Sublingual immunotherapy for cedar pollinosis possibly triggers eosinophilic esophagitis.

Sublingual immunotherapy (SLIT) is an effective and popular treatment for cedar pollinosis. Although SLIT can cause allergic side effects, eosinophilic esophagitis (EoE) is a lesser-known side effect of SLIT. A 26-year-old male with cedar pollinosis, wheat-dependent exercise-induced anaphylaxis, and food allergies to bananas and avocados presented with persistent throat itching, difficulty swallowing, heartburn, and anterior chest pain 8 days after starting SLIT for cedar pollinosis. Laboratory examination showed remarkably elevated eosinophils, and esophagogastroduodenoscopy revealed linear furrows in the entire esophagus. Histological examination of an esophageal biopsy specimen revealed high eosinophil levels. The patient was strongly suspected with EoE triggered by SLIT. The patient was advised to switch from the swallow to the spit method for SLIT, and the symptoms associated with SLIT-triggered EoE were reduced after switching to the spit method. This case highlights the importance of recognizing SLIT-triggered EoE as a potential side effect of SLIT for cedar pollinosis, especially with the increasing use of SLIT in clinical practice. EoE can occur within a month after initiating SLIT in patients with multiple allergic conditions, as observed in our case. Furthermore, the spit method should be recommended for patients who experience SLIT-triggered EoE before discontinuing SLIT.

Long-Term Efficacy and Safety of Subcutaneous Immunotherapy in Monosensitized and Polysensitized Children With Allergic Rhinitis.

OBJECTIVE: To evaluate the efficacy and safety of dust mite subcutaneous immunotherapy (SCIT) in monosensitized and polysensitized children with allergic rhinitis (AR). STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. METHODS: One hundred thirty children were enrolled and categorized into 2 groups: monosensitized to only dust mites and polysensitized to at least 1 additional allergen beyond dust mites. All patients received SCIT targeting dust mites for 3 years, followed by a 5-year monitoring period. The Total Nasal Symptom Score (TNSS), Symptom and Medication Score (SMS), Visual Analogue Scale (VAS), and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) were assessed before SCIT (T0); at 1 (T1) and 2 (T2) years of SCIT; immediately after SCIT (T3); and 2 years post-SCIT (T5). Safety was assessed based on adverse events (AEs). RESULTS: Fifty-one monosensitized and 50 polysensitized children completed the study. At T3, 47 monosensitized and 46 polysensitized children were effectively treated, with no significant between-group difference in efficacy (P > .05). The TNSS, SMS, VAS scores, and RQLQ score were significantly lower at T1, T2, T3, and T5 than at T0 in both groups (P < .05). The differences in the TNSS, SMS, VAS score, and RQLQ score between the 2 groups were nonsignificant at T0, T1, T2, and T3 (P > .05), but significant at T5 (P < .05). No serious AEs were reported. CONCLUSION: Monosensitized and polysensitized children exhibited similar beneficial efficacy and safety after 3 years of dust mite SCIT. Monosensitized children derived more benefits 2 years after discontinuation.

Efficacy and safety of Artemisia annua sublingual immunotherapy in patients with seasonal allergic rhinoconjunctivitis over two pollen seasons.

OBJECTIVE: This study investigates the efficacy and safety of sublingual immunotherapy (SLIT) with A. annua allergens in patients with seasonal allergic rhinoconjunctivitis over two pollen seasons. METHODS: Seventy patients with moderate-severe seasonal allergic rhinoconjunctivitis were divided evenly into the SLIT and control groups. The SLIT last from 3 months before the summer-autumn pollen season in 2021 till the end of the summer-autumn pollen season in 2022. The daily individual symptom score, total rhinoconjunctivitis symptom score (dTRSS), total medication score (dTMS), combined score of medication and rhinoconjunctivitis symptom (dCSMRS), visual analog scale (VAS) score, and adverse events (AEs) were evaluated. RESULTS: The average pollen concentration in 2022 was twice that previous two-year during the pollen season. Fifty-six patients completed treatments (SLIT group: 29, control group: 27). Compared with baseline, the individual symptoms, dTRSS, dTMS, dCSMRS, and VAS scores of SLIT group declined in 2021. After 16 months of SLIT, all efficacy indexes in 2022 were still lower than baseline and equivalent to those in 2021. In control group, the efficacy indexes in 2022 were higher than that in 2020 and 2021. The efficacy indexes of SLIT group were lower than those of control group in 2021 and 2022. SLIT is effective for both mono- and poly-sensitized patients. AEs incidence in SLIT group was 82.7% without severe AEs. CONCLUSIONS: The A. annua-SLIT can obtain efficacy and safety over two pollen seasons for patients with moderate-severe seasonal allergic rhinoconjunctivitis.

