[CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY WITH CEDAR POLLEN IN A YEAR OF MASSIVE CEDAR POLLEN DISPERSAL AND ITS EFFECT ON JAPANESE CYPRESS POLLINOSIS].

BACKGROUND: We investigated the effect of sublingual immunotherapy (SLIT) on Japanese cedar and cypress pollinosis in a mass scattering year of cedar pollen (total counts: 12353 grains/cm2, approximately four times the average). METHODS: SLIT patients of 84 in the first year, 107 in the second year and 67 in the third year treated with Cedarcure® were included. During the 2023 cedar and cypress pollen dispersal season, nasal and eye symptoms and general symptoms were examined using a visual analog scale (VAS). RESULTS: The VAS during the cedar season significantly decreased to improve with the number of years of SLIT, but the VAS during the cypress period slightly increased. A questionnaire survey before SLIT revealed that only 0.9% to 3.6% of patients had strong cypress symptoms. However, sneezing (p＜0.01), rhinorrhea, itchy eyes and total symptoms (p＜0.05) in the third year of SLIT were significantly stronger during the cypress period than during the cedar period. The VAS of total symptoms during the Japanese cedar pollen season were not affected by the pollen count, and the cure rate was affected by SLIT in the third year. CONCLUSION: The clinical efficacy of cedar SLIT on cedar pollinosis was high even in a mass scattering year, and the effect increased with the number of years of treatment. On the other hand, it was shown that the clinical efficacy on cypress pollinosis was insufficient.

[A MULTICENTER CLINICAL SURVEY ABOUT THE PREVALENCE OF JAPANESE CYPRESS POLLINOSIS AND THE EFFICACY OF SUBLINGUAL IMMUNOTHERAPY WITH JAPANESE CEDAR POLLEN EXTRACT DURING JAPANESE CYPRESS POLLEN DISPERSAL PERIOD].

BACKGROUND: Little is known whether sublingual immunotherapy using Japanese cedar pollen extract (cedar SLIT) is effective for not only Japanese cedar pollinosis but also Japanese cypress pollinosis. We investigated the prevalence rate of Japanese cypress pollinosis, efficacy of cedar SLIT on cypress pollinosis and patients' wish to receive cypress SLIT. METHODS: We investigated a multi-center (31 institutions), cross-sectional survey using a self-administrated questionnaire with four questions for patients received cedar SLIT aged from 5 to 69 years old. RESULTS: 2523 subjects were enrolled for analysis. 83.4% of them had pollinosis symptoms during cypress season before cedar SLIT. In such patients, 37.4% experienced lessened efficacy of cedar SLIT during cypress season. Both the prevalence of cypress pollinosis and the lessened efficacy of cedar SLIT on cypress pollinosis were significantly seen in western Japan as compared to eastern Japan. 76.1% of the subject having cypress pollinosis before SLIT wished to receive cypress SLIT if it is available. CONCLUSION: A lessened efficacy of cedar SLIT during cypress season was broadly seen in Japan, and further showed a regional difference. Together with the finding of high wish by patients, these results suggest a development of cypress SLIT is desirable.

Immunological effects of sublingual immunotherapy with Japanese cedar pollen extract in patients with combined Japanese cedar and Japanese cypress pollinosis.

Sublingual immunotherapy (SLIT) with Japanese cedar (JCe) pollinosis was expected to be effective for Japanese cypress (JCy) pollinosis. However, only a half of JCy pollinosis patients clinically improved. Therefore, we examined the immunological effect of SLIT for JCy pollinosis. Peripheral blood mononuclear cells (PBMCs) from patients with JCe and JCy pollinosis who did and did not receive SLIT were incubated with Cry j 1, Cha o 1 and Cha o 3 antigens. Basophil activation test (BAT) were performed. Production of IL-5 and IL-17 induced by antigens was inhibited in the SLIT group. Cry j 1-specific production of IL-10 was increased, and serum Cry j 1-specific IgE and -IgG4 were elevated. However, Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4 was not increased. Antigens-specific BAT did not decrease after SLIT. New SLIT with JCe and JCy is needed for patients with combined JCe and JCy pollinosis.

Safety profile and immunological response of dual sublingual immunotherapy with house dust mite tablet and Japanese cedar pollen tablet.

