Alpha-gal Syndrome: When a Tick-Bite Turns to a Meat Allergy
It is widely known that tick bites can lead to a variety of infectious diseases, but did you know that tick bites can also trigger allergic reactions to red meat? Alpha-gal syndrome (AGS) is an allergic disease triggered by the bite of the lone star tick that can lead to severe hypersensitivity reactions and anaphylaxis in patients following exposure to red meat. In recent years, reports of patients with hypersensitivity reactions following the consumption of red meat have been increasing—but why is that?
Knowledge on how to diagnose AGS remains scarce among medical professionals, and treatment options are limited to allergic symptom management. However, a few helpful tools exist when encountering this illness.
Why Is Alpha-gal Syndrome Becoming More Prevalent?
In the U.S., AGS is triggered by the bite of Ambylomma americanum (a.k.a. the lone star tick), which also carries Ehrlichia rickettsia the causitive agent of ehrlichiosis and Rickettsia spp. the causitive agent of Rocky Mountain spotted fever. The lone star tick is the most human-biting tick in the U.S., and it is endemic to many states. A. americanum has expanded its distribution beyond its original range, now reaching the upper midwestern and northeastern regions of the U.S., as well as extending into eastern Canada. Factors like the changing climate play a pivotal role in the increasing geographic range of A. americanum and lead to a growing number of tick bites and associated diseases. Rising temperatures do not only contribute to the ongoing expansion of certain tick species into new geographical areas, but also lengthen their active seasons. This extension may result in changes to host availability, vector numbers, interactions among vectors, and it may alter the prevalence of infections within tick populations.
Outside of the U.S., other tick species have been linked to the development of alpha-gal syndrome and provide increased opportunity for spread. Other species that may be involved with the development of AGS include Ixodes ricinus (Europe), Ixodes holocyclus (Australia), Ixodes cajennense, Ixodes nipponensis, Amblyomma sculptum, Amblyomma variegatum and Haemaphysalis longicornis.
Patients with red meat allergy produce specific IgE antibodies to carbohydrate galactose-α-1,3-galactose (alpha-gal), a carbohydrate found in most mammalian cell membranes. IgE (Immunoglobulin E) antibody production is a response of the immune system to certain allergens. When an individual is exposed to an allergen, which can include foods, dust, pollen and other substances, IgE antibodies specific to that allergen may be produced through the interaction of specific immune cells. Those IgE antibodies then bind to receptors on immune cells, leading to primary sensitization. In the case of AGS, it seems like primary sensitization happens through the tick's saliva. Subsequent exposure to an allergen may then lead to the release of various chemicals, such as histamine or prostaglandins, into surrounding tissues, which causes allergic symptoms. Likewise, patients with AGS experience symptoms after new exposure to the allergenic molecule when eating red meat.
Although, in recent years, reports of AGS are increasing, and research on this topic is of growing interest, alpha-gal is not new. The carbohydrate has been a long-known obstacle for the transplantation of porcine organs into humans. It causes complex biological reactions that activate the complement system, a complex cascade of proteins that act in a coordinated manner to protect the host from pathogens. Ultimately this response results in the destruction of the transplanted organ. Hypersensitivity to alpha-gal is also well described after treatment of patients with therapeutics containing the carbohydrate, for example the monoclonal antibody Cetuximab, which is used to treat advanced bowel cancer and head and neck cancers.
The Role of Tick Saliva in Transmission of AGS and Other Tick-Borne Diseases
Tick saliva is a composition of several hundred molecules, possessing functionalities that extend beyond the simple facilitation of pathogen transfer. Notably, infectious agents, such as bacteria and viruses etc., actively exploit these salivary components to aid disease transmission. Evidence indicates that tick saliva exhibits immunomodulatory properties, suggesting a pivotal role in regulating the complex dynamics inherent to host responses.
