Allergy immunotherapy (AIT) is a treatment option for respiratory allergy that is complementary to pharmacotherapy, with a distinct mechanism of action. Alternative methods to subcutaneous administration of AIT that enable patients to safely self-administer AIT is considered an unmet clinical need.

The sublingual immunotherapy tablet (SLIT-tablet) is an orally disintegrating pharmaceutical formulation (oral lyophilisate) containing standardized allergens. SLIT-tablets have been developed for sublingual immunotherapy (SLIT) of cedar-pollen, grass-pollen, ragweed-pollen, tree-pollen, and house dust mite allergies. It is a once-daily tablet treatment to be self-administered after the first dose has been provided under the supervision of a physician with experience in the diagnosis and treatment of allergic diseases. Once the first dose is adequately tolerated, subsequent doses may be self-administered. SLIT-tablets have proven efficacy for allergic rhinitis (AR) with and without conjunctivitis (C) and allergic asthma (AA) in adults, children, and poly-sensitized allergic patients. Meta-analyses indicate that SLIT-tablets have superior or similar efficacy compared with anti-allergic pharmacotherapies for seasonal AR and superior efficacy for perennial AR. SLIT-tablets have also demonstrated clinically relevant improvements of asthma, with significant reductions in the following: daily inhaled corticosteroid use, risk of asthma exacerbations, and asthma symptoms. SLIT-tablets are generally well tolerated, with a low risk of systemic allergic reactions. The most common treatment-related adverse events are mild-moderate oral reactions. Current evidence supports SLIT-tablets to be considered as an alternative or add-on treatment to pharmacotherapy for AR/C and asthma. Future SLIT developments may include early intervention to prevent the development or progression of allergic disease in children.

Sublingual immunotherapy (SLIT) has been proven to be safe and effective from an abundance of Western literature, but data from Asia is less complete. This review aims to examine the basic science, safety and efficacy of SLIT in Asian patients, and to determine future research needs in Asia. We performed a literature search on PUBMED, Scopus, and Cochrane Library database for articles on SLIT originating from Asian countries through Nov 2017. There were 18 randomized, double-blind, placebo-controlled trials, of which 9 involved solely paediatric subjects. Overall, sublingual immunotherapy is safe and is efficacious in Asian populations in allergic rhinitis (AR) and asthma. House dust-mite SLIT is effective in both mono- and polysensitized AR patients. Efficacy of SLIT is comparable to subcutaneous immunotherapy. Data on long term efficacy is lacking. A disproportionate majority of research originates from China and Japan, reflecting an asymmetry of access to SLIT within Asia. Significant disparities exist in the development of the allergy speciality, prescription patterns of SLIT, and pharmacological potencies of different SLIT products within and between Asian nations. We conclude that current available evidence suggests SLIT is efficacious in Asians but data quality of evidence is hampered by non-placebo controlled studies with methodological limitations. More data is needed in South and Southeast Asian populations. Future efforts may be directed towards improving access to SLIT in developing countries, standardization of SLIT dosage, and evaluating long term clinical outcomes.

Japanese cedar pollen (JCP) and house dust mite (HDM) are two major allergens that cause allergic rhinitis (AR) in Japan and the prevalence of AR is increasing. Pharmacothearpy is a commonly used treatment, but the level of patient satisfaction is very low. Allergen immunotherapy (AIT) is the only therapeutic modality that provides not only symptom relief but also quality of life improvement that leads to a high rate of satisfaction. In particular, sublingual immunotherapy (SLIT) is a safe and effective treatment for AR. Here we introduce a large-scale double-blind, placebo-controlled trial of SLIT in Japanese patients using JCP droplets or HDM tablets conducted in Japan. The immediate future of SLIT in Japan is also discussed.

