Severe Airway Hyperresponsiveness Research Articles

Airway Responsiveness to Inhaled Aspirin is Influenced by Airway Hyperresponsiveness in Asthmatic Patients

Background/AimsMany patients with aspirin-induced asthma have severe methacholine airway hyperresponsiveness (AHR), suggesting a relationship between aspirin and methacholine in airway response. This study was performed to determine whether methacholine AHR affects the response of asthmatics to inhaled aspirin.MethodsThe clinical records of 207 asthmatic patients who underwent inhalation challenges with both aspirin and methacholine were reviewed retrospectively. An oral aspirin challenge was performed in patients with a negative inhalation response. The bronchial reactivity index (BRindex) was calculated from the percent decrease in lung function divided by the last dose of the stimulus.ResultsForty-one (20.9%) and 14 (7.1%) patients showed a positive response to aspirin following an inhalation and oral challenge, respectively. Only 24.3 and 14.3% of the responders had a history of aspirin intolerance, respectively. The methacholine BRindex was significantly higher in the inhalation responders (1.46 ± 0.02) than in the oral responders (1.36 ± 0.03, p < 0.01) and in non-responders (n = 141, 1.37 ± 0.01, p < 0.001). The aspirin BRindex was significantly correlated with the methacholine BRindex (r = 0.270, p < 0.001). Three of four patients who received the oral challenge, despite a positive inhalation test, showed negative responses to the oral challenge. Two of these patients had severe AHR.ConclusionsA considerable number of asthmatic patients with no history of aspirin intolerance responded to the inhalation aspirin challenge. The airway response to aspirin was significantly correlated with methacholine-AHR, and a false-positive response to aspirin inhalation test seemed to occur primarily in patients with severe AHR.

Limitations of questioning asthma to assess asthma control in general practice

The monitoring of children with asthma in primary care is based on the occurrence and frequency of asthma symptoms. We questioned whether the current approach is adequate to identify all children in whom a sufficient level of asthma control is not achieved. The aim of this study is to illustrate that in some children asthma was incorrectly considered controlled, because the children failed to report current symptoms of asthma. One hundred and nineteen children were identified with recent wheezing plus moderate or severe airway hyperresponsiveness. We analyzed whether these children reported current symptoms of asthma (as normally questioned during a routine visit). In 20 children (18%) current asthma symptoms were absent despite moderately or severe airway hyperresponsiveness and wheezing in the last year. In addition, the usage of controller medication was very poor. We conclude that the general practitioner has insufficient tools to adequately assess asthma control in all children. The assessment of airway hyperresponsiveness as an additional guide to manage asthma in children in general practice is recommended. In this way, better asthma control can be achieved.

Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17

Exposure to ozone, which is a major component of air pollution, induces a form of asthma that occurs in the absence of adaptive immunity. Although ozone-induced asthma is characterized by airway neutrophilia, and not eosinophilia, it is nevertheless associated with airway hyperreactivity (AHR), which is a cardinal feature of asthma. Because AHR induced by allergens requires the presence of natural killer T (NKT) cells, we asked whether ozone-induced AHR had similar requirements. We found that repeated exposure of wild-type (WT) mice to ozone induced severe AHR associated with an increase in airway NKT cells, neutrophils, and macrophages. Surprisingly, NKT cell–deficient (CD1d−/− and Jα18−/−) mice failed to develop ozone-induced AHR. Further, treatment of WT mice with an anti-CD1d mAb blocked NKT cell activation and prevented ozone-induced AHR. Moreover, ozone-induced, but not allergen-induced, AHR was associated with NKT cells producing interleukin (IL)-17, and failed to occur in IL-17−/− mice nor in WT mice treated with anti–IL-17 mAb. Thus, ozone exposure induces AHR that requires the presence of NKT cells and IL-17 production. Because NKT cells are required for the development of two very disparate forms of AHR (ozone- and allergen-induced), our results strongly suggest that NKT cells mediate a unifying pathogenic mechanism for several distinct forms of asthma, and represent a unique target for effective asthma therapy.

