Fumihiro Mitsunobu

Changes in the Proportions of Bronchoalveolar Lymphocytes, Neutrophils and Basophilic Cells and the Release of Histamine and Leukotrienes from Bronchoalveolar Cells in Patients with Steroid-Dependent Intractable Asthma

The proportion of inflammatory cells in bronchoalveolar lavage (BAL) fluid and the release of chemical mediators from BAL and peripheral blood cells were examined in 40 patients with steroid-dependent intractable asthma (SDIA) to clarify the effects of a long-term glucocorticoid regimen on these cells. The proportion of BAL lymphocytes was significantly reduced (p < 0.01) and the proportion of BAL neutrophils was significantly increased (p < 0.01) in SDIA patients compared with non-SDIA patients. The proportion of basophilic cells (mast cells and basophils) in BAL fluid was significantly lower in SDIA patients compared to non-SDIA patients (p < 0.02). The values of six ventilatory parameters were significantly lower in SDIA patients with a high proportion of BAL neutrophils (more than 10%) compared with the values in non-SDIA patients. The release of histamine and leukotriene C4 (LTC4) from the BAL cells of patients with atopic asthma was significantly reduced in SDIA patients compared with non-SDIA patients (p < 0.05). These results show that the changes in the proportion of BAL cells are observed in patients with SDIA, and these changes are related to suppressed ventilatory function and a reduction in the release of histamine and LTC4 from BAL cells.

Vertebral Fracture and Cortical Bone Changes in Corticosteroid-Induced Osteoporosis

Abstract: Despite an intriguing understanding of trabecular bone dynamics, little is known about corticosteroid-induced cortical bone loss and fractures. Recently, we verified a steroid-induced decrease in cortical bone volume and density using peripheral quantitative computed tomography (pQCT) in adult asthmatic patients given oral corticosteroids. Subsequently, the pQCT parameters and presence of vertebral fractures were investigated to further clarify the role of cortical bone quality in fractures in 86 postmenopausal (>5 years after menopause) asthmatic patients on high-dose oral steroid (>10 g cumulative oral prednisolone) (steroid group) and 194 age-matched controls (control group). Cortical and trabecular bone was subjected to measurement of various parameters using pQCT (Stratec XCT960). Relative Cortical Volume (RCV) was calculated by dividing the cortical area by the total bone area. Strength Strain Index (SSI) was determined in the radius based on the density distribution around the axis. Spinal fracture was assessed on lateral radiographs. Patients treated with high doses of oral steroid (>10 g cumulative oral prednisolone) were found to have an increased risk of fracture compared with control women receiving no steroid medication (odds ratio, 8.85; 95% CI, 4.21–18.60) after adjustment was made for years since menopause, body mass index and RCV. In both groups, the diagnostic and predictive ability of the pQCT parameters for vertebral fracture was assessed by the areas under their receiver operating characteristic (ROC) curves. All parameters were found to be significant predictors (p<0.0001) in the control group. In the steroid group, however, the cortical bone mineral density (BMD) (p= 0.001), RCV (p<0.0001) and SSI (p= 0.001) were found to be significant predictors, but not trabecular BMD (p= 0.176). For comparison between the two groups, thresholds of all parameters for vertebral fracture were also calculated by the point of coincidence of sensitivity with specificity in ROC testing and the 90th percentile value. Although a rise in fracture threshold in the steroid group was suggested, considerable difference in the values obtained by the two methods of calculation precluded any conclusion. High-dose oral steroid administration was associated with an increased risk of fracture. Cortical bone parameters obtained by pQCT could play a role as good predictors of future corticosteroid-induced vertebral fractures.

Mucus Hypersecretion and Eosinophils in Bronchoalveolar Lavage Fluid in Adult Patients with Bronchial Asthma

Mucus hypersecretion was clinically analyzed in 46 adult patients with bronchial asthma, including 22 with steroid-dependent intractable asthma (SDIA). A large amount of expectoration, over 50 ml/day, was observed in 16 of these patients (34.8%), of whom 12 (75.0%) had SDIA and 13 (81.3%) were women. The mean amount of expectoration increased with increasing patient age, although no significant difference was found among the six age groups. A large amount of expectoration (over 50 ml/day) was clearly correlated with an increased proportion of eosinophils in bronchoalveolar lavage (BAL) fluid. The proportion of BAL eosinophils was significantly higher in patients with expectoration between 50 and 99 ml/day (p < 0.05) and over 100 ml/day (p < 0.01) than in patients whose expectoration volume was between 30 and 49 ml/day. These results show that in bronchial asthma patients, mucus hypersecretion is more often observed clinically in those with SDIA and in women, and that this hypersecretion is closely correlated with BAL eosinophilia, which is a feature of the pathophysiological changes that occur in the airways of these patients.

