Bronchial hyperresponsiveness is a common feature in patients with chronic urticaria.

BACKGROUND: Chronic urticaria (CU) is a skin disorder characterized by long-lasting release of histamine, and sometimes leukotrienes, from both mast cells and basophils. Although both these substances are potent inductors of contraction of airway smooth muscle, pulmonary function and airway hyperresponsiveness have not been systematically investigated in patients with CU. OBJECTIVE: To assess pulmonary function and airway hyperresponsiveness in patients with CU. METHODS: Twenty-six clinically well-characterized adult patients with CU (M/F 8/18; mean age 47 years) underwent pulmonary function tests and methacholine provocation during a phase of moderate activity of their disease. Twenty-six adult asthmatic patients submitted to methacholine provocation were used as controls. RESULTS: Two patients (8%) had overt asthma on baseline pulmonary function tests. Twenty (77%) patients with a normal baseline pulmonary function showed significant bronchial hyperresponsiveness on methacholine provocation. Altogether, 22/26 (85%) patients had asthma or abnormal bronchial reactivity. Airway hyperresponsiveness was not associated with gender, disease duration, intolerance to NSAID, positive autologous serum skin test or respiratory allergy. On average, asthmatic controls showed a much severer airway hyperresponsiveness than urticaria patients (p < 0.01). CONCLUSION: Patients with CU frequently show bronchial hyperresponsiveness. Prospective studies are needed to assess whether they are at risk for bronchial asthma.     

Mannitol and AMP do not induce bronchoconstriction in eosinophilic bronchitis: Further evidence for dissociation between airway inflammation and bronchial hyperresponsiveness

Background and objective: Eosinophilic bronchitis (EB) shares many pathological features with asthma. However, patients with EB do not develop the characteristic physiological abnormalities of asthma: variable airflow obstruction and bronchial hyperresponsiveness (BHR) to a direct bronchial challenge with methacholine. Indirect bronchial challenges with AMP and mannitol are dependent on the presence of airway inflammation, and positive in 10% of asthmatic subjects who have a negative response to methacholine. We have therefore investigated whether subjects with EB are responsive to indirect airway challenge with AMP and mannitol. Methods: Subjects with asthma, EB and healthy controls attended on up to four occasions. After screening, subjects performed bronchial provocation tests to methacholine and then either AMP or mannitol. Each challenge was followed immediately by sputum induction for the measurement of airway inflammation and mast cell‐derived histamine. Results: No subjects with EB responded to either AMP (n = 5) or mannitol (n = 7) while 4/8 and 7/10 subjects with asthma responded to the respective challenges (P = 0.057 for AMP, P = 0.004 for mannitol). There was no difference in induced sputum concentrations of histamine or eosinophil cell counts following methacholine challenge compared with AMP or mannitol. Conclusions: The airways of patients with EB are not responsive to either direct or indirect bronchial challenge. This supports the view that it is the presence of functionally abnormal airway smooth muscle that is the key determinant of BHR in asthma, and that while this may be aggravated by the presence of mucosal airway inflammation, it is not caused by it.     

Roles of hyperresponsiveness and airway inflammation in bronchial asthma

Bronchial hyperresponsiveness is one important feature of bronchial asthma, and evidence has been accumulated that airway inflammation contributes to the specific airway response in asthmatic patients. Increase in airway responsiveness following viral infection, exposure to allergen, ozone or chemical sensitizers supports the evidence for a link between hyperresponsiveness and airway inflammation. However, as only some respiratory tract infections induce an increase in hyperresponsiveness, and patients with chronic bronchitis and cystic fibrosis have less airway hyperresponsiveness than asthmatics, airway inflammation is considered to be only one of many factors contributing to the hyperresponsiveness of asthmatic airways.     

