Effect of rush immunotherapy in house-dust-mite (HDM)-sensitive adult bronchial asthma: changes in in vivo and in vitro responses to HDM.

An open study was conducted to evaluate the changes in in vivo and in vitro responses to house-dust-mite (HDM) after rush immunotherapy (RI). A 7-day RI protocol using an extract containing HDM allergen was administered to 12 subjects with HDM-sensitive asthma, and the effects on bronchial responsiveness and serum antibody levels were evaluated up to 16 or 20 weeks after RI. The levels of HDM-specific IgG, IgG1 and IgG4 antibodies were significantly elevated from 4 or 8 weeks after RI. Provocative doses causing a 20% fall in FEV1 (PD20) by allergen inhalation were elevated in all subjects at 16 to 20 weeks after RI. There was a high correlation between the increase in log-PD20 and the increase in the ratio of HDM-specific IgG4 to IgG1 (r = 0.68, p < 0.05). The results suggest that RI elicits the improvement of allergen-specific bronchial responsiveness and the increase in serum antibody levels within a relatively short period.

[Clinical significance of allergen specific immunotherapy in adult house-dust-mite-sensitive bronchial asthma: impact on disease severity and medical cost].

The objective of this study was to evaluate the clinical significance of allergen-specific immunotherapy in house-dust-mite-sensitive adult bronchial asthma. Fifty patients treated with rush immunotherapy using house dust antigen were examined. The disease severity was compared between before and a year after the maintenance immunotherapy: reduction in the severity was observed in 27 patients (54.0%) following the treatment. The response rate was greater in the patients with step 3 (moderate, persistent) or step 4 (severe, persistent), disease period less than 10 years, or reversible airway obstruction. Patients who showed favorable clinical response also demonstrated the reduction in medical costs. These results suggest that allergen immunotherapy reduces the disease severity and medical cost in a certain population of adult atopic asthma.

[The analysis of factors contributing to the safety and efficacy of rush immunotherapy in bronchial asthma].

In order to establish guidelines for the optimal use of rush immunotherapy (RI) in mite-sensitive adult bronchial asthmatics, we clinically analyzed 38 cases treated with RI. In all cases, it was possible to reach a maintenance dose greater than 0.10 ml of 1/10 solution of house dust (HD) within 10 days. Most of the systemic reactions occurred after doses greater than 0.15 ml of 1/10 solution. The patients who showed the maximum size of skin reaction > or = 8 cm were susceptible to systemic reactions. Prior to the occurrence of asthma, most cases complained of some prodrome of airway irritation. The clinical efficacy of RI was significantly lower in patients whose FEV1% was < 70%, and no difference was observed between patients whose maintenance dose was 0.10 ml and those whose maintenance dose was greater than 0.20 ml. These results suggest: 1) RI should be performed on patients whose FEV1% is > or = 70%, 2) 0.10 ml of 1/10 solution is an optimal dose, 3) when a local skin reaction is > or = 8 cm in diameter and/or a prodrome of airway irritation occurs, one should be careful when increasing the dosage.

[The long-term effect of high-dose beclomethasone dipropionate on the pituitary-adrenal function].

The pituitary-adrenal function was studied in seven asthmatic subjects who had been received daily inhalations of 800 to 1,000 micrograms of beclomethasone dipropionate (BDP) over a year. None of the subjects had taken oral corticosteroids for at least six months prior to the study. As indices of pituitary-adrenal function, 1) circadian rhythm of plasma ACTH and cortisol, 2) urine 17-OHCS and 17-KS, and 3) the response of cortisol in rapid ACTH test were examined. All subjects showed normal circadian rhythms of plasma ACTH and cortisol levels. Urinary 17-OHCS and 17-KS excretions over a 24-hour period were also within the normal range. Plasma cortisol levels in the rapid ACTH test were significantly increased and judged as normal responses in all subjects. These results indicate that long-term treatment with BDP ranging from 800 to 1,000 micrograms/day induces no suppressive effect on the pituitary-adrenal function.

[The inhibitory effect of long-acting beta-adrenergic agonists, mabuterol, clenbuterol and fenoterol on "morning dipping" in patients with asthma].

