Friday, June 1, 2012

Component Testing (Pt.2) - Why Should We Care?

So, in Part 1 of this labor of love, I talked about EIA vs. component testing for allergies. If you followed the science, you can start to see some situations where component testing might be helpful to figure out what's going on with our kids:

1. To identify cross-reactivity between food and pollen.

There are six peanut allergens that are currently the focus of component testing: Ara h 1, 2, 3, 5, 8 and 9. It's important to note that there are at least 24 identified, potentially allergenic epitopes just for Ara h 1!

The first three are what are known as seed storage proteins. They're important to the plant to ensure the next generation of little plants is grown. As a result, they're extremely durable and usually make it intact through break-down process in the stomach. Ara h 9 is a lipid transfer protein, responsible for moving fats across membranes within the cell. Again, it's a pretty hardy little beast.

In contrast, Ara h 5 and 8 are wimps. They also have homologues across many other plants, especially pollen from those plants, so the chances of cross-reactivity on a traditional allergen panel are high.

The traditional method of testing that uses a natural extract cannot tell these two types of results apart. One recent study showed that 11.8% of kids tested using a traditional RAST test showed up positive for peanut. However, when challenge tests were conducted, only a quarter of the kids actually reacted when they ate peanut. This roughly correlates with the estimated 1-2% rate of peanut allergy in the population.

The uKnow test is currently being marketed to parents whose kids had a positive peanut test but who have  never experienced an actual reaction to peanut. If you are in that category, this test could change your life.

Remember those look-alike proteins, or homologues? In the case of kids who test positive, but who really don't have a peanut allergy, there's a distinctive pattern that shows up:

Remember that Ara h 8 is a wimp. It mostly breaks down in the stomach to the point that the body doesn't react to it. That's why it often causes an itchy mouth but limited other symptoms.

This may be the explanation for the fabled "mild" peanut allergy. These kids will all have itchy mouths. Some of them may even have a few systemic symptoms. But, the thought is that they are not likely to tip over into serious anaphylaxis. (Of course, whether you're ready to turn in your epinephrine injector under those circumstances is between you and your doctor.)

Another great example of where the test is useful is my son's situation. His January RAST for hazelnut was ~3, yet the RAST just taken for the FAHF-2 study in April was a 12. That's a huge increase for a RAST in just four months!

It turns out that hazelnut (Cor a 1) and Birch (evil birch Bet v 1!) are strong homologues.1 The large increase in his number during tree pollen season is a good indicator that we're probably looking at a less serious form of hazelnut allergy. We're hopeful that a component test can take this worry off his plate.

2. Possibly: to provide more information on the timeline to outgrow milk/egg allergy.

Milk and egg allergies are really tough on parents! For 17 years now, we've asked the question of our allergist that I'm sure all of you MA/EA parents ask each time: "when will my kid OUTGROW this allergy?!"

There are some things scientists have found out about these allergies. As with peanut, if kids are allergic to multiple allergenic proteins, it generally makes the allergy more persistent. Additionally, if a child's body can recognize epitopes when they're not folded up in a protein, that also means they're likely to have the allergy longer, maybe lifelong, and potentially have more serious reactions.

A traditional RAST test can crudely test for the different components of milk: whey, casein, α-lactalbumin, β-lactalbumin, but it can't identify specific epitopes and it can't demonstrate whether the allergy is to "folded" proteins (not as bad) or the "unfolded" strand of protein (bad). The component test, though, gets down to just the very small (sometimes just 10 amino acids) unfolded "hot spot" on the protein that's causing the problem.

For milk and egg, there are "hot spots" that have been associated with severe, persistent allergies. For egg, these hot spots are all on a protein called ovomucoid.2  For the persistent milk allergy kids, the epitopes were associated with the casein protein.3

So is this test really able to tell which kids will outgrow their milk and egg allergies? The answer is maybe. Some doctors are already using it to look at patterns in milk/egg and determine whether introducing baked milk will be helpful in speeding up the tolerance process. It's definitely something to ask your allergist about.

