The immunologic hallmark of atopic allergy and asthma is an increased production of IgE and T helper (h) type 2 cell cytokines (interleukin (IL)-4, IL-5, IL-9 and IL-13) by Th cells reacting to common environmental allergens. All of us inhale allergens and healthy non-atopics produce allergen-specific IgG1, IgG4 and the Th1 cytokine interferon-α, as well as IL-12 from macrophages. We now have many modalities of immunomodulation to decrease the effect of IL-4 or IL-5 or production and level of IgE or agents to shift the immune response from a Th2 to a Th1 response, thereby decreasing the allergic inflammatory response in the airways. In the present review we focus on conventional immunotherapy, mycobacterial vaccines, DNA vaccines using cytosine guanosine, inhibitors of IL-4 and IL-5 and anti-IgE: Omalizumab.

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In the 1990s, the definition of asthma changed as we realized that asthma is fundamentally an inflammatory disorder. It was also shown in both adults and children that treatment should be initiated with anti-inflammatory medication (preferably inhaled steroids) and delayed treatment may worsen lung function outcome. There is increasing evidence that, in both children and adults, early and effective therapy with inhaled steroids results in long-term remission in the majority of patients. In future, even intermittent asthma symptoms will be treated with inhaled steroids. The first signs of asthma should be treated effectively, even in small babies. In children with atopic dermatitis, early pharmacotherapy may prevent asthma and in children with hay fever, specific immunotherapy may reduce the asthma risk. Airway eosinophilia predisposes a patient to asthma. The benefit of early intervention in patients who show eosinophilic airway inflammation but have normal or near normal lung function has been recently demonstrated. It seems that we should treat 'asthma even before asthma', if the disease is defined in terms of lung function. Persistent asthma is difficult to reverse, but early stages of asthma could be more responsive to novel therapies, such as drugs modifying the pro-inflammatory cytokines or monoclonal antibodies against IgE. The emerging new methods to assess airway inflammation will cast light on the origin of asthma, as well as on the determinants of disease persistence. Along with the development of practical inflammatory markers, the doctor gets a clearer picture of the disease. This means a better understanding for the doctor and better tailored treatment for the patient and this will further improve treatment results.

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Background: The effect of short-term corticosteroid treatment for airway inflammation in asthma is not well known. To investigate this effect, we analyzed bronchial mucosal biopsy samples.
Methods: We obtained endobronchial biopsy specimens from subjects with asthma with or without corticosteroid pretreatment. Samples obtained were analyzed by immunohistochemical staining (CD4, CD25 and EG2).
Results: Activated eosinophils were significantly reduced in the corticosteroid-premedicated group (CS+) compared with the unpremedicated (CS-) group. In contrast, no significant reduction was observed in CD4-positive T lymphocytes between the two groups. The number of CD25-positive T lymphocytes was more suppressed in the premedicated than in the unpremedicated group.
Conclusions: The effect of corticosteroid on eosinophils in bronchial mucosa develops within a few days. However, for a clinically significant effect, long-term corticosteroid treatment may be needed to inactivate and displace T lymphocytes from the airway mucosa.

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Background: Mortality from asthma in Japan still remains at a higher level than in Europe and America and how to decrease that mortality rate is an important issue. For the prevention of death from asthma, it is essential to study the risk factors. However, there has been almost no such study performed in Japan and, for this reason, we performed the present study to elucidate the background of the recent cases of death from asthma.
Methods: This study was performed on cases of death from asthma at the Tokyo Medical Examiner's Office over a period of 5 years (1993-1997).
Results: There were 456 cases under study, with the age at death ranging from 4 to 96 years (average age 58.5 years). The male to female ratio was 1.8 : 1 and there was a tendency for a marked increase in the number of cases of death from asthma in women aged 60 years and older. The annual number of deaths was lowest in 1997, being 67 cases. The monthly number of deaths was higher in December and February and was lower in the months of June, July and September. Among the cases investigated, 60.2% died within 3 h after the onset of an asthmatic attack. In the cases of patients living alone, the chance of receiving emergency medical care was significantly lower compared with cases where patients lived with other people. Of the cases of death from asthma, 36.6% of patients were in the habit of drinking and 27.7% smoked. In an investigation of the 247 deaths that occurred during the 3 year period from 1995 to 1997, there were 140 cases (56.7%) for which emergency medical care was offered to treat the asthmatic attack. In 126 cases (90.0%), cardiopulmonary arrest was observed on arrival at hospital. Of these cases, a heart beat was restored in 27 patients (21.4%). In 133 of 456 deaths (29.2%), patients had used a metered dose inhaler (MDI). Among these cases, 80 patients (60.2%) seemed to have been using a MDI up to the time immediately before death.
Conclusions: Those living alone have a significantly lower likelihood of receiving emergency medical care immediately before death compared with those living with other people. The cases of acute death within 3 h after the onset of the asthma attack accounted for 60.2% of all cases and this seems to be important for future studies of the medical care of deaths due to asthma.

