Peanut Threshold Study

[Macabre]

http://www.aacijournal.com/content/9/1/35/abstract

Abstract (provisional)

Background
The eliciting dose (ED) for a peanut allergic reaction in 5% of the peanut allergic population, the ED05, is 1.5 mg of peanut protein. This ED05 was derived from oral food challenges (OFC) that use graded, incremental doses administered at fixed time intervals. Individual patients' threshold doses were used to generate population dose-distribution curves using probability distributions from which the ED05 was then determined. It is important to clinically validate that this dose is predictive of the allergenic response in a further unselected group of peanut-allergic individuals.

Methods/Aims: This is a multi-centre study involving three national level referral and teaching centres. (Cork University Hospital, Ireland, Royal Children's Hospital Melbourne, Australia and Massachusetts General Hospital, Boston, U.S.A.) The study is now in process and will continue to run until all centres have recruited 125 participates in each respective centre.

A total of 375 participants, aged 1--18 years will be recruited during routine Allergy appointments in the centres. The aim is to assess the precision of the predicted ED05 using a single dose (6 mg peanut = 1.5 mg of peanut protein) in the form of a cookie. Validated Food Allergy related Quality of Life Questionnaires-(FAQLQ) will be self-administered prior to OFC and 1 month after challenge to assess the impact of a single dose OFC on FAQL. Serological and cell based in vitro studies will be performed.

Conclusion
The validation of the ED05 threshold for allergic reactions in peanut allergic subjects has potential value for public health measures. The single dose OFC, based upon the statistical dose-distribution analysis of past challenge trials, promises an efficient approach to identify the most highly sensitive patients within any given food-allergic population.



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Full PDF

http://www.aacijournal.com/content/pdf/1710-1492-9-35.pdf

[CMdeux]

WOw-- thanks Mac.

Well, I'll have to think this one over.

The good news, I suppose, is that the ED is much more realistic, IMO, than what I frankly rather expected to be seeing coming out of the recent penchant for IOFC's. 

The bad news is that I think that it is still invalid to be assuming that there is a single normal distribution that includes all peanut-allergic patients.  I'm not convinced that is actually true.  Nor am I convinced that this is going to capture the population that they'd really like to capture-- the super-responders like my DD.

Those people have generally already experienced severe anaphylaxis from a very tiny amount (maybe even as little as "who the hell knows, but it shouldn't have been possible in any case") and are therefore unlikely to volunteer to repeat the experience.

QOL survey aside, I mean.   

Let me look to see who they are excluding and why.

[CMdeux]

Peanut allergic patients are usually advised to avoid foods that are labelled as "may contain" peanut. A recent study by Madsen et al. (2012) has showed that it is understood and accepted by clinicians, patients and food producers that zero risk is not a realistic or attainable option [18]. However clinical risk communications that are not specific may increase anxiety and risk taking behaviours without increasing awareness, confidence or safety [7].

Okay-- this makes more sense now.  I thought as much.

Two of the authors are Hourihane (he of the "epi is being WAyyyyyyyyy overprescribed" and "handing out epipens makes patients too nervous") and Taylor ("oil is free of protein").  In other words, they have a particular axe to grind here and have been doing so for YEARS.... in order to "prove" that some patients are just... erm-- "misguided" in their belief that low-level exposures are actually... dangerous or anything.  In other words, they are admirably concerned that a majority of diagnosed patients are being freaked out unnecessarily, and avoiding WAY more than they need to.  This is probably the case.  On the other hand, I think that most of their efforts are ripe for misuse and abuse on the part of those who would seek to deny needed accommodations and information to those at the very sensitive end of things, too-- and BOTH of these researchers have a long history of attaching their names to print information which is simply not factual.  In other words, it's rank speculation, and in the direction that they personally prefer.

Some of the interesting features-- only OBJECTIVE criteria for reaction are going to 'count' and some of what they consider "subjective" seems pretty harsh to me personally.