NOTE: Right now, ISAC (Immuno Solid Phase Allergen) testing is being done by one experimental laboratory (Phadia), with only 103 components from 47 allergens available.4  Your allergist may not have a relationship with this lab or be ready to roll this out to patients.

3. Future hope: to separate "potent" epitopes from less harmful ones and find the pattern for life-threatening allergies.

This is where we start to get into weighing the cost of the test against the information it provides. If you have a child who has already experienced a reaction to peanut, why might you want to have the test done?

So far, 95% of people who react to peanut in real life and who have had component testing show a sensitivity to Ara h 2. However, there also seems to be a correlation between how many epitopes of peanut you're allergic to and how allergic you are.5  The current theory for why is related to T cells, the first type of immune cell that responds to the allergen. (The Allergist Mom just did an awesome post on all the science behind this if you are interested.)

T cells are specific to the epitopes to which they bond, but the T cells all compete for the same pool of resources (the "antigen presenting cells" Allergist Mom mentions). Like fighting kids, they're fine if they think all the toys in the room are available to them, but when they see other kids who might want the same toys, they get upset and all hell breaks loose. So...the more epitopes a peanut-allergic person is sensitized to, the more likely it is that their reaction will be severe.6 

However, so far there is no "smoking gun" epitope, or pattern of epitopes on any of the allergenic proteins, that signals potentially fatal reactions. Like fingerprints, the patterns from person to person can be very different. Scientists are still busily identifying and characterizing all the epitopes for peanut. Plus, different populations show different patterns of epitope sensitization, and even allergen sensitization (for example, Ara h 9 is more prevalent in Mediterranean populations). In order to answer these questions, they'll need a lot more data from people willing to take the test. However, those people taking the test will probably not benefit right away.

Are you willing to spend the money to get a picture of your kid's epitope "fingerprint", even though the data to understand what it means is not yet available? We're still thinking about this one.

4. Future hope: to help determine potential pitfalls for MFA kids.

When my son was around age 4, we went through a horrible period where we thought he had idiopathic anaphylaxis. Instead, it turned out that he had developed allergies to a wide range of legumes. The probable culprit? Ara h 1, which shares a seed pod protein with many other legumes.

The problem is that not all kids who are positive for Ara h 1 have allergies to other legumes! There's likely some other mechanism involved in sensitizing children to these look-alike proteins. (Remember the faces from the homologue example? Some people are just better at telling faces - and proteins - apart than others.)

This test has great potential to eventually tease out these linked proteins, far better than the crude botanical family relationships many of us use today. It's definitely not ready for prime time. But maybe someday soon, your doctor will be able to look at your child's peanut epitope pattern and make a good guess as to which tree nuts may or may not be a problem.

So...all in all, component testing is promising...but probably not 100% there yet for anything except for identifying those peanut allergies that are most likely cross-reactions to pollen. But what a gift this will be to those parents who are terrified their child is peanut allergic on the basis of testing only! And apparently, that's a good percentage of the kids out there.

PLEASE NOTE: these are MY thoughts on the value of this testing only. You should definitely discuss this with your physician. Additionally, I would love to hear from others interested in the science as to how they see this playing out in future.

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  1. Wow! What a great post! My 2 year old son has RAST and skin tested positive to peanut but I don't know for sure if he has ever been exposed to it. He just had a horrible time this pollen/grass/tree season with really bad allergy shiners (which have since cleared up once we upped his Zyrtec and added Nasonex). His father is allergic to every tree and grass known to man, along with hazelnuts, almonds and pistachios and has OAS (most fruits due to his birch allergy probably). Is it possible, maybe, that my son is actually not allergic to peanuts after all and just has bad allergy to outdoor allergens? (He is too young for them to do skin tests for outdoor allergens.) Or am I just confused?

  2. Ali, your situation is what this test is meant for! Yes, it's possible. I would definitely ask your allergist. Just don't be surprised if he/she is not knowledgeable or enthusiastic yet - this is really new science. You may even need to print out and bring some of the Phadia info:

    (Man, those guys should be paying me a kick-back!)

  3. They should be paying you a kick-back! Do you have any idea how much the Uknow Peanut testing is? Or any of the other testing from Phadia? I am assuming that, since this is new science, insurance is not interested in covering it.

