Bronchial histamine reactivity: its relationship to the reactivity of the bronchi to allergens

The aim of this study was to examine the proposal that the magnitude of the response of the bronchi to an immediate allergic reaction depends not only on the degree of sensitization of the bronchi by allergen specific IgE antibody but also on the reactivity of the bronchi to the vasoactive mediators which are released during immediate allergic reactions. This was done by determining the bronchial reactivity to Dermatophagoides pteronyssinus and to histamine of both symptomatic and asymptomatic groups of atopic subjects who had comparable serum levels of D. pteronyssinus specific IgE. Positive bronchial responses to the D. pteronyssinus extract were recorded with both the symptomatic and asymptomatic subjects, the mean bronchial threshold dose of allergen being significantly higher in the asymptomatic than in the asthmatic patients. There was a highly significant correlation between the serum level of allergen specific IgE and the bronchial threshold dose of allergen extract and also between the bronchial threshold dose of allergen extract and of histamine in all groups of subjects. The ability to predict bronchial reactivity to the allergen from the serum level of allergen specific IgE within each group was significantly better if the bronchial reactivity to histamine was included in the correlation analysis. This supports the hypothesis that whether a particular subject who is producing specific IgE antibody will develop symptoms on the inhalation of that allergen depends not only on the amount of allergen which he inhales and on the degree of sensitization of his bronchi but also on the reactivity of his bronchi to the vasoactive mediators which are released by allergen–IgE interaction.     

Atopy and bronchial responsiveness in random population sample of 527 children and adolescents.

The relationship between bronchial responsiveness, lung function, and results of skin prick testing was studied in 527 children and adolescents from Copenhagen. All participants completed a questionnaire concerning allergic symptoms (asthma, rhinitis, atopic dermatitis, and urticaria). Furthermore, skin prick test reactivity to nine common aeroallergens, lung function, serum IgE and bronchial responsiveness to histamine and exercise were measured. A total of 53 subjects were atopic, (skin prick 3+), 105 subjects had moderate skin reactivity (1-2+), and 366 subjects had no signs of atopic disease (prick test negative); 58% of the subjects with skin test reactivity (1-3+) were asymptomatic. Increasing degree of atopy was correlated significantly with symptoms such as asthma, rhinitis, dermatitis, and urticaria (P less than .001); increasing level of IgE (P less than .001); month of birth (P = .001); and family history of allergic diseases (P less than .05). The most important markers for the degree of bronchial responsiveness to inhaled histamine were the presence of respiratory symptoms (P less than .001), the degree of atopy (P = .001), a history of asthma in at least two first degree relatives (P less than .01), and the skin reactivity to house dust mites (P = .001), horse epithelium (P = .01), Alternaria iridis, and dog epithelium (P less than .05). In contrast, the degree of bronchial responsiveness to exercise was significantly correlated with asthma (P less than .001), the level of IgE (P less than .05), month of birth (P less than .001), and birth weight (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Airway responsiveness to histamine as a test for overall severity of asthma in children

Seventy-eight children who had a history of asthma were studied while they were symptom-free. There was a highly significant correlation between the dose of aerosolized histamine that produced a decrease in FEV₁ of 20% and each of the features in the history that indicated severity of asthma. The correlation was strengthened by the combination of these features into a weighted asthma history score. None of the subjects with mildly increased bronchial reactivity had a history score of severe asthma, and none with markedly increased bronchial reactivity had mild asthma. There was also a highly significant correlation between histamine dose and the results of spirometric tests for airway obstruction. However, the correlation between asthma history score and provocative histamine dose was highly significant even in the 21 subjects who were apparently free of airway obstruction at the time of testing. Furthermore, the correlation between asthma history score and histamine dose was stronger than that between asthma score and any spirometric test, indicating that the histamine test more accurately assessed the overall severity of the asthma. Measurement of bronchial responsiveness to histamine is a useful adjunct to history in determining the severity of asthma in an individual and should be considered as an objective way of grading subjects according to severity of asthma in a clinical study.     

A clinical study of concanavalin A-induced histamine release utilizing a single isotopic enzymatic assay of histamine.