Chronic eosinophilic pneumonia (CEP) is an inflammatory disease characterized by accumulations of eosinophils in the lung with unknown etiology. Although corticosteroid treatment dramatically resolves these inflammations, relapse is common during the course of the disease. Approximately 50% of patients with CEP experience relapse. Subsequent to persistent disease and repeated relapse, and in cases of combined severe asthma, some CEP patients are administered corticosteroids indefinitely. Similar to patients with severe asthma who are often steroid dependent, a number of CEP patients exhibit prolonged persistent impairment of pulmonary function. Thus, CEP should be considered a potentially chronic disease requiring long-term management, rather than an acute or sub-acute disease requiring short-time therapy only. This review summarizes previous CEP studies, as well as our own cohort data, and discusses the long-term management of CEP with a particular focus on relapse, the prevalence of maintenance therapy, and persistent impairment of pulmonary function.

Background: Poly(γ-glutamic acid) (PGA) is an allergen in natto, fermented soybeans, which causes late-onset anaphylaxis. We hypothesized that jellyfish stings sensitize adults to PGA because a surfer had allergies to both natto and jellyfish, whose sting contains PGA. The aim of the study was to identify behavioral factors, such as marine sports, associated with PGA sensitization.

Methods: Outpatients diagnosed with food allergies based on relevant clinical history, positive skin test and/or food challenge test answered a questionnaire during a regular visit in 2016.

Results: Questionnaire data from 140 outpatients were analyzed. These patients were divided into two groups: natto allergy group (13 patients, M:F = 10:3, mean age 40.6 years) and non-natto allergy group (127 patients, M:F = 46:81, mean age 44.5 years). All patients with natto allergy had positive results in skin prick test and basophil activation test with PGA. Of these, 92.3% had a marine sport hobby, especially surfing (84.6%). PGA sensitization was independently associated with marine sports (odds ratio, 278.0, 95 percent confidence interval, 36.9－6315.9, p < 0.001) adjusted for male sex and sea bathing, but not with male sex or sea bathing. In addition, although there was no significant difference in the experience of marine sports between natto and non-natto allergy groups, the natto allergy group participated significantly more frequently in marine sports than the non-natto allergy group (p < 0.001). There was no significant difference between natto consumption amount and PGA sensitization.

Conclusions: Surfing is a risk factor for PGA sensitization in those with allergy to natto.

Background: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial.

Methods: Japanese patients aged 5－65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI-121900).

Results: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction.

Conclusions: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU.

Background: Many studies have attempted to clarify the factors associated with serum periostin levels in asthmatic patients. However, these results were based on studies of subjects mainly characterized by high eosinophil counts, which may present as an obstacle for clarification in the identification of other factors associated with serum periostin levels. The aim of this study was to determine the factors associated with serum periostin levels in healthy subjects. We also assessed some factors in asthmatic subjects to confirm their extrapolation for management of asthma.

Methods: Serum periostin levels were measured in 230 healthy subjects. Clinical factors of interest included body mass index (BMI) and allergic rhinitis (AR). Additionally, we confirmed whether these factors were associated with serum periostin in 206 asthmatic subjects. We further evaluated several obesity-related parameters, such as abdominal fat distribution and adipocytokine levels.

Results: Smoking status, blood eosinophil count, total immunoglobulin E, and the presence of AR were associated with serum periostin in healthy subjects. There was a negative association between BMI and serum periostin in both healthy and asthmatic subjects, while there was a tendency of a positive association with AR in asthmatic subjects. There were no differential associations observed for subcutaneous and abdominal fat in relation to serum periostin in asthmatic subjects. Serum periostin was significantly associated with serum levels of adiponectin, but not with leptin.

Conclusions: Our results provided clarity as to the factors associated with serum periostin levels, which could be helpful in the interpretation of serum periostin levels in clinical practice.

Background: Anaphylaxis and immediate-type fish roe allergies have been reported worldwide, and, in Japan, fish roe is the sixth most common food allergen. No oral food challenges (OFCs) have used pollock roe (PR), which is reported to have high cross-reactivity with salmon roe (SR). Therefore, we administered an OFC using cooked PR to evaluate PR- and SR-specific immunoglobulin E (IgE) levels and allergic reactions in patients with PR sensitivity.

Methods: This retrospective study evaluating patient characteristics and responses to OFCs was conducted with 10－20 g of cooked PR, between April 2006 and November 2016.