First-in-human phase 2 trial with mite allergoids coupled to mannan in subcutaneous and sublingual immunotherapy.

BACKGROUND: Polymerized allergens conjugated to non-oxidized mannan (PM-allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM-allergoids are readily taken up by DCs and induce Treg cells. This first-in-human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM-allergoid (PM-HDM) administered subcutaneously (SC) or sublingually (SL). METHODS: In a randomized, double-blind, double-dummy, placebo-controlled trial, 196 subjects received placebo or PM-HDM at 500, 1000, 3000, or 5000 mannan-conjugated therapeutic units (mTU)/mL in 9-arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers. RESULTS: No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL (p = 0.004) and 5000 mTU SC (p = 0.011). CSMS improvement over placebo reached 70% (p < 0.001) in active 3000 mTU SC and 40% (p = 0.015) in 5000 mTU SL groups. CONCLUSIONS: PM-HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.

A case series of sublingual immunotherapy-induced eosinophilic esophagitis: stop or spit.

We experienced six cases with eosinophilic esophagitis (EoE). They complained of dysphagia, heartburn, or retrosternal discomfort. Endoscopy revealed typical findings of EoE and biopsy examination showed significant eosinophil infiltration in the esophageal epithelium. They received sublingual immunotherapy (SLIT) for allergic rhinitis. Discontinuation or spit method during SLIT resulted in improvement of symptoms, and endoscopic and histological remission. Previously six cases with SLIT-induced EoE has been reported. Our case series suggest that SLIT is clearly associated with the development of EoE by entering of aeroallergens from the luminal side of the esophagus and spit method during SLIT might be one of the therapeutic options for SLIT-induced EoE.

Comparative analysis of sublingual immunotherapy medicines for adherence and clinical outcomes.

OBJECTIVE: Sublingual immunotherapy (SLIT) has been considered as an effective and safe alternative to the subcutaneous route. However, different modalities and administration methods may lead to significant changes in their adherence and clinical outcomes. The purpose of this study was to compare the adherence, efficacy, and side effects of SLIT medicines: SLITone®, Lais®, and Staloral®. SUBJECTS AND METHODS: Eighty-two patients suffering from AR symptoms and sensitized only to house dust mite allergens were included. The patients were treated with SLITone®, Lais®, or Staloral®. Treatment outcomes related to efficacy, dropout rate, and adverse events were evaluated. The visual analogue scale (VAS) including sneezing, rhinorrhea, nasal obstruction, and itching was scored from 0 (normal) to 10 (severe), before and after SLIT. Dropout rate was defined as the number of patients who discontinue SLIT of oneself compared to the number of patients who receive SLIT. RESULTS: All of the nasal symptoms and total symptom scores were significantly decreased in SLITone®, Lais®, and Staloral®. Furthermore, there were significant difference in the improvement of rhinorrhea and TNSS between SLITone® and Staloral® group (p = 0.011 and p = 0.001, respectively). Four patients out of 26 in SLITone® group, 4 patients out of 30 in Lais® group, and 11 patients out of 26 in Staloral® group have stopped SLIT of themselves. The dropout rate was significantly higher in the Staloral® group than other two groups (p = 0.024). Only one patient complained adverse reaction such as swelling of mouth floor in the Staloral® group. CONCLUSION: Although all three SLIT medicines are effective in improving AR symptoms, the adherence to SLIT assessed in accordance with dropout rate was the lowest in the Staloral®.

[Efficacy, safety and compliance of immunotherapy in the treatment of allergic rhinitis: a Meta-analysis].

