Key words
Allergy, eliciting dose, food challenge, lowest observed adverse effect
level, peanut.
To the Editor:
Oral food challenges (OFC) are the gold standard diagnostic for food
allergy, but not without limitation. Administering incremental doses
every 15-30min differs from a real-world exposure where ingestion occurs
at a single episode. Blumchen et al. reported a median time to objective
symptoms of 55min (range 5-210min);1 if doses are
given every 15min, this could significantly overestimate the reaction
threshold.1,2 This could also occur due to incremental
dosing causing transient desensitisation.3 With OFC
increasingly used to determine starting doses for oral immunotherapy and
guide dietary avoidance,4 we assessed how clinical
thresholds and symptoms at OFC compare to an ingestion more
representative of real-world consumption.
Seventeen peanut-allergic adults (median age 24 years, range 18-40)
underwent initial double-blind, placebo-controlled food challenge
(DBPCFC) to peanut, as part of a clinical trial (TRACE Peanut study;
ClinicalTrials.gov Identifier: NCT02665793). Detailed methods are
described elsewhere.5 Doses were given every 30
minutes (using a water-continuous dessert matrix) according to the
following schedule: 3μg, 30μg, 300μg, 3mg, 30mg, 100mg, 300mg and 1000mg
of peanut protein (or placebo), until stopping criteria were
met.5 Participants returned for two further DBPCFC.
The first was an “abbreviated” DBPCFC using the same matrix, with the
first active dose equivalent to the maximum tolerated dose at baseline
DBPCFC (see Fig 1 and Table S1); this was done as a safety measure.
Subjects allocated (by computer randomization) to placebo had two
placebo doses first (Fig 1). The third DBPCFC used the same abbreviated
protocol, but with the appropriate dose given as peanut butter (Kraft
Foods) mixed into a soya-based spread (Wowbutter) and eaten as a small
3cm sandwich (Kingsmill 50/50 bread). Triangle testing demonstrated the
suitability of Wowbutter for blinding, and prior tolerance to this was
demonstrated in all participants. The study was approved by the NHS
Human Research Authority (reference 15/LO/0286), and written informed
consent from all participants.
At baseline DBPCFC, the median cumulative eliciting dose (cumED) was
133mg (IQR 83.3-433.3mg) peanut protein; 2/17 patients had anaphylaxis
(WAO 2020 criteria). Median cumED at abbreviated challenge was 133mg
(IQR 33.3-433.3mg) (Fig 2A). The shift in cumED was not significant
(p=0.10, Wilcoxon sign-rank test), and there was no major differences in
clinical symptoms observed (Fig S1). Fourteen subjects underwent the
third DBPCFC using peanut butter sandwiches (one had too low a cumED for
the appropriate dose to be accurately measured, and two declined).
Median cumED at this challenge was 433mg (IQR 33.3-1433.3mg),
representing a non-significant half-log increase in cumED
(p>0.05; Fig 2B).
In a systematic review and meta-analysis of peanut-DBPCFC, 69% of
peanut allergic-individuals show a shift in cumED over time; in 56%,
this is limited to a half-log difference, equivalent to 1 dosing
interval with a PRACTALL-based semi-log dosing
regimen.6 Indeed, Dua et al reported a fall of around
0.5-log (equivalent to 1 dosing increment) at subsequent OFC in these
same participants.5 Therefore, the non-significant
shift in cumED with an abbreviated challenge protocol is entirely
consistent with the inherent “noise” in determining cumED at OFC. We
undertook a post hoc power calculation; our sample size would have been
sufficient to detect a 1-log difference in cumED with at least 90%
power i.e. greater than that due to the inherent intraindividual
variability.
In summary, we did not find a significant difference in either cumED or
symptoms following DBPCFC with a 30-minutely incremental dosing
protocol, compared to an abbreviated challenge which is more
representative of a normal consumption episode. In addition, there was
no significant difference in cumED between baseline DBPCFC and a more
“real-world” exposure to peanut butter in a sandwich. Therefore, using
threshold data from OFC (with 30 minute dosing intervals) is a valid
approach to individual allergen risk management.
Olaya Álvarez García,1,2
Joan Bartra,1,3
Monica Ruiz-Garcia,1
Isabel J. Skypala,1,4
Stephen R. Durham,1,4
Robert J. Boyle,1
E.N. Clare Mills,5
Paul J. Turner1