To the editor:
Cow’s milk allergy (CMA) is the most common food allergy in children,
with a prevalence of 1 to 3% (1). While the vast majority of CMAs clear
after five years (2), some children have a persistent and severe disease
associated with a risk of life-threatening allergic reactions (3). For
those patients, oral immunotherapy (OIT) is now recommended (4); it
consists in a tolerance induction by daily ingestion of allergen.
However, in the most severe cases which react with a very low quantity
of cow’s milk (CM), classic OIT cannot be initiated due to the
impossibility of increasing the daily doses of CM. The adjunction of
omalizumab, a monoclonal anti-IgE antibody, to OIT (oma-OIT), could be a
safe and effective alternative in those cases; however, only a few
studies have been published to decisively assess both the safety and
efficiency of oma-OIT (5–8). The aim of our study was to evaluate both
the effectiveness and safety in an oma-OIT protocol in children with
persistent and very severe CMA.
In this study performed in Lyon, France, children who initiated an
oma-OIT protocol for a persistent and very severe CMA were included.
These patients were considered as severely allergic due to failure in
initiation of a classic OIT to CM or an history of severe reaction with
very small amounts of CM. Initiation of oma-OIT was decided in a
concertation meeting of allergist experts in OIT. Briefly, the oma-OIT
protocol was performed as following: (1) subcutaneous omalizumab was
administrated at a frequency (every 2 or 4 weeks) and a dose that
depended on the patient’s weight and total IgE (same dose used as the
one recommended for severe asthma); (2) after 16 weeks of omalizumab use
alone, OIT was initiated. The induction phase began with the
introduction of diluted amounts of CM (first daily dose: 1 mg of CM
proteins), followed by introduction of non-diluted doses and daily
increases of CM doses until a predefined threshold. Oral food challenges
(OFCs) were performed every month or two months at hospital, under the
supervision of a medical team trained for the management of high-risk
OFCs, in order to establish the cumulative tolerated dose (CTD) and the
new threshold to reach by up-dosing. After each OFC, the new threshold
was reached at home in one week, and maintained for several weeks, until
the next OFC. Allergy tests were usually performed at each OFC (skin
prick-test [SPT], specific IgE [sIgE] to CM and CM components
and specific IgG4 [sIgG4] to CM, Phadia 250 Thermofisher, Uppsala,
Sweden). Additionally, the patients and their parents reported any
allergic reactions which occurred at home in a notebook, if applicable.
We retrospectively collected the general characteristics of each patient
at the initiation of the protocol. We also collected the initial grade
and the most severe grade of allergic reactions to CM, using the Ring
and Meissmer classification (9), the results of OFCs, the allergy tests
and allergic reactions and the use of epinephrine during OFCs and at
home. In addition, we collected responses from a satisfaction survey
which was completed by the children and their parents after
OFC4.
In order to evaluate the effectiveness of the initiation of oma-OIT
protocol, the primary outcome was the change in the CTD of ingested
fresh CM between OFC1 and OFC4. The
secondary outcomes were the changes in allergy tests, the occurrence of
allergic reactions during OFCs and at home, and the results of the
satisfaction survey. Statistical tests were performed using GraphPad
Prism version 8.02 for Windows, GraphPad Software, La Jolla California
USA, www.graphpad.com.
Eight children (3 boys and 5 girls, median age of 14.5 years
[12-16]) with very severe CMA who received an oma-OIT treatment were
included in this study (Table 1). The median administrated dose of
omalizumab was 487.5 mg [300-600] every 2 or 4 weeks. The median
time between OFC1 and OFC4 was 127 days
[84-427] for a total number of 1,342 ingested doses at home. After
four OFCs (Table I and Figure S1), the CTD of CM was significantly
increased (median CTD1 = 0.96 mg [0.64;15.04] and
CTD4 = 160 mg [12.8;480], 167-fold change, p =
0.0078 ). The anti-CM sIgE moderately decreased (sIgE1 =
476.0 kU/L [227.0;2048.0] and sIgE4 = 460.0 kU/L
[97.2;1482.0], change -3.4%, p = 0.0391 ) and ratio anti-CM
sIgG4/sIgE increased (sIgG4/sIgE1 = 8.6 [1.8;16.2]
and sIgG4/sIgE4 = 17.5 [3.3;223.1], change +103.5%,p = 0.0313 ). There were no significant changes in SPT wheal and
anti-CM component sIgEs. During the 32 OFCs performed in the 8 children
under oma-OIT, 8 allergic reactions occurred in 6 children: 4 were grade
1 and 4 grade 2 according to the Ring and Meissner classification. These
children were treated with oral antihistamine; none needed an
epinephrine administration. Among the 1,342 ingested doses at home, two
doses induced allergic reactions in two children: one grade 2 and one
grade 3. The severe reaction was treated by epinephrine at home. Of
note, a reactogenic cofactor (physical activity) without adaptation of
the protocol was found for this severe reaction. Finally, all the
children and their parents were globally very satisfied with the oma-OIT
protocol, even if they expressed relative anxiety due to the risk of
adverse reactions during the OFCs and the dose intake (Table S1).
Interestingly, omalizumab injections were not considered as a constraint
by most of the children and their parents (Table S1).
Thus, in this cohort of children with very severe CMA, the adjunction of
omalizumab to OIT was effective and globally well tolerated, during the
first months of the protocol. The main limitations of our study are the
absence of a control group (placebo or no treatment), the limited size
of our cohort, and the duration of follow-up. These are preliminary
results and they need to be confirmed. Moreover, our patients were more
severe than those included in previous studies, in terms of initial CTD
and sIgE (5–8). Thus, this preliminary study encourages continuation of
further oma-OIT protocols in cohorts of patients with very severe CMA.