BACKGROUND: There have been no studies of dual administration of sublingual immunotherapy (SLIT) tablets for perennial and seasonal allergic rhinitis. This trial (JapicCTI-184014) was conducted to investigate the safety profile and immunological response during dual therapy with SQ house dust mite (HDM) and Japanese cedar pollen (JCP) SLIT tablets. METHODS: This was a multicenter, open-label, randomized trial of 109 Japanese patients with coexisting HDM and JCP allergic rhinitis who had positive tests for HDM- and JCP specific IgE (≥0.7 kU/L). Patients were allocated to receive HDM (N = 54) or JCP (N = 55) SLIT tablets alone for 4 weeks followed by 8 weeks of dual therapy with both SLIT tablets administered within 5 min of each other. Adverse events (AEs), adverse drug reactions (ADRs), and serum IgE and IgG4 specific for HDM (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and JCP were recorded. RESULTS: The percentage of subjects with AEs and ADRs was similar between the two groups and between the two periods of monotherapy and dual therapy. Most AEs and ADRs were mild in severity, and no serious events were observed. The most common ADRs were local events in the oral cavity. Levels of IgE and IgG4 specific for HDM (D. farinae, D. pteronyssinus) and JCP were increased after treatment with HDM and JCP SLIT tablets, respectively. CONCLUSIONS: Dual therapy with both SLIT tablets administered within 5 min after 4 weeks of monotherapy with HDM or JCP tablet was well tolerated and induced the expected immunological responses.

[CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY IN A LARGE AMOUNT OF POLLEN DISPARSAL AND IT'S IMPACT OF TREATMENT YEAR].

BACKGROUND: It past 4 years in 2018 after the first treatment of sublingual immunotherapy (SLIT) for Japanese cedar pollinosis. The purpose of this study is to clear the clinical efficacy of SLIT in a large amount of pollen dispersal in 2018 (total 5041 grain). METHODS: The subjects were 270 SLIT (83 forth year of treatment, 72 third year, 48 second year, 67 first year), 320 primary pharmacotherapy that started therapies before pollen dispersal, and 424 untreated. The clinical efficacy was evaluated with symptom scores of Japanese rhinoconjuctivitis quality of life questionnaire No1, medication scores and combined total nasal symptom-medication scores, and visual analog scale of nose, eye and total symptoms. RESULTS: Each SLIT was significantly better than untreated in all assessments, and better than primary pharmacotherapy in assessments of total symptom. SLITs of third and forth year of treatment were also better than primary pharmacotherapy in nasal symptoms. SLIT patients, whose symptom scores of nose and eye were 0 and 1 point without any rescue drugs, accounted for 41.0%, 31.9%, 18.8%, 20.9% in the order from the fourth year to the first year. Of them, patients with score 0 occupied 12.0%, 12.5%, 4.2%, 4.5%, in order. There was no patient who needs treatments for adverse events. CONCLUSION: SLIT was significantly effective compared with primary pharmacotherapy or untreated group in a large amount of pollen dispersal. It was better to treat at least for 4 years.

[CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY IN THE THIRD TREATED YEAR WITH JAPANESE CEDAR POLLINOSIS IN 2017].

It past 3 years in 2017 after the first purchase of the drug for sublingual immunotherapy (SLIT) for Japanese Cedar pollinosis (JCP). We reported the clinical efficacy of SLIT in the first and the second treated year. PURPOSE: The purpose of this study is to clear the clinical efficacy of SLIT in the third treated year by comparing with other therapies, such as subcutaneous immunotherapy (SCIT), or other pharmacotherapy. METHODS: We compared the clinical efficacy in 2017, of 112 SLIT in the third treated year with 38 SCIT, 364 primary pharmacotherapy that started therapies before pollen dispersal, 254 pharmacotherapy that started therapies after pollen disposal, or 333 non-treatment. The clinical efficacy was evaluated with symptom scores, total nasal symptom scores and combined total nasal symptom-medication scores (TNSMS), symptoms of nose and eye by visual analog scale (VAS), quality of life (QOL) scores by Japanese rhino-conjunctivitis QOL questionnaire (JRQLQ No1). RESULTS: Both SCIT and SLIT showed good clinical efficacy without significant difference in every assessment. Both SCIT and SLIT were significantly better than other pharmacotherapy in most assessment. Patients, whose symptom scores of nose and eye were 0 and 1 point without any rescue drugs, accounted for 9 and 24% of total SLIT, respectively. CONCLUSION: SLIT in the third treated year showed good clinical efficacy in reducing symptoms and TNSMS of JCP, and in improving QOL. SLIT was significantly effective compared with other pharmacotherapies.

