Hyperresponsiveness In Asthmatic Patients Research Articles

Seasonal differences in airway hyperresponsiveness in asthmatic patients: relationship with allergen exposure and sensitization to house dust mites

SummaryBackground The degree of airway hyperresponsiveness in allergic asthmatic patients may be influenced by changes in environmental exposure to inhalant allergens.Objective This study investigates the relationship between seasonal changes in exposure to house dust mite (HDM) allergens and non‐specific airway hyperresponsiveness in asthmatic patients with multiple sensitizations to inhaled allergens.Methods In 43 asthmatic patients sensitized to several inhalant allergens, lung function (FEV1), airway hyperresponsiveness (PC20 histamine), serum total IgE, house dust mite (HDM) specific IgE and number of peripheral blood eosinophils were measured during autumn 1990 (September‐November) and spring 1991 (March—May). During each season. floor dust samples were collected twice from living‐ and bedrooms and the concentration of the HDM allergens Der p 1 and Der p 2 determined.Results More severe airway hyperresponsiveness (lower PC20 histamine) during autumn was only found in patients sensitized to HDM(n= 32; autumn: 2.05mg/mL, spring: 4.51mg/mL (geometric means), P <0.0 1), whereas in patients not sensitized to HDM (n= 11) similar values were observed in both seasons (3.44 and 4.52 mg/mL. respectively, P= 0.56). More severe airway hyperresponsiveness of HDM sensitized patients in autumn was significantly associated with higher Der p 1 concentrations in floor dust. Aside from airway hyperresponsiveness, seasonal changes in serum total IgE and number of peripheral blood eosinophils were seen in patients sensitized to HDM,Conclusions In allergic asthmatic patients, airway hyperresponsiveness may increase during autumn, depending on sensitization to HDM and an increase of exposure to HDM allergen.

Relationship between the inflammatory infiltrate in bronchial biopsy specimens and clinical severity of asthma in patients treated with inhaled steroids.

Current guidelines on the management of asthma advocate the use of anti-inflammatory treatment in all but mild disease. They define disease control in terms of clinical criteria such as lung function and symptoms. However, the relationship between the clinical control of the disease and inflammation of the airways is not clear. A cross sectional study was therefore undertaken to investigate the relationship between airways inflammation and measures of clinical control and bronchial hyperresponsiveness in asthmatic patients treated with inhaled steroids. Twenty six atopic adults (19-45 years) with mild to moderate asthma (baseline forced expiratory volume in one second (FEV1) > or = 50% predicted, concentration of histamine causing a 20% fall in FEV1 (PC20) 0.02-7.6 mg/ml) on regular treatment with inhaled steroids entered the study. Diary card recordings during the two weeks before a methacholine challenge test and bronchoscopic examination were used to determine peak flow variability, symptom scores, and use of beta 2 agonists. Biopsy specimens were taken by fibreoptic bronchoscopy from the carina of the right lower and middle lobes, and from the main carina. Immunohistochemical staining was performed on cryostat sections with monoclonal antibodies against: eosinophil cationic protein (EG1, EG2), mast cell tryptase (AA1), CD45, CD22, CD3, CD4, CD8, CD25, and CD45RO. The number of positively stained cells in the lamina propria was counted twice by using an interactive display system. There were no differences in cell numbers between the three sites from which biopsy specimens were taken. The PC20 for methacholine was inversely related to the average number of total leucocytes, EG1+, and EG2+ cells, mast cells, CD8+, and CD45RO+ cells in the lamina propria. These relationships were similar for each of the biopsy sites. Symptom scores, beta 2 agonist usage, FEV1, and peak flow variability were not related to any of the cell counts. Infiltration of inflammatory cells in the lamina propria of the airways seems to persist in asthmatic outpatients despite regular treatment with inhaled steroids. The number of infiltrating leucocytes such as mast cells, (activated) eosinophils, CD8+, and CD45RO+ cells in bronchial biopsy specimens from these patients appears to be reflected by airway hyperresponsiveness to methacholine, but not by symptoms or lung function. These findings may have implications for the adjustment of anti-inflammatory treatment of patients with asthma.

Chronic allergen exposure enhances cholinergic neurotransmission in sensitized guinea-pigs

Airway hyperresponsiveness in asthmatic patients may be related to cholinergic hyperresponsiveness. In this study, we examined whether chronic allergen exposure induces cholinergic hyperresponsiveness in ovalbumin (OA) sensitized guinea-pig airways. Three weeks after active sensitization, ovalbumin (0.03%, for 3 min, challenged group) or saline inhalation (control group) was repeated every day for 4 weeks. Cholinergic responses were assessed by isometric tracheal contraction after electrical field stimulation (EFS) or exogenously applied acetylcholine (ACh). The contractions were expressed as a percentage of the maximum response to ACh (10(-3) M) (AChmax). We calculated the effective frequencies producing 25% of AChmax (EF25) from frequency-response curves. EFS-induced contractile responses were significantly enhanced in the challenged group (logEF25 = 0.66 +/- 0.08 (mean +/- SEM)) compared with the control group (logEF25 = 1.12 +/- 0.16). In contrast, exogenous ACh-mediated contractile tracheal responses were almost the same in both groups. We conclude that repeated allergen inhalation causes cholinergic airway hyperresponsiveness, presumably due to the facilitation of cholinergic neurotransmission. This mechanism may be involved in the airway hyperresponsiveness in asthmatic airways.

