Degree Of Airway Hyperresponsiveness Research Articles

Airway Hyperresponsiveness and Eosinophilic Airway Inflammation In Patients With Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disorder, and described as the first clinical manifestation of the atopic march. AD typically presents in infancy, predating the development of allergic asthma (AA) and allergic rhinitis. Studies in adults with AD showed that 58–72% of patients had airway hyperresponsiveness (AHR) consistent with asthma, however there was no relationship between severity of AD and degree of airway hyperresponsiveness.

Airway hyperresponsiveness development and the toxicity of PM2.5.

Airway hyperresponsiveness (AHR) is characterized by excessive bronchoconstriction in response to nonspecific stimuli, thereby leading to airway stenosis and increased airway resistance. AHR is recognized as a key characteristic of asthma and is associated with significant morbidity. At present, many studies on the molecular mechanisms of AHR have mainly focused on the imbalance in Th1/Th2 cell function and the abnormal contraction of airway smooth muscle cells. However, the specific mechanisms of AHR remain unclear and need to be systematically elaborated. In addition, the effect of air pollution on the respiratory system has become a worldwide concern. To date, numerous studies have indicated that certain concentrations of fine particulate matter (PM2.5) can increase airway responsiveness and induce acute exacerbation of asthma. Of note, the concentration of PM2.5 does correlate with the degree of AHR. Numerous studies exploring the toxicity of PM2.5 have mainly focused on the inflammatory response, oxidative stress, genotoxicity, apoptosis, autophagy, and so on. However, there have been few reviews systematically elaborating the molecular mechanisms by which PM2.5 induces AHR. The present review separately sheds light on the underlying molecular mechanisms of AHR and PM2.5-induced AHR.

Expression of nerve growth factor and matrix metallopeptidase-9/tissue inhibitor of metalloproteinase-1 in asthmatic patients

Objective: The aim of this study was to measure the level of nerve growth factor (NGF) in bronchial specimens from humans and to determine whether it correlated with not only clinical characteristics of asthma such as percent eosinophils, Th2 cytokine levels, and pulmonary function, but also metallopeptidase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1). Methods: Fifty-three people participated; 42 had asthma. The participants underwent bronchoscopy and the specimens were analyzed. The participants’ clinical data including pulmonary function tests were reviewed. Results: Bronchoalveolar lavage fluid (BALF) from patients with asthma had a significantly higher level of NGF compared with that from participants without asthma. NGF level showed a positive correlation with the percentage of eosinophils in both BALF and serum. The concentration of NGF did not correlate with that of Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 in BALF or parameters of pulmonary function including degree of airway hyperresponsiveness (ARH). The levels of MMP-9 and TIMP-1 in BALF were higher in asthma patients than in participants without asthma. The levels of NGF correlated with TIMP-1 levels but not with MMP-9 in the whole participants. Conclusions: This study shows that NGF correlates with levels of eosinophils, a major effector cell in asthma. The high expression of NGF and TIMP-1 in asthma patients and the moderate correlation between NGF and TIMP-1 in the entire group of asthma subjects suggest a possible association between NGF and TIMP-1, which may influence asthma pathogenesis.

Bronchial reactivity indices are determinants of health-related quality of life in patients with stable asthma

BackgroundA very weak relationship has been reported between the health-related quality of life (HRQL) of patients with asthma and their degree of airway hyper-responsiveness (AHR), evaluated in terms of sensitivity....