Concanavalin A (Con A)-induced histamine release from cells of subjects with extrinsic asthma, intrinsic asthma or urticaria and normal individuals was examined utilizing a single isotopic enzymatic assay for histamine. Maximum histamine release by Con A occurred with 0.9 to 4.5 microgram/ml. The mean percentage of maximum histamine release by Con A from cells of donors with extrinsic asthma was 36(+/- 19.3)% while that from cells of normal individuals was 21.4(+/- 23.7)%. However, there was no significant difference between the two groups. The higher reactivity to Con A of cells from individuals with intrinsic asthma or urticaria was not observed compared to that of the normal group. The histamine release by Con A was not correlated with IgE level in the plasma (r = 0.35). It was observed that compound 48/80 inhibited the enzymatic reaction in the isotopic, enzymatic assay.     

Frequency and intensity of late asthmatic reactions after bronchial allergen challenge in asthma and rhinitis

The occurrence of late asthmatic reactions after bronchial allergen challenge was studied in 50 house dust mite allergic patients subdivided in three groups: one group had asthma without nasal symptoms, another group had rhinitis without pulmonary symptoms and a third group had a combination of both asthma and rhinitis. Late asthmatic reactions were present in 80% of asthmatic patients and in 18.7% of rhinitis patients. The degree of non-specific bronchial reactivity to histamine (provocative dose 15 or PD15 histamine) and the degree of immediate reactivity to allergen (PD15 house dust mite) did not differ significantly between patients with and without late asthmatic reactions. These findings suggest that an important difference between asthma and rhinitis is the lack of late asthmatic reactions in rhinitis patients, whereas the degree of immediate bronchial reactivity to the allergen is similar in asthma and rhinitis.     

Lack of association between HLA-DQ and -DR genotypes and asthma in southern Chinese patients

Asthma is an inflammatory disease with a strong genetic predisposition. We have studied a group of unrelated asthmatic patients of southern Chinese origin on their HLA-DR and -DQ regions using molecular techniques and compared them with 104 healthy controls of the same ethnic origin. Restriction fragment length polymorphism (RFLP) was used to genotype the MHC class II DR β, DQ α and DQ β loci of the subjects. Polymerase chain reaction (PCR) using sequence specific primer (SSP) for DQ β genes was also performed. No significant difference was found in the HLA-DQ and -DR loci between the patients and the controls. All patients had their serum IgE antibody levels measured, bronchial reactivity assessed by histamine broncho-provocation and cutaneous reactivity to common allergens determined by skin-prick tests to Dermatophagoides pteronyssinus, Dermatophagoides farinae, mixed grass pollens, Aspergillus fumigatus, cat fur and dog dander and they were classified respectively. The HLA-DR and -DQ genotypes of these subgroups of patients were compared. There was no significant difference among these subgroups of patients according to their serum IgE levels, the degree of bronchial reactivity and whether they were positive for the skin tests for the various allergens respectively. The results suggest that HLA-DQ and -DR genotypes are not associated with asthma in southern Chinese people.     

Serum immunoglobulin E levels predict human airway reactivity in vitro

BACKGROUND: Airway hyperresponsiveness to non-specific stimuli is one characteristic feature of airway diseases such as bronchial asthma and chronic bronchitis. Until now, studies aiming to demonstrate a relationship between in vivo conditions associated with airway hyperreactivity and in vitro airway responsiveness have been inconclusive. OBJECTIVE: Since serum immunoglobulin (Ig) E is believed to be one determinant of airway reactivity in vivo, we studied whether in vitro airway reactivity in lung resection material from patients with elevated levels of serum IgE was increased as compared with patients with undetectable IgE. By this approach, we aimed to elucidate the role of circulating IgE for bronchial smooth muscle reactivity in vitro. METHODS: Bronchial rings from nine patients with total serum IgE levels above 200 U/mL and 10 patients with total serum IgE levels below 10 U/mL were passively sensitized, i.e. incubated overnight with buffer or sensitizing serum containing high levels of total IgE (> 250 U/mL). Afterwards, contractile responses to histamine were assessed in the organ bath. RESULTS: Histamine responsiveness was significantly increased in airways obtained from patients with IgE levels above 200 U/mL as compared with airways from patients with IgE levels below 10 U/mL (P < 0.05). Passive sensitization of bronchi from patients with low IgE significantly increased histamine responsiveness, as compared with non-sensitized controls from the same patients (P < 0.05). In contrast, passive sensitization of airways from patients with elevated IgE did not further increase responsiveness. There was no difference in histamine reactivity between non-passively sensitized and passively sensitized tissue preparations from patients with IgE above 200 U/mL and passively sensitized tissues from patients with IgE below 10 U/mL. CONCLUSION: Our findings reveal that elevated levels of serum IgE predict airway hyperresponsiveness to histamine in vitro. At the same time, they indicate that the in vitro model of passive sensitization, in addition to its ability to induce allergen responses, also mimics conditions of non-specific airway hyperreactivity, which are relevant under in vivo conditions.     