组胺、乙酰甲胆碱检测气道高反应性不良反应比较

目的 观察组胺与乙酰甲胆碱检测气道高反应性时所出现的不良反应.方法 采用德国耶格（JAEGER）肺功能仪-支气管激发试验检测系统,对60例处于缓解期（肺功能检测正常）的轻度支气管哮喘患者,分别实施组胺与乙酰甲胆碱（乙酰甲胆碱与组胺）支气管激发试验检测.结果 ①60例支气管哮喘患者检测支气管激发试验,激发剂的选择无论是组胺还是乙酰甲胆碱均提示支气管激发试验阳性,支持存在气道高反应性;②支气管激发试验检测过程可见组胺药物不良反应明显大于乙酰甲胆碱,其不良反应程度与随着吸入药物浓度增大、吸入时间延长而增加.结论 药物支气管激发试验激发剂的选择应首选乙酰甲胆碱,组胺应慎选或不选.     

Provocative challenges to help diagnose and monitor asthma: exercise, methacholine, adenosine, and mannitol

PURPOSE OF REVIEW: To review bronchial provocations tests used in the measurement of bronchial hyperresponsiveness to help in the diagnosis of asthma. RECENT FINDINGS: The bronchial provocations tests reviewed include exercise, methacholine, AMP and mannitol, with reference to methodology and monitoring of treatment. SUMMARY: Methacholine is used for identifying bronchial hyperresponsiveness and to guide treatment. Exercise is used as a bronchial provocation test because demonstrating prevention of exercise-induced asthma is an indication for use of a drug. Both of these tests are being used to study tolerance to beta2 agonists. There is increasing use of eucapnic voluntary hyperpnea as a surrogate bronchial provocation test for exercise to identify exercise-induced asthma, particularly in athletes. For methacholine and AMP there is concern about the different breathing patterns used to inhale these aerosols and the impact they have on the cutoff point for identifying bronchial hyperresponsiveness. A new test that uses a kit containing prepacked capsules of different doses of mannitol and a delivery device is discussed. There is increasing interest in using tests that act indirectly by release of mediators because the bronchial hyperresponsiveness itself is an indicator of the presence of inflammation. Since treatment of inflammation leads to loss of bronchial hyperresponsiveness to indirect stimuli, these tests are well suited to identify success of treatment.     

组胺、乙酰甲胆碱检测气道高反应性不良反应比较

目的 观察组胺与乙酰甲胆碱检测气道高反应性时所出现的不良反应.方法 采用德国耶格(JAEGER)肺功能仪-支气管激发试验检测系统,对60例处于缓解期(肺功能检测正常)的轻度支气管哮喘患者,分别实施组胺与乙酰甲胆碱(乙酰甲胆碱与组胺)支气管激发试验检测.结果 .①60例支气管哮喘患者检测支气管激发试验,激发剂的选择无论是组胺还是乙酰甲胆碱均提示支气管激发试验阳性,支持存在气道高反应性;②支气管激发试验检测过程可见组胺药物不良反应明显大于乙酰甲胆碱.其不良反应程度与随着吸入药物浓度增大、吸人时间延长而增加.结论 药物支气管激发试验激发剂的选择应首选乙酰甲胆碱,组胺应慎选或不选.     

P—选择素在速激肽类致气道高反应性中的作用

目的 探讨黏附分子Ｐ－选择素和速激肽类Ｐ－物质、血管活性肠肽（ＶＩＰ）与气道高反应性的关系。方法 测定５７例支气管哮喘病人（激素治疗组２７例,非激素治疗组３０例）和２２例正常人的气道反应性,观察血浆Ｐ－选择素、Ｐ－物质和ＶＩＰ的变化。结果５３例哮喘病人气道激发试验阳性（９２．９８％）,４例阴性（７．０２％）,２２例正常人全部阴性。非激素治疗组患者血浆Ｐ－选择素和Ｐ－物质较正常人及激素治疗组显著升     

完全控制的支气管哮喘患者肺功能和气道高反应性测定

目的检测完全控制的支气管哮喘患者肺功能和气道反应,探讨其临床意义。方法选择71例完全控制的支气管哮喘患者,测定肺功能和气道反应性。选择30名急性发作期支气管哮喘患者和15名健康老年人作为对照。结果71例完全控制的支气管哮喘患者中,49例(84.5%)支气管激发试验阳性,9例(15.5%)支气管激发试验阴性。完全控制哮喘组和哮喘组患者FEV1占预计值%和FEV1/FVC分比较差异有统计学意义(P0.01);完全控制哮喘组和健康对照组受试对象FEV1占预计值%和FEV1/FVC比较差异无统计学意义(P0.05)。结论完全控制的支气管哮喘患者多数存在气道高反应性,测定患者气道反应性有助于指导哮喘治疗。     