We examined the inhibitory effect of the long-acting beta-adrenergic agonists, mabuterol, clenbuterol and fenoterol on "morning dipping" in ten patients with nocturnal asthma. On the first night, as a control experiment, the subjects received no beta-adrenergic agonist. On the succeeding three nights at 8:00 PM, each subject was orally administered 50 micrograms of mabuterol, 40 micrograms of clenbuterol and 5 mg of fenoterol in a randomized, crossover fashion. Pulmonary function tests (FVC, FEV1.0, PEFR, V50 and V25) were performed at 8:00 PM (just before administration of beta-adrenergic agonist), 9:00 PM, 10:00 PM, 6:00 AM and 8:00 AM. On the night when clenbuterol was administered, there was a significant inhibition of morning dipping at 6:00 AM in FVC (p less than 0.01), FEV1.0 (p less than 0.01), PEFR (p less than 0.01), V50 (p less than 0.01) and V25 (p less than 0.05) compared with the control night. On the nights when mabuterol and fenoterol were administered, there was a significant inhibition of morning dipping at 6:00 AM in FVC (p less than 0.01) and FEV1.0 (p less than 0.01) compared with the control night. Palpitations associated with clenbuterol administration were seen in two subjects. The effect of each beta-adrenergic agonist varied inconsistently among the subjects. These results indicate that clenbuterol is the most effective in inhibiting morning dipping among the long-acting beta-adrenergic agonists examined, but individualization in the choice of beta-adrenergic agonist is mandatory in order to achieve the maximum effect.

[Allergic characteristics of bronchial asthma in the elderly].

Allergic characteristics were investigated in asthma patients older than 60 years of age. Among these asthmatic patients: 1. About 37% showed negative immediate skin response to all antigen extracts tested. 2. The frequency of positive immediate skin response to house dust, house dust mite, Japanese cedar and Alternaria decreased with aging. 3. There was no difference in the frequency of positive immediate skin response to Candida antigen among patients in different age groups. Candida was the antigen that most frequently produced positive immediate skin response among the patients over 50 years old. 4. There was no difference between skin-positive elderly asthmatics and young asthmatics in the frequency of positive IgE antibody titer, bronchial response, conjunctival response and histamine release from peripheral leukocytes by specific antigens. These findings show that atopic asthmatics are less frequently found in elderly asthmatic patients than in young patients. Nevertheless, there is no difference in the characteristics of atopy, except in the response to Candida antigen.

[Clinical evaluation of whole blood histamine release test simultaneously testing multiple allergens--correlated with bronchial provocation test].

We compared the efficacy of the novel histamine release test (HRT), which allows the determination of many allergens at the same time using a small amount of whole blood, with other conventional allergen diagnostic tests. HRT and RAST were both performed along with bronchial provocation tests (BPT) on 44 bronchial asthma patients in whom the etiologic allergen could not be determined by either intracutaneous tests (ICT) or ophthalmic response tests (ORT). The HRT uses a microtiterplate on which glass fibers have 10 kinds of allergens affixed. The histamine release ability at 6 different concentrations of each kind of allergen was examined. The concordance of HRT with respect to BPT was the highest at 82% in comparison with RAST at 66%, ICT at 55% and ORT at 60%. With each of the allergens, HRT had the highest concordance with BPT. On the other hand, RAST, ICT and ORT showed different results depending on the allergens. The positive predictive value of HRT was the highest at 76% compared with RAST at 59%, ICT at 51% and ORT at 64%. From these results, we concluded that HRT is a more useful diagnostic method for the confirmation of a clinical allergy than other conventional diagnostic methods.

[A clinical evaluation of rush immunotherapy in adult patients with severe bronchial asthma].

Rush immunotherapy (RIT) using house dust (HD) antigen were performed in ten adult patients with chronic severe bronchial asthma who had mite allergy. All cases have reached to the maintenance dose of 10(-1) X 0.50 ml within 10 days and been able to introduce maintenance therapy smoothly. After the RIT, remarkable improvement of asthmatic symptom was seen in 4 cases and one of them was considered to be completely cured of the asthma. Although side effects such as local skin reaction, rhinorrhea and asthmatic attack were seen, severe side effect was not observed at all. IgE-RAST scores for both HD and mite were unchanged before and after RIT. On the other hand, the values of specific IgG4 for both HD and mite antibody were significantly increased 2 or 4 weeks after RIT. These results indicated that RIT can be performed safely and securely, and rapid immunological response as well as clinical effectiveness are able to be expected for adult severe asthmatics.