Effect of histamine and methacholine on nasal airway resistance in atopic and nonatopic subjects: Comparison with bronchial challenge and skin test responses

Serial nasal, intracutaneous, or bronchial challenges were carried out with solutions containing 2- or 3-fold increments in histamine (H) or methacholine (Meth) concentration until nasal airway resistance (NAR) increased by more than 100%, a large intracutaneous reaction was elicited, or FEV₁ decreased by 20% or more. Thirty nonatopic and 48 asymptomatic atopic subjects were studied, the latter group divided into rhinitic patients with and without asthma. Several types of data analysis demonstrated there was no significant difference in the nasal or cutaneous effects of H or Meth between the atopic and nonatopic groups. Comparable results were obtained in a subgroup of 39 subjects (13 normal, 13 atopic, and 13 atopic with asthma) who underwent all six test sequences (i.e., nasal, cutaneous, and bronchial with both drugs). As expected, the asthmatics showed significantly increased bronchial reactivity to both agents. In comparison with Meth, H had a much greater effect on the nasal mucosa and skin than on the bronchi. It is concluded that, contrary to bronchial responses, but in accord with cutaneous reactivity, the nasal responses of nonatopic subjects, atopic persons with allergic rhinitis alone, and subjects with both allergic rhinitis and asthma show no intergroup differences on testing with H or Meth.     

Immunologic and nonimmunologic mechanisms in asthma due to western red cedar (Thuja plicata)

Occupational asthma due to western red cedar (Thuja plicata) is the most common form of occupational asthma in British Columbia, occurring in about 5% of the exposed workers. Plicatic acid, uniquely present in western red cedar, was found to be the agent responsible for the asthmatic reactions. Inhalation provocation tests with an extract of western red cedar or plicatic acid induced late asthmatic reactions alone in 44%, dual (immediate and late) reactions in 49%, and immediate reactions alone in 7% of the 185 patients. Of the 75 patients who left the industry and were no longer exposed to the wood, only 50% recovered completely after an average period of 3 yr; the remaining half continued to have recurrent attacks of asthma. Specific IgE antibodies to crude red cedar extract or plicatic acid-human serum albumin conjugate were found in less than 40% of the patients by the RAST, while IgG antibodies were not detected. There was no correlation between the presence and absence of specific IgE antibodies and the type of asthmatic reaction induced during inhalation challenge. IgE antibodies were not found in exposed subjects with no asthmatic reaction on inhalation challenge. There was significant correlation between the degree of nonspecific bronchial hyperreactivity and the degree of bronchial reactivity to plicatic acid during immediate or late asthnatic reactions. The degree of nonspecific bronchial hyperreactivity was increased after late asthmatic reactions induced by plicatic acid. On the other hand, the degree of nonspecific bronchial hyperreactivity was reduced and gradually returned to normal among patients who became asymptomatic after exposure was discontinued. These findings suggest that nonspecific bronchial hyperreactivity plays an important role in the pathogenesis of red cedar asthma. The mechanism of bronchial hyperreactivity induced by red cedar exposure is unknown; an immunologic mechanism may be important. Direct release of histamine from human basophils and mast cells and direct activation of the complement system by plicatic acid are unlikely pathogenetic mechanisms.     