Residential exposure to mould and dampness is associated with adverse respiratory health

Indoor exposure to mould and dampness is frequently associated with asthma symptoms with and without lung function changes. However, the mechanisms contributing to this threat to respiratory health are only partly understood. To investigate the contribution of recent exposure to mould and dampness in the living room or bedroom to respiratory health in a general practice-based cohort of 526 asthmatic children. Parents were questioned about home characteristics, including moulds and dampness. The level of asthma control was evaluated in their participating children by means of asthma symptoms, peak expiratory flow (PEF) variability, severity of airway hyperresponsiveness (AHR), and medication usage. Children exposed to indoor moulds and dampness more often had severe AHR compared with non-exposed (42% vs. 16%; P< or =0.001). They also showed an increased PEF variability (11.3% vs. 8.4%; P=0.03) and, however, not significant, more frequent asthma symptoms. The use of controller medication was not significantly different between exposed and non-exposed children. After adjustment for gender, age, smoking, exposure to parental smoking, parental education, pet ownership, presence of inhalant allergy, use of controller medication, health care center, and season of study assessment, the odds ratio for severe AHR in exposed children was 3.95 [95% confidence interval (CI): 1.82-8.57]. We found a consistent association between reported moulds and dampness in the living room or the child's bedroom and an increased risk for severe AHR in a general practice-based cohort of asthmatic children, even after adjustment for gender, presence of inhalant allergy, and use of controller medication.

Severe airway hyperresponsiveness was not predictable with the use of current tools in asthmatic children in general practice

Objective To evaluate whether moderate to severe airway hyperresponsiveness (AHR) could be suspected with the use of routinely available clinical and environmental information. Study Design and Setting Cross-sectional study of asthma in 526 asthmatics aged 7–17 years and treated in general practice. Results Moderate to severe AHR was present in 48% ( n = 253) of the participants. The presence of inhalation allergy, nocturnal symptoms, and usage of β 2-mimetics were significantly associated with moderate to severe AHR. If all three factors were present, the probability of the presence of moderate to severe and severe AHR was 76% and 36%, respectively. If all three were absent, the probability decreased to 11% and 5%, respectively. In 319 subjects (64%) AHR could not be adequately predicted with routinely available information. Conclusion Moderate and severe AHR could not be suspected with the use of routinely available clinical and environmental information in the majority of children. Except for a subgroup of children, our models were not helpful in deciding in which child an inhaled corticosteroid should be started or whether the dose should be increased or decreased. We recommend measuring the severity of AHR in these children by means of an inhalation challenge test.

Lung CD11c+ cells from mice deficient in Epstein‐Barr virus‐induced gene 3 (EBI‐3) prevent airway hyper‐responsiveness in experimental asthma

Epstein-Barr virus-induced gene (EBI)-3 codes for a soluble type 1 cytokine receptor homologous to the p40 subunit of IL-12 that is expressed by antigen-presenting cells following activation. Here, we analyzed the functional role of EBI-3 in a murine model of asthma associated with airway hyper-responsiveness (AHR) in ovalbumin-sensitized mice. Upon allergen challenge, EBI-3-/- mice showed less severe AHR, decreased numbers and degranulation of eosinophils and a significantly reduced number of VCAM-1+ cells in the lungs as compared to wild-type littermates. We thus analyzed lung CD11c+ cells before and after allergen challenge in these mice and found that before allergen challenge, lung CD11c+ cells isolated from EBI-3-/- mice express markers of a more plasmacytoid phenotype without releasing IFN-alpha as compared to those from wild-type littermates. Moreover, allergen challenge induced the development of myeloid CD11c+ cells in the lungs of EBI-3-/- mice, which released increased amounts of IL-10 and IL-12 while not expressing IFN-alpha. Finally, inhibition of EBI-3 expression in lung DC could prevent AHR in adoptive transfer studies by suppressing mediator release of effector cells into the airways. These results indicate a novel role for EBI-3 in controlling local immune responses in the lungs in experimental asthma.