Results: We assessed 51 patients (median age: 6.8 years). All had PR sensitization, 6 (12%) with a history of immediate reactions to PR, and 18 (35%) of immediate reactions to SR. Median PR-specific and SR-specific IgE values were 3.4 kUA/L and 9.9 kUA/L, respectively. Seven patients (14%) had a positive OFC. There was no anaphylaxis. Induced symptoms were mild and included localized urticaria, throat pruritus, intermittent cough, and mild abdominal pain. We treated one patient with mild abdominal pain with oral antihistamines. There were no significant differences in history of immediate reaction to PR and PR-specific IgE titers between OFC-positive and OFC-negative patients, although significant differences were found for PR-specific IgE titers adjusted for SR-specific IgE (p = 0.025) and PR-specific IgE/SR-specific IgE ratio (p = 0.009).

Conclusions: Increased PR-specific IgE/SR-specific IgE ratio or PR-specific IgE levels adjusted for SR-specific IgE levels were risk factors for OFC positivity.

Background: The emedastine patch was developed in Japan as the first transdermal drug delivery system of emedastine difumarate for allergic rhinitis.

Methods: A multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison was conducted in patients with seasonal allergic rhinitis. Patients were administered Emedastine patches (4 or 8 mg), placebo, or levocetirizine hydrochloride (5 mg tablet) once daily for 2 weeks (double-dummy technique). The primary objective was superiority to placebo by the change of the total nasal symptom score (sneezing, rhinorrhea, and nasal congestion) in Week 2. Levocetirizine was a reference drug and not a comparator in this study.

Results: A total of 1276 patients were randomized to receive the 4 mg emedastine patch (n = 384), 8 mg emedastine patch (n = 382), placebo (n = 384), or levocetirizine (n = 126). The least squares mean (LSM) of the change from baseline of the total nasal symptom score (TNSS) in Week 2 was significantly larger in both emedastine patch groups than in the placebo group (adjusted p < 0.0001). In secondary analysis, LSM of the change in the TNSS was −1.20, −1.49, −0.44, and −1.32 in the 4 mg emedastine patch, 8 mg patch, placebo, and levocetirizine, respectively. Reductions in the number of episodes and scores of individual nasal symptoms were all significantly larger throughout the day in the emedastine patch groups than the placebo group (all p < 0.05). No clinically significant safety problems occurred.

Conclusions: The emedastine patch (4 and 8 mg) effectively and safely controlled symptoms of seasonal allergic rhinitis with sustained action throughout the day. Study registration: JapicCTI-153092.

Background: Direct contact of food proteins with eczematous lesions is thought to be the main cause of epicutaneous sensitization. To further investigate the development and pathogenesis of food allergy in vivo, a good mouse model of epicutaneous sensitization is needed. However, a fundamental problem in that regard is that the optimal age for epicutaneous sensitization of mice is unknown. In this study, we attempted to elucidate that optimal age.

Methods: Dorsal skin of wild-type BALB/c female mice (1, 3, 8 and 24 weeks old) was shaved, depilated and tape-stripped. A Finn chamber containing a 20-μl-aliquot of 20-mg/ml (OVA) was applied to the tape-stripped skin on 3 consecutive days/week, for 3 weeks. The body temperature was measured after intraperitoneal OVA challenge. Serum OVA-specific IgE titers and OVA-induced cytokine production by spleen cells were measured by ELISA. Dendritic cells (DCs) that migrated to the draining lymph nodes were quantified by FITC-labeled OVA and flow cytometry. The mRNA expression levels in the dorsal skin were measured by qPCR.

Results: A significant age-dependent body temperature decline was observed after OVA challenge. The serum OVA-specific IgE titer, OVA-induced cytokine production (i.e., IL-4, IL-5 and IL-13) by spleen cells, and number of FITC-OVA-engulfing DCs increased with age. In addition, mRNA for IL-33, but not TSLP or IL-25, was significantly induced in the skin by tape-stripping and increased with age.