Tachyphylaxis to inhaled histamine in asthma: its significance and relationship to basal airway responsiveness

Although some studies have clearly demonstrated tachyphylaxis to inhaled histamine in subjects with asthma, other studies have not. We speculated that histamine tachyphylaxis might be related to the degree of bronchial hyperreactivity (BHR) to histamine. We undertook three successive bronchial histamine challenges in two groups of 10 subjects with asthma chosen on the basis of their baseline BHR. In the group with mild asthma, the baseline provocative concentration of histamine causing a 20% fall in FEV1 (PC20) was greater than 2.5 mg/ml, and in the group with severe asthma, the baseline PC20 histamine was less than 1 mg/ml. The second and third histamine challenges in each subject were performed when FEV1 values had recovered to within 5% of the baseline FEV1 before the first challenge. There was no significant shift in reactivity to histamine from the first to the third challenge in either group. The geometric mean PC20 (+/- geometric SE) for the group with mild asthma was 4.27 (3.86 to 4.72) mg/ml for the first challenge and 5.42 (4.47 to 6.57) mg/ml for the third challenge. There was a mean increase of 0.34 doubling dilutions in PC20 for the group with mild asthma from the first to the third challenge, although this did not reach statistical significance. For the group with severe asthma, the geometric mean PC20 was 0.48 (0.39 to 0.59) mg/ml for the first challenge and 0.47 (0.38 to 0.59) mg/ml for the third challenge. There was no trend in this group toward any increase in PC20.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhancement of IgE synthesis and histamine release by T cell factors derived from atopic patients with bronchial asthma

Culture supernatants of unstimulated T cells (TCS) derived from normal donors or from atopic patients with bronchial asthma were tested for their ability to regulate the spontaneous IgE synthesis by B cells of normal and atopic subjects. The same TCS were also tested for their influence on the histamine release from leukocytes of house dust mites-sensitive patients. Addition of TCS to B cell cultures from allergic donors induced a dose-dependent increase of the spontaneous IgE production without affecting the synthesis of IgG, IgM, and IgA. The potentiating activity of TCS was observed only in B cell cultures spontaneously producing IgE; TCS were still active on irradiated B cells. The maximal IgE-enhancing activity was observed when TCS were added at the onset of B cell cultures. The supernatants of T cells lysed at day 0 did not contain IgE-potentiating factors. The antigen-induced but not the spontaneous histamine release from leukocytes of house dust mite-sensitive patients was enhanced by pretreatment with TCS from allergic donors. The enhancing activities of TCS on IgE synthesis and on histamine release could be removed by absorption with IgE-Sepharose and subsequently recovered by elution with glycine buffer. The results indicate that T cells of patients with asthma spontaneously release IgE-binding factors capable of increasing both the spontaneous IgE synthesis by B cells and the antigen-induced histamine release.     

Lack of tachyphylaxis to histamine in both moderate and mild asthmatic subjects

While some studies have clearly shown that tachyphylaxis occurs in asthmatic subjects when challenged consecutively with inhaled histamine, others were unable to demonstrate this phenomenon. There is reason to believe that these conflicting findings may be related to the different degrees of bronchial reactivity in the subjects studied. We selected 2 groups of 10 asthmatics on the basis of their degree of bronchial reactivity: a group with PC₂₀<1 mg/ml (moderate asthmatics); and a group with PC₂₀>2.5 mg/ml (mild asthmatics). Each subject underwent 3 successive histamine challenges, allowing recovery of FEV₁ after each to within 5% of the baseline value prior to the first challenge. Test results were recorded as the provoking concentration of histamine needed to produce a 20% fall in FEV₁ (PC₂₀). No significant change in histamine reactivity occurred in either group. However, one moderate and two mild asthmatics appeared to develop some tachyphylaxis. We conclude that tachyphylaxis to histamine is not a general phenomenon in asthma.     