Virus-induced airway hyperresponsiveness. Role of inflammatory cells and mediators.

Viral respiratory infections induce airway hyperresponsiveness in asthmatic patients, in healthy persons, and in a number of animal species. In asthmatics the degree of airway hyperresponsiveness is associated with the severity of exacerbations. The respiratory tract of an asthmatic is inflamed, and these inflammatory cells might be involved in modulating airway responsiveness. In contrast, no data are available on the role of bronchoalveolar cells in the airways of "healthy" persons or asthmatic patients suffering a respiratory tract infection. Because of the lack of information on this issue, the present review has been written. A number of animal studies have now been performed suggesting the involvement of inflammatory cells during a viral respiratory infection. The changes in number and activity of bronchoalveolar cells after a viral infection have been compared with changes in airway morphology and the development of airway hyperresponsiveness. Based on these data we suggested, the following hypothesis: Viruses damage the epithelial layer of the respiratory tract and activate bronchoalveolar cells. Subsequently, a number of mediators are released that can stimulate metachromatic cells, which in turn release products that increase vascular permeability and attract inflammatory cells that might cause additional epithelial damage. Finally, the released mediators and the morphologic changes together results in airway obstruction and the development of hyperresponsiveness.

Virus-induced Airway Hyperresponsiveness: Role of Inflammatory Cells and Mediators

Viral respiratory infections induce airway hyperresponsiveness in asthmatic patients, in healthy persons, and in a number of animal species. In asthmatics the degree of airway hyperresponsiveness is associated with the severity of exacerbations. The respiratory tract of an asthmatic is inflamed, and these inflammatory cells might be involved in modulating airway responsiveness. In contrast, no data are available on the role of bronchoalveolar cells in the airways of “healthy” persons or asthmatic patients suffering a respiratory tract infection. Because of the lack of information on this issue, the present review has been written. A number of animal studies have now been performed suggesting the involvement of inflammatory cells during a viral respiratory infection. The changes in number and activity of bronchoalveolar cells after a viral infection have been compared with changes in airway morphology and the development of airway hyperresponsiveness. Based on these data we suggested, the following hypothesis: Viruses damage the epithelial layer of the respiratory tract and activate bronchoalveolar cells. Subsequently, a number of mediators are released that can stimulate metachromatic cells, which in turn release products that increase vascular permeability and attract inflammatory cells that might cause additional epithelial damage. Finally, the released mediators and the morphologic changes together result in airway obstruction and the development of hyperresponsiveness.

Tumor necrosis factor alpha modulates mitogenic responses of human cultured airway smooth muscle.

Airway wall remodeling, including hyperplasia of airway smooth muscle, is regarded as an important contributor to airway hyperresponsiveness in asthmatic patients. The effects of the proinflammatory cytokine, tumor necrosis factor alpha (TNF alpha) on the mitogenic responses of human cultured airway smooth muscle have been investigated. Lower concentrations of TNF alpha (0.3 to 30 pM) had a small, delayed (48-h incubation), stimulatory effect on DNA synthesis that was blocked by dexamethasone (1 microM), aspirin (100 microM), or primaquine (30 microM) pretreatment, indicating that this effect was secondary to the release of cyclooxygenase products. TNF alpha (300 pM; 24- to 48-h incubation) alone had no effect on cell number or DNA or protein synthesis, but markedly reduced the stimulatory effects of thrombin (0.3 U/ml). TNF alpha (300 pM) also inhibited mitogenic responses to fetal calf serum (10%), epidermal growth factor (300 pM), and the thromboxane A2 mimetic U46619 (100 nM), indicating a nonselective effect. The inhibitory effects of TNF alpha (300 pM) were not blocked by pretreating the cells with the cyclooxygenase inhibitor aspirin (100 microM), the 5-lipoxygenase inhibitor CGS 8515 (3 microM), or the nitric oxide synthase inhibitor nitro-iminoethyl-L-ornithine (100 microM), suggesting that neither arachidonic acid metabolites nor nitric oxide were mediators of the inhibitory effect. The phospholipase A2 inhibitor primaquine (30 microM) had no effect on the inhibitory responses to TNF alpha, whereas the anti-inflammatory steroid dexamethasone (1 microM) prevented TNF alpha inhibition of mitogenic responses. Thus, concentrations of TNF alpha, within the range detected in bronchoalveolar lavage fluid from asthmatics, suppress mitogenic responses by a mechanism that is sensitive to inhibition by anti-inflammatory steroids, but does not appear to involve established targets for modulation by steroids, including arachidonic acid metabolism or induction of nitric oxide synthase.