[Hypersensitivity pneumonitis caused by a factory humidifier. A case report].

A 64-year-old man was hospitalized for productive cough and dyspnea. Both chest radiographs and CT scans showed areas of ground-glass opacity in the middle and lower lung fields on both sides. The BAL and TBLB findings were compatible with hypersensitivity pneumonitis. The serum was negative for antibodies against Trichosporon species, and the result of a lymphocyte stimulating test for administered drugs including a Chinese medicine was also negative. A humidifier was suspected as the cause because it had been used for more than 10 years in the factory where the patient had been working. An inhalation test using the humidifier fluid successfully provoked dyspnea, fever and fine crackle, and laboratory tests demonstrated hypoxemia, reduction in vital capacity and the elevation of CRP. Agar gel diffusion using the patient's serum showed a precipitating line against Cephalosporium acremonium, but this line did not fuse with any precipitating line formed between the humidifier fluid and the serum, indicating that no Cephalosporium was Present in the humidifier fluid. Since a high level of beta-D glucan was detected in the humidifier fluid, an unidentified fungus was suspected to be the antigen.

[Clinical evaluation of urinary leukotriene E4 levels in asymptomatic bronchial asthma].

To evaluate the significance of peptide leukotrienes (LTC4, D4, E4) in asymptomatic asthmatic patients, we measured urinary LTE4 levels which is thought to reflect in vivo production of peptide LTs. Urinary LTE4, was extracted using C18 solid phase column and measured by radioimmunoassay. There was no significant difference in urinary LTE4 levels among asthmatics with different severity or between atopic and non-atopic asthmatics. Urinary LTE4 levels were significantly elevated in asthmatics compared with normal controls (p < 0.05). When compared with normal controls, urinary LTE4 levels were significantly elevated in moderate to severe asthma (p < 0.05), and non-atopic asthmatics (p < 0.001). Urinary LTE4 levels were significantly elevated in aspirin-sensitive asthmatics compared with aspirin-tolerant asthmatics (p < 0.05). There was no significant difference in urinary LTE4 levels among aspirin-sensitive asthmatics with different severity. These results suggest that increased production of peptide LTs is a characteristic in aspirin-sensitive asthma, and that the severity and type of asthma and the presence of aspirin-sensitive asthma should be taken into consideration in the analysis of urinary LTE4 levels.

[A trial of new protocol of rush immunotherapy with standardized mite antigen].

The objective of the present study was (1) to establish a new protocol of rush immunotherapy (IT) using a purified mite antigen for the treatment of house-dust-mite-sensitive bronchial asthma. Ten adult asthmatics were enrolled in the initial trial which was based on a 7-day protocol using a house-dust antigen, to determine the optimal maintenance dose of mite antigen. No systemic side effects were observed when the antigen dose was lower than 50 AU. Consequently, the duration of rush IT was shortened to 5 days, and the maintenance dose was determined as 50 AU in the new protocol. To confirm its safety, another ten asthmatics were enrolled in a second trial. Rush IT using the new protocol was able to be performed without any systemic side effects in all patients except one who showed urticaria at 40 AU. These results suggest that the 5-day protocol of rush IT using the mite antigen is safe in patients with house-dust-mite-sensitive asthma.

[Idiopathic pulmonary fibrosis of the upper lobe: a case report].

A 26-year-old man was admitted to our hospital complaining of exertional dyspnea. Chest x-ray films disclosed reticulonodular shadows predominantly in the upper fields of both lungs, but no apical cap. Lung biopsy specimens obtained from the upper lobe by video-assisted thoracoscopy revealed subpleural elasto-fibrosis. Also, specimens obtained from the lower lobes disclosed micro-honeycombing due to peri-lobular fibrosis resembling usual interstitial pneumonia. Although pneumothorax occurred repeatedly, the lungs reinflated on each occasion without artificial intervention. Similar radiographic findings had been obtained on the patient's father, who died of idiopathic pulmonary fibrosis at the age of 56. Idiopathic pulmonary upper lobe fibrosis was conclusively diagnosed because the patient exhibited most of the features originally described by Amitani et al.

Eosinophil transmigration across VCAM-1-expressing endothelial cells is upregulated by antigen-stimulated mononuclear cells.