Tools used to measure airway remodelling in research

Airway remodelling refers to changes in the airway structure and includes subepithelial fibrosis, increased smooth muscle mass, submucosal gland enlargement, neovascularisation and epithelial alterations. Remodelling is observed in response to chronic injury and is seen not only in asthma but in all airway diseases. Remodelling is associated with more severe airflow obstruction and airway hyperresponsiveness in asthma; however, the clinical significance of this is still a matter of debate. Research should be pursued to better understand the accurate implication of airway remodelling in disease and its therapeutic modulation. To allow research in this field, accurate and standardised methods should be utilised to measure airway alterations in disease and following therapy. The standard detection of structural alterations is through direct analyses of airway tissues obtained during a post mortem, surgically or by flexible bronchoscopy. To avoid invasive techniques, other tools have been developed to indirectly measure remodelling, including induced sputum, bronchoalveolar lavage fluid, blood and urine analyses, physiological and radiological assessments, as well as in vitro techniques. Although of great interest, the exact significance of airway remodelling measurements gained through such indirect techniques is uncertain and further research is needed. Despite their invasive nature, direct methods should be favoured to adequately measure airway remodelling in disease and its modulation by therapy.

Inflammatory and Remodeling Events in Asthma with Chronic Exposure to House Dust Mites: A Murine Model

Although animal models with ovalbumin have been used to study chronic asthma, there are difficulties in inducing recurrence as well as in maintaining chronic inflammation in this system. Using a murine model of house dust mite (HDM)-induced bronchial asthma, we examined the airway remodeling process in response to the chronic exposure to HDM. During the seventh and twelfth weeks of study, HDM were inhaled through the nose for three consecutive days and airway responsiveness was measured. Twenty-four hours later, bronchoalveolar lavage and histological examination were performed. The degree of overproduction of mucus, subepithelial fibrosis, and the thickness of the peribronchial smooth muscle in the experimental group was clearly increased compared to the control group. In addition, HDM-exposed mice demonstrated severe airway hyperreactivity to methacholine. In the bronchoalveolar lavage fluid, the number of total cells and eosinophils was increased; during the twelfth week, the number of neutrophils increased in the experimental group. With regard to changes in cytokines, the concentrations of IL-4, IL-13, and transforming growth factor-beta (TGF-β) were increased in the experimental group. The data suggest that eosinophils, IL-4, IL-13, and TGF-β might play an important role in the airway remodeling process and that neutrophils may be involved with increased exposure time.

Association between the IL‐4 promoter polymorphisms and asthma or severity of hyperresponsiveness in Taiwanese

Recent family-based studies have revealed a linkage between human chromosome 5q31 and asthma, elevated serum IgE levels and airway hyperresponsiveness (AHR). Among the candidate genes in this region is the gene encoding IL-4. This gene could be a candidate gene for asthma. The aim of this prospective case-control study was to assess the frequency of polymorphisms in the IL-4 gene promoter among asthmatic patients from Taiwan. The study consisted of 167 patients with asthma and 111 healthy subjects. PCR amplification followed by Bsm F1 restriction digestion were used to assign genotypes at the IL-4 promoter C-589T locus. Pulmonary function tests, methacholine challenge tests, total IgE, specific IgE antibodies against common inhalant allergens and total eosinophil counts were assessed in asthmatic patients. The T allele frequency for the C-589T IL-4 gene promoter in asthma patients was higher than for normal subjects (P < 0.0001). The frequency discrepancy was found to be even higher for asthmatic patients with severe AHR (P < 0.05). There were no significant differences for the T allele frequency among asthmatic patients with the various other phenotypes such as high versus normal total eosinophil, high versus normal total IgE and high versus normal levels of specific IgE against mite, cockroach or cat dander, or dog dander. Polymorphism in the promoter of the IL-4 gene is associated with asthma and is a disease modifier in terms of the severity of AHR.