Effects of Long-Term Glucocorticoid Therapy on Bronchoalveolar Cells in Adult Patients with Bronchial Asthma

The effects of long-term glucocorticoid therapy on airway inflammation were examined in 84 asthma patients. The proportion of lymphocytes in bronchoalveolar lavage (BAL) fluid was significantly decreased in patients with steroid-dependent intractable asthma (SDIA) compared to results in non-SDIA patients, while BAL neutrophils were significantly increased in SDIA patients compared to results in non-SDIA patients. Regarding age, in patients under the age of 69 (except those between 30 and 39), BAL lymphocyte number was significantly decreased in SDIA compared with non-SDIA subjects, and in patients between 50 and 69, BAL neutrophils were significantly increased in SDIA compared with non-SDIA subjects. The number of BAL lymphocytes was significantly lower in patients with serum cortisol levels of less than 5.0 micrograms/dl than in those with levels of more than 5.1 micrograms/dl. BAL lymphocyte number was also significantly lower in patients who had received glucocorticoid therapy for more than 6 years than in those who had received such therapy for 2 years. These results show that long-term glucocorticoid therapy decreases the number of lymphocytes and increases neutrophil numbers in the airways.

Effects of Glucocorticoids on Humoral and Cellular Immunity and on Airway Inflammation in Patients with Steroid-Dependent Intractable Asthma

The effects of glucocorticoids on the proportion of lymphocytes in bronchoalveolar lavage (BAL) fluid in relation to humoral and cellular immunity were studied in 56 patients with steroid-dependent intractable asthma. To analyze the mechanism responsible for reduced numbers of BAL lymphocytes, we divided the subjects into 4 groups according to their BAL lymphocyte proportions: 0-4.9%, 5.0-9.9%, 10.0-14.9%, and 15.0-20.0%. Serum IgG levels and the peripheral lymphocyte count were significantly reduced in patients with a low proportion of BAL lymphocytes (less than 9.9%) than in those with more than 10% BAL lymphocytes. Delayed cutaneous reactivity to purified protein derivative was suppressed in patients with a low proportion of BAL lymphocytes (less than 4.9%). The mean proportion of BAL neutrophils tended to increase as the proportion of BAL lymphocytes decreased. These results show that the reduction in BAL lymphocytes produced by glucocorticoids is associated with suppressed humoral and cellular immunity, and that under such conditions the proportion of BAL neutrophils increases.

The use of computed tomography to assess asthma severity

Purpose of reviewChronic inflammation in asthma can also lead to airway remodeling, which contributes to airway narrowing. It may be possible to assess and quantify the extent of airway remodeling in vivo using computed tomography. This review examines recent developments in the evaluation of asthma severity using computed tomography, and the effect of treatment assessed by computed tomography. Recent findingsAsthma patients have thicker airways on computed tomography scans than do healthy control individuals, and the degree of thickening is related to the severity of disease, airflow obstruction, and airway reactivity. Recent studies have indicated that patients with severe asthma and irreversible airflow obstruction had longer disease duration, a greater inflammatory process and more airway abnormalities, assessed by high-resolution computed tomography, suggestive of airway remodeling. Other studies have shown that high-resolution computed tomography lung density correlates with airflow limitation and lung volume (but not with lung transfer factor), and also correlates with patient age and severity of asthma. More recently, two publications demonstrated the effect of treatment on airway wall thickness and lung density assessed by computed tomography in patients with asthma. SummaryHigh-resolution computed tomography is one of the most useful tools for imaging airways and parenchyma. Computed tomography scanning may be useful in determining which patients might benefit from more or less treatment. With additional advances in technology, it is likely that quantitative assessment by computed tomography will ultimately be a valuable tool for the study and treatment of chronic airway diseases. Abbreviations AHR: airway hyperresponsiveness; BO: bronchiolitis obliterans; COPD: chronic obstructive pulmonary disease; CT: computed tomography; E/I ratio: ratio of the average computed tomography-determined values for the bilateral upper and lower lung segments at full expiration to that at full inspiration; E/I ratio_RA950: ratio of expiratory RA950 to inspiratory RA950; FEV1: forced expiratory volume in one second; HRCT: high-resolution computed tomography; LAA: low attenuation area; MLD: mean lung density; RA950: relative area of the lungs showing attenuation values less than −950 Hounsfield units; RV: residual volume; T/D: ratio of airway wall thickness to outer diameter; WA%: percentage wall area.

