Approaches to immunotherapies for Japanese cedar pollinosis

Japanese cedar (Cryptomeria japonica; CJ) pollinosis is a typical type I allergy induced by CJ pollen and one of the most common allergic diseases in Japan. New immunotherapies have been developed for treatment of CJ pollinosis. We focus here on new immunotherapies for CJ pollinosis including sublingual immunotherapy with crude extract of CJ antigen, oral immunotherapy with transgenic rice expressing CJ allergens, a peptide vaccine using T cell epitopes of CJ allergens, DNA vaccines encoding either the CJ allergen gene or T cell epitope gene, and adjuvant-conjugated vaccines using CJ allergen conjugated with adjuvants such as CpG oligodeoxynucleotide or pullulan.     

Effect of Asian sand dust on Japanese cedar pollinosis

Objective

Asian sand dust (ASD), originating in the deserts of Mongolia and China, spreads over large areas and is associated with adverse effects on human health in East Asia, including asthma, heart disease, and some allergic diseases. However, the effect of ASD on patients with seasonal allergic rhinitis caused by Japanese cedar pollen (SAR-JCP), the most common form of allergic rhinitis, remains unclear. The aim of this study was to investigate the effect of ASD on SAR-JCP patients.

Methods

A total of 41 patients with SAR-JCP recorded nasal and ocular allergic symptom scores in a diary. We assessed the influence of ASD events on patients with SAR-JCP during the JCP season and before and after the JCP season.

Results

ASD events did not influence nasal and ocular allergy symptoms during the JCP season. Scores for sneezing and runny nose were significantly increased by ASD events in the pre-JCP season. Ocular symptom scores were significantly increased by ASD events in the post-JCP season.

Conclusion

Our results suggest that ASD may exacerbate allergy symptoms even before mass scattering of JCP, which usually does not cause allergic symptoms in patients with SAR-JCP. ASD also induced conjunctivitis symptoms after the JCP season. However, we did not observe any adverse effects of ASD on allergic symptoms during the JCP season.     

Oral allergy syndrome in patients with Japanese cedar pollinosis

Patients with pollinosis sometimes complain of oral symptoms (itching and tingling with or without edema of the lips, mouth and tongue) after eating fresh fruits and vegetables. This condition has been termed Oral Allergy Syndrome (OAS). Twenty-three patients with Japanese cedar pollinosis and OAS for fresh fruits and vegetables were included in this study. Their mean age was 31.3 years (range = 5 to 62). The fruits that caused OAS in these patients included melon, apple, peach, and kiwi fruit. Most patients with OAS exhibited hypersensitivity to more than two foods. Specific IgE antibodies to inhaled allergens of mite, Japanese cedar pollen, birch pollen, melon, apple, peach, and kiwi were evaluated using the Pharmacia CAP system. Eleven of the 16 subjects with specific IgE antibodies for birch pollen, did not suffer symptoms during the birch and alder pollen season. In subjects with specific IgE antibodies for fruits, 13 out of 20 patients showed specific IgE antibodies for apple, and 8 out of 9 patients with OAS for apples were also positive for specific IgE antibodies for apples. On the other hand, 17 patients had no specific IgE antibodies for melon, and only two patients and one patient showed specific IgE antibodies for kiwi fruit and peach, respectively. These results suggest that the evaluation of specific IgE antibodies to birch pollen and apple may be useful for diagnosing OAS in patients with Japanese cedar pollinosis.     

Epidemiology of Japanese cedar pollinosis: result of the survey in Mibu-machi

The prevalence rate of Japanese cedar pollinosis has increased since 1979. We conducted a survey of the residents of Mibu-mach, Tochigi, in 1988 and 1996 using a questionnaire to determine the prevalence rate of cedar pollinosis. Results showed its rate was 15.6% in 1988, and 25.6% in 1996. Age distribution analysis of patients with Japanese cedar pollinosis showed the highest prevalence in patients between the ages of 10 to 49 years in 1988, and between the ages of 10 to 59 years old in 1996. Within these age groups, the majority of the patients were females, but males were more prevalent than females in the age group under 19 years old. The prevalence rate of patients by age group revealed the same pattern as the age distribution of the patients. Age distribution of cedar pollinosis showed a peak in patients in their thirties both in 1988 and 1996. In conclusion, the numbers of patients with Japanese cedar pollinosis has been increasing remarkably in Mibu-mach. As climate or environmental conditions are varied in different geographical regions in Japan, further epidemiological studies in various regions of the country are required to clarify the actual prevalence rate of cedar pollinosis.     