Effects of overexpression of IL-10, IL-12, TGF-β and IL-4 on allergen induced change in bronchial responsiveness

BackgroundAn increasing prevalence of allergic diseases, such as atopic dermatitis, allergic rhinitis and bronchial asthma, has been noted worldwide. Allergic asthma strongly correlates with airway inflammation caused by the unregulated production of cytokines secreted by allergen-specific type-2 T helper (Th2) cells. This study aims to explore the therapeutic effect of the airway gene transfer of IL-12, IL-10 and TGF-β on airway inflammation in a mouse model of allergic asthma.MethodsBALB/c mice were sensitized to ovalbumin (OVA) by intraperitoneal injections with OVA and challenged by nebulized OVA. Different cytokine gene plasmids or non-coding vector plasmids were instilled daily into the trachea up to one day before the inhalatory OVA challenge phase.ResultsIntratracheal administration of IL-10, IL-12 or TGF-β can efficiently inhibit antigen-induced airway hyper-responsiveness and is able to largely significantly lower the number of eosinophils and neutrophils in bronchoalveolar lavage fluid of ovalbumin (OVA) sensitized and challenged mice during the effector phase. Furthermore, the effect of IL-10 plasmids is more remarkable than any other cytokine gene plasmid. On the other hand, local administration of IL-4 gene plasmids before antigen challenge can induce severe airway hyper-responsiveness (AHR) and airway eosinophilia.ConclusionOur data demonstrated that anti- inflammatory cytokines, particularly IL-10, have the therapeutic potential for the alleviation of airway inflammation in murine model of asthma.

Severe Airway Hyperresponsiveness in School-aged Boys with a High Body Mass Index

BackgroundAn association between obesity and asthma has been reported. The prevalence of airway hyperresponsiveness (AHR), results of skin prick tests, body mass index (BMI), and asthma symptoms were examined in schoolchildren.MethodsThe results of BMI (kg/m2) determination, skin prick testing, spirometry, asthma questionnaires, and methacholine challenge tests were obtained in a cross-sectional survey of 667 schoolchildren. The methacholine concentration causing a 20% fall in FEV1 (PC20) was used as the threshold of AHR. If the PC20 was less than 16 mg/mL, the subject was considered to have methachloine mediated AHR.ResultsThe mean BMI was 17.1±0.09 kg/m2. The prevalence of AHR was 42.7%. The sensitization rate to common inhalant allergens was 30.3%. PC20 in children with BMIs ≥17.1 kg/m2 was significantly lower than that in children with BMIs 17.1 kg/m2. The mean BMIs of boys and girls were not significantly different. The levels of PC20 by sex were not different. The children were grouped by sex into percentile of BMI. PC20 in boys was lower in the obese group than in the non-weight and overweight groups (p<0.05). PC20 in boys and girls with atopy was significantly lower than in those without atopy. In a multiple logistic regression model that included all of the children and adjusted for confounding variables, independent associations with AHR were seen with BMI, asthma symptoms, and atopy.ConclusionsBMI had an association with AHR in school-age boys.

Relationship of serum IL-13 and eotaxin level with airway hyperresponsiveness in children with asthma