A 5-lipoxygenase inhibitor, FR110302, inhibits ozone-induced airway hyperresponsiveness in guinea pigs and dogs.

Airway hyperresponsiveness is a key feature of asthma, and attenuating airway hyperresponsiveness is an important part of asthma therapy. In the present study we examined the inhibitory effect of a potent 5-lipoxygenase inhibitor, FR110302, on airway hyperresponsiveness induced by ozone exposure in guinea pigs and dogs. Respiratory resistance (Rrs) was measured by a forced oscillation method. Airway responsiveness was determined from the dose-response curve of Rrs to acetylcholine. Guinea pigs were exposed to 2.5 ppm ozone for 1 h. In a control group of guinea pigs, delta log PC100 (the index of the ozone-induced airway hyperresponsiveness) was 0.58 +/- 0.04 (log mg/ml). Treatment with FR110302 (10 or 100 mg/kg p.o.) significantly diminished delta log PC100 (10 mg/kg: 0.22 +/- 0.10; 100 mg/kg; 0.11 +/- 0.06). Dogs were exposed to 3 ppm ozone for 2 h. In a control group of dogs, delta log Dmin (another index of the ozone-induced airway hyperresponsiveness) was 1.24 +/- 0.15 (log unit). Treatment with FR110302 (1 or 3.2 mg/kg p.o.) significantly diminished delta log Dmin (1 mg/kg: 0.60 +/- 0.18; 3.2 mg/kg: 0.27 +/- 0.12). These results suggest that FR110302 may be a useful drug for attenuating airway hyperresponsiveness in asthmatic patients.

Unimodal Distribution of Bronchial Hyperresponsiveness to Methacholine in Asthmatic Patients

Distribution of bronchial hyperresponsiveness to methacholine was assessed in 791 consecutive patients who were referred to the outpatient clinic of the pulmonary department due to asthmatic or persistent lower airway symptoms. Bronchial asthma was diagnosed in 319 patients. Clinical sensitivity of methacholine challenge for the disease was 89 percent and specificity, 76 percent. The degree of bronchial hyperresponsiveness in the entire group of asthmatic patients was unimodally log normal distributed. Of the 82 patients with allergic rhinitis without concurrent asthma, 27 percent had bronchial hyperresponsiveness, but of a markedly lesser degree than in the hyperresponsive asthmatic patients. In 49 patients with chronic bronchitis, 22 percent had hyperresponsiveness. The present data indicate that the degree of bronchial hyperresponsiveness in asthmatic patients is unimodally distributed, supporting the view that both genetic and environmental factors have an impact upon its development. Although the degree of bronchial hyperresponsiveness in asthma is more pronounced than in allergic rhinitis or in chronic bronchitis, a marked overlap exists.

Refractoriness for ultrasonically nebulized distilled water and histamine after histamine challenge

Refractoriness for bronchial provocation frequently occurs after different challenge tests used to assess bronchial hyperresponsiveness in asthmatic patients. We investigated whether histamine inhalation could cause refractoriness for bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) and whether histamine causes tachyphylaxis for a subsequent histamine challenge in nine stable asthmatic patients. Preinhalation of histamine induced a significant diminished bronchoconstrictor response to UNDW cumulative dose of inhaled UNDW causing a 20% fall in forced expired volume in 1 s. The mean increased from 3.5 +/- 0.8 to 11.8 +/- 2.6 (SE) ml after histamine challenge (P less than 0.01). However, repeated inhalation of histamine did not change the bronchoconstrictor response to histamine within 1 h after rechallenge (P greater than 0.5). The magnitude of refractoriness for UNDW inhalation after preinhalation of histamine was correlated to the bronchoconstrictor response to histamine (r = 0.73, P less than 0.05). We conclude that inhaled histamine can induce refractoriness for UNDW, which seems to be related to the degree of bronchial hyperresponsiveness.

Prophylaxis in Childhood Asthma

Opinions on the pathogenesis of bronchial asthma have changed considerably in recent years. An immunologic mechanism to explain the state of bronchial hyperresponsiveness in asthmatic patients was not widely accepted in the past. However, with increasing knowledge of immunologic, biochemical and neurogenic mechanisms, a better understanding of the pathophysiology of asthma has evolved. This has encouraged investigators to develop new drugs to control asthmatic symptoms. The treatment of asthma consists of measures to control acute attacks and to prevent recurrences. We try to present in this paper a comprehensive review of asthma prophylaxis in children. This includes environmental control, parent/patient education, physiotherapy/psychotherapy, allergy extract immunotherapy and drug prophylaxis. The pharmacologic actions, advantages and disadvantages of drugs used for prophylaxis are discussed. A double-blind investigation on the safety and efficacy of Ketotifen among Filipino asthmatic patients demonstrated beneficial results compared with other countries. An algorithm of the use of various drugs in the prophylaxis of childhood asthma is presented.