Asthma treatments have changed radically due to elucidation of morbidity and development of medicine/treatment strategies. The Global Initiative for Asthma consists of a six-part asthma management program and seven defined states for controlled asthma worldwide. However, considering the present status of asthma in infants through to young adult patients, it is extremely difficult to implement these ideal programs and to attain their goals. At the Pediatric Unit in the National Minami Fukuoka Chest Hospital, the number of out-patients and patients hospitalized due to asthma attacks increased continuously from 1975 until 1987 at respective rates of 4.9-fold (from 466 to 2295 patients) and 10.6-fold (from 118 to 1245 cases). Thereafter, the number of out-patients has remained stable (1999 patients in 1997), while the number of hospitalizations has decreased (766 in 1997). However, the age-specific distribution of hospitalized patients has changed remarkably. There are two peaks: one in the infant population and another in older elementary school students. In the past, the incidence of hospitalization was higher among older elementary school students, although now the situation has been reversed, with as many as 53.6% (323 patients) of patients aged between 0 and 3 years of age being hospitalized in 1999 and more patients being identified with complications. This reversal could be largely attributable to the fact that whereas strong medications and therapies, such as round the clock therapy with theophylline, disodium cromoglycate inhalation and inhalation of steroids, have become standard treatments for older elementary school children with asthma, these therapies, especially steroid inhalation, may be difficult to use for the treatment of infants and, therefore, pediatricians are hesitant to use these treatment strategies. The elevated incidence rate of asthma and its higher incidence in younger children may also be an underlying cause. In contrast, asthma mortality at our pediatric unit has never increased, on average one patient yearly, and most of these cases were deaths at home or deaths on the way to hospital. With regard to asthma death statistics in Japan, a sudden increase in deaths due to asthma was noted among children aged 10-14 years in the 1960s, whereas no such increase in deaths due to asthma has been noted since the 1970s. This suggests a big step ahead in terms of the treatment and management of children with bronchial asthma. However, the long-term prognosis of severe childhood refractory asthma is not good. In our prognosis study on severe asthma patients who were hospitalized 20 years ago, 27.2% experienced remission and 12.7% died, and residual impaired pulmonary function was noted in many cases. Among the 24 cases of death, we have been notified that 20 cases of sudden death were patients aged between 10 and 29 years of age. The mortality rate in patients aged 15-29 years in Japan increased threefold during the subsequent 10 years from 1980. Although this rate has apparently started to decrease in the past 5 years, compared with the estimated bronchial asthma incidence rate from the International Study of Asthma and Allergies in Childhood (ISAAC) study, the bronchial asthma mortality rate in Japan is definitely higher than in Western countries. These data suggest difficulty in the management of adolescent and young adult patients with severe asthma, who often have a psychological/social/economic handicap. The relatively high asthma mortality rate in Japan may be attributable to: (i) a greater number of patients with severe asthma; (ii) the poor medical supply system; (iii) a lack of asthma education for both physicians and patients; and (iv) problematic treatment regimens. In present paper, the first point is discussed in relation to the ISAAC study, the second point is discussed with regard to the system for out-patients' overnight visits, the third point is discussed with regard to the

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There is a major problem from asthma in Japan due to its high prevalence, morbidity, economic cost and mortality. The striking feature of the time trends in asthma mortality in Japan is the two epidemics of asthma mortality in young people that occurred at the same time as similar epidemics in a number of other countries. These epidemics are likely to be due, at least in part, to the overuse of specific β-adrenergic receptor agonist drugs, namely isoprenaline and fenoterol. Following recent warnings by the Japanese Ministry of Health and Welfare against the use of fenoterol and the resulting reduction in fenoterol sales, together with other changes in management consistent with the recommendations of the Japanese Asthma Guidelines, the asthma mortality rate has again fallen in Japan. However, Japan still has case fatality rates that are disproportionately greater than those in other countries. One approach that can be taken to reduce the high asthma mortality rate in Japan is to develop and implement a community based asthma self-management plan system of care whereby patients are provided with a practical system by which they can assess the severity of their asthma, a treatment regimen for both long-term therapy and management of a severe attack, and written guidelines provided by their medical practitioners in which assessment and treatment are integrated in a simple format. In controlled studies, this management approach has been shown not only to markedly reduce asthma mortality, in terms of reduction in hospital admissions and nocturnal wakening, but also to markedly reduce mortality from asthma. The Japanese Asthma Guidelines have advocated this approach, which is referred to as the 'asthma management zone system'. Through implementation of this system of care, together with other management initiatives, it is likely that the mortality rate from asthma will fall further over forthcoming years.