Association between Sputum Natural Killer T Cells and Eosinophilic Airway Inflammation in Human Asthma

Background: Natural killer T (NKT) cells play an essential role in the development of airway hyperresponsiveness (AHR) in murine asthma. However, their role in the pathogenesis of human asthma has not been defined. The present study investigated whether NKT cells were associated with AHR or airway inflammation in human asthma. Methods: We measured the number of NKT cells in peripheral blood and induced sputum obtained from 61 asthmatics, 10 patients with eosinophilic bronchitis (EB) and 17 controls. EB was used as a disease control model to investigate the mechanisms of AHR in asthma outside the influence of eosinophilic airway inflammation. The quantities of CD3+CD56+ NKT cells, 6B11+ NKT cells and Vα24+ NKT cells were measured by flow cytometry. Results: The measurement of NKT cells did not differ among the 3 groups in peripheral blood. However, in sputum, CD3+CD56+ NKT cells and Vα24+ NKT cells were significantly increased in patients with asthma and EB compared to controls, and 6B11+ NKT cells were also increased in patients with asthma and EB, although not significantly. There was no difference in the measurements of sputum NKT cells between asthmatics and patients with EB. Sputum Vα24+ NKT cells were inversely associated with the degree of AHR in asthmatics. Conclusions: Sputum NKT cells might play an important role in the pathogenesis of eosinophilic airway inflammation in human chronic stable asthma. However, functional studies on airway NKT cells are needed to elucidate the association between NKT cells and AHR.

Serum IL-13 Receptor Alpha2 Levels Correlate Inversely with the Degree of Airway Hyperresponsiveness Among Mouse Strains

RationaleIL-13 is a central cytokine in allergic inflammation and asthma. It mediates its effects through the heterodimeric IL-4Rα/IL-13Rα1 complex. IL-13Rα2 has been postulated to be a decoy receptor, because it binds IL-13 with high affinity, yet does not lead to signaling through the Jak-Stat pathway. Since overexpression of IL-13Rα2 has been shown to inhibit IL-13 responses, we hypothesized that the differences in airway hyper-responsiveness (AHR) observed among the various strains used in murine models of asthma may be due to variations in serum IL-13Rα2 prior to sensitization.MethodsBALB/c, A/J, FVB/n, C3H/Hej, and C57BL/6 mice (n = 4-5) were kept in specific pathogen free conditions. Blood was obtained from the lateral tail veins of mice. ELISA was used to measure IL-13Rα2 protein in mouse serum.ResultsBALB/c and A/J mice, which have been reported to have increased AHR compared to the other mouse strains, had 10.3 ng/ml and 14.3 ng/ml of serum IL-13Rα2, respectively. These levels were significantly lower than that of FVB/n (20.3 ng/ml; p < 0.03), C3H/Hej (22.6 ng/ml; p < 0.04), and C57BL/6 (19.9 ng/ml; p < 0.02), strains that develop less AHR after allergen challenge.ConclusionsSerum IL-13Rα2 protein at baseline is inversely correlated with the previously published reports of strain specific AHR in murine asthma models. This suggests that circulating IL-13Rα2 may be one factor in determining the propensity for or severity of atopic asthma. RationaleIL-13 is a central cytokine in allergic inflammation and asthma. It mediates its effects through the heterodimeric IL-4Rα/IL-13Rα1 complex. IL-13Rα2 has been postulated to be a decoy receptor, because it binds IL-13 with high affinity, yet does not lead to signaling through the Jak-Stat pathway. Since overexpression of IL-13Rα2 has been shown to inhibit IL-13 responses, we hypothesized that the differences in airway hyper-responsiveness (AHR) observed among the various strains used in murine models of asthma may be due to variations in serum IL-13Rα2 prior to sensitization. IL-13 is a central cytokine in allergic inflammation and asthma. It mediates its effects through the heterodimeric IL-4Rα/IL-13Rα1 complex. IL-13Rα2 has been postulated to be a decoy receptor, because it binds IL-13 with high affinity, yet does not lead to signaling through the Jak-Stat pathway. Since overexpression of IL-13Rα2 has been shown to inhibit IL-13 responses, we hypothesized that the differences in airway hyper-responsiveness (AHR) observed among the various strains used in murine models of asthma may be due to variations in serum IL-13Rα2 prior to sensitization. MethodsBALB/c, A/J, FVB/n, C3H/Hej, and C57BL/6 mice (n = 4-5) were kept in specific pathogen free conditions. Blood was obtained from the lateral tail veins of mice. ELISA was used to measure IL-13Rα2 protein in mouse serum. BALB/c, A/J, FVB/n, C3H/Hej, and C57BL/6 mice (n = 4-5) were kept in specific pathogen free conditions. Blood was obtained from the lateral tail veins of mice. ELISA was used to measure IL-13Rα2 protein in mouse serum. ResultsBALB/c and A/J mice, which have been reported to have increased AHR compared to the other mouse strains, had 10.3 ng/ml and 14.3 ng/ml of serum IL-13Rα2, respectively. These levels were significantly lower than that of FVB/n (20.3 ng/ml; p < 0.03), C3H/Hej (22.6 ng/ml; p < 0.04), and C57BL/6 (19.9 ng/ml; p < 0.02), strains that develop less AHR after allergen challenge. BALB/c and A/J mice, which have been reported to have increased AHR compared to the other mouse strains, had 10.3 ng/ml and 14.3 ng/ml of serum IL-13Rα2, respectively. These levels were significantly lower than that of FVB/n (20.3 ng/ml; p < 0.03), C3H/Hej (22.6 ng/ml; p < 0.04), and C57BL/6 (19.9 ng/ml; p < 0.02), strains that develop less AHR after allergen challenge. ConclusionsSerum IL-13Rα2 protein at baseline is inversely correlated with the previously published reports of strain specific AHR in murine asthma models. This suggests that circulating IL-13Rα2 may be one factor in determining the propensity for or severity of atopic asthma. Serum IL-13Rα2 protein at baseline is inversely correlated with the previously published reports of strain specific AHR in murine asthma models. This suggests that circulating IL-13Rα2 may be one factor in determining the propensity for or severity of atopic asthma.