Toll样受体4与支气管哮喘气道高反应

气道高反应性是支气管哮喘的基本特征.气道高反应的机制目前尚未完全阐明.当前支气管哮喘的治疗亦不能有效地抑制气道高反应性和气道重塑.近来发现,Toll样受体是一种属于Ⅰ型跨膜蛋白的天然免疫模式识别受体.TLR4通过调控气道炎症,促进气道平滑肌增生,参与气道重塑等方式参与气道高反应性过程.本文主要探讨TLR4与在支气管哮喘...     

Comparison of central and peripheral airway involvement before and during methacholine, mannitol and eucapnic hyperventilation challenges in mild asthmatics

Introduction: Testing for airway hyperresponsiveness with indirect stimuli as exercise or mannitol has been proposed to better reflect underlying airway inflammation, as compared with methacholine (MCh), believed to act directly on airway smooth muscle cells. Objective: To investigate whether different direct and indirect stimuli induces different patterns of obstruction, recorded as central and peripheral resistance, and to see whether baseline resistance could predict a positive response to direct or indirect provocation. Methods: Thirty‐four mild asthmatics and 15 controls underwent MCh, mannitol and eucapnic voluntary hyperventilation (EVH) challenge tests. The response was evaluated with spirometry and impulse oscillometry (IOS). Results: Twenty‐three out of 34 asthmatics were positive to either EVH (22) or mannitol (13). Those positive to mannitol had a significant increased baseline value of IOS parameters such as ΔR5‐R20 and AX. Twelve of the asthmatics had a 10% fall or more in forced expiratory volume in 1 s (FEV₁) in all three challenge tests. However, the response pattern measured by IOS did not differ between the tests. When the limit for a positive mannitol provocation was set to 10% fall in FEV₁, 16 out of 19 mannitol‐positive patients were also positive to EVH. Conclusion: Even in mild asthmatics, a substantial number had a positive indirect test. Mannitol FEV₁ provocative dose to decrease FEV₁ by 10% from baseline (PD10) was closely associated to EVH10%. No difference in bronchoconstrictive pattern could be seen between the different provocation tests, but those positive to mannitol had more peripheral airway involvement at baseline. This supports the idea that peripheral airway involvement is an important predictor of asthma airway reactivity. Please cite this paper as: Aronsson D, Tufvesson E, Bjermer L. Comparison of central and peripheral airway involvement before and during methacholine, mannitol and eucapnic hyperventilation challenges in mild asthmatics. Clin Respir J 2011; 5: 10–18.     

Airway hyperresponsiveness and pulmonary function in adult asthma.

BACKGROUND: Airway hyperresponsiveness (AHR) is a very important factor in the pathogenesis of bronchial asthma. OBJECTIVES: To examine the relationship between airway obstruction and AHR in adult asthma. METHODS: This study was a retrospective study in 161 adult asthmatic patients. Nonspecific AHR to methacholine was measured. We examined the correlations between AHR and pulmonary function, severity of asthma, type of asthma and age. RESULTS: In the moderate and severe groups, peripheral airway obstruction was more aggravated compared to the mild group, and AHR was significantly more severe. Analysis of AHR by age showed that the degree of airway obstruction increased with aging, but age did not clearly correlate with airway sensitivity. Airway reactivity decreased with aging. Aspirin-induced asthma tended to be severe. In fatal asthma, central airway obstruction was significantly more severe. Although AHR in fatal asthma did not significantly differ from that in the severe group, airway sensitivity and airway reactivity tended to be increased. CONCLUSIONS: AHR is an important factor determining the severity of asthma, and airway obstruction is an important index for the prediction of death from asthma. An evaluation of the degree of AHR and airway obstruction is considered to be the first step in controlling asthma.     