Bronchial allergen challenge in subjects with low levels of allergic sensitization to indoor allergens

BACKGROUND: Low skin reactivity to common inhalant allergens is frequently found in asymptomatic individuals as well as in patients with respiratory complaints. However, most studies on bronchial allergen challenge concern patients with high levels of allergic sensitization. The present study was directed to bronchial reactions after allergen challenge in subjects with low skin reactivity to Dermatophagoides pteronyssinus or cat dander. METHODS: Titrated intracutaneous skin tests, skin prick tests, specific IgE assays, histamine release on washed leukocytes, and bronchial histamine and allergen-challenge tests were performed in 20 subjects with an intracutaneous skin test threshold for cat dander (Felis domesticus) or D. pteronyssinus above 0.1 BU/ml (mean wheal diameter in skin prick test with 10000 BU/ml: 4.4mm). Ten of the 20 patients had specific IgE below the detection limit in at least one of the three IgE assays which were done. Fifteen patients had a specific IgE level below 2 kU/I in all three tests. As a positive control group, the same parameters were studied in seven moderately sensitized patients with an intracutaneous skin test threshold below 0.1 BU/ml (mean wheal diameter with 10000 BU/ml: 7.2mm). RESULTS: The 20 subjects with low levels of allergic sensitization had an early decrease in FEV1 of 8.6% (P<0.01) and a mean late decrease of 6.3% (P<0.05). There was a trend for decrease in PC20 histamine 24h after allergen challenge (-0.4 doubling doses, P=0.09). CONCLUSIONS: In this group of subjects with low levels of allergic sensitization, a statistically significant early and late decrease in FEV1 was found. However, the decrease in lung function was small and unnoticed by most patients. The increase in nonspecific bronchial hyperresponsiveness after bronchial allergen challenge did not reach statistical significance in the study group. The results indicate that allergen exposure in patients with low levels of allergic sensitization may lead to airways changes in the absence of acute symptoms.     

Recurrent nocturnal asthma after bronchoprovocation with Western Red Cedar sawdust: association with acute increase in non-allergic bronchial responsiveness

Recurrent nocturnal asthma following a single exposure to Western Red Cedar sawdust was documented by measurements of peak flow rates in two sensitized subjects. The nocturnal asthma followed a dual asthmatic response in the first subject and a late (non-immediate) asthmatic response in the second. Both subjects developed a 10-fold reduction in the dose of histamine required to decrease the FEV₁ by 20%. This cedar-induced increase in non-specific bronchial reactivity was maximal at the time of the recurrent nocturnal asthma, and persisted after nocturnal asthma had ceased and after FEV₁ had returned to normal. We hypothesize that the enhanced non-specific bronchial reactivity which occurs following late asthmatic responses to bronchial challenge is the cause of recurrent nocturnal asthma following single exposure to a sensitizing agent.     

Baker's asthma

Seven bakers with respiratory symptoms were evaluated by skin tests, RAST assay for specific IgE antibodies to rye and wheat, inhalation challenge with methacholine for the determination of non-specific bronchial reactivity, and bronchoprovocation with rye and wheat extracts for the determination of antigen-specific bronchial reactivity. An immediate asthmatic response to antigen challenge was observed in four subjects and all of them had a high level of flour-specific IgE antibodies. The serum RAST values provided a more accurate predictive value than the degree of cutaneous sensitivity determined by skin testing with respect to the bronchial response to antigenic challenge. Among those who reacted positively to antigenic bronchoprovocation, a much lower antigen dose was required to elicit a positive reaction if the subject also had an increased degree of non-specific bronchial reactivity. An elevated RAST value was not found in thirty-eight asymptomatic bakers or in ten asthmatics who had no occupational exposure to flour. Thus, baker's asthma appears to he a form of allergic asthma to cereal flours mediated by specific IgF antibodies. Both the level of serum IgE antibodies and the degree of non-specific bronchial reactivity are important factors which may influence a baker's bronchial response upon inhalation of cereal flours.     

Age-dependent relationship between bronchial hyperresponsiveness to methacholine and total serum IgE level in asthmatic children.