COMPARISON OF THE 2 BRONCHIAL PROVOCATION TESTS OF DIFFERENT DOSAGE CONCENTRATION GRADIENTS FOR INFANTS

INTRODUCTION: Bronchial provocation tests (BPTs) assist in diagnosing and evaluating the curative effect of asthma. OBJECTIVE: The objective of this study was to compare the sensitivity, reliability, and safety between 2 tidal breathing methods in BPT. METHODS: Sixty-five infants, including those with asthma and chronic cough, were divided into groups A and B at random. BPT by the improvement of tidal breathing method was performed in group A (35 infants), and the traditional tidal breathing method was performed in group B (30 infants). In 10 normal infants (control subjects), the traditional tidal breathing method was used. In addition, we observed arterial oxygen saturation, respiratory system resistance, %T-PF, percent of tidal volume of peak tidal expiratory flow, and lung symptoms and monitored the vital sign and adverse effects of the test. RESULTS: Results of the BPTs for all children with asthma were positive. The positive rates for children with chronic cough were 69.57% and 60.00% in groups A and B, respectively; the results of BPTs in control subjects were completely negative. There was no significant difference in positive rate, and both methods had a similar degree of airway hyperresponsiveness; however, in group A, the effect was of shorter duration and the test was more efficient. During the BPT, 6 infants in group A and 9 in group B had cough, but none exhibited an acute asthma episode. CONCLUSIONS: The improved tidal breathing method, used as a BPT, outweighs the traditional method in sensitivity, specificity, efficiency of detection, dosage of medicine, and safety.

Comparative study to elucidate the mechanism underlying the difference in airway hyperresponsiveness between two mouse strains