BACKGROUND: Adhesion to and transmigration across endothelial cells expressing vascular cell adhesion molecule 1 (VCAM-1) may be key steps in the development of selective eosinophil accumulation at the allergic inflammation sites. There is evidence that cytokines/chemokines produced by CD4+ T cells play a prominent role in these processes. OBJECTIVE: The objective of this study was to evaluate whether eosinophil migration across human pulmonary microvascular endothelial cells (HPMEC) expressing VCAM-1 is modulated by the supernatants of antigen-stimulated mononuclear cells obtained from atopic asthmatics. METHODS: Peripheral blood mononuclear cells (PBMC) were isolated from Dermatophagoides farinae (Df)-sensitive asthmatic subjects and cultured for 96 h at 37 degrees C in the presence or absence of 1 microg/ml Df antigen. Eosinophils were isolated from blood of healthy subjects and placed on the HPMEC monolayers cultured on a transwell filter (3-microm pore size) stimulated with IL-4 plus TNF-alpha (both at 100 pM, 24 h) The supernatants of PBMC were then applied to the lower compartment and the transmigration of eosinophils was examined. RESULTS: The supernatants of PBMC stimulated with Df significantly enhanced the eosinophil transmigration across VCAM-1-expressing HPMEC (% migration: 7.6 +/- 0.6 by the supernatants of PBMC cultured without Df vs. 12.3 +/- 1.2 by the PBMC cultured with Df, p < 0.01, n = 8). The enhanced migration, but not spontaneous migration, was blocked by the anti-alpha4 integrin antibody. Moreover, the enhanced transmigration was blocked by anti-CCR3 antibody. CONCLUSION: The antigen-stimulated PBMC from atopic asthmatics produce an activity to induce eosinophil migration across VCAM-1-expressing endothelial cells. This activity appears to involve CCR3 as an essential molecule.

[The influence of repirinast, an anti-allergic drug, on theophylline pharmacokinetics in patients with bronchial asthma].

In order to clarify whether repirinast, an inhibitor of chemical mediator release, could influence the pharmacokinetics of theophylline, a loading test using intravenous injection of aminophylline was performed in 10 subjects with bronchial asthma before and after treatment with 300 mg/day of repirinast. There was no significant difference in theophylline half-life before treatment (7.25 +/- 2.43 hr) and after treatment (7.82 +/- 3.35 hr). There was no significant difference in theophylline clearance before treatment (0.047 +/- 0.018 L/kg/hr) and after treatment (0.047 +/- 0.020 L/kg/hr). These results demonstrated that repirinast does not modify theophylline pharmacokinetics significantly.

Eosinophil-adhesion-inducing activity produced by antigen-stimulated mononuclear cells involves GM-CSF.

BACKGROUND: The initial step of eosinophil accumulation in allergic inflammation is adhesion of circulating eosinophils to vascular endothelial cells (EC). There is evidence that the adhesive property of circulating eosinophils is upregulated following antigen exposure. Although the exact mechanism remains to be established, cytokine(s) produced by antigen-stimulated mononuclear cells is (are) likely key factor(s). OBJECTIVE: The objective of this study was to examine the factor(s) responsible for eosinophil adhesion and migration induced by the antigen-stimulated mononuclear cells obtained from atopic asthmatics. METHODS: Peripheral blood mononuclear cells (PBMC) isolated from house-dust-mite-sensitive bronchial asthmatics were cultured for 96 h in the presence or absence of 1 microg/ml Dermatophagoides farinae (Df) antigen. Eosinophils were isolated from peripheral blood of healthy subjects. Eosinophil-adhesion-inducing activity in the culture supernatants of PBMC was examined by the ability to modify the adhesion of eosinophils to human pulmonary microvascular endothelial cells (HPMEC) in the presence or absence of anti-cytokine/chemokine antibodies. Eosinophil migration induced by the supernatants was also examined. RESULTS: Eosinophil adhesion to HPMEC was significantly augmented by the supernatants of Df-stimulated PBMC, which was significantly inhibited by anti-GM-CSF, but not by anti-IL-5, anti-RANTES, or isotype-matched controls. On the other hand, eosinophil migration induced by the supernatants was inhibited by anti-GM-CSF and partly by anti-RANTES. CONCLUSION: Both eosinophil adhesion and migration induced by the antigen-stimulated PBMC involve GM-CSF. In contrast, RANTES is involved only in the eosinophil migration. These molecules may participate in the development of eosinophil accumulation at the allergic inflammation sites.

