Diagnosing Alpha-Gal Syndrome

How is Alpha-Gal Syndrome Diagnosed? Updated 12-8-2017 Considering alpha-gal syndrome(AGS) is relatively new to medicine in the grand scheme of things, diagnosing the ailment can be tricky, to say the least1. From symptoms that are easily confused with other more famous or common issues, to a general lack of common knowledge on the subject, doctors are put to the test when called on to recognize this condition.  It's no wonder the majority currently known cases came about after an average of more than 7 years of symptoms with patients self diagnosing and teaching their doctors rather than the other way around.11  Thankfully, this is starting to change with more and more people being diagnosed correctly within a year of symptom onset, and we have written this article to help with that process.  Multiple factors are taken into account when a specialist diagnoses alpha-gal syndrome, some of which we describe below.  If you are concerned you may have alpha-gal syndrome, talk to your doctor about finding and seeing a specialist experienced with the condition for definitive answers.   Should someone wish to investigate if their symptom set may be alpha-gal related, several tools are available to help your doctor make the diagnosis. Disclaimer: We are not doctors, nor medical professionals. If you are experiencing any potentially threatening symptoms of alpha-gal syndrome, be sure to seek medical assistance immediately and then follow up with your family doctor to receive the help you need.

History of Delayed Reactions

The most distinctive feature of alpha-gal syndrome is the delay experienced between consumption of mammal meat (and other mammal products in sensitive tive individuals) and the onset of an acute allergic reaction.  This delay is usually around 2-8 hours after mammal meat has been consumed and may be longer for other mammal products.   Additionally, these acute symptoms are somewhat more diverse than what is classically associated with an allergic reaction or anaphylaxis.  Acute digestive distress involving cramping, nausea, diarrhea and constipation is a very common presentation.  Urticaria (aka hives), rash, flushing, swelling and/or itching is the other common clear acute response.  Blood pressure drops resulting in an inability to stand, tunnel vision, blacking out and/or headache or even cardiac arrest are also very common.  Slightly less common are asthmatic reactions and throat closings, though in people with a history of this type of reaction from other allergies or a predisposition, throat closings and asthma from eating mammal can still occur.  When any of these symptom groups occur together, it is known as anaphylaxis.  While alpha-gal syndrome has a variety of additional more chronic symptoms that result from constant low level exposure to alpha-gal, it is the dramatic acute reactions with their distinctive time delay that sets alpha-gal syndrome apart from other similar conditions.  Additionally, it is important to note that alpha-gal syndrome reactions do not always happen after every exposure to meat, so a single instance of eating a hamburger and being fine does not eliminate AGS(but does eliminate a traditional beef protein allergy).

Indications of Delayed Reactions

In people who do not eat mammal meat regularly, it is fairly easy to see the pattern of eating mammal meat and then a reaction occurring 2-8 hours later, but in people who consume a lot of mammal products, it can be much harder to notice, especially if they don't react on every exposure as mentioned above.  In those who consume mammal meat primarily for dinner, reactions in the middle of the night or first thing in the morning are frequently reported.  Very few conditions share this tendency to occur in the middle of the night, so this strongly suggest a delayed food consumption reaction. If a person is experiencing what is thought to be random allergic reactions, or seems to be allergic to everything, alpha-gal syndrome should be considered as the time delay and inconsistency of reactions can appear as either of these scenarios on the surface.  A past diagnosis of irritable bowel syndrome, idiopathic hypotension, chronic urticaria or any kind of mast cell activation condition in which alpha-gal syndrome was not already eliminated as a possible cause should be re-examined as a probable case of alpha-gal syndrome as these diagnoses are based on the inability to find a reason for reactions.  If AGS was never checked for, it could have been missed.  Many cases of alpha-gal syndrome have been found by re-examining idiopathic chronic conditions. The single most important component of an alpha-gal syndrome diagnosis is this delayed reaction.  Additional evidence and testing are simply to help rule out other conditions that may present similarly.  Mild cases of alpha-gal syndrome may lack dramatic reactions, which will make diagnosis significantly more challenging.  In such cases, additional evidence gathering is vital, though a diet change can also be used to confirm or eliminate AGS as a diagnosis provided the person in question is up for it.