Regarding AGS, certain variables have yet to be discerned, as not all individuals exposed to alpha-gal-containing tick saliva subsequently acquire a red meat allergy. Notably, research indicates that ticks engorged with human blood exhibit a considerably heightened production of alpha-gal within their salivary glands compared to those feeding on other mammalian hosts. One study showed significant variability in alpha-gal levels among individual ticks and across diverse geographical locations. This heterogeneity may contribute to the understanding of why not all who are exposed to tick saliva develop AGS. The study also mentioned a noteworthy increase in alpha-gal concentrations within tick salivary glands throughout the duration of the blood meal. While the details of this process remain incompletely understood, the timely removal of ticks during their early feeding stages may potentially mitigate the risk of alpha-gal syndrome. Further investigations are imperative to completely understand the mechanisms at play in primary sensitization and the development of AGS.
Clinical signs of red meat allergy may range from skin manifestations, such as hives, and abdominal symptoms, like nausea, vomiting, cramps and diarrhea. More severe symptoms may include shortness of breath, swelling of the airways and death.
Symptoms commonly start 3-6 hours after the consumption of red meat, such as pork, beef, lamb and other types of mammalian meats. This late onset is different from other food allergies, where symptoms usually start within the first hour of consumption. In fact, in many cases, after primary sensitization, years of consuming red meat pass before patients experience clinical symptoms.
Currently, the most reliable laboratory test for diagnosing AGS is serological testing for alpha-gal-specific IgE antibodies via ImmunoCAP assay. Diagnosis is more likely when positive sIgE (specific IgE antibodies to a certain allergen) antibody levels exceed ≥2 IU/ml or >2% of the patients total IgE level. The total IgE reflects more of a general marker that may be elevated in the case of various immune-related conditions. It is important to mention that the presence of alpha-gal-specific IgE antibodies do not necessarily diagnose the clinical syndrome, though it may be helpful for clinicians to know which patients could possibly develop AGS in the future.
When diagnosing AGS, it is important to consider multiple factors, including clinical presentation, indicative serological results (alpha-gal-specific antibodies, total IgE levels) and risk factors, like tick exposure and geography. It is also important to mention that only a small percentage of patients develop red meat allergy, despite the fact that hundreds of thousands of people get bitten by lone star ticks and may become sensitized to alpha-gal every year.
Alpha-gal Syndrome Treatment and ManagementIt is possible to treat allergic symptoms, however there are no direct treatment options available for AGS. Patients with known AGS are advised to carry self-injectable epinephrine and antihistamines. A vital part of AGS management is educating patients on the importance of avoiding additional tick bites because continuous exposure may increase IgE titers to alpha-gal, whereas avoiding being bitten may decrease them over time.
Patients who have this allergy should avoid consuming mammalian products, which can be difficult, as it is not always obvious which products contain mammalian meat. Alpha-gal-carrying proteins can even be found in mammalian milk, and alpha-gal-specific IgE antibodies may recognize alpha-gal in dairy products. While most patients do not experience reactions to dairy products, a small group of affected AGS patients (<10%) receive the suggestion to exclude dairy products from their diets to reduce the risk of allergic reaction.
There have also been reports of AGS patients having allergic reactions after consuming gelatin or tuna contaminated with dolphin meat. Furthermore, patients with AGS should avoid treatment with medication derived from mammals, including monoclonal antibodies, or gelatin-containing medications. Valve replacement with bovine or porcine heart valves may also trigger hypersensitivity reactions and lead to faster decay of the valve. One way around this issue may be to use pig donors in whom the alpha-gal gene has been removed (i.e., alpha-gal knock out pigs).
Still, those who experience an alpha-gal allergy frequently experience symptoms months or even years after cutting out red meat, and while some reach a condition comparable to remission, the symptoms may resurface following new tick bites. For many people, AGS appears to be a long-lasting illness with a severe impact on mental health.
Yet, research shows that a large number of medical professionals in the U.S. are unaware of AGS, and among the health care providers who are familiar with the disease, knowledge about how to diagnose and treat it is limited. Red meat allergy is a topic of ongoing research, and many questions remain unanswered, however progress has been made in recent years to better understand AGS.
In an era of ongoing climatic changes, medical practitioners may have to transcend the boundaries of their regional knowledge pertinent to vector borne diseases in order to better diagnose and treat affected patients.
Climate change will necessitate a collaborative vector control and prevention plan. ASM held a Congressional briefing, entitled "The Evolving Threat of Vector Borne Diseases and Harnessing Science to Address It," in July 2022 to advocate for strong federal funding for research and public health efforts to better understand how to address these disease threats.