The mechanism underlying airway hyperresponsiveness (AHR), a characteristic feature of asthma, remains obscure. We attempted to elucidate the mechanism responsible for the different degrees of AHR in two mouse strains, BALB/c and C57BL/6, following exposure to an anaphylactic trigger. When ovalbumin (OVA)-sensitized mice were challenged daily with OVA for up to three consecutive days, the BALB/c mice showed a higher degree of airway responsiveness to methacholine than did C57BL/6. Following the OVA challenge, eosinophils and macrophages in bronchoalveolar lavage fluid (BALF) from BALB/c increased significantly in number compared to those from C57BL/6. BALB/c mice also exhibited a higher serum IgE level than that of C57BL/6 after OVA challenge. The enhanced AHR and eosinophilic infiltration in BALF were significantly reduced by pretreatment with a selective cysteinyl-leukotriene type 1 receptor (cysLT 1R) antagonist, montelukast. In the in vitro study, cysLT production was significantly lower in the dissected lung tissue from BALB/c than in tissue from C57BL/6 when both groups were stimulated with saline. The lungs from BALB/c generated significantly larger amounts of cysLTs on incubation with OVA rather than with saline, while the lungs from C57BL/6 did not show any significant increase in cysLTs with antigen stimulation. Significant upregulation of cysLT 1R and cysLT 2R mRNA expression was induced by OVA challenge in the lungs of BALB/c, but not in those of C57BL/6. It is suggested that, after an anaphylactic reaction, the degree of AHR is dependent on the genetic background and that cysLTs play an important role in the mechanism involved.

The links between allergen skin test sensitivity, airway responsiveness and airway response to allergen

The allergen-induced early asthmatic response [provocation concentration (PC)20, the concentration causing a 20% forced expiratory volume in 1 s (FEV)1 fall] depends on the level of IgE sensitivity and the degree of nonallergic airway hyperresponsiveness (AHR) and can be predicted from histamine PC20 and allergen skin test endpoint. We examined the relationships between allergen PC20, methacholine PC20, and allergen skin test endpoint and assessed the accuracy of both the histamine PC20-based prediction of allergen PC20 (using methacholine) and a new methacholine PC20-based prediction equation. From 158 allergen challenges, the allergen PC20, the methacholine PC20, and the skin test endpoint were recorded and relationships between these three were sought. We compared the measured allergen PC20 to that predicted from the previous histamine PC20-based and the new methacholine-based formulae. In single regressions, allergen PC20 correlated with both methacholine PC20 (r=0.25, P=0.0015) and skin test endpoint (r=0.52, P <0.00005). The relationship was improved by multiple regression of log-allergen PC20vs. log-methacholine PC20 and log-endpoint (r=0.61, P <0.00005). The histamine-based formula predicted allergen PC20 to within 2 doubling concentrations in 80% and within 3 in 92%. The new methacholine-based formula to within 2 and 3 concentrations in 81% and 94%, respectively; only nine of 158 subjects were outside the 3 concentrations. We have confirmed the dependence of the allergen-induced early asthmatic response upon the level of allergic sensitivity and the degree of AHR, the latter as assessed by methacholine challenge. The allergen PC20 can be predicted to within 3 doubling concentrations in 94% of cases.

Determinants of physical fitness in children with asthma.

This study was designed to examine the relationships among weight, asthma severity, physical activity, and aerobic fitness in children with asthma. Sixty-four asthmatic children 8 to 12 years old (53% female) were assessed while attending a summer asthma camp. Measures included height and weight, spirometry, histamine bronchial provocation challenge, maximal aerobic power, and questionnaires to quantify habitual activity, perceived activity limitations due to asthma, perceived competence in physical activity, and attitudes toward physical activity. Asthma severity was determined from spirometric indices (forced expiratory volume during the first second), degree of airway hyperresponsiveness, and amount of medication prescribed. There was no correlation between asthma severity and aerobic fitness. Only perceived competence at physical activity was found to have a significant correlation with aerobic fitness. Appropriate-weight, overweight, or obese (defined by body mass index) children all had similar results for maximum aerobic power and level of habitual activity. However, overweight or obese children reported greater limitation of physical activity. Their asthma-impairment scores were higher than the scores of appropriate-weight peers, although standard measures of pulmonary function were no different among groups. The higher asthma-severity scores were related to greater medication needs in the overweight or obese children with asthma. Lower maximum aerobic power in asthmatic children is related more to how capable they perceive themselves than to asthma severity. Overweight asthmatic children experience greater limitation of physical activity and thus are prescribed more medication, although by standard measures of asthma severity, they are very similar to normal-weight peers with asthma. Efforts should be directed at understanding the reasons responsible for reduced exercise tolerance before escalating pharmacologic treatment.