Objective: By use of Meta analysis to compare efficacy, safety and compliance of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) on allergic rhinitis (AR). Methods: Cochrane Library, Pubmed, Embase, CNKI Database, Wan Fang and Chinese Sci-tech Journal Database (from established time to May of 2018) were searched for trials about the AR treated by SCIT and SLIT. The relevant literatures were screened, and the randomized controlled studies were chosen. Nasal symptom scores, visual analogue scale (VAS) scores, adverse reactions and compliance were used as the outcome indicators, and the methodological quality of the literatures was evaluated strictly. The extracted data were analyzed by RevMan 5.3 and Stata 14 software. Results: A total of 20 randomized controlled studies were included, the overall quality of which was relatively high. No publication bias was found. There was no significant difference in nasal symptom scores, VAS scores and compliance between SCIT and SLIT (SMD value was 0.03, 0.14, respectively, RR=1.12; 95%CI value was -0.17-0.23, -0.03-0.31, 0.92-1.35, respectively, all P>0.05); SLIT group resulted in lower overall incidence of adverse reactions than that of SCIT group (RR=1.79, 95%CI: 1.42-2.26, P<0.05). Conclusion: Both SCIT and SLIT have similar eppecacy and compliance for treatment of AR, while adverse reactions are more frequently observed in SCIT.

[ANALYSIS OF BACKGROUNDS AND LEVEL OF UNDERSTANDING OF TREATMENT OF POOR ADHERENCE AND DROPOUT CASES ON SUBLINGUAL IMMUNOTHERAPY FOR JAPANESE CEDAR POLLINOSIS IN THE FIRST FOLLOW-UP YEAR].

BACKGROUND: We considered the factors of poor adherence to and dropout from sublingual immunotherapy (SLIT) by verifying patient backgrounds 1 year after start of treatment. METHODS: We recruited 38 patients who began SLIT between November 2014 and September 2015. We analyzed their attributes and level of understanding of the treatment, and conducted a self-reported survey on factors behind dropout cases and poor adherence cases. RESULTS: Four patients dropped out 1 year after start of treatment. Three left for reasons related to anxiety about side effects. There were five cases of poor adherence. There was no significant difference between good adherence, poor adherence, and dropout regarding level of understanding of the treatment (p=0.59). In the comparison between good and poor adherence groups, except four dropout patients, the adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients. Continuous rate of SLIT achieved about 90%, suggesting relatively high level of adherence. CONCLUSION: It appears possible that anxiety related to side effects could be a factor affecting dropout from SLIT. There was no significant difference regarding level of understanding of the treatment. The adherence tended to be poor in patients with short duration of disease, smoking patients, and young patients.

Tolerability of the SQ Tree SLIT Tablet in Adults.

PURPOSE: The tree pollen sublingual immunotherapy (SLIT)-tablet (ALK, Denmark) is being developed for the treatment of tree pollen induced allergic rhinitis with or without conjunctivitis. The objective of this Phase I trial was to investigate the tolerability and acceptable dose range of the SQ tree SLIT-tablet in adults with allergic rhinoconjunctivitis. METHODS: The trial was a randomized, double-blind, placebo-controlled, dose escalation Phase I trial that included 70 adults (aged 19-61 years) with birch pollen-induced rhinoconjunctivitis with or without mild to moderate asthma. The trial included 6 different dosage groups that were randomized 3:1 to active treatment or placebo once daily for 28 days. Adverse events (AEs) were coded in the Medical Dictionary for Regulatory Activities by medically qualified personnel. Immunologic assessments included IgE and IgE-blocking factor. FINDINGS: Most (96%) reported AEs were mild, and only 5 severe events (0.2%) were reported. The most frequently reported investigational medicinal product-related AEs were oral pruritus, ear pruritus, mouth edema, sensation of foreign body, throat irritation, pharyngolaryngeal pain, dry throat, tongue blistering, eye pruritus, and headache. The trial included doses ranging from 1 to 24 development units (DU), and the mean number of investigational medicinal product-related AEs per participant was highest in the 24 DU group. The 12 and 24 DU doses induced statistically significant changes from baseline compared with placebo in birch specific IgE and IgE-blocking factor. IMPLICATIONS: The trial found that doses up to 12 DU of the SQ tree SLIT tablet have a tolerability profile suitable for at-home administration. An immunomodulatory effect was found for all doses included in the trial, and doses up to 12 DU were thus chosen for further clinical development of the SQ tree SLIT tablet. EudraCT identifier: 2007-003234-42.

[Efficacy and safety of specific sublingual immunotherapy in children with allergic asthma and rhinitis].