  4. My daughter is scheduled for peanut component testing next month. Her older brother had an anaphylactic reaction to peanuts so she's always avoided. She tested positive to skin prick testing so we've been assuming she's severely allergic too. I'm so excited to get the results of the component testing so I'll know for sure.

  5. Ali, the Uknow test is $300. I don't know what all it encompasses. There's a web site:

    We're going to try to do it through our physician rather than direct because we're interested in everything else other than peanut (milk and hazelnut). (The results need interpretation, so I can't imagine what the point is of having the test done independently of your doctor...) If I find out more this summer, I'll post it in my blog.

  6. Steph, that's awesome! I hope you'll let us know how it goes.

  7. I had the uKnow testing done through our allergist's office and they actually had it at half-price ($150).
    We did it because my daughter had only been diagnosed via blood testing and has never eaten a peanut in her life. It turns out she tested highly positive to Ara h 2, so it's definitely still off limits. Though not great news, the confirmation was worth the price. I have also had several of the other component tests done and I found your additional information fascinating, but I don't know of any doctors around here, who can adequately interpret the results. Do you know of any great resources I might be able to contact? You can see my daughter's values on this page:

    Thank you for the informative post!

  8. Selena, the lab that runs the tests should have offered your physician a consult regarding the results. However, the bottom line is that until all the epitopes for these allergens are mapped, the information you already have (that she's persistently allergic to milk, soy, and peanut) may be all the test can tell you.

    I did sit through a presentation with the clinical director at Thermo Fisher last summer -- he would be another resource to go to if your doctor has additional questions.

    It sounds like FAHF-2 is a good bet for you guys at some point in the future. Desensitization is definitely tougher when you're dealing with whole lists of allergens.

  9. My son fit this profile exactly. Reacted to hazelnut at around 2. Tested positive to peanut, but never ingested. We practiced strict avoidance for 4+ years. Based on his Uknow test scores, we found that he was high on the "wimpy" protein. It took us a few months to work up the courage to challenge - but he passed! Just wanted to share for anyone else who comes across this page in their searches..

  10. I just came across this new peanut component panel from Quest Diagnostics :
    The panel look exactly like the same as the UKnow Peanut panel but it is fully covered under insurance. Has anyone had this instead of the Uknow Peanut? Could Quest have a competitive peanut component test? What do you think?

  11. My guess is that this is the same test. Phadia is the company that does the uKnow test and they make the Immunocap analyzer (I think). The Quest test is referencing it by brand name.

    Glad it's covered, either way!

  12. Ah ha...saw this after I posted the message above:

    (Thermo Fisher is the company that owns Phadia now.)

  13. Hi - I am looking for some understanding of the results of the ISAC test that my daughter's allergist ran. Brief back history of allergies (milk (outgrew) soy (outgrew) legumes (tests negative now) egg, sesame, peanut.
    The test result suggests that my daughter (now 12) has outgrown peanut and her allergist wants to do an oral food challenge when we are next in the UK in August this year. I will paste the results below and would love to know what you think. I am still trying to get my head around this...
    Results of laboratory investigations: Results of Multiplex Immuno Solid-phase Allergen Chip
    (ISAC; the in vitro diagnostic tool for allergy which is based exclusively on allergen components, thus
    enabling component-resolved diagnostics) - Of the 112 species-specific and cross-reactive
    components from multiple sources including foods (egg, milk, chicken, fish, shrimp, peanut, tree nuts,
    seeds, pulses, fruits) aeroallergens (grasses, trees, weeds, animals, mites, moulds, insects),
    hymenoptera venoms, latex and parasites, the test confirmed sensitisation to egg components
    ovomucoid and ovalbumin (Gal d 1 and Gal d 2) and sesame storage protein Ses i 1. The results are
    consistent with the diagnosis of allergy to egg and sesame. Specific IgE was negative to the
    remaining 109 allergen components, including all six peanut components (Ara h 1, 2, 3, 6, 8 and 9),
    three hazelnut components (Cor a 1, 8 and 9), three walnut components (Jug r 1, 2 and 3), as well as
    the storage proteins of cashew nut and brazil nut.
    These results strongly suggest (but do not prove) the absence of allergy to peanut and tree nuts. This
    can be unequivocally confirmed using oral food challenge.

