Title: Sublingual-swallow immunotherapy was effective and safe
in severe cow’s milk protein allergy: A pediatric case
Author: Masaya kato, M.D.; Shigemi Yoshihara, M.D., Ph.D
Affiliations: Department of Pediatrics, Dokkyo Medical
University, Tochigi 321-0293, Japan
Corresponding author: Masaya Kato
Department of Pediatrics, Dokkyo Medical University
880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan
Phone: +81-282-87-2155, Fax: +81-282-86-7521
E-mail: m-kato@dokkyomed.ac.jp
Word, figure, and table count: 746 words, 1 figure.
Financial support: This research received no external funding.
Consent statement: Written informed consent was obtained from
the patient’s parent and the patient for publication of this report and
images.
To the editor: Although an increasing number of patients with
food allergy have been able to achieve tolerance and desensitization
through oral immunotherapy, many children with severe Cow‘s milk (CM)
allergy do not progress to oral immunotherapy and do not reach
desensitization. We report a case in which sublingual-swallow
immunotherapy was used to safely increase the dose of CM to 25 ml in a
12-year-old male patient who had a threshold of 1.2 ml of CM for
induction of allergy symptoms.
The patient had a history of five anaphylactic shocks since infancy
after consuming less than 3 ml of CM, and had, therefore, eliminated CM
completely from his diet. At age 11, the patient participated in a
clinical study involving epicutaneous immunotherapy; however, that did
not improve his symptom elicitation threshold. At age 12,
casein-specific IgE 6.83 UA/ml, casein-specific IgG4
0.59 mgA/L and oral food challenge (OFC) of CM showed
urticaria at 1.2 ml. Tingling of oral cavity was observed in OFC of 0.2
ml of CM, but no other symptoms were noted.
We started sublingual-swallow
immunotherapy, in which the patient held 0.2 ml of CM under his tongue
for 2 minutes before consuming it orally, once a day. Initially, the
patient complained of tingling in the oral cavity; however this
disappeared within one week of therapy. The dose of CM was increased by
0.1 ml every week with no adverse events observed. As the amount
increased, it could not be held only under the tongue, so it was held in
the oral cavity. The dose was increased by 0.1 ml per day, 2 months
after the start of therapy, but no allergic reaction was observed. After
3 months, the patient was able to consume 10 ml, and after 6 months, up
to 30 ml of CM. Since he could not hold more than 20 ml, this amount was
held in the oral cavity for 2 minutes before swallowing, while the rest
was swallowed without holding. We performed OFC using a pancake
containing 25 ml of CM, but no allergy-related symptoms were observed.
Thereafter, at the patient’s request, he was given dairy products
equivalent to 25 ml of milk 2–3 times a week. After a 2-week ban on CM
at 14 months, an oral tolerance test (sweet bread equivalent to 25 ml of
milk) was conducted, and the patient complained of mild oral discomfort,
but consumed the entire amount without major symptoms. Casein-specific
IgG4 levels increased, whereas casein-specific IgE levels decreased for
the duration of this therapy. (Figure 1).
Keet et al.1 reported that sublingual immunotherapy
(SLIT) with CM was inferior to oral immunotherapy (OIT). However, the
study compared three milk protein doses during the maintenance phase of
immunotherapy: 7 mg in the SLIT group, 1 g in the OIT B group, and 2 g
in the OIT A group, suggesting that increasing the SLIT dose may
increase efficacy. A French pilot study reported that milk thresholds
increased from an average of 39 ml (range 4–106 ml) to 143 ml (range
44–≥200 ml) after 6 months of treatment by holding milk under the
tongue for 2 minutes and then spitting it out (starting at 0.1 ml and
increasing to 1.0 ml).2 SLIT induces IL-10-producing
regulatory T cells,3 promotes antigen-specific IgG4
production, and suppresses IgE production.4 In
addition, since the oral mucosa is devoid of inflammatory cells, such as
mast cells, basophils, and eosinophils, and rich in antigen-presenting
cells, such as dendritic cells, SLIT induces immune tolerance with fewer
adverse reactions.5
During OFC and OIT for milk allergy, we experience that food such as
pancakes require chewing, and are more successful than swallowing milk.
This may lead to sublingual immune tolerance. In addition, holding the
food in the oral cavity allows the patient to spit it out if symptoms
are strong, which is safer than swallowing it. There have been reports
of success with the combination of OIT and
omalizumab,6.7 but not everyone can afford this
treatment due to the high cost of medical care. In this respect, the
present method is easy to perform because the dairy product is simply
held in the oral cavity for two minutes and then swallowed. In this
case, the patient’s oral tingling disappeared after one week of
treatment, suggesting that the treatment induced immune tolerance by the
sublingual mucosa, and we believe it is worthwhile to try it for severe
CM allergy. We plan to perform this therapy on more cases and conduct a
comparative study with OIT in future.