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More than one mechanism contributes to persistent increases in eosinophils in the nasal cavity and paranasal sinus. The levels of eotaxin in lavage samples obtained after antigen challenge showed strong correlation with lavage levels of eosinophil counts and eosinophil protein-X. In the eosinophil endothelial transmigration (TEM) assay using nasal microvascular endothelial cells, eotaxin showed the most potent effect among various eosinophil chemoattractants. In addition, treatment of eosinophils with anti-CCR3 mono- clonal antibody significantly blocked eosinophil TEM induced by homogenate of nasal mucosa. These results indicate that eotaxin has an important role in eosinophil-dependent inflammation in nasal mucosa and suggest that blocking eotaxin or CCR-3 may be useful for new therapeutic tools of allergic rhinitis. Several mechanisms for eosinophilic inflammation in paranasal sinus may be proposed: a series of reaction systems may be involved, such as swollen mucosa caused by type I allergic reactions in the nasal cavity, closure of natural orifices, a hypoxic state in the maxillary sinus, accelerated production of eotaxin and RANTES from fibroblasts and eosinophilic infiltration. These reaction systems would include tumor necrosis factor-α and interferon-γ, as well as Th2 cytokines, including interleukin-4 and -13, so that this phenomenon hardly occurs in infective rhinitis.

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Asthma is a disease of usually reversible airways obstruction that has prominent inflammation of the mucosa as an underlying feature. It is a disease of varying severity, with some individuals suffering from only occasional symptoms and others having daily symptoms and requiring large doses of inhaled and oral corticosteroids. Although the different forms of asthma have some common pathological features, the extent of change varies from mild to severe forms. The only cell type that has been widely correlated with disease severity has been the eosinophils, but it is evident that altered function and responsiveness of T cells to steroids plays a key role as a determinant of asthma severity. More recently, attention has focused on restructuring of the airways, which results in, or possibly develops in parallel with, inflammation. This restructuring consists of changes throughout the bronchial wall, beginning with changes in the epithelium, increased collagen deposition, increased microvasculature, hypertrophy and hyperplasia of submucosal glands, goblet metaplasia within the epithelium, hypertrophy and hyperplasia of smooth muscle and, finally, poorly defined changes in the adventitia. Novel treatments have been, and continue to be, developed to target specific components of inflammation and remodeling. However, to date, none has lead to a marked improvement in disease control and further efforts are needed to better understand the mechanisms of asthma, in particular those that are not responsive to corticosteroids.

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Hundreds of compounds have been tested over the years in a search for adjuvants to incorporate with antigens or allergens to enhance the immune response. Despite this, aluminum salts have been the only adjuvants that have been both registered for clinical application and used on a large scale until recently. Salts of aluminum, such as aluminum hydroxide, have been used as general immunologic adjuvants for several decades. Some allergen vaccines used for the treatment of allergy are still formulated with aluminum-based adjuvants. These formulations have generally proved efficacious and have a good safety profile compared with simple aqueous extracts. However, there is reported sensitivity and toxicity associated with use of aluminum. In addition, aluminum salts are known to be potent stimulators of T helper (h) 2 cell activity. Because Th2 activity directs towards an allergic response, aluminum salts are potentially counterproductive when used as adjuvants in the immunologic treatment of type 1 hypersensitivity. Many soluble and insoluble molecules have been reported to have adjuvant activity in experimental systems. Some of these have been used clinically, but side effects, such as local granuloma formation, have led to their withdrawal from clinical use. Newer depot-type adjuvants, such as insoluble calcium salts, tyrosine (now registered) and coupled alginates, may eliminate some of the potential problems of aluminum salts and are currently used in some allergy vaccines but have not as yet formed a complete replacement. Liposomes, iscoms and biodegradable microspheres are now being considered for clinical use as adjuvants for both oral and parenteral routes. Soluble adjuvants that are capable of directing the immune response in a more selective way are currently in development for use in allergy vaccines. One of these, the Th1-directing adjuvant monophosphoryl lipid A (MPL^®; Corixa, Seattle, WA, USA), is now in clinical use in allergy vaccines formulated with the depot adjuvant L-tyrosine. Other ways of stimulating a Th1 response using immunostimulatory DNA sequences (immunostimulatory DNA sequences (ISS) or CpG motifs) as 'built-in' adjuvants are being studied. Further interesting adjuvants reported in the literature, such as Montanide ISA 720, SAF-m, RC-529 and QS21, may also be applicable to allergy vaccination.