Enhanced Clinical Efficacy of Sublingual Immunotherapy for Japanese Cedar Pollinosis in the Second Year of Treatment.

Sublingual immunotherapy (SLIT) is thought to have enhanced efficacy in the second year of treatment. We studied treatment efficacy in both the first and the second years of treatment (2015 and 2016, respectively) in patients who began SLIT in 2014. Methods: We compared 132 patients who underwent SLIT (age, 41.8 ± 17.5 years; male-to-female ratio, 75: 57) and a control group of 56 patients who underwent primary pharmacotherapy (age, 44.9 ± 13.5 years; male-to-female ratio, 25: 31). The study was performed during the peak pollen seasons of 2015 and 2016. Pollen dispersal was similar in 2015 and 2016 (2,509 grains/cm2 and 3,505 grains/cm2, respectively). The clinical efficacy of SLIT was evaluated by assessing nasal and eye symptoms and total symptoms with symptom scores and combined symptom-medication scores, visual analog scale scores, and quality of life (QOL) scores according to the Japanese rhino-conjunctivitis QOL questionnaire (JRQLQ No. 1). QOL was also evaluated with JRQLQ No. 1. The first endpoint was enhanced efficacy of SLIT in the second year compared with that in the first year. Results: With respect to nasal and eye symptoms, the assessments in the primary pharmacotherapy group were unchanged in the second year; however, most of these assessments in the SLIT group demonstrated significantly enhanced efficacy of SLIT in the second year. In QOL of SLIT, only 2 of 17 showed significantly enhanced efficacy of SLIT in the second year. Conclusion: SLIT shows enhanced efficacy in the second year.

CLINICAL EFFICACY OF SUBLINGUAL IMMUNOTHERAPY IN THE SECOND TREATED YEAR FOR 133 PATIENTS WITH JAPANESE CEDAR POLLINOSIS IN 2016.

It past 2 years in 2016 after the first purchase of the drug for sublingual immunotherapy (SLIT) for Japanese Cedar pollinosis (JCP). PURPOSE: The purpose of this study is to clear the clinical efficacy of SLIT in the second treated year by comparing with other therapies, such as subcutaneous immunotherapy (SCIT), or other pharmacotherapy. METHODS: We started SLIT at our clinic in October-December, 2014. We compared the clinical efficacy in 2016, of 133 SLIT with 46 SCIT, 351 primary pharmacotherapy that started therapies before pollen dispersal, 221 pharmacotherapy that started therapies after pollen disposal, or 337 non-treatment. The clinical efficacy was evaluated with symptom scores and combined symptom-medication scores (SMS), symptoms of nose and eye by visual analog scale (VAS), quality of life (QOL) scores by Japanese rhino-conjunctivitis QOL questionnaire (JRQLQ No1). RESULTS: Fourteen cases by unknown reasons and 3 cases by inevitable reasons were dropped out for 2 years. Both SCIT and SLIT showed good clinical efficacy without significant difference in every assessment. Both SCIT and SLIT were significantly better than other pharmacotherapy in most assessment. Patients, whose symptom scores of nose and eye were 0 or 1 point without any rescue drugs, accounted for 26.3% of total SLIT. CONCLUSION: SLIT in the second treated year showed good clinical efficacy in reducing symptoms and SMS of JCP, and in improving QOL. SLIT was significantly effective compaired with other pharmacotherapies.

Adherence and Clinical Outcome of Sublingual Immunotherapy for Japanese Cedar Pollinosis.