Different Roles of Histamine and Leukotriene C4 in the Airways Between Patients with Atopic and Nonatopic Asthma

The release of histamine and leukotriene C4 (LTC4) from bronchoalveolar lavage (BAL) cells and peripheral blood stimulated with Ca ionophore A23187 was compared between atopic and nonatopic asthma. The proportion of basophilic cells in BAL fluid was significantly higher in atopic than in nonatopic asthma (p < 0.01); however, no significant differences were present in the other BAL cells between the two asthma types. The concentration of histamine in BAL fluid was significantly higher in younger patients (20-59 years) with atopic than in nonatopic asthma (p < 0.01). In contrast, the concentration of LTC4 was significantly higher in nonatopic than in younger patients with atopic asthma (p < 0.01). The release of histamine from BAL cells (p < 0.001) and peripheral blood (p < 0.01) was significantly larger in younger patients with atopic than in nonatopic asthma. The generation of LTC4 by BAL cells was significantly larger in nonatopic than in younger (p < 0.01) and older patients with atopic asthma (60+ years) (p < 0.05). These results suggest that both histamine and LTC4 participate in the onset mechanism of atopic asthma, and only LTC4 participates in that of nonatopic asthma.

Performance of the first Japanese large-scale facility for radon inhalation experiments with small animals

A radon test facility for small animals was developed in order to increase the statistical validity of differences of the biological response in various radon environments. This paper illustrates the performances of that facility, the first large-scale facility of its kind in Japan. The facility has a capability to conduct approximately 150 mouse-scale tests at the same time. The apparatus for exposing small animals to radon has six animal chamber groups with five independent cages each. Different radon concentrations in each animal chamber group are available. Because the first target of this study is to examine the in vivo behaviour of radon and its effects, the major functions to control radon and to eliminate thoron were examined experimentally. Additionally, radon progeny concentrations and their particle size distributions in the cages were also examined experimentally to be considered in future projects.

An Increased Level of Specific IgG4 Antibodies Against Candida albicans in Patients with Bronchial Asthma

Specific IgG4 antibodies against Candida albicans in sera were measured in 76 asthmatics. The increased level of specific IgG4 was found in cases 10-40 years old sensitive to house dust mite and/or Candida albicans, in cases with steroid-dependent intractable asthma (SDIA) and in elderly cases. The frequency of SDIA was the highest in cases 41 to 60 years old with higher frequency of increased IgG4 antibodies. The results show that specific IgG4 increases in relation to IgE-mediated immune response, long-term steroid therapy, and aging. All of these conditions may induce depressed cell-mediated immunity.

Spa Therapy for Bronchial Asthma Studies at the Misasa Medical Center

Bronchial asthma is usually well-controlled with bronchodilators and antiallergic medication. However, some patients cannot control asthmatic attacks without relying on oral glucocorticoids and their long-term use is associated with side effects of hypertension, diabetes, osteoporosis, and adrenal insufficiency as a result of suppressed adrenal function. These patients, who are diagnosed as having steroid-dependent intractable asthma (SDIA), represent the greatest challenge for physicians, and many attempts to wean these patients to a lower dose of corticosteroid have often been unsuccessful. In light of the prevalent use of alternative and complementary medicine in the United States, many alternative treatments have been explored except one nonpharmacologic therapy widely used in Europe and Japan—spa therapy. There have only been a few studies conducted at the Dead Sea, Israel, for pulmonary diseases and, of those studies, most involved primarily chronic obstructive pulmonary diseases (COPD) and climatotherapy.1,2 But the most extensive research on spa therapy for pulmonary diseases has been conducted at the Misasa Medical Center, at the Okayama University Medical School, Tottori, Japan, for more than 20 years. Although the Japanese balneologists (spa physicians) at the Misasa Medical Center have extensive experience in treating other pulmonary diseases, this review of their research will be limited only to bronchial asthma. At the Misasa Medical Center, spa therapy consists of swimming training in a hot spring pool for 30 minutes; 5 times per week; inhalation of 1.0 mL of iodine salt solution (KI 134 mg/L and NaCl 14.664 g/L), twice per day; and fango therapy. Fango therapy is a treatment involving mud taken from the Ningyo pass and heated to 70–80 C before being packed with cloth (40–43 C) to make compresses. For our research fango was applied to patients’ backs for 30 minutes, 5 times per week. Patients’ responses to therapy was evaluated according to the following guidelines:3 • Marked efficacy—Patients’ asthma attacks clearly disappeared and need for glucocorticoid treatment was reduced. • Moderate efficacy—Asthmatic attacks clearly reduced but patients still had occasional dyspnea with wheezing, or the dose of glucocorticoid could not be reduced, despite relief from symptoms • Slight efficacy—Slight reduction in asthmatic attacks but patients had persistent dyspnea and wheezing and still required glucocorticoid medications • No efficacy—No change in asthmatic attacks without reduction of glucocorticoid medications.