Essentially all asthmatics demonstrate a marked sensitivity to inhaled methacholine and histamine, termed non-specific bronchial (airway) hyperresponsiveness (BHR). Airway hyperresponsiveness is a characteristic not only of asthmatics, but can be found in many persons with allergic rhinitis as well as in members of asthmatics' families. The presence of BHR usually precedes the development of clinically identifiable asthma. In recent years there has been an emphasis on inflammation, inducing hyperresponsiveness. However, these factors increase airway hyperresponsiveness by a magnitude of only three-fold compared with normal subjects. The important question is not why asthmatics respond, but why normal subjects do not. The normal subjects are quite able to maintain normal airway function in the presence of high concentrations of methacholine or histamine in vivo but not in vitro, suggesting the presence of protective mechanisms in vivo that are either lacking in, or are less effective in, the asthmatic subjects. There is a strong correlation between the degree of airway hyperresponsiveness and the severity of asthma. In order to determine whether methacholine sensitivity could be used as a potential genetic marker, we studied 750 subjects from 53 asthma families and 26 control families. The best sensitivity and specificity is at 200 breath units. Only 6% of the allergic rhinitis subjects showed a high positive response, but 30% overlapped with asthmatics in that they reacted with 200 breath units or less. There was a group of non-atopic subjects from asthma families who responded by 200 breath units, but there was a significantly lower percentage from normal families. Being from an asthma family is a risk factor in terms of subsequent development of asthma and increased airway reactivity. The parent data suggest that airway reactivity is transmitted to succeeding generations. Studies of twins have revealed that the concordance of asthma is higher in monozygotic than in dizygotic twins, but environmental factors are at least as important as genetic factors. Animal models of asthma comparing genetic strains can provide an important link between airway hyperresponsiveness and the allergic response. The inheritance of asthma fits a polygenetic pattern rather than a single-gene pattern.

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The role of allergy, particularly allergic rhinitis (AR), in otitis media with effusion (OME) is discussed. Because both OME and AR are common in young children, these disorders are occasionally seen in the same patient. Many clinical and experimental reports have discounted the allergies as a cause of middle ear effusion (MEE) because type I allergic reactions in the nose cause eustachian tube dysfunction but do not induce MEE, because the associated tubal dysfunction has a short duration. It has been shown that allergy-induced tubal dysfunction significantly disturbs the clearance of MEE. Since clinical and experimental studies have demonstrated the efficacy of allergy treatment in patients or animals having both diseases, combination treatment for allergy and OME in patients with both diseases should be initiated.

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The levels of naturally occurring IgG, IgG1 and IgG2 antibodies against polyvalent pneumococcal capsular polysaccharide antigen (Pneumovax^®) were compared between atopic and nonatopic children with different ages, 6-12 months and 1, 2, 3, 4, 5-9 and 10-15 years, by enzyme-linked immunosorbent assay. Children with asthma, atopic dermatitis food allergy or a combination of these, and those having serum IgE levels exceeding 50 IU/mL at 6-12 months old and 100 IU/mL at more than 1-year-old were included as atopic groups. Asymptomatic children whose serum IgE levels were less than these atopic standards and those not having detectable IgE antibodies to Dermatophagoides farinae comprised the nonatopic groups. Geometric mean levels of IgG and IgG₁ antibodies against pneumococcal antigen increased steadily with age, and that of IgG2 antibodies was low until 3 years of age and then gradually increased age-dependently up to 15 years of age. The levels of IgG antibody as well as IgG1 and IgG2 antibodies were not significantly different between atopic and nonatopic children in any age group. This suggests that the immune response to the most common bacterial pathogen in the respiratory tract does not influence atopic status.

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Skin prick tests (SPT) were performed on 2113 atopic patients (407 children and 1706 adults) with asthma and/or rhinitis at 24 allergy clinics in Iceland, Norway, Denmark, Sweden, Estonia, Lithuania and Russia. Test extracts were Dermatophagoides pteronyssinus (D. pteronyssinus), Dermatophagoides farinae (D. farinae), cat, dog, horse, birch, timothy, mugwort, Cladosporium, Alternaria, cockroach, chironomids (red mosquito larvae, RML) and shrimp. Among the allergens, timothy followed by cat, birch and dog gave the highest number of positive SPT. Positive SPT with house dust mites (HDM), furred animals, RML and Cladosporium were more common in asthmatics than in patients with rhinitis; birch and timothy more common in patients with rhinitis. Sensitization against D. pteronyssinus, horse, timothy and Cladosporium was more common in men than in women. Although the general sensitization pattern of the atopic patients at the participating centers showed similarities, there were also significant differences between centers. Positive SPT with furred animals were most prevalent in Northern and Central Sweden and St Petersburg, and least common in Siberia and Denmark. Pollen allergy was most common in Novosibirsk and on the west coast of Sweden, and less common in Vladivostok. Sensitization against HDM was most common in Lithuania and least prevalent in Northern Sweden and Finland. Insect allergens gave the most positive reactions in St Petersburg and the least positive reaction in Novosibirsk. Sensitization against multiple allergens was found in 74% of the patients and a mono-allergy in 26%. The degree of atopy was higher in males than in females and higher in asthmatics than in patients with rhinitis. The month of birth of the patients did not influence significantly the test results. It is concluded that although the sensitization pattern shows similarities in different regions, it is also influenced to some extent by residence as well as by diagnosis, sex and age of the patients.