Combined intratumor cisplatinum injection and Nd:YAG laser therapy

OBJECTIVES/HYPOTHESIS: Interstitial laser therapy (ILT) has become useful for tumor palliation in patients with advanced head and neck cancer. Cisplatinum chemotherapy also is a frequent adjuvant treatment for recurrent tumors, but systemic toxicity limits application. Intratumor cisplatinum injection combined with ILT may improve therapy of these recurrent tumors with reduced toxicity. STUDY DESIGN: Prospective. Tumor transplants were injected with cisplatinum in a gel implant before ILT to evaluate treatment response and toxicity in a preclinical study. METHODS: UCLA-P3 human squamous cell carcinoma tumors were grown as subcutaneous transplants in nude mice and treated by intratumor injection of 2 mg/mL cisplatinum in a slow-release, collagen-based gel carrier 4 hours before interstitial implantation of Nd:YAG laser fiberoptics to induce local tumor hyperthermia. Treatment efficacy and toxicity were followed for 12 weeks after combined drug and laser therapy compared with ILT alone. RESULTS: Combined cisplatinum gel and ILT was a significant improvement (P < .01 by chi-square test) and induced 57% complete responses without regrowth in 21 transplanted tumors compared with only 24% in 21 tumors after ILT alone during 12-week follow-up. Recurrences in both cases appeared to result from nonuniform laser energy delivery within tumors via the implanted fiberoptic tip. CONCLUSIONS: The results of this experimental combined cisplatinum and ILT study suggest it may be possible to improve treatment of advanced head and neck cancer by intratumor injection of gel implants containing the drug followed by interstitial Nd:YAG laser hyperthermia.     

Long-term sublingual immunotherapy provides better effects for patients with Japanese cedar pollinosis

ObjectiveJapanese cedar pollinosis is an endemic disease affecting a large proportion of Japan's population. Five seasons have passed since sublingual immunotherapy (SLIT) for Japanese cedar pollinosis was included in the public insurance coverage in Japan. In this study, we evaluated the clinical effects of long-term SLIT for Japanese cedar pollinosis on upper respiratory symptoms primarily represented by nasal symptoms and inflammation of the respiratory tract in the 2019 season, in which considerable amount of cedar pollen was dispersed.MethodsThis study involved 95 patients who were undergoing SLIT for Japanese cedar pollinosis after the initiation at some point between 2014 and 2018, and this group of patients was compared with a control group comprising 21 patients receiving preseasonal prophylactic treatment (with a second-generation antihistaminic drug). We evaluated the patients’ nasal/eye symptoms, total nasal symptom and medication score (TNSMS), and quality of life according to relevant guidelines. In addition, the levels of peripheral blood eosinophils, serum total IgE, Japanese cedar antigen-specific IgE, Cryj1-specific IgG4, and fractional exhaled nitric oxide (FENO) were measured as objective indices.ResultsFrom the fourth season (SLIT4), nasal discharge, sneezing, nasal obstruction symptoms, and TNSMS significantly decreased compared with those in the preseasonal prophylactic treatment and SLIT1 groups. In the patients suspected to have eosinophilic airway inflammation (with a baseline FENO ≥25 ppb), the interannual variability of FENO levels significantly reduced after 5 years of treatment.ConclusionThe efficacy of SLIT was noted from the first year of treatment, even in a year when pollen profusely dispersed. Thus, long-term continuous treatment with SLIT may alleviate nasal symptoms as well as eosinophilic airway inflammation.     

Seasonal variation of nasal surface basophilic cells and eosinophils in Japanese cedar pollinosis

Nasal pollinosis is caused by pollens of trees and grasses as allergen floating in the air during the seasons of blossom. In Japan, cedar pollinosis is the most prevalent of seasonal allergic rhinitis. We studied the seasonal variation of nasal mucosal basophilic cells (cells with basophilic and metachromatic granules) and eosinophils by nasal scraping of cedar pollinosis patients from June 1986 to May 1987, and found that during the season basophilic cells and eosinophils increased significantly, decreased but still remained for two or three monts after the season, and finally disappeared. The variation of eosinophils was more prominent than basophilic cells. The increase of both cells had close correlation with each other.     