Confounding factors

Some people with alpha-gal syndrome react to airborne mammal meat droplets produced during cooking or found in laundry products etc.  These reactions are not usually delayed more than 30 minutes, so if the affected person is also the cook, they may seem to present with immediate reactions to mammal meat consumption.  Airborne reactions are also more likely to cause asthma or throat closing reactions and often involve uncontrollable coughing fits in addition to the other acute presentations seen in consumption reactions. Alpha-gal syndrome involves more immune changes than the mammal meat allergy seen on the serface, and it is entirely possible that some people develope the other immune changes without the allergy, but for now it is the allergy element that is used in diagnosis.

History of Tick Bites

Those who have symptoms that could indicate alpha-gal syndrome should consider asking themselves “Have I been in an environment that could have ticks such as a forest or field with tall grass?” rather than “Do I remember being bitten by a tick?” as a tick need not fully attach to inflict the condition.  Minute hatchling ticks barely visible to the naked eye can also bite and cause alpha-gal syndrome2, and while the absence of a tick bite does not eliminate alpha-gal syndrome as the cause, the presence of such a bite lends strong evidence to support the diagnosis.  Why tick bites lead to the condition remains unclear, but it is well documented that they frequently play a role.3 In most of the world, the ixodes genus of ticks are thought to be responsible, but in the United States amblyomma americanum, the lone star tick, is the main offender.7  It seems it may not matter so much what tick inflicts the bite as all identified culprits to date have simply been the most aggressive species in their given geographic area.  While people predisposed to severe allergic reactions do get AGS, they seem to still get it from tick bites.  People who are resistant to allergies also get AGS from tick bites.  If a person knows they have been bitten by a tick, it is very strong evidence that their symptoms are indeed from alpha-gal syndrome, but lack of a known tick bite does not exclude AGS. For those who are concerned about recent ticks bites, it is worth noting that alpha-gal allergy symptoms usually take around 2 weeks to appear.  Just because someone has been bitten does not mean that they will develop alpha-gal syndrome, and just because someone was bitten in the past and did not develop it does not mean that they won’t develop alpha-gal syndrome after the next tick bite.  If a tick bite is suspected but not confirmed, a blood test can help clarify if the event was recent.4

Blood Test

Galactose-Alpha-1,3-Galactose sIgE Blood Test

Immunoassay blood tests have been developed to look for alpha-gal specific immunoglobulin E (sIgE) antibodies by several labs, and such a test is a good choice for recently acquired cases in which tick bite history is unclear.4  However, the results of this test alone are not enough for diagnosis as additional circumstances alter the accuracy of the test dramatically including time since onset, medications, current diet and even blood type. Instead it is best used in combination with additional information, and in some cases may not be worth pursuing. Specifically, it has recently become apparent that this blood test is only effective in establishing if a person has recently been bitten by a tick4 rather than if they have alpha-gal syndrome because in people who have recently been bitten, mature B cells appear to undergo class switching to suddenly produce sIgE in place of the normal sIgG found in healthy humans.5  It is this sIgE that the test measures, but it is actually a change induced in basophil cells and their kin that determine reactivity.8  People who were bitten a long time ago may test negative despite having alpha-gal syndrome because all of the altered B cells may have died off with little or no replacements made.  This is especially true of people with B+ blood (and to a lesser extent B-, AB+ and AB-) which have self tolerance systems that attempt to halt the production of new alpha-gal sIgE producing B cells.6  Initially, it was thought this made people with B+ blood resistant, but it is now known that it simply disrupts the test, with only minor changes to the condition's presentation.  Having a B blood type does not prevent someone from developing alpha-gal syndrome, though the full extent of immune changes may be slightly different.6 Additionally, B cells only produce sIgE if the antigen of concern is detected, which means people who have strict avoidance of alpha-gal containing products can also test negative while still being reactive.  This problem is not unique to alpha-gal allergy and is found in all food allergy tests of this kind.  The best time to test is within a few days of a major reaction after all drugs used to treat the reaction are out of the system and any antigens in the system that may eat up the antibodies have dissipated leaving the still active B cells to flood the blood with the antibodies the test is looking for. Meanwhile, nearly all people who do not have alpha-gal syndrome, but have been bitten by a tick recently will also test positive despite being entirely asymptomatic, this is a false positive.4  These findings come from a study evaluating australian individuals in high risk regions between 2013 and 2016. The longer it has been since such people have been bitten, the less likely they are to show as positive and it is likely that their numbers drop more quickly than true positive cases (excluding B+ blood type). Most labs do not report which form of alpha-gal molecules are used as the antigen in their test, which is problematic given recent collective findings that show vastly different performance between different antigen sources in different studies in which this factor was published.  It appears that the more commonly used biotin based alpha-gal is significantly less reliable than bovine thyroglobulin(bTG) which is a molecule heavily adorned with alpha-gal.12  If you get this test done, it may be worthwhile to contact the lab ahead and verify that they are using bTG and not biotin as these findings are new in 2017. It is now known that basophil activation is the best predictor of alpha-gal syndrome and that the alpha-gal sIgE is somewhat incidental,8 but the sIgE blood test can still be used to monitor a known case. Some people do recover from alpha-gal syndrome once their sIgE levels have dropped to zero, so for those hoping to recover, sIgE can be monitored to see if there is a possibility that recovery has occurred. Unfortunately though, a negative test is not a guarantee, so make sure you work with your doctor to safely investigate if alpha-gal foods can again be tolerated. It is also important to note that for the same reasons mentioned above, the actual amount of sIgE detected has no correlation with reaction severity from one person to the next.