BACKGROUND: A relationship between nonspecific bronchial hyperresponsiveness and allergic airway inflammation has been reported in children and in adults with asthma, but the relationship in infants with asthma is still unclear. OBJECTIVE: To evaluate the relationship between bronchial hyperresponsiveness and total serum IgE level throughout childhood. Bronchial reactivity to methacholine from the age of 1 to 16 years was studied by methacholine inhalation challenge using transcutaneous oxygen pressure (tcPO2) monitoring. METHODS: Two hundred one asthmatic children (boys:girls = 132:69; 7.3+/-4.0 years of age, mean +/- SD) were enrolled in this study. The tcPO2 was measured using a tcPO2 monitor. Serial doses of methacholine were doubled until a 10% decrease in tcPO2 from the baseline was reached. The cumulative dose of methacholine at the inflection point of tcPO2 was considered to represent the bronchial reactivity to methacholine. RESULTS: There was no relationship between the cumulative dose of methacholine at the inflection point of tcPO2 and total serum IgE level in the group of children aged 1 to 4 years (P = 0.212), but significant correlations were found in the groups aged 5 to 10 years and 11 to 16 years (P = 0.044 and P = 0.014, respectively). CONCLUSIONS: We conclude that there is an age-dependent relationship between bronchial reactivity to methacholine and the total serum IgE level and that inhaled allergens, which were more common allergens in older children, may have some effects on the degree of bronchial reactivity to methacholine in children with asthma.     

Chironomidae as a cause of IgE-mediated histamine release in patients with asthma

The present study was undertaken to assess the importance of Chironomidae as an allergen causing bronchial asthma in Japan, and to evaluate histamine release as an allergy test in chironomid-midge allergic patients. Extracts of Chironomidae (T. akamusi and C. Yoshimatsui) caused the release of histamine in six out of 13 allergic patients with positive skin tests. In contrast, histamine release induced by these allergens was not observed in leukocytes from two asthmatic patients and five control subjects without IgE antibody as evidenced by negative skin tests and RAST. There was a significant correlation between maximal histamine release and IgE antibody levels. Furthermore, a significant inverse relationship between the concentration of allergen causing 25% histamine release (HR25) and IgE antibody levels was observed. The correlation coefficients, however, between histamine release and RAST were not high, and there were discrepancies between the two tests in some cases. These results suggest that Chironomidae induce histamine release from leukocytes via IgE-mediated mechanism but histamine release cannot be replaced by RAST and also suggest that chironomid midge is one of the important allergens in Japan.     

Immunoallergological studies on chironomid antigen in bronchial asthma

Immuno-allergological studies on Tokunagayusurika akamusi (TA), a chironomid, were carried out in 217 patients with bronchial asthma. 1. Skin reaction to TA was positive in 72 (33.2%) out of the 217 patients with bronchial asthma. 2. Fifteen (13.8%) of the 109 patients showed a significant amount of histamine release (more than 15%) from basophils stimulated by TA antigen. 3. There was a significant correlation between skin reaction and histamine release by TA antigen. 4. A significant amount of basophil histamine release was observed in young patients, and in those who were under 40 years old of age at the onset of the disease. The serum IgE concentration of these patients was relatively high. 5. There was a significant correlation between basophil histamine release by TA antigen and specific IgE antibody to CTT. 6. There were no significant differences in skin reaction or histamine release by TA antigen between asthmatics in Okayama and Tottori prefectures.     

Studies on bronchial hyperreactivity, allergic responsiveness, and asthma in rural and urban children of the highlands of Papua New Guinea

The prevalence of asthma and allergic responsiveness in rural and urban children of the highlands of Papua New Guinea was studied. Bronchial provocation studies with histamine demonstrated significant bronchial hyperreactivity in 0.5% (1 in 195) rural and 1.7% (1 in 59) urban children, rates which were significantly lower than those observed in corresponding adult populations (7%). Urban children demonstrated a higher incidence of skin test reactivity toward Dermatophagoides pteronyssinus, Aspergillus fumigatus, and dog dander than did the rural children. However, there were no significant differences between these populations with regard to total serum IgE levels, the degree of parasitism as judged by stool examination, or allergic responses to Ascaris suum, plantain, and coffee bean husk. A more detailed study demonstrated age- and sex-related differences in total IgE and mite-specific RAST scores in the rural but not the urban population. These data suggest an active suppression of the capacity of children to mount an IgE response to environmental allergens such as the mite manifesting itself as low asthma prevalence. The data also indicate that, although the underlying defect of bronchial hyperreactivity in asthma may be genetically inherited, it is not revealed until the lung has received an allergen-induced inflammatory insult.