus. The clinical review notes that different ticks are responsible in different countries.

Two conclusions from this study deserve emphasis. First, a tick bite multiplied the chance of detecting antibodies, which confirms the link, but detecting specific IgE is not the same as clinical allergy: not everyone with a positive result has symptoms after meat. Second, sensitisation to alpha-gal did not appear to depend on infections transmitted by ticks, so it is not a marker of Lyme disease and does not call for antibacterial treatment.

In the Swedish cohort the clinical picture is fairly consistent: urticaria in 9 of 10 patients, gastrointestinal symptoms (abdominal pain, diarrhoea, nausea, vomiting) in almost 3 of 4, and anaphylaxis in nearly half. Some people have only intestinal symptoms without skin changes, which makes diagnosis harder still, because it resembles irritable bowel syndrome or indigestion. The intensity of symptoms is variable, and the dose and cofactors may also decide the reaction, although we do not give specific thresholds.

The Swedish study draws attention to the role of atopy: in atopic people (with airborne allergy, asthma, atopic dermatitis) the severity of symptoms, especially pulmonary ones in anaphylaxis, tends to be greater. Data on the influence of blood group are limited and are of no practical importance to the patient.

In practice the diagnosis therefore rests on two elements. The first is the history: when after a meal symptoms appeared, what the meal was, whether there were tick bites, whether the symptoms correspond to a delayed reaction. The second is the measurement of specific alpha-gal IgE in the blood. A positive result with a consistent history is enough in most cases; remember, however, that a positive result alone without symptoms is not a diagnosis of disease, as the Podlasie study confirms, in which antibodies were also found in people without symptoms. Skin tests with meat often give weak responses in alpha-gal syndrome, and intradermal tests or tests with fresh food are sometimes more reliable, as described in the first series of patients. A food challenge is performed in a centre prepared to treat severe reactions, not on your own.

The basis of management is avoiding mammalian meat: beef, pork, lamb, horse meat, mammalian game and products that contain them (cold cuts, sausages, pâtés, stocks, animal fats). The clinical review notes that in some cases avoiding dairy is also necessary. Poultry (chicken, turkey) and fish do not contain alpha-gal and in the first series of patients did not provoke specific IgE. The extent of the diet depends on the particular patient and their reactions, so it is worth agreeing it with an allergist and a dietitian instead of eliminating everything.

Reactions may depend on cofactors. The review by Wilson et al. mentions that cofactors can influence the clinical picture, and the literature on food allergy in adults points to exercise, alcohol and anti-inflammatory drugs as factors that lower the threshold of reaction; specific data for alpha-gal syndrome are, however, less detailed, so we give no precise thresholds. In practice it is sensible to avoid exercise, alcohol and anti-inflammatory drugs in the period after a meal if it is not certain that the food did not contain mammalian ingredients. Agree final recommendations with an allergist.

Since almost half the patients in the Swedish cohort had anaphylaxis, every patient should know the symptoms of a severe reaction and have a management plan. The EAACI anaphylaxis guidelines recommend intramuscular adrenaline as first-line treatment and access to autoinjectors for people at risk; we describe these principles in detail in the article on nut allergy in adults. In alpha-gal syndrome it is also important that the delay of the reaction means symptoms can appear when the patient is already away from home or asleep.

For many patients the most important question is: will I be able to eat meat again? According to the clinical review, levels of specific alpha-gal IgE often fall in people who avoid further tick bites, but the rate of decline is very variable. This means that in some patients the sensitisation may weaken over time, while in others it persists for a long time. There are no reliable data that would allow predicting in a given person whether and when this will happen, and reintroducing meat into the diet should take place only under the supervision of an allergist, after repeat assessment of antibodies and, if necessary, a controlled challenge.

Since further bites may sustain the sensitisation, it is important to limit exposure to ticks: suitable clothing when outdoors, using repellents according to the instructions, examining the skin carefully after returning and removing a tick quickly. These are general principles for preventing tick-borne diseases, which we discuss more widely in the article on Lyme disease; for alpha-gal, however, there are no studies showing that particular preventive methods shorten the duration of the sensitisation, so we treat them as sensible but not proven for this syndrome.

What we do not know: there are no reliable Polish data on the frequency of clinical alpha-gal syndrome; the Podlasie study concerned the detectability of antibodies, not the number of patients. The mechanism of the delay of the reaction is not fully explained. Data on cofactors are less detailed than for other allergies. It is not known which of those bitten by ticks will develop sensitisation. We do not discuss here the availability of tests or reimbursement rules in Poland, because we do not rely on sources confirming that information. The article does not replace an allergy consultation.

Alpha-gal syndrome is a reminder that food allergy does not always have an immediate course, and that a trace in the history, such as a tick bite, may matter many months later. The diagnosis is simple once someone thinks of it and the management effective, so it is worth remembering in every adult with unexplained night-time reactions after dinner.