What does the result number mean?

Some labs still quote the generic IgE test standard of a value less than 0.1 (undetectable) as negative, a value of 0.1-0.34 as equivocal(unsure), and a value greater than or equal to 0.35 as positive, but most have taken recent findings to heart and changed their ranges to simply detectable vs undetectable with a value of less than 0.1 as negative and any other value as positive.  This change came about after it was found that alpha-gal sIgE is incidental to reaction strength to reduce confusion in interpreting results. If someone has symptoms of AGS and tests positive, then they are more likely to have AGS than any of the other conditions it can be confused with.  Alpha-gal syndrome is not as rare as some seem to believe.  2-5% of people treated with an intravenous drug containing alpha-gal (cetuximab) react to it10, and this 2-5% is concentrated in tick endemic areas suggesting an even higher percentage of people bitten by ticks go on to develop AGS.  With tick populations skyrocketing and ranges expanding, it is very likely to become increasingly more common, even in areas not known to contain ticks as they can easily be spread through shipping routes. A positive test in someone without symptoms is not predictive of future development of symptoms.  In other words, it has no more meaning than finding a tick on someone.4 If someone with recent symptom onset who does not have B+ blood type tests negative in this blood test, then they likely do NOT have alpha-gal syndrome.  In such cases, alternative diagnosis' should be fully explored before returning to AGS as a possibility.  If no other diagnosis pans out, a diet change can be tried to see if it helps. A negative test in people who had symptom onset years ago, or are of the B+ blood type should be taken with a grain of salt.6 There is little value in testing someone who already has confirmed tick bites within a few months of symptom onset.4

Alpha-gal Basophil Reaction Test

This is a new test being developed that is expected to be more definitive8 than any of the current diagnostic methods.  It is still under development, but will work by maintaining live basophil cells filtered from a blood sample9 and then exposing them to alpha-gal containing molecules to see if they react.  Basophil reactions are thought to be at the core of the histamine response to mammal products in people with alpha-gal syndrome.