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Background: We investigated the relationship between peak expiratory flow (PEF), age and standing height in 2785 Japanese volunteers (1047 males), aged 15-84 years, who had never smoked and who satisfied other strict criteria of normality. Many reports of regression equations for PEF by country and ethnicity are prepared using Wright or mini-Wright PEF meters, which have been calibrated by human subjects. Yet, no study has been performed in any country to determine the reference values of PEF on the American Thoracic Society (ATS) scale, which is calibrated by a computer-driven mechanical pump.
Methods: Peak expiratory flow was measured with mini-Wright meters calibrated on the Wright scale. All subjects were taught how to perform a forced expiratory maneuver: the highest of three PEF values was recorded and standing height was measured. The Miles equation was used to convert mini-Wright PEF values (traditional scale) to values using the new 'mechanical' PEF, which the ATS has recommended (ATS scale). In the analysis of the data, a model based on age, age squared and age cubed was used to derive curvilinear regression equations for PEF on age and standing height for each sex.
Results: There was adequate representation of subjects of each sex at all ages to 74 years. Curves plotted from the regression equations rose during adolescence and early adulthood, reached maximum values at 35 years in males and 40 years in females and then declined in an approximately linear manner. For both sexes, standing height fell progressively with increasing age.
Conclusions: From the regression equations, predicted values of PEF can be derived for any Japanese adult aged 15-74 years. We were able to obtain predicted equations for PEF in normal Japanese adults using both the Wright and ATS scales. Direct comparison of our regressions with those reported in other populations was limited by differences in methodology and analysis. In comparable studies of Chinese and Indian populations, the PEF values in those studies were appreciably lower than ours. Our regressions were remarkably similar to those reported in a study of British subjects that used virtually identical entry criteria and methods.

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Background: There has recently been an accumulation of evidence suggesting that endothelial cells (EC) play a crucial role in the pathogenesis of bronchial asthma. We examined the prevalence and isotypes of anti-EC antibodies (AECA) in the sera of children with asthma and determined the antigenic targets associated with AECA reactivity.
Methods: Levels of each class of AECA were determined by cellular ELISA in 156 children with asthma and in 203 control children. Sodium dodecyl sulfate- polyacrylamide gel electrophoresis and western blot analysis were performed in samples that contained high levels of AECA.
Results: In the cellular ELISA, the IgE class of AECA was detected significantly more frequently in children with asthma (25/156; 16.0%) than in healthy controls (2/203; 1.0%; P > 0.01). There were no differences in the frequencies of detection of IgG, IgA and IgM classes of AECA between patients and controls. The IgE-AECA was more frequently detected in younger children (23/69 vs 2/87 for children younger and older than 4 years of age, respectively). There was no correlation between the level of IgE-AECA and that of total IgE or house dust mite-specific IgE. In western blot analysis, IgE antibodies against a component of EC with a molecular mass of 75 kDa were detected in 20 of 25 patients (80.0%) positive for IgE-AECA, but they were less frequently detected in patients negative for IgE-AECA (2/34 (5.9%); P < 0.01).
Conclusions: These results demonstrate that a small fraction of asthmatic children has IgE-AECA and that the antigenic target of IgE-AECA is a component of the EC with a molecular weight of 75 kDa.