Sublingual immunotherapy (SLIT) for Japanese cedar pollinosis is known to be effective. However, better SLIT adherence is needed to improve its safety and efficacy. 　Purpose: The purpose of this study was to evaluate SLIT adherence and its influence on clinical outcome. 　Methods: We conducted a detailed survey of 132 patients who have been receiving SLIT for 2 years on adherence at each visit using both questionnaires and direct calculation from prescription. Questionnaires on total symptoms using the visual analog scale (VAS), face scale, and total nasal symptom medication score (TNSMS) were obtained at the peak season for Japanese cedar pollinosis. 　Results: Good adherence by prescription for 2 years was observed in 83.1% ± 11.7% of patients. The adherence in the second year (80.8% ± 13.6%) was lower than that in the first year (88.5% ± 9.8%). However, adherence by questionnaire was 13.5% higher than that by prescription. VAS of total symptoms and adherence did not correlate; however, evaluations by VAS, face scale, and TNSMS were significantly improved if the adherence cut-off value was set to 70% or 75%. 　Conclusion: Our results suggest that SLIT adherence for Japanese cedar pollinosis is high and adequate adherence is required for better efficacy.

Severity assessment of Japanese cedar pollinosis using the practical guideline for the management of allergic rhinitis in Japan and the allergic rhinitis and its impact on asthma guideline.

BACKGROUND: This study intended to assess the severity of Japanese cedar pollinosis using the Practical Guideline for the Management of Allergic Rhinitis in Japan (PG-MARJ) and the Allergic Rhinitis and its Impact on Asthma (ARIA) Guideline. METHODS: An Internet questionnaire survey of patients with pollinosis was conducted in mid-May 2011 and responses were obtained from 3382 individuals who had potential symptoms of Japanese cedar pollinosis from February to early May 2011 and who had experienced such symptoms for at least two pollen seasons. RESULTS: According to PG-MARJ, 23.5% of the respondents had severest rhinitis, 29.4% severe rhinitis, 31.3% moderate rhinitis, 13.8% mild rhinitis and 2.0% asymptomatic rhinitis. According to ARIA, 67.2% of them had moderate/severe persistent rhinitis, 23.8% moderate/severe intermittent rhinitis, 4.4% mild persistent rhinitis and 4.6% mild intermittent rhinitis. CONCLUSIONS: Moderate to severe rhinitis was diagnosed in more than 80% of the respondents according to PG-MARJ, while moderate/severe rhinitis was diagnosed in more than 90% of the respondents according to ARIA. Most of the respondents suffered relatively severe pollinosis. More than 80% of the respondents had all the three major symptoms (i.e., sneezing, rhinorrhea and nasal blockage). Disagreement in the severity assessment between the two guidelines was noted in approximately 20% of the respondents.

SLIT improves cedar pollinosis by restoring IL-10 production from Tr1 and Monocytes∼IL-10 productivity is critical for becoming allergic∼.

BACKGROUND: Allergen-specific immunotherapy (SIT) is currently used for several allergic disorders and IL-10-producing regulatory T cells (Tr1) induced by SIT suppress allergic reactions. We investigated the relation between IL-10 production and acquiring allergy. METHODS: A prospective study was undertaken to evaluate the effect of SIT on IL-10 production in T cells and other cell fractions in children with pollinosis. In addition, blood samples were collected from non-allergic healthy controls and patients with pollinosis to compare the levels of IL-10 production. PBMC were cultured with pollen peptides or control allergens, and the IL-10 production from monocyte and CD4 T cell was analyzed. RESULTS: Monocytes and CD4 T cells from SIT group of patients produced high levels of IL-10, suggesting that the induction of IL-10 is essential for inducing T cell tolerance. IL-10 production from monocytes and T cells was significantly increased in non-allergic controls compared to patients with pollinosis. This high IL-10 production was observed even when PBMC were stimulated with antigens other than pollen peptides. CONCLUSIONS: IL-10 is critical for induction of specific T cell tolerance, and increased production of IL-10 by monocytes and T cells during inflammatory responses or after SIT may influence effector cells in allergy. Present data implicates that the low productivity of IL-10 by monocytes and T cells is closely related with sensitivity to multiple allergens, and resistance to allergic diseases. Augmentation of constitutive IL-10 production from immune system is a potential therapeutic approach for allergic disorders.

[Antigen specific sublingual immunotherapy for pediatric Japanese cedar pollinosis].