Functional Molecules in Allergic Bronchial Asthma

AbstractFor Abstract see ChemInform Abstract in Full Text.

Functional molecules in allergic bronchial asthma

Bronchial asthma is considered to be a chronic airway inflammatory disease, characterized by airway obstruction, airway eosinophilic inflammation, and airway hyperresponsiveness (AHR) to a variety of stimuli. AHR is thought to be an important symptom, because the severity of the disease is generally correlated with the degree of AHR. Recent clinical studies have demonstrated the involvement of airway inflammation in the development of allergen-induced AHR, although, the mechanism of allergen-induced AHR has not been fully elucidated and remains controversial. In vivo animal models might provide important information on this point. We have established a mouse model of allergic asthma, which is characterized by airway eosinophilia, IgE production, T helper type 2 (Th2) cytokine production in the airway, and AHR, and investigated the role of inflammatory cells and functional molecules. Results from gene-knockout and mutant mice demonstrated the involvement of T cells, mast cells, prostanoids, and Th2 cytokines including interleukin (IL)-4 and IL-5 in the development of allergen-induced airway inflammation and AHR. In contrast, treatment with anti-IL-4 monoclonal antibody (mAb) or anti-IL-5 mAb during allergen inhalation did not inhibit allergen-induced AHR, although the combination of these mAbs clearly inhibited the enhanced responsiveness. These data indicate that it is a better strategy for control of the disease to inhibit or suppress multifunctional molecules like corticosteroids rather than to inhibit a single factor, because bronchial asthma is a multifactorial disease.

Airway hyperresponsiveness: using bronchial challenge tests in research and management of asthma.

Bronchial challenge tests have been standardized in detail during the past two decades. They are providing relevant pathophysiological and clinical information about patients with asthma or chronic obstructive pulmonary disease (COPD), by allowing the measurement of the degree of airway hyperresponsiveness, which includes an increased sensitivity as well as increased maximal response to bronchoconstrictor stimuli. There are various types of challenges, to which the responses are not interchangeable. Responses to so-called "indirect" challenges are largely dependent on the state of activation of inflammatory or resident cells within the airways, and the state of activation can vary rapidly, either spontaneously or through intervention. Responses to "direct" challenges are dependent on less variable, rather chronic features of airways inflammation or remodeling. Bronchoprovocation tests provide integrated information about multiple pathophysiological pathways within the airway. This is in contrast to the measurements of cells, mediators, or cytokines in biological fluids, which provide only very specific information on selected inflammatory pathways. It has recently been shown that the outcome of asthma can substantially be improved when long-term treatment is not only guided by symptoms and lung function, but also by the degree of airway hyperresponsiveness to direct stimuli. Taken together, current data warrant a broader usage of bronchoprovocation tests in the research as well as clinical management of asthma and COPD. In asthma, it allows selective, individually targeted therapy of the patient as opposed to the currently recommended regimens that are (increasingly) unselective in their approach. The potential benefits of monitoring other phenotypic disease markers is currently under investigation.

Sensitization and exposure to pet allergens in asthmatics versus non-asthmatics with allergic rhinitis

In sensitized subjects with allergic rhinitis (AR) or asthma, allergen exposure provokes symptoms. Among non-asthmatics with AR, an association between allergen sensitization, pollen season and lower airway inflammation has been demonstrated. Our aims were to compare AR and asthma with regard to patterns of allergen sensitization, the degree of airway hyperresponsiveness (AHR) and levels of exhaled nitric oxide (ENO). Finally, we wanted to relate our findings to previous or current exposure to household pets.Four hundred and thirty-one adolescents with different clinical phenotypes were randomly selected from a large-scale epidemiological survey. They were investigated with allergy screening, measurements of ENO and a methacholine bronchoprovocation test.Sensitization to pet allergens (cat, dog and horse) was associated with increased AHR and ENO both in asthmatics and non-asthmatics with AR. The risk of being sensitized to cat allergens was significantly reduced in those who had kept cats vs. those who had never kept them. Keeping dogs or horses did not influence the risk of being sensitized to the respective allergens. Only in steroid-naive, non-smoking asthmatics, a trend towards increased ENO in those sensitized and exposed to cat or dog allergens was seen.Although sensitization towards pet allergens was associated with inflammation in the lower airways irrespective of clinical phenotype, keeping pets did not increase the risk of being sensitized to pet allergens.