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Background: The role of mushroom spores as inhalants in causing respiratory allergy has been well established. Although mushrooms are commonly used as food throughout the world, food allergy to mushrooms is not very common. A severe case of anaphylaxis in a 32-year-old woman who experienced facial edema and generalized urticaria minutes after eating mushroom curry is presented herein. The purpose of the present study was to identify the putative allergen in the cultivated mushroom Agaricus bisporus.
Methods: A combination of biochemical fractionation/analytical techniques (gel filtration, ultrafiltration, ion-moderated cation-exchange chromatography, high-pressure liquid chromatography and gas chromatography-mass spectrometry (GC-MS)) and allergy diagnostic tests (skin prick test (SPT), allergen-specific IgE) were used.
Results: The SPT with mushroom extract was strongly positive; however, allergen-specific IgE could not be detected by enzyme-linked immunosorbent assay. The SPT was also positive with cooked, steamed or dried mushroom extracts, suggesting the presence of a heat-stable allergen. Gel filtration of mushroom extract on Sephadex G-25, as analyzed by SPT, indicated the presence of a low molecular weight (< 1 kDa) allergen. Using ion-moderated cation-exchange chromatography, the allergen was isolated and identified as mannitol based on skin reactivity. Mannitol was confirmed by GC-MS analysis.
Conclusions: This is the first report of food allergy to cultivated mushroom A. bisporus and also the first report describing a low molecular weight allergen (mannitol) in mushroom.

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Background: The aim of the present study was to compare three bronchial challenge tests for assessing bronchial hyperresponsiveness (BHR) in twin pairs followed up from birth to school age.
Methods: We studied three different bronchial challenge tests (methacholine inhalation challenge, cold air inhalation challenge and exercise-bronchodilation tests) at school age in 29 children born at or before 38 weeks gestation (median 35 weeks gestation) from multiple pregnancies. The children had been followed up from birth and were examined at the age of 7-15 years (median age 10 years).
Results: Bronchial hyperresponsiveness was found in 28-34% of children when these tests were analyzed separately. Eight children (28%) were exercise responders; two of them and three additional children were bronchodilator responders. Thus, 11 children (38%) had a pathologic result in the exercise-bronchodilation test. Ten children (34%) responded to cold air and nine children (31%) responded to methacholine inhalation. At least one test was pathologic in 18 children (62%), but only two children (7%) responded in all three challenges. A positive result in the exercise-bronchodilation test was associated with cold air reactivity, but not with methacholine reactivity. The exercise and cold air tests detected predominantly the same children. No differences were found in bronchial challenge test results between children who, at birth, were appropriately grown and those who had intrauterine growth retardation.
Conclusions: Bronchial hyperresponsiveness was common (up to 62%) at school age in children born as moderately preterm. The outdoor exercise bronchodilation test found 61% of all BHR cases. Bronchial hyperresponsiveness was not associated with intrauterine growth status. The most sensitive test was the cold air inhalation challenge and a good agreement was seen between this test and the exercise challenge outdoors.

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Background: To identify risk factors for childhood wheezing and allergies, a questionnaire regarding family histories and environmental factors was added to the International Study of Asthma and Allergies in Childhood (ISAAC) Phase One questionnaire and the associations between current prevalence and risk factors were analyzed.
Methods: Questionnaires were completed by 4466 schoolchildren, who were 13-14 years of age, in Tochigi Prefecture. Children were divided into groups on the basis of risk factors and the severity of each allergic disease according to answers to the ISAAC questionnaire.
Results: In analyses of family histories, the odds ratios (OR) of children who have a family history with no symptoms were significantly lower by risk factor-based analyses compared with those children with a family history of symptoms of wheezing (OR = 2.34-4.39), rhinitis (1.76-2.68) and eczema (2.54-7.81), and significant correlations were observed between severity and family history in all diseases by the Mantel test (P < 0.001). Although the OR of household smoking was not significant, heavier smoking in a household had an effect on severity and showed a significant correlation with severity in rhinitis (P < 0.05) and eczema (P < 0.01). Regarding road traffic, the percentage of children living in an area with heavy traffic showed a significant correlation with the severity of wheezing (P < 0.05) and no children with severe wheezing lived in areas with light traffic. In addition, the mean percentage of children with current wheezing between school locations was significantly higher in the city area (10.2 ± 0.7%) compared with that in the suburbs (6.6 ± 0.9%; P = 0.01) and industrial areas (6.6 ± 0.7%; P = 0.01).
Conclusions: These results suggest that the family histories may have potential effects on the severity of allergic diseases and that household smoking for rhinitis and eczema and heavy road traffic for asthma may be more important modifiable risk factors for severity in Japan.

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