Inclusion criteria
Each patient must meet all of the following criteria to be enrolled in this study.
• Age between 1 to 18 years old and
• Demonstrate evidence of peanut allergy as defined by either
(a) History of unequivocal exposure (including accidental) and typical acute
allergic reaction within the preceding 2 years and positive peanut SPT/sIgE, or
(b) Positive oral food challenge with peanut performed within 2 years - either
open oral food challenge or DBPCFC (Double-blind, placebo-controlled food challenges)
(c) Peanut never ingested, but sensitisation to peanut above the 95% positive predictive value (PPV) for clinical allergy, i.e. peanut serum IgE ≥ to 15 kU/L (by CAP FEIA) and/or peanut SPT wheal size ≥ to 8 mm within 2 months of the single dose challenge.

Exclusion criteria
Patients meeting any of the following criteria will be excluded from the study
• Family or child does not consent to participate
• Medically unfit for challenge according to local unit OFC guidelines/protocol (e.g., high fever, unwell with intercurrent illness,
• Any objective sign of an acute allergic reaction
• Oral corticosteroids within 14 days prior to challenge
• Episode of anaphylaxis of any cause in 4 weeks prior to challenge
• Use of antihistamines within 5 days of oral food challenge
• Asthma that is not well controlled as demonstrated by FEVI < 85% of predicted best

emphasis mine--

I still cannot fathom that anyone with a child like mine WOULD consent.  Seriously.  Honestly, given that they do not issue exclusion criteria related to severe anaphylaxis history, this is going to have to be SOME kind of "informed" consent to gain IRB approval, actually... which means that I doubt that they are going to capture the low end, particularly in younger children.

In a more positive note, though-- they do plan to ask such patients/families to fill out some kind of questionnaire re: their decision to opt out.  No doubt that will all get rolled into "some families remain too anxious."     Given the authors heading things up, I think that VERY likely.

I wish that I could be more positive about that.  But this study seems almost intended to alienate and discredit families that refuse to participate by labeling them neurotic rather than rationally wary of provoking anaphylaxis in a protocol that will refuse to treat until symptoms become fairly severe.

positive OFC result are any objective signs occurring within 2 hours of ingestion. All objective signs will be recorded:
• 3 or more concurrent noncontact urticaria persisting for at least 5 minutes;
• perioral or periorbital angioedema;
• rhinoconjunctivitis
• diarrhoea
• vomiting (excluding gag reflex); or
• evidence of circulatory or respiratory compromise (anaphylaxis eg, persistent cough, wheeze, change in voice, stridor, difficulty breathing, and collapse) [10].

I don't necessarily think that they are on the wrong track, by the way, with a single-dose challenge.  Nor do I think that they are on the wrong track in establishing an ED₀₅.  I just think that this study is designed to not be very sensitive to the fact that they COULD be way, way, WAY wrong about where that level actually is...

and either way, they may well be eliminating the 1%-ers, and it would really, really, really be awesome to know who those people are, and it seems to me that DOUBLE-blinding things would be a much more sound means of doing this.  Actually, there is a lot of anecdote to suggest that even doctors can be fooled by things on that list which are inherently somatic, when you look at what happens in DBPCFC.

[twinturbo]

^

I think they're actually skirting a line to get past those pesky ethical opt out rules. Psychology experiments have covers sometimes to mask what the true nature of the experiment is. Grandpa the resident non-human researcher calls most human studies 'primitive' compared to non-human in terms of sampling, data. DH the resident human researcher doesn't think any of these anxiety or QOL on FA are very well designed because they never address stimulus properly.

$50 PFP gift certificate says that it's already rife with confirmation bias. Hence the spin that comes out in the conclusions that we all just need to read labels, follow our EAPs to live a normal life!... based on a very restricted set of data made to look that way in the first place.

[rebekahc]

I think by including

(c) Peanut never ingested, but sensitisation to peanut above the 95% positive predictive value (PPV) for clinical allergy, i.e. peanut serum IgE ≥ to 15 kU/L (by CAP FEIA) and/or peanut SPT wheal size ≥ to 8 mm within 2 months of the single dose challenge.

they're intentionally including those with false positives (perhaps to pad the numbers to support their bias).  The only way those with testing-alone diagnoses should be included is if they first demonstrate a clinical allergy by failing a food challenge.

[twinturbo]

I also wonder why peanut and no other allergen.

[Macabre]

That part makes sense to me--that the scope is narrow.