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Background: Despite improvements in air pollution, the prevalence and incidence of bronchial asthma, which has attracted a great deal of attention in relation to air pollution, is tending to increase in Japan as well as worldwide. Severe air pollution conditions currently exist in China due to sulfur dioxide and particulate matter, resulting from coal burning and motor vehicle exhaust gases associated with the rapid increase in the number of vehicles.
Methods: Using the same questionnaire in China and Japan, we conducted a comparative study of the prevalence of various respiratory symptoms among schoolchildren in Anshan (n = 4395), Taiyuan (n = 3784 in 1997; n = 3995 in 1999) and Chengdu (n = 7795 in 1991; n = 3000 in 1998) in China and in Yokohama (n = 4161) in Japan. The pollution concentrations in the survey area of China resembled the concentrations observed in heavy industry areas in Japan in the 1970s.
Results: Comparisons between schoolchildren in Japan and China showed that the prevalence of persistent cough and persistent phlegm (persistent congestion and phlegm) was higher among schoolchildren in China (e.g. the prevalence of persistent cough in boys in China was 2.4-8.1%, whereas the rate was only 2.1% for boys in Yokohama), whereas the prevalence of wheezing and asthma-like symptoms was higher among schoolchildren in Japan (e.g. the prevalence of asthma-like symptoms was 0.2-1.8% for boys in China, whereas this rate was 9.6% in Yokohama, Japan).
Conclusions: If China follows the same path as Japan, that is, proceeds with conversion from coal to oil as its primary energy source, the popularization of motor vehicles and chemical contamination of food, housing and clothing, there is a risk that the prevalence of bronchial asthma in Chinese children will increase in the same way as it has in Japan. It is hoped that research will be conducted to determine the cause of the increases in bronchial asthma in Japan and that preventive measures will be established so that Chinese children do not repeat the experience of Japanese schoolchildren.

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Background: Although the mechanisms controlling the resolution of inflammatory processes are still not clear, it is thought that a number of inflammatory cells, including neutrophils and eosinophils, and ingestion of these cells by macrophages may be involved in the apoptotic cell process in allergic or non-allergic nasal tissues. We postulated that apoptosis of inflammatory cells may occur in vivo in nasal mucosa, thus regulating allergic and non-allergic inflammation, and to test this hypothesis we examined apoptotic cells in the nasal tissue of surgical specimens.
Methods: Human turbinates were obtained after conchotomy performed on patients with nasal obstruction refractory to medication. Nasal tissues were fixed in formalin and embedded in paraffin. The paraffin-embedded tissues were stained for apoptotic cells by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5'-triphosphate (dUTP) nick end-labeling (TUNEL). To identify cell types undergoing apoptosis, double staining was performed by combining TUNEL and immunohistochemistry.
Results: The majority of TUNEL-positive cells were identified as leukocytes. Most TUNEL-positive cells found in these tissues represented granulocytes. A higher proportion of TUNEL-positive cells was found to be macrophages and most TUNEL-positive macrophages had intact nuclei and contained phagocytosed TUNEL-positive material (assumed to be apoptotic cells or bodies) in the cytoplasm.
Conclusions: These experiments represent the demonstration of cell type-specific apoptosis in human nasal mucosa. The results may have an important clinical implication and also promote further investigation to control the apoptosis of these cells in health and disease.

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Background: Flowcytometric analysis of purified eosinophils requires several hours to accomplish due mainly to purification of cells; moreover, it requires more than 20 mL blood and expensive reagents. The aim of the present study was to develop a method of direct flowcytometric analysis for eosinophils using whole blood.
Methods: Peripheral blood obtained from five healthy individuals (mean age 42 years) and 10 patients with eosinophilia (mean age 40.3 years) were used for analysis. We stained antigens (CD9 or CD16) and fixed cells with parabenzoquinone (PBQ) or paraformaldehyde (PFA) after hemolyzation followed by treatment with N-octyl-β-glucopyranoside (OG).
Results: On comparison of forward scatter with side scatter dot plots among samples treated with hemolyzation alone, PBQ fixation and PFA fixation, PBQ fixation showed the best results in discriminating eosinophils from other leukocyte fractions on the cytogram. Following fixation and permeabilization of cells, EG2, a secretory form of eosinophil cationic protein, was stained as an intracellular antigen. Flowcytometric analysis for EG2 showed a high positivity rate only in the eosinophil fraction. There were no differences in EG2 positivity or mean fluorescence intensity (MFI) between heparinized and EDTA-treated blood. Comparison of samples treated with OG at 6.0 and 7.4 mg/mL showed that the latter had a higher MFI for EG2 without significant change in the positivity rate.
Conclusions: The findings show that intra- and extracellular properties of eosinophils can be analyzed with whole blood using PBQ fixation and OG treatment at a concentration of 7.4 mg/mL. Direct flowcytometric analysis of eosinophils saves time and requires only a small amount of blood, both of which are advantageous for patients and laboratory workers.

