Key words
Allergy, anaphylaxis, cow’s milk, eliciting dose, food challenge, lowest
observed adverse effect level, thresholds.
To the Editor:
There are increasing data relating to predicting the outcomes of oral
food challenges (FC) to peanut, specifically severity of reaction and
eliciting dose.1 However, data are more limited for
other allergens such as cow’s milk (CM) protein, particularly in older
children and teenagers with persisting allergy to CM. Given that CM is a
major cause of severe and even fatal allergic
reactions,1 this is a significant knowledge gap. We
therefore analysed predictors of severity and eliciting dose in young
people undergoing double-blind placebo-controlled food challenges
(DBPCFC) to CM in the SOCMA study (Clinicaltrials.gov NCT02216175).
We recruited children and young people aged 6-18 years with a clinical
history of CM-allergy, presenting for clinical review in our hospitals.
Exclusion criteria were: medically unfit for challenge (e.g. high fever
or intercurrent illness); acute wheeze or poorly controlled asthma; oral
corticosteroids within 14 days of FC; anaphylaxis in the 4 weeks prior
to FC (to exclude patients in an anergic state); antihistamines within 5
days of FC. Subjects with a history of prior anaphylaxis were not
excluded. The study was approved by the NHS Human Research Authority
(reference 18/LO/1070) and the Hospital Infantil Universitario Niño
Jesus Ethics Committee (reference R0003/17). Written informed consent
was obtained for all participants.
98 participants (median age 10 years) were screened, of whom 93
underwent DBPCFC. The first challenge dose was 0.5mg CM protein (or
tapioca starch as placebo, dissolved in rice “milk” with Nesquik®
flavouring) followed by a 60 minute observation period. Subsequent doses
were given every 20-30 minutes, according to the following schedule:
3mg, 10mg, 30mg, 100mg, 300mg, 1000mg and 3000mg of CM protein (or
placebo), until stopping criteria (PRACTALL) were met. Eliciting dose
was defined as the lowest observed adverse effect level (LOAEL)
triggering objective symptoms.2 83 subjects (89%)
reacted with objective symptoms at challenge, of whom 16 (19%) had
anaphylaxis (WAO 2020 criteria) (Table S1). The median cumulative
eliciting dose (cumED) was 143.5mg (IQR 43.5-443.5mg) CM protein.
Baseline markers of sensitisation and other relevant information are
shown in Table 1. We did not identify any significant predictors for the
occurrence of anaphylaxis at OFC. There was a moderate and significant
correlation between specific IgE to CM protein/casein (both skin prick
test (SPT) and serum IgE) and LOAEL (p<0.0001). At
multivariate analysis, both SPT and serum IgE to casein were predictive
of LOAEL (p=0.007 and p=0.018, respectively; Table S2). Population dose
distributions were determined as previously
described,3 using an Interval-Censoring Survival
Analysis (ICSA) approach in R (v4.1.2, survival package v3.2-13). The
cumulative eliciting dose predicted to provoke reaction in 5% of the
population (ED05) was 2.5mg (95%CI 1.1-6.0) and 2.7mg
(95%CI 1.2-6.1) CM protein, estimated using Log-Normal and Log-Logistic
parametric models respectively. The dose-distributions are plotted in
Figure 1, and are not dissimilar to existing data for LOAEL to CM
protein in allergic individuals.4
Predicting reaction threshold and severity are important to improve the
management of food allergy, however the determinants of, and
relationship between, these parameters are significant knowledge gaps.
Identifying robust predictors could enable the reliable
risk-stratification of food-allergic individuals. In this series of
young people with CM-allergy undergoing DBPCFC – the largest reported
in the literature – we did identify any baseline marker which predicted
the occurrence of anaphylaxis at challenge, consistent with existing
data.1 There is one report of IgE-sensitisation being
predictive of severity in CM-allergy,5 however the
authors included non-reactive patients in their analysis which
significantly skewed the analyses, resulting in misleading
conclusions.6 IgE-sensitisation in our cohort,
particularly to casein, was predictive of LOAEL. Including an assessment
of casein IgE may therefore be of clinical utility when evaluating
patients with CM-allergy in the clinical setting.
Paul J. Turner1
Bettina Duca1
Sophia A Chastell1
Olaya Alvarez2
Raphaëlle Bazire3
Marta Vazquez-Ortiz1
Pablo Rodríguez del Río3