The Relation Between Bronchodilator Response, Airway Hyperresponsiveness and Serum Eosinophil Cationic Protein (ECP) Level in Moderate to Severe Asthmatics

Background Bronchial asthma is characterized by a reversible airway obstruction, airway hyperresponsiveness, and eosinophilic airway inflammation. The bronchodilator response(BDR) after short acting beta agonist inhalation and PC20 with methacholine inhalation are frequently used for diagnosing bronchial asthma, However, the relationship between the presence of a bronchodilator response and the degree of airway hyperresponsiveness is uncertain. Therefore, the availability of a eosinophil cationic protein(ECP) and a correlation ECP with a bronchodilator response and airway hyperresposiveness was investigated. Method A total 71 patients with a moderate to severe degree of bronchial asthma were enrolled and divided into two groups. 31 patients with a positive bronchodilator response and 38 patients with a negative bronchodilator response were evaluated. In both groups, the serum ECP, peripheral blood eosinophil counts, and total IgE level were measured and the methacholine bronchial provocation test was examined. Results There were no differences observed in age, sex, atopy, and baseline spirometry in both groups. The peripheral eosinophil counts showed no difference in both groups, but the ECP level in group 1 (bronchodilator responder group) was higher than in group 2(non-bronchodilator responder group) (22.4±20.7 vs 14.2±10.4, mean±SD). The PC20 in group 1 was significantly lower than in group 2 (1.14±1.68 vs 66±2.98). There was a significant positive correlation between the BDR and ECP, and a negative correlation between the bronchial hyperresponsiveness and ECP. Conclusion The bronchodilator response significantly correlated with the bronchial hyperresponsiveness and serum ECP in the moderate to severe asthma patients. Hence, the positive bronchodilator response is probably related with active bronchial inflammation and may be used as a valuable index in treatment, course and prognosis of bronchial asthma.

CONSEQUENCES OF LONG-TERM INFLAMMATION: The Natural History of Asthma

Although asthma is classically defined as reversible airflow obstruction, and often remits in younger subjects with milder disease, the natural history of asthma is that various degrees of airflow obstruction may persist and, in the long-term, asthma may become moderately to fully irreversible. Severe, irreversible airflow obstruction may develop despite apparently appropriate therapy and in the absence of other risk factors, such as smoking and environmental insults. All studies of subjects with persisting asthma show increased decline in lung function compared with normal subjects. Persistent abnormal physiology is reflected both in reduced airflow rates and in increased airway responsiveness. The cellular and molecular mechanisms of airway remodeling are described elsewhere in this issue. Questions not yet clearly answered are the reasons for these persistent abnormalities in some asthmatics, and which subjects are most at risk. Factors that adversely impact the outcome as adults identified relatively consistently among many longitudinal studies of the natural history of asthma include: Female gender. Environmental tobacco smoke exposure in childhood. Personal tobacco smoking in adolescence and adulthood. Age of onset of symptoms. Severity of childhood asthma. Duration of asthma. Severity of lung function abnormality in childhood. Bronchodilator reversibility. Degree of airway hyperresponsiveness. Delay in initiating anti-inflammatory therapy. Remission among adult asthmatics is uncommon, but is associated with better initial lung function, young age, male gender, and lesser degrees of airway responsiveness. The role of atopy remains controversial. Conversely, risk factors for death from asthma include older age, smoking, atopy, impaired lung function, and moderate to high reversibility. Treatment can improve lung function, reduce airway responsiveness, and improve quality of life. The overall effect of treatment on the natural history of the disease is not yet clear, despite significant short-term improvements from effective anti-inflammatory therapy.