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Background: In the present study, we tried to clarify whether nuclear hypersegmentation of peripheral blood eosinophils is correlated with peripheral eosinophil counts and/or the activity of atopic dermatitis (AD) in 79 patients.
Methods: We also compared the grades of skin scores, peripheral eosinophil counts, the rate of hypersegmentation of eosinophils and serum eosinophil cationic protein (ECP) concentrations in eight patients before and after treatment.
Results: There was a positive correlation between the skin scores of AD and peripheral eosinophil counts (P < 0.01), between the skin scores of AD and the number of nuclear lobes of eosinophils (P < 0.01) and between eosinophil counts and the number of nuclear lobes of eosinophils when the number of nuclear lobes of eosinophils was fewer than three (P < 0.01). A positive correlation was observed between serum ECP concentrations and eosinophil counts and/or skin scores of AD (P < 0.001). A negative correlation was observed between serum ECP concentrations and the number of nuclear lobes fewer than two (P < 0.05). During therapy, peripheral eosinophil counts and the degree of hypersegmented eosinophils decreased significantly, and this was associated with recovery of skin conditions, but not with serum ECP concentrations.
Conclusions: These results suggest that eosinophil hypersegmentation may reflect activated eosinophils and also that the observation of nuclear hypersegmentation in peripheral blood eosinophils is useful to recognize the disease activity of AD.

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Background: Interferon (IFN)-α is the only approved treatment for chronic hepatitis C. Interstitial pneumonia and, rarely, exacerbation of bronchial asthma have been reported as adverse pulmonary effects of IFN-α treatment. The purpose of the present study was to clarify whether IFN-α treatment affects pulmonary function and airway responsiveness in patients with chronic hepatitis C.
Methods: We studied 17 patients (nine males and eight females; mean age 46 years; range 30-62 years) with chronic active hepatitis C diagnosed by serum tests and liver biopsy. Pulmonary function tests included vital capacity (VC), forced expiratory volume in 1 s (FEV₁), forced expiratory flow in the middle half of the forced vital capacity (FVC_25-75%), total lung capacity and carbon monoxide diffusing capacity of the lung (D_LCO), which was adjusted for hemoglobin concentration. Airway responsiveness was measured by methacholine inhalation challenge and determination of the provocative concentration of methacholine causing a 20% fall in FEV₁ (PC₂₀). These tests were performed before and 3 months after initiation of IFN-α therapy.
Results: No patient developed interstitial pneumonia, although there was a tendency for the hemoglobin-adjusted D_LCO to decrease. Other pulmonary function test parameters were not affected. Overall, there was no significant change in PC₂₀ (from 15.0 to 11.4 mg/ mL). In three patients whose initial PC₂₀ was within the normal range, airway hyperresponsiveness was induced and one patient developed bronchial asthma after IFN-α therapy.
Conclusions: These findings suggest that IFN-α induces airway hyperresponsiveness to methacholine in a few patients with chronic hepatitis C.

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Background: Various mediators, such as thromboxane (TX) A₂, peptide leukotrienes (P-LT) and histamine, are involved in allergic nasal obstruction. The aim of the present study was to investigate the mechanism whereby olopatadine hydrochloride, a novel anti-allergic drug, ameliorated the allergic nasal obstruction.
Methods: The levels of TXB₂, P-LT and histamine in nasal lavage fluid (NLF) were measured after intranasal antigen challenge in sensitized guinea pigs.
Results: Histamine and TXB₂ levels in the NLF increased eight- and threefold, respectively, 10 min after antigen challenge, whereas the P-LT level was under the detection limit. Oral administration of olopatadine at 0.1, 1 and 3 mg/kg significantly inhibited the increases in TXB₂ and histamine levels. At 3 mg/kg, olopatadine also ameliorated the nasal obstruction caused 10 min after antigen challenge, as determined by acoustic rhinometry.
Conclusions: These results suggest that the amelioration by olopatadine of the allergic nasal obstruction involves the inhibition of the release of TXA₂ and histamine.

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