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Nasal symptoms and inflammatory cells changes over the course of perennial allergic rhinitis have been analyzed only rarely. We studied nasal symptoms, nasal physical findings, and laboratory data in five groups, which consisted of varying time periods during the course of perennial allergic rhinitis (< 1, 1-2, 2-3, 3-5 and 5+ years) of 354 patients at the time of the first visit to our allergy clinic. The mean values calculated from scored nasal symptoms (i.e. rhinorrhea, sneezing and nasal obstruction) and physical findings (i.e. inferior turbinate swelling and colour) showed significant differences among these groups. We also studied inflammatory cells, mast cells, EG2⁺ and total eosinophils, CD3⁺ and CD4⁺ T cells, and neutrophils in the nasal mucosa of five patients with a short history (< 1.5 years) of allergic rhinitis, and of 10 patients with a long history (> 3 years). The tissue density of mast cells in the epithelial layer and of eosinophils and CD4⁺ T cells in the subepithelial layer did differ between the two groups. These results indicate that perennial allergic rhinitis goes through a transition stage from onset to a few years, and thereafter becomes a chronic condition. Mast cells, eosinophils, and CD4⁺ T cells may be associated with ongoing allergic inflammation.

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Connective tissue-type mast cells degranulate in response to a neurogenic peptide, substance P, whereas bone marrow-derived mast cells (BMMC) do not respond to this stimulant when prepared with a combination of interleukin-3 and interleukin-4. In the present study we demonstrated that BMMC obtained from three different strains of mice, NC, BALB/c and C57BL/6, which are immature mast cells low in histamine content and unresponsive to substance P, increased 10 to 100-fold in their histamine content and acquired responsiveness to substance P after co-culture with NIH/3T3 fibroblasts in the presence of 10 ng/mL of stem cell factor (SCF). This change was observed after 1 week of co-culture and increased over a 3 week period, whereas 3T3 fibroblasts or SCF (100 ng/mL) alone was insufficient to duplicate this phenotypic change in BMMC. It is suggested that the response to substance P of mast cells is not through NK-1 receptors but rather through a different mechanism, since the reverse transcriptase-mediated polymerase chain reaction technique failed to show expression of NK-1 receptor mRNA in BMMC after co-culture as well as before co-culture.

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This study involved long-term analysis of children and adolescents with house dust mite sensitive allergic asthma to investigate the effect of immunotherapy (IT) with a house dust extract containing certain amounts of Dermatophagoides farinae (Der f1), and Dermatophagoides pteronyssinus (Der p1, Der p2). The medication requirements, peak expiratory flow (PEF) circadian variations, forced expiratory flow between 25 and 75% of the vital capacity (FEF_25-75), maximal expiratory flow at 50 and 25% vital capacity (V₅₀ and V₂₅), and specific airway resistance (SRaw) were evaluated over a 3-year period in patients treated with IT. When compared with the results for control asthmatic patients who had not been treated with IT, statistically significant amelioration regarding the PEF circadian variations, %FEF_25-75, %V₅₀ and %V₂₅ was observed in IT-treated patients during the study. Although the improvement for medication requirement during the study was not different statistically between the two groups, we concluded that long-term house dust IT may result in amelioration of pulmonary functions, which may account for its clinical effectiveness in the treatment of asthmatic patients.

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The purpose of this study was to evaluate the effect of newly developed selective phosphodiesterase (PDE) inhibitors, KF19514 (type I/IV) and cilostazol (type III), and theophylline on the secretions of tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β) from human peripheral monocytes stimulated by lipopolysaccharide (LPS). Human blood monocytes were incubated with LPS in the absence or presence of KF19514, cilostazol or theophylline. TNFα and IL-1β in the cell-free supernatants were measured with enzyme-linked immunosorbent assay. KF19514 showed significant inhibition on the release of TNFα (% inhibition ± SEM was 82.8 ± 7.4% at 1 μmol/L) and IL-1β (34.4 ± 7.5% at 10 μmol/L). In addition, KF19514 inhibited the expression of TNFα mRNA. Cilostazol inhibited the release of TNFα significantly (60.2 ± 8.9% at 30 μmol/L) but not IL-1β. Theophylline inhibited slightly but significantly the release of TNFα at a therapeutic concentration (17.4 ± 5.1% at 100 μmol/L). These results suggest that theophylline may not only have a bronchodilating action but also an anti-inflammatory property in the treatment of bronchial asthma, and that KF19514 may have an anti-inflammatory action on at least the transcriptional level.

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The definition of late-phase response (LPR) associated with nasal allergy is not as clear as that associated with asthma. Furthermore, LPR and immediate-phase response often act in concert to produce confounding symptoms due to repeated attacks over a short period of time. We examined the nasal airway resistance (NAR), allergic symptoms, eosinophil cationic protein and histamine concentration in nasal surface tissue 30 min before, and 10 min, 1, 3, 5, 7 and 9 h after a house dust (HD) nasal challenge test was performed twice on 10 patients with HD perennial nasal allergy. Nasal airway resistance readings after the HD nasal challenge test were classified into three types based on changes in NAR: type I (short-lasting, five cases); type II (prolonged, eight cases); and type III (biphasic, six cases). Delayed increases in NAR were not observed in type I patients with weak responses to nasal challenge. In type II patients, baseline NAR was elevated and numerous basophilic metachromatic cells (BC) were present in the epithelial layer. In type III patients, baseline NAR was not as elevated as it was in type II patients, but marked responses to challenge were noted. In all three types of changes in NAR, eosinophil leukocyte increased at late phase. Moreover, there was no correlation of change in NAR with an increase in the number of eosinophil leukocyte and BC at the epithelial layer in all three types, which suggests that further study is required to confirm the exact role of eosinophils and basophilic cells in LPR.

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