Airway mast cells and eosinophils correlate with clinical severity and airway hyperresponsiveness in corticosteroid-treated asthma

Background: The relationship between airway inflammation and asthma severity in corticosteroid-treated asthma is unclear. Objectives: Our purpose was to characterize the inflammatory cell profile of the airway lumen and epithelium in corticosteroid-treated asthma and to relate these findings to clinical and physiologic markers of asthma severity. Methods: Adults (n = 20) with asthma received standardized high-dose inhaled corticosteroid therapy with beclomethasone 2000 μg per day for 8 weeks. Airway responsiveness to methacholine and hypertonic (4.5%) saline solution was then assessed, followed by sputum induction and, 1 week later, bronchoscopy with bronchoalveolar lavage and bronchial brush biopsy to assess inflammatory cells. Results: Clinical asthma severity was associated with airway hyperresponsiveness. Metachromatic cells were the main granulocyte present in bronchial brush biopsy specimens and correlated with airway responsiveness to saline solution (r = –0.75), methacholine (r = –0.74), peak flow variability (r = 0.59), and clinical asthma severity (r = 0.57). Eosinophils were the main granulocyte present in sputum and correlated with airway responsiveness to saline solution (r = –0.63) but not with other clinical markers of asthma severity. Bronchoalveolar lavage cell counts were not related to clinical asthma severity. Conclusions: In asthmatic patients treated with cortico-steroids, the dominant inflammatory effector cell in the epithelium is the metachromatic cell, and in sputum it is the eosinophil. These cells correlate with the degree of airway hyperresponsiveness. Clinical asthma severity correlates with airway responsiveness and epithelial metachromatic cells. Induced sputum eosinophils and airway responsiveness to hypertonic saline solution may be useful markers of airway inflammation for clinical practice. (J Allergy Clin Immunol 2000;105:752-9.)

Development of wheezing in patients with cough variant asthma during an increase in airway responsiveness.

Two theories explaining the mechanism for the manifestation of cough without wheeze in patients with cough variant asthma (CVA) are either a higher wheezing threshold or a milder degree of airway hyperresponsiveness. A significant proportion of patients diagnosed as having CVA eventually develop wheezing. The aim of this study was to investigate whether this change in the manifestation of asthma was associated with a decrease in wheezing threshold and/or an increase in airway hyperresponsiveness. Thirty-six children (7-15 yrs) with CVA were prospectively studied for 4 yrs. Bronchial provocation tests with methacholine using the stepwise increasing concentration technique were performed annually to measure the provocative cumulative dose producing a 20% fall in forced expiratory volume in one second (PD20). Wheezing thresholds were additionally determined at the initiation of and the end of the study (development of wheezing, or after 4 yrs). Sixteen (Group 1) of 29 patients available for the follow-up developed clinical wheezing during the period; 13 patients (Group 2) stayed as CVA or their cough resolved. There was no significant change in wheezing thresholds from the initiation to the end of the study (Group 1: 40.9+/-8.2% versus 40.2+/-8.3%; Group 2: 41.4+/-7.1% versus 40.1+/-7.3%). Methacholine PD20 (geometric mean, range of 1 SD), expressed as breath unit (BU), significantly decreased in Group 1 patients as they developed wheezing (initial versus wheezing year: 60.8 BU, 29.2-126.5 versus 32.8 BU, 11.5-93.3; p<0.01), whereas the value did not change in Group 2 patients (initial versus after 4 yrs: 85.3 BU, 45.2-161.1 versus 84.3 BU, 39.7-179.1; NS). The results suggest that an increase in airway hyperresponsiveness, but not a decrease in wheezing threshold, may have a pathogenetic role in the development of wheezing during the course of cough variant asthma in childhood.