BACKGROUND: Sublingual immunotherapy (SLIT) for allergic rhinitis is commonly used in Europe, but not in Japan. Although some studies of SLIT for Japanese cedar pollinosis (JCP) were reported, all the subjects were adults. SLIT is an ideal treatment for children rather than for adults, because it overcomes subcutaneous immunotherapy in the complication of painful injections and habitual visits of a hospital. We tried an open pilot study of SLIT for pediatric JCP. METHODS: Ten pediatric patients with JCP (4 boys and 6 girls, mean ages; 8.5+/-2.2 years old) were treated according to a scheduled doses of SLIT with a therapeutic standardized Japanese cedar pollen extract. They were maintained at the doses of 2000JAU of allergen once a week during pollen scattering. Clinical efficacies during the pollen scattering in the first season were evaluated from their diary of symptoms and medications, visual analog scale (VAS) of symptoms, and a questionnaire for SLIT. RESULTS: The mean severity scores of nasal and ocular symptoms were low. VAS was also very short. Three of 10 patients had no symptoms without any drugs during the pollen season. Two patients were medicated within 5 days. CONCLUSIONS: SLIT was effective for pediatric Japanese cedar pollinosis.

[Influence of the difference in the pollen count on medical costs in an allergen-specific immunotherapy for Japanese cedar pollinosis].

BACKGROUND: We studied medical economic efficacy and influence by the different number of pollen scattering in patients treated with allergen-specific immunotherapy for Japanese cedar pollinosis. METHODS: We calculated medical treatment costs and the medicine expense from medical records in eighteen cedar pollinosis patients treated with allergen-specific immunotherapy (IT-G) and with medications (M-G). We examined with the same patients for three years of different pollen scattering, mass scattering year (2005), moderate scattering year (2003), a few scattering year (2004). Furthermore, satisfaction of treatment and symptom score measured by visual analog scale in both subjects was studied in a mass scattering year. RESULTS: Total medical costs at hospital was cheaper in IT-G than in M-G. The result was depended on prescribed medical costs. In addition, prescribed medicine agents and total medical costs did not increase by the mass scattering year of pollen. Satisfaction of treatment and symptom score in IT-G was better than that in M-G. CONCLUSION: Immunotherapy had a benefit on a medical economy.

Treatment results of alternating chemoradiotherapy for nasopharyngeal cancer using cisplatin and 5-fluorouracil--a phase II study.

The present study was conducted to evaluate the therapeutic results of alternating chemoradiotherapy for locally advanced nasopharyngeal cancer. The subjects were 87 patients with stage II-IVB nasopharyngeal cancer. Alternating chemoradiotherapy was performed; initially, chemotherapy was administered, and then radiotherapy (wide field), chemotherapy, radiotherapy (shrinking field), and chemotherapy were alternately performed. For chemotherapy, 5-FU at a dose of 800 mg/m2/24 h was intravenously administered for 5 days (days 1-5), and CDDP at a dose of 50 mg/m2/24h for 2 days was administered on day 6 and 7. The scheduled courses of alternating chemoradiotherapy were completed in 70 (80%) of 87 patients. Although 1 patient developed a transient neurological disturbance induced by hyper-ammonemia by metabolism of 5-FU, no severe adverse effects were noted in any other patients. In these 87 patients, the overall 5-year survival rate was 83% (95% confidence interval: 74-92%), and the progression free survival rate was 75% (95% CI: 66-85%). This method of alternating chemoradiotherapy yielded higher or at least similar survival rates and lower toxicities than concurrent chemoradiotherapy, and is worth trying in a randomized controlled study to compare with concurrent chemoradiotherapy.

[Prediction of the total Japanese cedar pollen counts based on male flower-setting conditions of standard trees].

We made a prediction of the Japanese cedar (Cryptomeria japonica) pollen counts at Tsu city based on male flower-setting conditions of standard trees. The 69 standard trees from 23 kinds of clones, planted at Mie Prefecture Science and Technology Promotion Center (Hakusan, Mie) in 1964, were selected. Male flower-setting conditions for 276 faces (69 trees x 4 points of the compass) were scored from 0 to 3. The average of scores and total pollen counts from 1988 to 2000 was analyzed. As the results, the average scores from standard trees and total pollen counts except two mass pollen-scattered years in 1995 and 2000 had a positive correlation (r = 0.914) by linear function. On the mass pollen-scattered years, pollen counts were influenced from the previous year. Therefore, the score of the present year minus that of the previous year were used for analysis. The average scores from male flower-setting conditions and pollen counts had a strong positive correlation (r = 0.994) when positive scores by taking account of the previous year were analyzed. We conclude that prediction of pollen counts are possible based on the male flower-setting conditions of standard trees.