Markers of airway inflammation and airway hyperresponsiveness in patients with well-controlled asthma.

In steroid-naive asthmatics, airway hyperresponsiveness correlates with noninvasive markers of airway inflammation. Whether this is also true in steroid-treated asthmatics, is unknown. In 31 stable asthmatics (mean age 45.4 yrs, range 22-69; 17 females) taking a median dose of 1,000 microg inhaled corticosteroids (ICS) per day (range 100-3,600 microg x day(-1)), airway responsiveness to the "direct" agent histamine and to the "indirect" agent mannitol, lung function (forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF)), exhaled nitric oxide (eNO), and number of inflammatory cells in induced sputum as a percentage of total cell count were measured. Of the 31 subjects, 16 were hyperresponsive to mannitol and 11 to histamine. The dose-response ratio (DRR: % fall in FEV1/cumulative dose) to both challenge tests was correlated (r=0.59, p=0.0004). However, DRR for histamine and DRR for mannitol were not related to basic lung function, eNO, per cent sputum eosinophils and ICS dose. In addition, NO was not related to basic lung function and per cent sputum eosinophils. In clinically well-controlled asthmatics taking inhaled corticosteroids, there is no relationship between markers of airway inflammation (such as exhaled nitric oxide and sputum eosinophils) and airway responsiveness to either direct (histamine) or indirect (mannitol) challenge. Airway hyperresponsiveness in clinically well-controlled asthmatics appears to be independent of eosinophilic airway inflammation.     

Monitoring asthma therapy using indirect bronchial provocation tests*

Objectives: Bronchial provocation tests that assess airway hyperresponsiveness (AHR) are known to be useful in assisting the diagnosis of asthma and in monitoring inhaled corticosteroid therapy. We reviewed the use of bronchial provocation tests that use stimuli that act indirectly for monitoring the benefits of inhaled corticosteroids. Data Source: Published clinical trials investigating the effect of inhaled corticosteroids on bronchial hyperresponsiveness in persons with asthma were used for this review. Study Selection: Studies using indirect stimuli to provoke airway narrowing such as exercise, eucapnic voluntary hyperventilation, cold air hyperventilation, hypertonic saline, mannitol, or adenosine monophosphate (AMP) to assess the effect of inhaled corticosteroids were selected. Results: Stimuli acting indirectly result in the release of a variety of bronchoconstricting mediators such as leukotrienes, prostaglandins, and histamine, from cells such as mast cells and eosinophils. A positive response to indirect stimuli is suggestive of active inflammation and AHR that is consistent with a diagnosis of asthma. Persons with a positive response to indirect stimuli benefit from daily treatment with inhaled corticosteroids. Symptoms and lung function are not useful to predict the long‐term success of inhaled corticosteroid dose as they usually resolve rapidly, and well before inflammation and AHR has resolved. Following treatment, AHR to indirect stimuli is attenuated. Further, during long‐term treatment, asthmatics can become as non‐responsive as non‐asthmatic healthy persons, suggesting that asthma is not active. Conclusions: Non‐responsiveness to indirect bronchial provocation tests following inhaled corticosteroids occurs weeks to months following the resolution of symptoms and lung function. Non‐responsiveness to indirect stimuli may provide a goal for adequate therapy with inhaled corticosteroids. Please cite this paper as: Brannan JD, Koskela H and Anderson SD. Monitoring asthma therapy using indirect bronchial provocation tests. The Clinical Respiratory Journal 2007;1:3–15.     

Determinants of the severity of exercise-induced bronchoconstriction in patients with asthma.