    Thanks in advance for your comments.

  14. I think that's wonderful! That's exactly the result you want to see before a food challenge!

    Did she ever have a reaction to peanut? If so, what was it like? If not, what led you or your doctor to conclude she had a peanut allergy?

    You do mention soy. There are some kids who have a primary allergy to soy, with cross-reactivity to peanut. I will cross my fingers that your daughter is one of the lucky ones!

  15. Really? That makes me so happy!

    I had wondered about the cross reactivity from soy. No, she has never had a reaction to peanut. We don't allow them in the house and are super careful with food and rarely eat out, so it is an unknown for us. That said, I have slipped up with egg and sesame in the past - she has had a painful reaction each time, but not anaphylactic.
    She still showed a severe reaction on skin testing in 2011 - we skipped a year of testing as nothing was really changing and we can only see the allergist when we visit England (we live in Dubai) so this these test results are from August 2013.
    My daughter burst into tears when she heard about the result. We have changed nothing in our routine, but she obviously felt like a huge weight had lifted. She is scared of doing the test - we'll have to see how we handle that.
    What worries me is that we always had a false negative on milk allergy from blood tests. She was highly allergic - even a kiss from somebody who had milk in their tea would bring up a red mark, but it was always negative. She outgrew it around the age of 8 and can now eat pizza without even getting eczema.

    Thanl you so much for your support - I was so happy when I read about your son's green pea challenge :-D

  16. Just keep in mind (and tell her as well) that close to 10% of the population will show a positive response on a skin test, yet a much smaller group (<1%) is actually allergic. The odds of her passing this test without having every had a peanut reaction is about 90%. Add the component result and her odds are probably 99%. The tests aren't perfect (as you've learned from your milk experience), but this component test has proved very reliable.

    More bedtime reading if you're interested:

    Please come back and tell me if (WHEN!) she passes.

  17. Thank you for the link - How interesting that ethnicity is a part of allergic reaction. I took a few daysto get round to reading it as I have been reading up on the peanut allergy "cure" which has been very much in the UK news this week. Have you been following it?

    I will definitely report back on the food challenge in August! Thanks again :)

  18. Food Challenge update - not good news.
    Sadly my daughter went to do the peanut challenge today and she didn't pass the pre-challenge skin test. She had a 7mm welt from actual peanut crushed with saline and smaller welts from peanut butter and peanut extract (5mm)
    We are so disappointed, even though we hadn't changed anything in our routine, it still feels like a backward step. Sigh....

    1. Sorry, Wildhunt! It's tough when a challenge fails, but I hope you'll agree that it's good to know. :(

  19. My kids had the ISAC test and have positive results to peanut Ara h 1, 2 and 6. I have seen a lot of information on Ara h 1, 2, 3, 8 and 9 but nothing on Ara h 6. I did a google search and it brought me to this great article but still no info on Ara h 6. Does anyone have info on this new component and is it associated with a severe allergic reaction like Ara h 2?

  20. Here's a link for you:

    In conclusion, Ara h 6 is a major peanut allergen, with comparable immunoreactivity to Ara h 2.

    So...yes, probably a meaningful marker.

  21. Hi. My son's component test came back and it wasn't good. His arah2 came back at a 3 and arah8 came back .6 --I haven't seen anything on what constitutes a high arah2 level. I am wondering if it means anything that he is mostly allergic to arah2 and 8 ie not all? Also does a component number go up and make allergy worse or less. I find it so difucult to get any answers from our doc over the holidays.

  22. This just helped me understand this testing so much better.

    My son Asher just had the blood test done yesterday.

  23. This helps me too. Thank you. My son who is 14 months old just got his blood test and his IgE came high for milk and tomatoes which is confusing since he has never had symptoms around it. He was drinking milk based formula since day 1 and whole milk since 11 months old. The only symtom he had was persistent cough and ear infections which were due to daycare but while we were traveling, the Ped did this test.

    Any words of advice for us? Very confused.


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