Purpose:Asthma is characterized by the presence of airway hyperresponsiveness(AHR) and inflammation. The extensive eosinophil infiltration into the lung is the hallmark of asthma and contributes to the damage of respiratory epithelium during late phase airway responses. Eotaxin is the major eosinophil chemoattractant found in bronchoalveolar lavage(BAL) fluid of allergic inflammation. IL-13 has been known to induce the expression of exotaxin and eosinophilia. IL-13 also induces airway inflammation, mucus production and leads to marked fibrosis, airway remodeling and AHR. We investigated whether serum IL-13 levels can reflect the presence of airway hyperresponsiveness in children with asthma, and the relationship between serum IL-13 and eotaxin levels. Methods:Using sandwich enzyme-linked immunosorbent assay, the serum IL-13 and eotaxin levels were measured in 13 atopic asthmatics, 5 atopic non-asthmatics and 12 control subjects. Metacholine challenge tests were performed in all subjects. Airway hyperresponsiveness to metacholine was expressed as provocative concentration of metacholine causing a 20% fall in FEV1[PC20 mg/mL]. PC20 value of 25 mg/mL was used as a cut-off for defining a AHR. Results:Serum IL-13 levels showed positive correlation with eotaxin levels. Serum IL-13 and eotaxin levels showed no differences among atopic asthmatics, atopic non-asthmatics and control subjects. And there were no differences serum IL-13 and eotaxin levels in children with and without AHR and atopy. Serum IL-13 and eotaxin levels did not correlate with logPC20 levels. Conclusion:IL-13 is closely related to the eotaxin release. But serum IL-13 and eotaxin per se can't predict the severity of airway hyperresponsiveness. IL-13 and eotaxin may have local effect on respiratory epithelium or there can be some factors to induce airway hyperresponsiveness other than serum IL-13 in asthmatic airways

Respiratory Tolerance Is Inhibited by the Administration of Corticosteroids

Corticosteroids constitute the most effective current anti-inflammatory therapy for acute and chronic forms of allergic diseases and asthma. Corticosteroids are highly effective in inhibiting the effector function of Th2 cells, eosinophils, and epithelial cells. However, treatment with corticosteroids may also limit beneficial T cell responses, including respiratory tolerance and the development of regulatory T cells (T(Reg)), which actively suppress inflammation in allergic diseases. To examine this possibility, we investigated the effects of corticosteroid administration on the development of respiratory tolerance. Respiratory exposure to Ag-induced T cell tolerance and prevented the subsequent development of allergen-induced airway hyperreactivity. However, treatment with dexamethasone during the delivery of respiratory Ag prevented tolerance, such that allergen sensitization and severe airway hyperreactivity subsequently occurred. Treatment with dexamethasone during respiratory exposure to allergen eliminated the development of IL-10-secreting dendritic cells, which was required for the induction of IL-10-producing allergen-specific T(Reg) cells. Therefore, because allergen-specific T(Reg) cells normally develop to prevent allergic disease and asthma, our results suggest that treatment with corticosteroids, which limit the development of T(Reg) cells and tolerance to allergens, could enhance subsequent Th2 responses and aggravate the long-term course of allergic diseases and asthma.

Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice

Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice. Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates. Nrf2 disruption resulted in an increased expression of the T helper type 2 cytokines interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid and in splenocytes after allergen challenge. The enhanced severity of the asthmatic response from disruption of the Nrf2 pathway was a result of a lowered antioxidant status of the lungs caused by lower basal expression, as well as marked attenuation, of the transcriptional induction of multiple antioxidant genes. Our studies suggest that the responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to allergen-mediated asthma.

Polymorphism of tandem repeat in promoter of 5‐lipoxygenase in ASA‐intolerant asthma: a positive association with airway hyperresponsiveness

5-Lipooxygenase (ALOX5) and 5-lipoxygenase-activating protein (ALOX5AP) are known as key enzymes in cysteinyl-leukotriene (cys-LT) production, critical mediators in aspirin acetylsalicyclic acid (ASA)-intolerant asthma (AIA). To date, studies of the promoter region of ALOX5 gene has revealed the potential influence of a variable number of tandem repeats of a Sp1- and Egr1-binding motif, on the transcription rate. To understand the pathological process that arises from cys-LT overproduction in AIA, we genotyped ALOX5 Sp1 and ALOX5AP poly(A) repeat promoter polymorphism by fluorescent-based capillary electrophoresis in the Korean population. No significant differences in allele and genotype frequencies of the ALOX5 and ALOX5AP promoter polymorphisms were observed between the three groups. However, there was a strong association of the ALOX5 Sp1 repeat polymorphism with airway hyperresponsiveness (AHR; PC20 methacholine); AIA patients carrying a mutant allele (n > 5 or n < 5 repeats) showed increased AHR compared to AIA patients with wild-type genotype (P=0.003). Although the alleles of the ALOX5 and ALOX5AP promoter cannot be considered as a prominent risk factor in the development of AIA, the genetic variant of tandem repeat (GGGCGG; Sp1-binding motif) in ALOX5 promoter is associated with the severity of airway hyperresponsiveness in AIA patients.

STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation

When wild-type BALB/c mice were transferred with OVA-specific Th2 cells followed by OVA inhalation, a severe eosinophilia, mucus hypersecretion and airway hyper-responsiveness (AHR) was induced in parallel with a marked elevation of IL-4, IL-5 and IL-13 levels in bronchoalveolar lavage fluid (BALF). However, neither eosinophilia, AHR nor mucus hypersecretion was induced in Th2 cell-transferred STAT6-/- mice. The failure of eosinophilia was not due to the defect of Th2 cytokine production in BALF of STAT6-/- mice transferred with Th2 cells, but because of the defect of STAT6-dependent eotaxin production. Indeed, intranasal administration of eotaxin reconstituted pulmonary eosinophilia but not AHR and mucus hypersecretion in OVA-inhalated STAT6-/- mice. These results initially provided direct evidence that STAT6-dependent eotaxin production is essential for pulmonary eosinophilia. We also dissociated the role of STAT6 for eosinophilia from that for AHR and mucus hypersecretion. Thus, STAT6 also plays a critical role at late phase of Th2-dependent allergy induction.

Respiratory Syncytial Virus in Allergic Lung Inflammation Increases Muc5ac and Gob-5

Respiratory syncytial virus (RSV) is associated with wheezing and childhood asthma. We previously reported that RSV infection prolongs methacholine-induced airway hyperresponsiveness in ovalbumin (OVA)-sensitized mice. In addition, allergically sensitized RSV-infected (OVA/RSV) mice had more abundant airway epithelial mucus production compared with OVA mice 14 days after infection, whereas there was almost no mucus in mice that were only RSV infected. We hypothesized that this increased mucus was associated with mucosal expression of Muc5ac, a mucus gene expression in airways, and gob-5, a member of the Ca(2)(+)-activated chloride channel family. By histochemical analysis, we found that there was significantly increased staining for gob-5 and Muc5ac in the airways of OVA/RSV mice compared with either OVA mice or allergically sensitized mice that were challenged with inactivated RSV, and virtually no detectable staining in the RSV group. These findings were confirmed by Western blot analysis. The increased mucus expression in the OVA/RSV group was associated with increased lung levels of interleukin-17, a factor known to stimulate airway mucin gene expression. The impact of virus infection combined with allergic inflammation on mucus production may partially explain the more severe disease and airway hyperresponsiveness associated with RSV in the setting of atopy.

Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse.

Interleukin (IL)-18 was originally regarded to induce T helper cell (Th)1-related cytokines. In general, factors favoring interferon (IFN)-γ production are believed to abolish allergic diseases. Thus, we tested the role of IL-18 in regulation of bronchial asthma. To avoid a background response of host-derived T cells, we administered memory type Th1 or Th2 cells into unsensitized mice and examined their role in induction of bronchial asthma. Administration of antigen (Ag) induced both airway inflammation and airway hyperresponsiveness (AHR) in mice receiving memory Th2 cells. In contrast, the same treatment induced only airway inflammation but not AHR in mice receiving memory Th1 cells. However, these mice developed striking AHR when they were coadministered with IL-18. Furthermore, mice having received IFN-γ–expressing Th1 cells sorted from polarized Th1 cells developed severe airway inflammation and AHR after intranasal administration of Ag and IL-18. Thus, Th1 cells become harmful when they are stimulated with Ag and IL-18. Newly polarized Th1 cells and IFN-γ–expressing Th1 cells, both of which express IL-18 receptor α chain strongly, produce IFN-γ, IL-9, IL-13, granulocyte/macrophage colony-stimulating factor, tumor necrosis factor α, regulated on activation, normal T cell expressed and secreted, and macrophage inflammatory protein 1α upon stimulation with Ag, IL-2, and IL-18 in vitro. Thus, Ag and IL-18 stimulate memory Th1 cells to induce severe airway inflammation and AHR in the naive host.