AIM: In examining the mechanisms of exercise-induced bronchoconstriction (EIB), it is important to determine which factors most strongly affect the severity of EIB. We determined such factors in patients with asthma by stepwise multiple-regression analysis. METHODS: Twenty-three patients with asthma underwent pulmonary function tests, methacholine provocation test, and sputum induction. Eosinophilic inflammatory indices and airway vascular permeability index (ratio of albumin concentrations in induced sputum and serum) were examined in sputum samples, and then an exercise test was performed by all asthmatics. RESULTS: There was a significant correlation between the severity of EIB and degree of eosinophilic inflammation in induced sputum. Moreover, there was a significant correlation between the severity of EIB and airway vascular permeability index. Although we could not find a significant correlation between the severity of EIB and 1-sec forced expired volume, 20% provocation concentration of (PC20) methacholine tended to be correlated with the severity of EIB. By stepwise multiple-regression analysis, we also found that airway vascular permeability index, eosinophil cationic protein levels in sputum, and PC20 methacholine are independent predictors of the severity of EIB. CONCLUSION: We found that airway vascular hyperpermeability, eosinophilic inflammation, and bronchial hyperreactivity are independent factors predicting the severity of EIB.     

Bronchial hyperresponsiveness and exhaled nitric oxide in patients with cardiac disease

BACKGROUND: Increased concentrations of exhaled nitric oxide (NO) correlate with increased airway inflammation and measurement of exhaled NO is a noninvasive method for the management of bronchial asthma. In various cardiac diseases, bronchial hyperresponsiveness is observed, as is bronchial asthma. However, there have been few studies on the relationship between exhaled NO and bronchial responsiveness in cardiac diseases. OBJECTIVE: The aim of this study was to clarify the association between exhaled NO and bronchial hyperresponsiveness in patients with cardiac disease. METHODS: We measured expired NO and bronchial responsiveness to inhaled methacholine in 19 patients with cardiac diseases and 17 with bronchial asthma. We divided the cardiac disease patients into two groups according to their bronchial responsiveness to inhaled methacholine: BHR(+) group consisted of 12 patients with bronchial hyperresponsiveness and BHR(-) group consisted of 7 patients without bronchial hyperresponsiveness. RESULTS: The concentration of exhaled NO in the asthmatic patients was significantly higher than that in the BHR(+) and BHR(-) groups (142.0 +/- 17.0, 33.6 +/- 6.4 and 42.3 +/- 10.3 ppb, respectively, p < 0.01). There was no significant difference in exhaled NO between BHR(+) and BHR(-) groups. There were also no significant differences in the parameters of bronchial hyperresponsiveness between the cardiac BHR(+) and bronchial asthma groups. These results indicate that bronchial hyperresponsiveness in patients with cardiac diseases is not a consequence of eosinophilic inflammation or of exhaled NO. CONCLUSION: We conclude that bronchial hyperresponsiveness in patients with cardiac diseases can occur independently of NO production.     

Dysfonctionnement nasal chronique et obstruction des voies aériennes périphériques

Allergic rhinitis often occur at the same time with many upper and lower airway diseases in which there is asthma. Many patients without clinical asthma may have an asymptomatic bronchial hyperreactivity and an allergic rhinitis at the same time. An overview of these actual knowledges is done including clinical, respiratory functional explorations, therapeutic studies, as well as those observed in chronic nasal dysfunctions (allergic or non allergic eosinophilic rhinitis, nasal polyposis, chronic rhinitis).Objectives. – The aim of this study is to determine bronchial hyperresponsiveness of a chronic nasal dysfunction population having allergic or non allergic rhinitis.Material and methods. – Retrospective study of respiratory functional explorations (using a methacholine provocation test) among non asthmatic patients consulting for rhinology-allergy diseases but with broncho-pulmonary symptomatology.Results. – It has been observed an allergic rhinitis population without upper bronchial hyperreactivity but with a small airway obstruction revealed or worsened during the methacholine bronchoprovocation test.Conclusion. – Chronic nasal dysfunction and small airway obstruction are correlated. This association shows an airway inflammation from the nose through the small bronchi. As upper bronchial hyperreactivity can precede asthma, a small airway obstruction could precede a bronchial hyperreactivity. Nasal chronic dysfunction treatment could act upon small airway obstruction, or central bronchial hyperreactivity or asthma appearance.     

Asymptomatic airway hyperresponsiveness: relationships with airway inflammation and remodelling.