[CMdeux]

Yes, that part made sense to me, as well.  Peanut is also the one that both Hourihane and Taylor have the biggest beef with, as well-- BOTH authors have speculated and fairly publically doubted reports of VERY low level threshold doses in peanut.  It's also one of the few for which any literature has been published ever regarding threshold dosing.  (All of those studies had participants that reacted-- often with "subjective" symptoms such as oral itching, etc. to the LOWEST doses in the study.)



It's also clear that there are a very large number of people in the world who are feeling MOST inconvenienced by peanut restrictions.  Most people with persistent milk,wheat, or egg allergy just know from the outset that it's a no-win thing and so they don't even try, no matter how much they might actually need it.  Or they negotiate individual situations one at a time.

I'm still trying to figure out how on earth this got IRB approval anywhere.

[twinturbo]

It just gets better doesn't it.

[booandbrimom]

Frankly, this has been one of the nice side outcomes of my son's clinical trial. They tested him, we know he's not super-sensitive, and now we don't worry about cross-contamination or even "may contain." That's been a pretty big life changer.

I realize not everyone will be willing to sign up for this, but I'm just saying that it can change your life to find out where you really stand.

[CMdeux]

Absolutely-- but that's why I think that until/unless diagnostic criteria change to require a challenge, then it's going to be tough to define an ED₀₅...

because mostly, people below that level (whatever it is) pretty much never go long without getting a swift and scary reminder that they aren't like other people...   

The upshot being that they kind of already know.  Once you know that your threshold is "not visible to the naked eye" amounts, it's a bit irrelevant beyond that, because there's really only so much that you can DO about that and still live even remotely normally.  KWIM?

[maeve]

I think by including

(c) Peanut never ingested, but sensitisation to peanut above the 95% positive predictive value (PPV) for clinical allergy, i.e. peanut serum IgE ≥ to 15 kU/L (by CAP FEIA) and/or peanut SPT wheal size ≥ to 8 mm within 2 months of the single dose challenge.

they're intentionally including those with false positives (perhaps to pad the numbers to support their bias).  The only way those with testing-alone diagnoses should be included is if they first demonstrate a clinical allergy by failing a food challenge.

Not everyone who is diagnosed by exceeding the PPV alone is a false positive.  DD was diagnosed with peanut this way and 9 months later had an anaphylactic reaction.

[Janelle205]

While I don't really expect there to be studies on my most potent allergens anytime in the near future, I think that another issue is that for at least some of us, those thresholds can change rather dramatically.  When I started working at daycare, I had no reason to believe that I needed an apple free environment, because I'd only ever gotten localized hives from contact, and apple is in SO MANY things.  But my sensitivity has definitely changed, in apparent defiance to the fact that I am on maintenance pred and can tolerate some of my 'lesser' allergens now. 

When I was working as a camp director, I would regularly maintain the compost program, which generally included lots of apples.  I would scrape bowls of applesauce into the receptacle.  I at one point actually rode the receptacle around the dining hall, and you know that there has to be residue on the top of the container.  At one point I was able to cut apples to give to students as a part of our living history program.  Fast forward - in the past year I had a 'should have epi'd' moment from juice residue from touching the outside of a used juice pouch.  Hives everywhere, difficulty breathing.  The main reason that I did not epi was really because my step-daughter was having a hard time and I did not want her to be responsible for almost accidentally killing me.  Which is not how I would have presented it to her, but she does know that I could die, and she can put the pieces together.

[rebekahc]

I know not everyone is a false positive - but a 95% PPV (by definition) means that 5% are falsely positive.  IMO a study for threshold dose should only include those who are actually allergic.  Otherwise, the threshold will be skewed higher.  There's also the consideration that those who test allergic, but have never had a reaction, are more likely to participate in this study.  That would further skew the threshold (and support the researchers' bias). 

[maeve]

PPV doesn't correllate to the sensitivity of the individual.  You could have someone who while just barely above the PPV threshold reacts to minute amounts of an allergen and also have the converse where someone has high RAST levels but is only ingestive reactive.  For example, McC's son's RAST levels are significantly lower than my DD's and have been for quite a while; however, he's had more reactions and airborne reactions. Whereas my DD has not.  I don't think I'm being any more careful in controlling DD's environment than McC. In fact, I might be a little more loose.  Our kiddos just have different reaction thresholds that in no way correllate to their test results.

So even in a group pulled from 95% PPV, you will have people with varying thresholds.