Measurement of quality of life during different clinical phases of Japanese cedar pollinosis

OBJECTIVE: To assess Quality of Life (QOL) scores in patients with Japanese cedar (Cryptomeria japonica, CJ) pollinosis. METHODS: QOL was measured intraseasonally and extraseasonally in patients (n = 69) using the Medical Outcomes Study Short-Form Health Survey, and compared with healthy control subjects (n = 50). The differences in intraseasonal QOL scores between short and long disease duration groups were studied. The relation of intraseasonal QOL scores to nose symptoms was evaluated using Spearman's rank correlation. RESULTS: Significant decrease was observed in two of eight QOL items in intraseasonal measurements of patients. These QOL impairments improved extraseasonally. Scores for emotional problems in patients with long disease duration were less impaired than those with short disease duration. QOL scores in patients correlated poorly with the severity of nasal symptom. CONCLUSIONS: This is the first study to report QOL impairment in CJ pollinosis. Based on the findings long disease duration may improve emotional problems, and the correlation between disease severity and QOL is low.     

Relationship between airborne pollen count and treatment outcome in Japanese cedar pollinosis patients

In Japan, information on daily Japanese cedar pollen counts is made public during pollen season. If symptom severity and treatment outcome are predictable according to these pollen counts, management of seasonal allergic rhinitis may become more precise. The aims of the study were to evaluate the relationship between airborne pollen counts, symptom severity and treatment outcome in Japanese cedar pollinosis patients. In the randomized study, patients with moderate to most severe Japanese pollinosis were treated with fexofenadine (60 mg BD) or fexofenadine and nasal corticosteroids for 2 weeks. During the same period daily airborne pollen counts were measured. A total of 105 adult patients were enrolled. No difference of treatment efficacy was seen among groups. Detailed results of efficacy and safety were previously described elsewhere. In univariate analysis, the mean cumulative amount of airborne pollen exposure for 4 days prior to the study tended to affect symptom severity (P = 0.053) and the mean cumulative amount of airborne pollen during the treatment period tended to show difference among five treatment outcome categories (P = 0.066). In multivariate analysis, the mean cumulative amount of airborne pollen exposure for 4 days prior to the study was identified as the only significant factor of symptom severity (P = 0.0327) and cumulative amount of airborne pollen during the treatment period (P = 0.027) and allergic history (P = 0.027) were significant factors of treatment outcomes. No serious adverse effect was reported during the study. The amount of airborne pollen may be predictive of both symptom severity and treatment outcome.     

Nd：YAG激光对兔咽部黏膜热损伤的研究

目的探讨NdYAG激光功率密度与黏膜组织热损伤程度的关系，以及激光照射后黏膜组织愈合的过程。方法激光功率密度221W／cm     

Interstitial Nd:YAG laser therapy. Color-Doppler imaging (CDI)-guided laser therapy of hemangiomas and vascular malformations

BACKGROUND AND OBJECTIVE: Ultrasound-(US-) guided Nd:YAG laser therapy has been reported to be promising among different other options for treatment of hemangiomas and vascular malformations.The concept of CDI-guided interstitial laser therapy is therefore a further development based on the above mentioned therapeutic regime. PATIENTS AND METHODS: We examined 55 patients suffering from vascular lesions of different localization and extent pre-, intra-, and post-operatively using color-Doppler imaging (CDI). All vascular lesions were classified due to their vascularization pattern.As accurate diagnosis was imperative we decided on possible laser treatment depending on the CDI-classification. RESULTS: Intra-operative use of CDI rendered possible fiber-guidance by sonographic navigation and therefore precise treatment of aberrant vessels and well-perfused tumor areas. In 34 cases (62%) we observed complete, in 21 cases (38%) partial regression of vascular lesions. CDI allowed post-operative proof of diminution of tumor vascularization in all cases. CONCLUSIONS: CDI-guided interstitial Nd:YAG laser therapy is a minimally-invasive technique which allows replacement of conventional surgical procedures while achieving good cosmetic and functional results.CDI broadens the therapeutic possibilities in contrast to the former therapeutic concept of US-guided laser therapy due to pre-, intra and post-operative utilization of this imaging technique while significantly diminishing the intra-operative risk for the patient.     

纤维喉镜下Nd:YAG激光治疗760例声带息肉和小结的疗效分析

目的 评价纤维喉镜下激光治疗声带息肉和声带小结疗效。方法 对随访2年以上的760例声带息肉（516例）和小结（224例）病人进行了总结、分析。结果 声带息肉和小结一次性治愈率分别为96％、99％，末彻底治愈的20例声带息肉病人、3例声小结病人经再次激光治疗后痊愈。结论 纤维喉镜下引导导激光是治疗声带息肉和小结的有效方法，具有痛苦小、反应轻、恢复快、复发率低的优点。     

Effects of sublingual immunotherapy on nasal symptoms and sleep disturbance in patients with Japanese cedar pollinosis

