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.DAffiliations: Department of Pediatrics, Dokkyo Medical University, Tochigi 321-0293, JapanCorresponding author: Masaya KatoDepartment of Pediatrics, Dokkyo Medical University880 Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, JapanPhone: +81-282-87-2155, Fax: +81-282-86-7521E-mail: m-kato@dokkyomed.ac.jpWord, 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.5During 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.