Sex differences in asthma, atopy, and airway hyperresponsiveness in a university population

A male predominance in atopy, a preadolescent male predominance in asthma, and a female predominance in airway hyperresponsiveness (AHR) have been previously documented, mostly in separate populations. We examined gender differences in a single population of 500 randomly selected university students from a previous publication which addressed sensitivity and specificity of histamine bronchoprovocation (Cockcroft et al. J Allergy Clin Immunol. 1992;89:23-30). In these 500 subjects (age 21.8 +/- 1.5 years) we assessed gender differences in asthma, atopy, and AHR. We compared our findings with those in the literature from a PUBMED search using the keywords gender, asthma, atopy, AHR, and bronchial reactivity. A diagnosis of asthma made by another physician was seen in 31, a male-to-female ratio of 2.9:1 (P = 0.004). Our definition of asthma increased the total to 52 and reduced the male-to-female ratio to 1.2:1. Atopy was seen in 190, male-to-female ratio of 1.5:1 (P = 0.001). Borderline to mild AHR had a female predominance with a male-to-female ratio of 1:1.5 (P = 0.02), whereas moderate AHR had a marked predominance with a male-to-female ratio of 7:1 (P = 0.03). In our population, the associations among gender and asthma, atopy, and AHR were similar to those seen in the literature with the exception of males having more severe AHR. This may be the one factor contributing to the higher prevalence of asthma (including previous doctor-diagnosed asthma in our population) in boys and young men.

Determinants of airway hyperresponsiveness in mild asthma

Patients with mild asthma may have coexisting severe airway hyperresponsiveness (AHR), although the reasons for this are uncertain. To evaluate the factors that determine AHR in mild asthma. We performed a retrospective database evaluation of two groups of patients with mild asthma with forced expiratory volume in 1 second (FEV1) of 80% or more than predicted. Group A (n = 92; mean inhaled corticosteroid dose, 491 microg) had moderate-to-severe AHR to methacholine (provocative dose causing a 20% decrease in FEV1 [methacholine PD20], < or = 100 microg), whereas group B (n = 92; mean inhaled corticosteroid dose, 509 microg) had borderline AHR (methacholine PD20, > or = 800 microg). Both groups were matched for age, sex, inhaled corticosteroid use, and FEV1. From our database, we found 361 patients with an FEV1 of 80% or more than predicted of whom 123 (34%) had a methacholine PD20 of 100 microg or less and 138 (38%) had a methacholine PD20 of 800 microg or more. The methacholine PD20 geometric means (geometric SE) of groups A and B were 25 microg (3 microg) and 5,392 microg (295 microg), respectively. Despite matched mean values for FEV1, compared with group B, group A had a lower predicted forced expiratory flow between 25% and 75% (71% vs 81%, P = 0.007). A greater proportion of group A compared with group B patients were sensitized to house-dust mite (76% vs 54%, P = 0.002). No significant differences were found between groups in terms of presence of rhinitis and sensitization to other individual aeroallergens. Increased sensitization to house-dust mite and reduced small airway caliber were associated with moderate-to-severe AHR in mild asthma. Skin prick testing to common aeroallergens, especially house-dust mite, should be a routine part in the evaluation of asthmatic patients, including those patients with mild disease.