Alpha-gal Blood Panel

This is a 4 part test developed to collect as much data as possible to help in diagnosing alpha-gal syndrome.  It consists of an alpha-gal sIgE test as discussed above, plus 3 additional sIgE tests looking for antibodies against proteins in the meat of cattle(beef), swine(pork) and sheep(lamb).  These proteins may or may not have alpha-gal incorporated in them, and alone these tests do not indicate alpha-gal syndrome or a lack of alpha-gal syndrome.  Instead this test provides more evidence that when taken together can help lead to a diagnosis. In those who have reaction delays between 30 minutes and 2 hours, the grey area, this panel can help weed out protein allergies vs alpha-gal allergy.  If only one meat has been reacted to and the only positive test in the panel is to that meat, then there is a good chance the person is allergic only to that meat protein and does not have alpha-gal syndrome.  If the person is positive for 2 or more of any of the tests, then they most likely have AGS, though if the pair happens to be pork and beef, pork-cat syndrome should also be considered a possibility. In people who have had only one sudden reaction, especially those who had this reaction after eating pork kidney, a positive on the alpha-gal test indicates AGS is more likely than pork-cat syndrome.  A positive on the pork test but a negative on the alpha-gal test suggests pork-cat syndrome or a pork allergy may be more likely.  This is also true if beef and pork are positive while alpha-gal is negative (but only in this scenario). In people with clearly delayed reactions, a positive on the alpha-gal, beef or pork test is a good indicator that the person has alpha-gal syndrome.   Lamb is a very poor predictor of alpha-gal syndrome12, so if it is the only positive, it is less likely the person has AGS.  The more of these tests that come back positive, the more likely it is that the person has alpha-gal syndrome, but these tests have the same limitations described in the solo alpha-gal sIgE test.

Food Challenge

While not recommended, a more definitive single test known as an oral challenge13 can be done.  This red meat challenge, under the supervision of medical professionals, can verify alpha-gal syndrome in patients who experience clear reactions, but is considered extremely risky and to be avoided unless necessary do to the inconsistent time delay in the reaction.  It's a common myth that alpha-gal reactions are just like those of any other food allergy, and some of the symptoms can be quite dangerous; it is extremely important to note that this test should only be done under the supervision of medical professionals who can intervene and prevent the reaction from becoming lethal if necessary. When positive, such a test results in the patient experiencing a large clear cut reaction roughly 2-8 hours after eating the meat, so be prepared to spend the whole day at your allergists and to have a massive reaction if going this route.  Oral challenges are the gold standard for food allergy testing, but alpha-gal syndrome offers up some additional challenges since reactions are delayed.  Individuals with mild AGS may not react to meat consistently leading to a false negative if this test is only done once. It may be of interest to know that reactions actually begin much sooner than outward symptoms suggest.  The body begins acting metabolically atypical during the digestive process, seemly holding back absorbtion of the offending molecules until finally accepting them in a sudden flood.  Research into this matter has only just begun, but it may someday offer a means of less risky oral challenge or a test that can pick up milder cases of alpha-gal syndrome.  Alternatively, this research could lead to understanding risk factors for developing AGS, or even unique ways in which to treat it.

Skin Prick Tests

Traditional skin prick tests against meat extracts are very poor predictors of alpha-gal syndrome2 and can not be used to help diagnose or exclude it when taken alone.  However, a skin prick test against the drug Cetuximab (which cross reacts with AGS) is slightly more reliable, but false negatives can still occur.  Scratch tests using raw meat rather than commercially prepared testing solutions are also more accurate in producing a response.  In general, skin prick tests are not used due to the frequency of false negatives encountered, but when positive for numerous alpha-gal sources can lend a little more evidence for revealing the bigger picture, just like the blood panel tests.  It is important to note that skin prick tests may be positive even when other type of allergies are at play, so several positive skin prick tests to different mammals is not enough evidence on it's own.

Food Journal

Another somewhat safer option is to keep a detailed food and symptom journal to get a clearer case history.  Experienced allergists may be able to diagnose the condition with just case history and may choose to skip any formal testing if the pattern is clear enough from the beginning.  Often they will propose an elimination diet to see if symptoms are alleviated at the same time the journal is begun.  An additional benefit of food journals and elimination diets is that they can detect the causal relationship between the consumption of alpha-gal containing products and less clear reaction symptoms over a longer period of time. Creating a food journal is pretty easy, but requires dedication to be effective. It's important that each meal (and even snacks) are recorded thoroughly to make sure that everything is fully noted and able to be tracked down the road.  Symptoms, even those thought to be unrelated or trivial must also be diligently recorded.  Since alpha-gal reactions are typically delayed, pairing a specific reaction to a food entry can be tricky, but an experienced allergist can make short work of finding the characteristic alpha-gal reaction pattern from a well written journal.