ObjectiveJapanese cedar (JC) pollinosis is the most common seasonal allergic rhinitis (AR) in Japan. AR reduces the quality of life not only because of nasal symptoms but also because of sleep disturbance. In the present study, we investigated the effects of sublingual immunotherapy (SLIT) with a standardized JC pollen extract on nasal symptoms and AR-related sleep disturbance in patients with JC pollinosis.MethodsIn the present non-randomized controlled study, we assigned thirty-one patients with JC pollinosis who received SLIT into the SLIT group, and another thirty-eight patients with JC pollinosis who visited our hospital without treatment into the untreated group. We evaluated nasal symptoms and sleep disturbance using the classification of the severity of AR symptoms and the Athens Insomnia Scale, respectively.ResultsThe nasal symptom scores and the Athens Insomnia Scale scores of patients in the SLIT group were both significantly lower than those of patients in the untreated group. There was a significant correlation between total nasal symptom scores and the Athens Insomnia Scale scores.ConclusionsThese findings suggested that SLIT with JC pollen extract suppressed nasal symptoms in patients with JC pollinosis, leading to improvements in AR-related sleep disturbance and daytime troubles with daily life.     

Nd: YAG laser treatment for adult hypopharyngeal haemangioma

Adult hypopharyngeal haemangioma is an uncommon neoplasm. We present three cases of adult hypopharyngeal haemangioma which were successfully treated with a neodymium: yttrium-aluminium-garnet (Nd: YAG) laser in our hospital between 2000 and 2003. The patients in this series experienced no untoward events from the use of the laser. Excessive bleeding and airway problems were not encountered. Postoperative pain was minimal. Excellent long-term function and a full resolution of symptoms can be obtained using Nd: YAG laser. The laser provides a bloodless field and complete healing of the hypopharynx, without stenosis or scar formation.     

The add-on effect of an intranasal antihistamine with an intranasal corticosteroid in Japanese cedar pollinosis

ObjectiveCombination intranasal drugs with a corticosteroid and antihistamine are available in several countries with better effect than treatments with single agents. However, it remains unclear whether this effect is also seen in Japanese cedar pollinosis (JCP), the most prevalent seasonal allergic rhinitis in Japan. We investigated the effect of an add-on intranasal antihistamine with an intranasal corticosteroid in JCP during the pollen dispersal period. (UMIN000025508)MethodsWe performed a double-blinded, randomized, placebo-controlled trial from March 1 to 14, 2017. Patients (n = 20 per group) received either a mometasone furoate nasal spray (MFNS) plus a levocabastine nasal spray (levocabastine group) or MFNS plus a placebo nasal spray (placebo group). The primary endpoint was the difference in the total nasal symptom score (TNSS) after treatment between the two groups. Differences in the total ocular symptom score, total symptom score, total medication score, total symptom-medication score, and five individual symptoms as well as safety were the secondary endpoints.ResultsThe change in the TNSS from baseline was significantly greater in the levocabastine group than in the placebo group. A significant reduction in the TNSS was observed more than 6 days earlier in the levocabastine group than in the placebo group. Such add-on effects were also seen in the secondary endpoints. Both treatments were well-tolerated.ConclusionThe intranasal antihistamine provided better control of not only nasal symptoms, but also of ocular symptoms, and decreased the need for rescue medications when added to intranasal corticosteroid treatment in JCP patients.     

Use of the Nd:YAG laser in otorhinolaryngology]

The Nd:YAG laser is suitable for the treatment of various otorhinolaryngological clinical disorders. These include the palliative reduction of tumor size in sites with difficult access, treatment of hemangiomas and reduction of hyperplastic turbinates. Within certain limits, other indications are treatment of recurrent epistaxis and recurrent polyposis. Palliative reduction of malignancies in the nasopharynx, esophagus, and bronchial system (laser power density: 1500-8000 W/cm2) must sometimes be carried out in several sessions in order to avoid complications due to the laser (i.e., perforation of the bronchial or esophageal wall, lesions of adjacent vessels or nerves). Nd:YAG laser treatment of hemangiomas (500-3000 W/cm2) can lead to excellent results. To avoid excessive thermal lesions, vascular tissue is cooled with ice cubes or with an ice-cold Ringer's solution. The laser process is continued until the onset of tissue blanching. Carbonizations of the tissue are to be avoided. In Nd:YAG laser therapy of hyperplastic lower nasal conchae (approx. 1000 W/cm2), results are based on submucous scarring in which the covering epithelium is maintained. The objective of Nd:YAG laser treatment of recurrent epistaxis in patients with Osler's disease (500 W/cm2) is to reduce the incidence of hemorrhage. Use of the laser in recurrent polyposis is best confined to patients who refuse conventional surgical revision operations. Laser light (500-3500 W/cm2) should only be applied for a short period of time (0.5 s) to avoid creating a rarefying osteitis.     