How do we monitor asthma control?

The present consensus on asthma management includes avoidance of triggers, education, regular follow-up, and an action plan that relies on symptoms and lung function measurements for the monitoring of disease severity. Inclusion of objective measurements for monitoring seems to be important because patients and physicians may not always recognize asthma symptoms or their severity. However, the additional value of monitoring peak flow and symptoms in guiding asthma therapy has not been well established. Furthermore, it can be questioned whether a treatment strategy which is solely based on optimizing symptoms and lung function leads to optimal control of asthma in each individual patient, since airway hyperresponsiveness (AHR) and airways inflammation may persist. The chronicity of such abnormalities may lead to airways remodelling, thereby worsening the long-term outcome of asthma. It has been shown that AHR provides prognostic information on asthma control, because it can serve as a valuable noninvasive surrogate marker of airways inflammation when added to the guides of asthma therapy. A limited increase in dose of inhaled steroids, instead of applying an increased dose indiscriminately, can be successfully tailored to the needs of the individual patient based on the degree of AHR. Such a strategy leads to both a better clinical outcome and a better histologic outcome. The present worldwide effort is to find alternative markers of airways inflammation in asthma that can be easily implemented in routine practice. In the near future, longitudinal studies will determine which parameter is potentially most useful in guiding asthma management.

Airway eosinophilic inflammation and bronchial hyperresponsiveness after allergen inhalation challenge in asthma.

Allergen exposure in atopic asthmatic patients is associated with recruitment and activation of eosinophils in the airways. Once activated, eosinophils release toxic products, including the eosinophil cationic protein (ECP), able to damage bronchial structures and to increase bronchial hyperresponsiveness. With this background, the present study was designed to evaluate whether ECP levels in bronchoalveolar lavage (BAL) fluid could reflect, better than BAL eosinophil counts, the cellular activation that follows allergen exposure in atopic asthmatics. Twenty-two atopic patients attended the laboratory on two separate days. On the 1st day, they underwent methacholine (MCh) inhalation challenge to detect the degree of nonspecific bronchial hyperresponsiveness. On the 2nd day, they underwent fiberoptic bronchoscopy and BAL, at baseline or 4-6 h after allergen inhalation challenge. In this latter patient group, MCh challenge was repeated 3-5 h after allergen challenge, 1 h before fiberoptic bronchoscopy. The analysis of the mean baseline FEV1 values and the degree of bronchial reactivity to MCh (MCh Pd20) on the 1st study day did not demonstrate differences between the two patient groups (p > 0.1, each comparison). In addition, in the allergen-challenged group, MCh Pd20 was decreased significantly after allergen challenge (151.4 micrograms/ml and 67.6 micrograms/ml, respectively, before and after challenge; p < 0.05). Evaluation of the different BAL cell types demonstrated that the proportions of eosinophils and epithelial cells were increased significantly in the allergen-challenged group compared with the group evaluated at baseline (p < 0.01 and p < 0.05, respectively). Moreover, ECP levels, corrected by the correspondent albumin levels (ECP/Alb), were higher in the allergen-challenged group compared with the group evaluated at baseline (p < 0.05). In addition, although a positive correlation was demonstrated between BAL eosinophil percentages and ECP/Alb values (r = 0.72, p < 0.05) in the group evaluated at baseline, no links were found between these parameters in the allergen-challenged group (p > 0.1). However, in this latter group, a weak positive correlation was demonstrated between eosinophil percentages and delta Mch, i.e., the increased non-specific bronchial reactivity, which is observed after allergen challenge (r = 0.55; p < 0.05). Thus, in stable asthmatic patients an ongoing activation of eosinophils parallels their migration, but this eosinophilic inflammation is not strictly related to bronchial reactivity to Mch. By contrast, after allergen inhalation challenge, eosinophil recruitment and activation seem to follow different temporal kinetics, and eosinophilic inflammation may be partially associated with the degree of airway hyperresponsiveness.