Elimination Diet

An elimination diet13 can not only help identify AGS, but can also be used to determine individual tolerance levels.  An elimination diet typically works in one of two ways: Additive Method: A patient may begin with a diet that's very restrictive in nature, but slowly adds in foods to test for tolerance and reactions as they go. If reactions persist despite the minimalistic diet, a different minimalistic diet should be tried.  Once symptoms end, new foods can be slowly added.  This offers the opportunity to start with what you're sure of and build upon it from there. Subtractive Method: The subtractive method works in the exact opposite way the additive method does. Proponents of this method start by removing a single food at a time (for instance first mammal meat, then dairy, then gelatin, and so on) until symptoms end. Those experiencing high sensitivity symptoms such as joint pain or extreme fatigue may need to eliminate all trace sources to find relief, and usually benefit most from the additive method.  An additional benefit of the additive method is that it may also uncover other food allergies and intolerances.  Those suffering from extreme reactions only may be of lower sensitivity and will find the subtractive method easier to implement.  Most doctors will recommend starting with the subtractive method for this reason.

Tolerance Levels

In the end, some people have very low tolerance, while others can tolerate all sources of alpha-gal contaminated food with the exception of fatty meats and organs like beef steak and pork kidney.  Some people are highly sensitive and will experience milder symptoms with smaller exposures, while others have low sensitivity and only have large clear reactions or none at all with no inbetweens.  About half of patients are high tolerance, low sensitivity reacting only to one or more red meats and not to cross contamination, carrageenan, gelatin, dairy or other trace sources.  Someone who was once only reactive to beef may later become reactive to all sources, and someone who was once reactive to all sources may later become less reactive or even fully recover.  AGS is highly inconsistent in how it presents over time.  The only consistent factor is that their is a delay between eating and a reaction (excluding pork kidney reactions).

Pork-cat Syndrome

It is worth noting that an additional condition very similar to alpha-gal syndrome was described back in the 90s. Pork-cat syndrome should be suspected if reactions seem limited to pork (and rarely beef) products and the alpha-gal blood test comes back negative, or if reactions to red meat happen in less than an hour.  Oddly, people with pork-cat syndrome will test positive for allergies to cats, but sometimes do not have clear allergic reactions to pet cats.15  Instead, they have massive allergic reactions to pork.  This is how it got its name. Unlike alpha-gal syndrome, pork-cat syndrome is caused by a protein (like most food allergies), and reactions occur in less than an hour.  At this time, it is thought that pork-cat syndrome is more like a classic allergy with an unusual cross reaction rather than something as unique as the alpha-gal allergy. It was originally assumed that keeping cats caused the condition, but the allergy is rare outside of Europe lending evidence to the theory that keeping cats is not directly related beyond the fact that doing so may make it worse.  It is not unheard of for someone to have both alpha-gal syndrome and pork-cat syndrome at the same time, and early studies frequently confused the two leading to muddled data.  Now that both conditions have blood tests, newer data sets are able to avoid this problem by only including patients who test blood positive to the condition of interest. While diagnosing alpha-gal syndrome still has a long way to go as far as consistency and assurance of results is concerned, progress is being made on a regular and consistent basis.  For now, dealing with the symptoms and reactions that result continues to be one of the most difficult aspects of the condition.