Exhaled and nasal nitric oxide in patients with Japanese cedar pollinosis and effects of nasal steroids

INTRODUCTION: Nitric oxide (NO) is produced by the action of NO synthase (NOS) using L-arginine as a substrate in various cells and found in air exhaled by humans. Previous studies suggest that almost all exhaled NO is derived from the upper airways and increases in patients with untreated asthma and allergic rhinitis. Exhaled NO is inhibited by treatment with inhalation of steroids that may be caused by inhibition of inducible nitric oxide synthase (iNOS). The purpose of this study is to determine whether exhaled and nasal NO increases in patients with Japanese cedar pollinosis compared with nonallergic healthy subjects, and whether it is affected by treatment with nasal steroids. Furthermore, we investigated its relation to nasal function and allergic rhinitis. SUBJECTS AND METHODS: 10 patients with Japanese cedar pollinosis and 5 healthy normal subjects were tested. All subjects had no history of respiratory infection for at least 2 weeks and did not smoke. Exhaled NO was collected in a sampling bag from oral and nasal breathing, and nasal NO was sampled directly from the nasal cavity. Both were measured by a chemiluminescence NO analyzer, ML9841, at a detection limit of 1 part per billion (ppb). Subjects used nasal steroids for 2 weeks and were measured similarly afterwards. RESULTS: NO concentrations in nasal air and air exhaled from the nose in patients with Japanese cedar pollinosis (277.9 +/- 59.5 ppb, 34.4 +/- 3.9 ppb, n = 10) were higher than the normal subjects (153.3 +/- 30.6 ppb, 19.9 +/- 3.4 ppb, n = 5) (p < 0.05). NO exhaled from the mouth was not significantly different between patients (20.5 +/- 4.9 ppb) and normal subjects (23.7 +/- 2.6 ppb). In patients with Japanese cedar pollinosis, the concentration of nasal NO and nasal exhaled NO were significantly decreased after treatment with nasal steroids (144.0 +/- 21.0 ppb, 26.1 +/- 3.0 ppb) (p < 0.01, p < 0.05), but there was no change in oral exhaled NO (17.2 +/- 3.3 ppb). In normal subjects, oral (22.5 +/- 5.3 ppb), nasal exhaled NO (19.1 +/- 2.3 ppb), and nasal NO (151.2 +/- 24.8 ppb) were not changed. CONCLUSION: In patients with Japanese cedar pollinosis, nasal NO was increased and decreased by nasal steroids. These results suggest that increased nasal NO in patients with allergic rhinitis is produced by induction of iNOS and that nasal NO produces the symptoms of nasal obstruction and rhinorrhea.     

Costimulatory molecule expression on allergen-stimulated PBMC in cedar pollinosis subjects

B7-1 (CD80) and B7-2 (CD86) play important roles in the differentiation of Th1 and Th2 phenotypes. CD40-CD40L interaction supports the expression of CD80 and CD86 on antigen-presenting cells. Blocking studies suggest these molecules also play important roles in sensitization to a cedar pollen antigen by, but very few studies have concerned their effects on subsequent induction by antigens. We investigated the roles of CD80, CD86, and CD40 in the differentiation of Th1 and Th2 subsets after stimulation with the antigen in subjects with cedar pollinosis. Peripheral blood mononuclear cells (PBMC) were isolated from 12 subjects with pollinosis and 11 healthy controls and stimulated with cedar pollen extract. After in vitro stimulation, CD80, CD86, and CD40 expression on CD19+ cells were analyzed by flow cytometry. The production of type 1 and type 2 cytokines in culture supernatants was measured by FLISA. Proliferation studies were conducted in the presence or absence of anti-CD40 or CD86 mAbs. After in vitro stimulation, CD86 and CD40 were significantly up-regulated following stimulation in pollinosis subjects (p = 0.02 and p = 0.04). A significantly higher level of IL-5 (p = 0.02) was produced by PBMC of pollinosis subjects than by those of controls. Allergen-induced proliferation and IL-5 production of PBMC of pollinosis subjects were inhibited by anti-CD86 mAb but not CD40 mAb. These results indicate that the Th2 response predominated in pollinosis subjects and that CD86 rather than CD80 may be the costimulatory molecule involved in the allergen-induced activation of PBMC.