To study the physiopathology and significance of asymptomatic airway hyperresponsiveness (AHR), the clinical and bronchial immunohistological parameters were evaluated in subjects with asymptomatic and symptomatic AHR. Asymptomatic subjects with AHR (eight females/two males, no respiratory symptoms, provocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20) <8 mg x mL(-1) and no treatment) were compared with asthmatic subjects paired for age, sex and PC20, and with nonatopic, nonasthmatic controls paired for age and sex. All three groups were evaluated once at baseline, whilst the asymptomatic AHR subjects were re-evaluated after 1 and 2 yrs. Measurements included spirometry, methacholine challenge, serum immunoglobulin (Ig)E, blood eosinophils, and bronchoscopy (at baseline and after 2 yrs only). At first evaluation, the mean blood eosinophil count, total serum IgE level, atopic index, baseline forced expiratory volume in one second (FEV1) and the degree of bronchial epithelial desquamation of the asymptomatic AHR subjects were similar to those of asthmatic subjects. However, they presented focal rather than the continuous bronchial subepithelial fibrosis observed in asthmatics. Their mucosal CD3, CD4, CD25, EG1 and EG2-positive cell counts were intermediate between those of the control subjects and asthmatics. At the end of the 2-yr follow-up, four of them had developed asthma symptoms. At this time, bronchial biopsies revealed an increase in the extent of subepithelial fibrosis and in the number of CD25 and CD4-positive cells, and a decrease in the number of CD8+ cells, particularly in subjects who developed asthma symptoms. These data suggest that asymptomatic airway hyperresponsiveness is associated with airway inflammation and remodelling, and that the appearance of asthma symptoms is associated with an increase in these features, particularly the CD4/CD8 ratio and airway fibrosis. Consequently, this study proposes an association between asymptomatic airway hyperresponsiveness and airway inflammation, structural changes and asthma although these relationships remain to be further evaluated.     

Mechanisms of bronchial hyperresponsiveness: the interaction of endothelin-1 and other cytokines

Bronchial hyperresponsiveness (BHR) is a fundamental characteristic of asthma and has become part of a more recent definition of asthma. Data show a close link between bronchial hyperresponsiveness (both transient and persistent) and airway inflammation. Airway inflammation is orchestrated by a complex network of cytokines. It has been considered that endothelin-1 is involved in bronchoconstriction and airway structural remodelling and has several pro-inflammatory properties of potential relevance to asthma. We focus on endothelin-1, its activities and interaction with other cytokines in the pathogenesis of asthma.     

Effects of esophageal acid perfusion on airway hyperresponsiveness in patients with bronchial asthma

STUDY OBJECTIVES: The effects of gastroesophageal reflux on airway hyperresponsiveness in patients with bronchial asthma have yet to be studied in significant detail. The purpose of the present study was to determine how esophageal acid perfusion could change airway responsiveness in patients with bronchial asthma. PATIENTS AND INTERVENTIONS: In seven patients with bronchial asthma (mean +/- SD age, 55.1 +/- 6.4 years; four women and three men), esophageal pH was monitored by a pH meter and airway responsiveness was evaluated by aerosol inhalation of methacholine, during esophageal perfusion through an esophageal tube filled with either saline solution or 0. 1N hydrochloric acid (HCl), the order of which was selected at random, in 1-week intervals. Spirometry was also performed during esophageal pH monitoring. RESULTS: A significant decrease in the geometric mean of airway sensitivity or the concentration of methacholine causing a 35% fall in respiratory conductance was observed during esophageal HCl perfusion compared with that of saline solution perfusion (p < 0.01 or p < 0.003), although no significant changes were observed in vital capacity, FEV(1), peak expiratory flow, respiratory resistance, or slope of respiratory conductance during the periods of saline solution and HCl perfusion. CONCLUSION: We concluded that an increase in airway hyperresponsiveness was induced when HCl stimulated the esophagus in patients with bronchial asthma. These results suggest that esophageal reflux is one of the important factors that aggravate asthmatic status.     

Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice

RATIONALE: Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans. OBJECTIVES: To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor-deficient mice. METHODS: Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure. MEASUREMENTS AND MAIN RESULTS: Estrogen receptor-alpha knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-alpha also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge. CONCLUSIONS: These data suggest that estrogen receptor-alpha is a critical regulator of airway hyperresponsiveness in mice.