Conclusions: Twenty-four-week-old mice showed the greatest DC migration, Th2 polarization, IgE production and body temperature decline. Skin-derived IL-33 is likely to play key roles in those changes.

Background: Topical corticosteroids (TCS) can induce adverse effects, such as skin atrophy. Although TCS can cause increases in intraocular pressure (IOP), the effects of daily TCS use on IOP have not been fully elucidated. We evaluated the clinical doses of TCS and the change in the IOP during the daily treatment of atopic dermatitis (AD).

Methods: We collected clinical data on a total of 65 patients who were diagnosed with AD and underwent 2 or more IOP measurements at our hospital.

Results: Mean monthly facial steroid volumes of ≤11.8 g and ≤15.0 g of TCS were applied to 90% of the patients aged 2－12 years and those aged ≥13 years, respectively. During the treatment, there were no TCS-related increases in IOP in any patient.

Conclusions: Our study suggests that TCS might not cause increases in IOP at the abovementioned doses. However, the IOP of steroid responders is known to be highly responsive to steroids. Therefore, patients who have steroids applied to their eyelids had better undergo regular IOP measurements at ophthalmological clinics.

Background: IL-10 is a major anti-inflammatory cytokine that prevents inflammation-mediated tissue damage. We characterized the production of IL-10 by sinonasal tissue cells following exposure to Staphylococcus aureus enterotoxin B (SEB), which elicits cellular responses and is associated with the pathogenesis of eosinophilic chronic rhinosinusitis (ECRS).

Methods: Dispersed nasal polyp (NP) cells and uncinate tissue (UT) cells were prepared from patients with CRS with and without NP, respectively. Cells were incubated with SEB, and then the levels of IL-10 in the cell supernatants were determined. The effect of neutralizing IL-10 on SEB-induced IL-5, IL-13, IFN-γ, and IL-17A production was examined. Expression of IL-10 in NPs was also determined.

Results: IL-10 was expressed in infiltrating inflammatory cells in NPs. NP cells, especially non-adherent NP cells, produced substantial amounts of IL-10 in response to SEB. Although baseline production of IL-10 was significantly higher in NP cells than UT cells, the degree of IL-10 response to SEB was not significantly different between the cell types. The degree of IL-10 production was negatively correlated with the degree of eosinophilia both in tissues and peripheral blood whereas positively correlated with the 1-s forced expiratory volume/forced vital capacity ratio. Patients with severe ECRS displayed a significant decrease in IL-10 production compared with those with non-ECRS. IL-10 neutralization significantly augmented SEB-induced IL-13 and IFN-γ production by NP cells.

Conclusions: Impaired IL-10 production in response to SEB in NP may exacerbate the pathophysiology of ECRS including eosinophilia and lower airway obstruction.

Background: Clinical trials on oral immunotherapy (OIT) have been increasing for nearly a decade; however, several national guidelines do not recommend OIT as a standardized procedure. The aim of this study was to obtain insights into the current use and practice of OIT in Japan.

Methods: A first questionnaire was mailed to 524 training and teaching facilities of the Japan Pediatric Society. The first survey requested information on the implementation of OIT, whereas the second survey aimed to gather more detailed information on OIT, such as its safety.

Results: In total, 360 facilities (69%) responded to the survey; among them, 102 (28%) provided OIT to 7973 patients [1544 received OIT while hospitalized (inpatient OIT), whereas 6429 received OIT without hospitalization (outpatient OIT)]. Approval for OIT was obtained from an ethics committee or institutional review board in 89% and 31% of facilities for inpatient and outpatient OIT, respectively. In inpatient OIT, immediate allergic reactions requiring treatment occurred in 68% of patients while hospitalized, and in another 56%, following discharge. In contrast, 11% of patients developed immediate allergic reactions in outpatient OIT. Adrenaline injections at home were required in 2%. Sixteen patients developed adverse reactions other than immediate allergic reactions, among which eosinophilic gastroenteritis was most common.

Conclusions: OIT is widely provided not only as clinical research but also as general practice in Japan. However, because there is a high risk of developing anaphylaxis at home, OIT should be conducted carefully as in a clinical research setting taking safety into consideration.