Further Reading

  1. Commins, Scott P. et al. (2009) Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose. Journal of Allergy and Clinical Immunology, 123(2), 426-433.e2. http://dx.doi.org/10.1016/j.jaci.2008.10.05
  2. Steinke, J. W., Platts-Mills, T. A. E., & Commins, S. P. (2015). The alpha gal story: Lessons learned from connecting the dots. The Journal of Allergy and Clinical Immunology, 135(3), 589–597. http://doi.org/10.1016/j.jaci.2014.12.1947
  3. Commins, Scott P. et al. (2011) The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. The Journal of Allergy and Clinical Immunology, 127(5), 1286–1293.e6. https://doi.org/10.1016/j.jaci.2011.02.019
  4. Li, J et al. (2017) SPECIFIC IGE TO GALACTOSE-ALPHA-1,3-GALACTOSE (ALPHA-GAL) DOES NOT ADD TO THE DIAGNOSIS OF MAMMALIAN MEAT ALLERGY IN A TICK-ENDEMIC POPULATION. Internal Medicine Journal, 47(S5), 18. http://doi.org/10.1111/imj.44_13578
  5. Cabezas-Cruz, Alejandro et al. (2017) Salivary Prostaglandin E2: Role in Tick-Induced Allergy to Red Meat. Trends in Parasitology, 33(7), 495-498. http://dx.doi.org/10.1016/j.pt.2017.03.004
  6. Rispens, Theo et al. (2013) IgE Production to α-Gal Is Accompanied by Elevated Levels of Specific IgG1 Antibodies and Low Amounts of IgE to Blood Group B. Plos One. http://doi.org/10.1371/journal.pone.0055566
  7. Nunen, Sheryl. (2015) Tick-induced allergies: mammalian meat allergy, tick anaphylaxis and their significance. Asia Pacific Allergy, 5(1), 3-36. https://doi.org/10.5415/apallergy.2015.5.1.3
  8. Choudhary, Shailesh et al. (2017) Association of Alpha-gal Red Meat Allergy Severity with Concentration of Antigen in Basophil Activation. Journal of Allergy and Clinical Immunology, 139(2S), AB125. http://dx.doi.org/10.1016/j.jaci.2016.12.406
  9. Rose, Chloe et al. (2017) Development of an Acoustofluidic Platform for Rapid Basophil Enrichment. Journal of Allergy and Clinical Immunology,  139(2S), AB125. http://dx.doi.org/10.1016/j.jaci.2016.12.403
  10. Maier, Sabine et al. (2014) A retrospective analysis of cross-reacting cetuximab IgE antibody and its association with severe infusion reactions. Cancer Medicine, 4(1), 36-42. http://dx.doi.org/10.1002/cam4.333
  11. Flaherty, Mary et al. (2017) Diagnosis of Life-Threatening Alpha-Gal Food Allergy Appears to Be Patient Driven. Journal of Primary Care & Community Health. https://doi.org/10.1177/2150131917705714
  12. Brestoff, Jonathan et al. (2017) Diagnosis of red meat allergy with antigen-specific IgE tests in serum. The Journal of Allergy and Clinical Immunology, 140(2), 608-610.e5. http://dx.doi.org/10.1016/j.jaci.2017.01.032
  13. Muraro A, Werfel T, Hoffmann-Sommergruber K, et al.(2014) EAACI Food Allergy and Anaphylaxis Guidelines. Diagnosis and management of food allergy. European Journal of Allergy and Clinical Immunology, 69(8) 1008–1025. http://doi.org/10.1111/all.12429
  14. Fischer, J. et al. (2016) Clinical spectrum of α-Gal syndrome: from immediate-type to delayed immediate-type reactions to mammalian innards and meat. Allergo Journal International, 25(2) 55. French. https://doi.org/10.1007/s40629-016-0099-z
  15. Sabbah, A. et al. (1994) The pork-cat syndrome or crossed allergy between pork meat and cat epithelia. Allerg Immunol (Paris), 26(5) 173-174, 177-180. https://www.ncbi.nlm.nih.gov/pubmed/7522011
  16. What is Alpha-Gal Syndrome? (2017) https://alphagalsyndrome.blogspot.com/2018/01/what-is-alpha-gal-syndrome.html
  17. Symptoms of Alpha-Gal Syndrome (2017) https://alphagalsyndrome.blogspot.com/2018/01/symptoms-of-alpha-gal-syndrome.html
  18. 5 Big Myths About Alpha-Gal Syndrome (2017) https://alphagalsyndrome.blogspot.com/2018/01/5-big-myths-about-alpha-gal-syndrome.html

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