Objective:To evaluate the efficacy and safety of specific sublingual immunotherapy (SLIT) with Dermatophagoides farina drops in different courses with allergic asthma and allergic rhinitis.Method:This study retrospectively analyzed the efficacy of SLIT in 158 children with allergic asthma and rhinitis which induced by house dust mites. The children were treated with Dermatophagoides farina drops; clinical observation and follow-up study were conducted. According to the treatment duration, children were divided into 4 groups (1-year, 2-year, 3-year, and 4-year). Symptom scores and medication scores were recorded at each visit. Asthma symptom scores (day and night), the rhinitis symptom scoresand medication scores were evaluated in 4 groups before and after SLIT. The adverse events during the treatment were collected.Result:There were significant differences in asthma symptom scores (day, night), asthma medication scores, rhinitis symptom scores, rhinitis medication scores among children who accepted 1-year, 2-year, 3-year and 4-year SLI treatment as compared with baseline (P< 0.01). As compared with 1-year, 2-year, 3-year groups, the asthma medication scores of 4-year group had obviously decrease (P< 0.05). Rhinitis medication score of SLIT3 years group was significantly lower than 2 years group (P< 0.05). Asthma symptom scores in the day, asthma symptom scores at night, rhinitis symptom scores of four groups children had no statistically significant difference (P>0.05).Conclusion:Different courses of sublingual immunotherapy with Dermatophagoides farina drops had significant effects; the 4-year course of treatment showed the best effect.

Effect of Lactobacillus rhamnosus GG and vitamin D supplementation on the immunologic effectiveness of grass-specific sublingual immunotherapy in children with allergy.

BACKGROUND: An important issue in sublingual immunotherapy (SLIT) is how to improve efficacy. OBJECTIVE: To compare the clinical and immunologic efficacy of SLIT given alone and, to enhance clinical efficacy, given with probiotic or vitamin D supplementation. METHODS: One hundred children, ages 5-12 years, sensitive to grass pollen, with allergic rhinitis participated in a 5-month prospective, randomized, double-blind, placebo-controlled trial. Children received 5-grass SLIT 300 IR tablets with either vitamin D 1000 IU daily supplementation, probiotic, or placebo. The control group included children with allergy who did not qualify for immunotherapy. Primary end points included a symptom-medication score, lung function, and exhaled nitric oxide concentration. The secondary end point was the immunologic efficacy measured by the following: CD4(+)CD25(+)Foxp3(+) (forkhead box P3) cells, Toll-like receptor (TLR) 4, interleukin (IL) 1, IL-6, tumor necrosis factor, IL-10, and transforming growth factor ß-1 levels in cell culture supernatants. RESULTS: Reduction in the symptom-medication score and improvement in lung function as well as a significant increase in the percentage of CD4(+)CD25(+)Foxp3(+) in children who received SLIT in all the groups were observed compared with control group. In the SLIT-probiotic group, between-group analysis showed significantly higher CD4(+)CD25(+)Foxp3(+) induction compared with the SLIT group and higher reduction in the percentage of TLR-positive cell group compared with the SLIT-vitamin D group (Fig. 1). An increase in CD4(+)CD25(+)Foxp3(+) induction, reduction in TLR-positive cells recruitment and an increase in transforming growth factor ß-1 production were independently associated with a better clinical effect of SLIT in children. CONCLUSIONS: We demonstrated the clinical and immunologic effect of probiotic and vitamin D supplementation on SLIT. Probiotic supplementation showed better clinical and immunologic response in children with allergic rhinitis.

Immunotherapy in all aspects.

Allergen immunotherapy is a form of long-term treatment that decreases symptoms for many people with allergic rhinitis, allergic asthma, conjunctivitis (eye allergy) or stinging insect allergy. In this review, we presented the important topics in immunotherapy. The important aspects of immunotherapy are considered to be "Immunological responses to immunotherapy"; "The principal types of immunotherapy"; "Effectiveness"; "Indications"; "Contraindications"; "Allergen immunotherapy in children"; "Safety"; and "Anaphylactic reactions after immunotherapy". The principal types of immunotherapy are subcutaneous immunotherapy (SCIT) and sublingual immunotherapy. Both of them can be used in indicated cases. When using SCIT, physicians must be more careful because of reported rare fatal cases. The risks and benefits of continuing allergen immunotherapy in patients who have experienced severe systemic reactions should be carefully considered.