Effect of immunotherapy on the production of eosinophil adhesion-inducing activity from mononuclear cells in house-dust-mite-sensitive bronchial asthma.

An initial step of eosinophil (EOS) accumulation in the sites of allergic inflammation is the adhesion to endothelial cells. There is increasing evidence that immunotherapy (IT) modulates the production of cytokines from mononuclear cells and hence attenuates allergic inflammation. To examine whether IT modifies the production of factor(s) which induce EOS adhesion, peripheral blood mononuclear cells (PBMC) from house-dust-mite-sensitive asthmatics treated with or without IT were cultured for 96 h in the presence or absence of 1/microg/ml Dermatophagoides farinae antigen. EOS were isolated from the peripheral blood of healthy subjects. EOS adhesion-inducing activity (EAIA) in the PBMC culture supernatants was examined by the ability to modify EOS adhesion to paraformaldehyde-fixed human umbilical vein endothelial cells (HUVEC) which were stimulated with IL-4 plus TNF-alpha. In asthmatics without IT, the addition of D. farinae antigen significantly promoted the production of EAIA from PBMC (EOS adhesion: 22.4+/-13.1% by medium control vs. 30.5+/-18.9% by D. farinae, n=10, p=0.023). This enhancing effect was blocked by an anti-beta2-integrin antibody. In contrast, the addition of D. farinae did not modulate EAIA production from PBMC in asthmatics treated with IT (23.1+/-10.3% vs. 21.5+/-12.3%, n=10, p=NS). These results suggest that IT induces the inhibition of antigen-dependent production of EAIA from PBMC. This may contribute to the inhibitory effect of IT on eosinophil recruitment in allergic inflammation.

The evidence of platelet activation in bronchial asthma.

The possible involvement of platelets in bronchial asthma was investigated under three different conditions: (1) chronic asthma, (2) bronchial provocation inhaling house dust mite (HDM), and (3) status asthmaticus. Plasma levels of beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), and in part, platelet-activating factor (PAF) were measured. Approximately one third of the subjects with symptomatic or asymptomatic chronic asthma showed an increased level of beta-TG or PF4. Statistically significant differences occurred in beta-TG and PF4 levels only between healthy controls and symptomatic subjects. Five out of six subjects showed no elevation of beta-TG and PF4 during immediate asthmatic response. In two out of nine subjects with status asthmaticus, beta-TG or PF4 was elevated, and statistically significant correlations occurred between the initial level of PAF and that of beta-TG or PF4. Those results suggest that the platelet activation in the circulation is sometimes provoked in asthma, but plasma level of alpha-granule-derived proteins does not reflect the intensity or severity of asthma, and that PAF is likely to be a mediator responsible for the platelet activation.

Inhibition of analgesic-induced asthma by leukotriene receptor antagonist ONO-1078.

We evaluated the effect of ONO-1078, a selective leukotriene-C4, -D4, and -E4-receptor antagonist, on bronchoconstriction intensity during inhalation challenge with dipyrone (a pyrazolone derivative) in six aspirin-sensitive asthmatics. A double-blind, randomized, crossover design was used. After ingestion of 225 mg ONO-1078 or matching placebo, subjects underwent bronchial provocation with dipyrone on two occasions, separated by 4 wk. Aerosol inhalation of dipyrone was performed increasing the concentration stepwise from 0.08 to 10% (wt/vol). FEV1 was measured every 10 min up to 30 min after inhalation of each concentration. Threshold concentrations causing a fall in FEV1 > or = 20% of baseline value were 0.4% in four subjects and 2% in the other two on the placebo day. After pretreatment with ONO-1078, threshold concentration was 10% in two subjects, and no fall in FEV1 was observed in the other four, even after inhalation of 10% dipyrone. Values of PD20 were 21.9 +/- 8.2 units (mean +/- SEM) after placebo and 311.6 +/- 40.3 units after ONO-1078, respectively, and a statistically significant difference occurred (p < 0.001). Provocation of bronchoconstriction was completely inhibited in subjects whose plasma ONO-1078 levels were more than 0.5 microgram/ml. These results support the hypothesis that sulfidopeptide leukotriene-induced bronchoconstriction is one important component in the pathophysiology of aspirin-induced asthma.