Complementary roles of capsaicin cough sensitivity test and induced sputum test to methacholine bronchial provocation test in predicting response to inhaled corticosteroids in patients with chronic nonproductive cough.

BACKGROUND: The capsaicin cough sensitivity test (CCST), methacholine bronchial provocation test (MBPT), and induced sputum test (IST) are widely used in the clinical evaluation of chronic nonproductive cough. However, little is known about their roles in predicting response to inhaled corticosteroids (ICSs) in patients with chronic nonproductive cough. OBJECTIVE: To test the hypothesis that the CCST and IST play complementary roles to the MBPT for predicting the response to ICS treatment in patients with chronic nonproductive cough. METHODS: A total of 43 patients with chronic nonproductive cough who showed isolated capsaicin cough hypersensitivity (CCST group) and 55 patients with chronic nonproductive cough who had methacholine airway hyperresponsiveness (MBPT group) were enrolled. These patients underwent the IST followed by treatment with ICSs for 4 weeks. Measurement of symptom improvement was recorded by the visual analog scale. RESULTS: The response rates to ICS treatment in the CCST and MBPT groups were similar (74.5% vs 86.0%; P = .21). Only the neutrophil count in the IST group was significantly different in responders and nonresponders after the ICS treatments (P = .005 for the CCST group and P = .006 for the MBPT group). Interestingly, the absence of sputum neutrophilia used as a criterion for subgroup analysis increased response rates in the patients with either methacholine airway hyperresponsiveness or capsaicin cough hypersensitivity. CONCLUSIONS: In the present study, we demonstrate that CCST and IST play complementary roles to MBPT. By combining the results of these tests, we are able to identify more patients with chronic nonproductive cough and treat patients more successfully with ICSs by improving the response rate to ICS treatment.     

Eosinophilic tracheobronchitis and airway cough hypersensitivity in chronic non-productive cough

BACKGROUND: We have shown that some patients presenting with chronic bronchodilator-resistant non-productive cough have global atopic tendency and airway cough hypersensitivity without non-specific bronchial hyperresponsiveness, abbreviated as atopic cough. The cough is successfully treated with histamine H1-antagonists and/or glucocorticoids. OBJECTIVE: This prospective study was conducted to elucidate the histological feature of atopic cough. METHODS: Tracheal and bronchial mucosa obtained by transbronchoscopic biopsy and bronchoalveolar lavage (BAL) cell component were studied with special emphasis on eosinophils in eight non-smokers diagnosed with atopic cough, all of whom had increased sensitivity of cough response to inhaled capsaicin, normal lung function and bronchial responsiveness to methacholine and normal chest roentgenogram. Their cough completely resolved on histamine H1-antagonists and/or glucocorticoids. Transbronchoscopic tracheal and bronchial biopsy and BAL were also performed in healthy non-smokers as a control. RESULTS: A small number of eosinophils was detected in subepithelium of trachea in six of seven patients and in subepithelium of bronchi in seven of eight cough patients. The numbers of eosinophils in subepithelium of trachea and bronchi were significantly increased in the patients compared with control subjects. There was no BAL eosinophilia in any patients. CONCLUSION: It is concluded that eosinophilic tracheobronchitis and cough hypersensitivity are pathological and physiological characteristics of atopic cough.     

Hyperresponsiveness to tussive stimuli in cigarette smoke-exposed guinea-pigs: a role for capsaicin-sensitive, calcitonin gene-related peptide-containing nerves

Environmental pollutants may induce airway hyperresponsiveness to bronchonconstrictor stimuli, but if there is a concomitant change in other defensive reflexes, like the cough reflex, is not known. We have examined how two weeks' exposure to cigarette smoke influences airway sensitivity to inhaled irritants acting mainly through capsaicin-sensitive sensory neurons (citric acid, capsaicin) or rapidly adapting stretch receptors (cigarette smoke, histamine). Guinea-pigs were exposed, over a period of one hour, to cigarette smoke or room air, twice daily for 2 weeks. Twenty-four hours after the end of the smoke exposure coughing produced by nebulized citric acid (0.40 M) and capsaicin (30 microM) was enhanced 3.7 (P less than 0.001) and 2.5 (P less than 0.05) times, respectively, whereas the cigarette smoke-induced cough was unchanged. The enhanced responsiveness gradually returned to normal over a period of three weeks and was not mediated by cyclo-oxygenase products since it was not affected by indomethacin (3 mumols kg-1). In contrast, the broncho-constrictor responses to citric acid, capsaicin, cigarette smoke and histamine (0.70 mM) were not altered by inhalation of cigarette smoke. Smoke-exposed animals had a significantly (P less than 0.05) increased amount of calcitonin gene-related peptide-like material (CGRP, contained in capsaicin-sensitive sensory neurons) in tracheal tissue, suggesting that chronic irritation stimulates peptide synthesis. The amount of neuropeptide Y-like material (in autonomic motor nerves) in pulmonary tissue was not changed indicating some 'specificity' in the irritative effect of smoke. It is concluded that prolonged exposure to cigarette smoke produces a tussive hyperresponsiveness that seems to involve specifically capsaicin-sensitive, CGRP-containing sensory neurons mediating cough. The present data demonstrate the development of a 'sensory' hyperresponsiveness, separate from airway hyperresponsiveness to bronchoconstrictor agents.     

Relationship of airway symptoms from chemicals to capsaicin cough sensitivity in atopic subjects

BACKGROUND: It is well known that some patients with allergy complain of airway symptoms from chemicals (ASCs) and strong odours. However, the importance of such information for the treatment of allergic disease is not known. Such symptoms in non-allergic patients have previously been shown to be related to increased sensory nerve reactivity, which is expressed as increased cough sensitivity to inhaled capsaicin. OBJECTIVE: The aim of this study was to examine ASC in atopic patients and relate it to cough reaction to capsaicin inhalation. MATERIALS AND METHODS: Fifty-seven consecutively chosen, skin prick-positive patients with symptoms of the upper and/or lower airways completed a questionnaire concerning ASC. The patients were then divided into two groups, those with and those without such symptoms. Both groups were provoked with inhaled capsaicin in three increments and compared with 73 healthy control subjects. RESULTS: Out of 57 atopic patients, 34 reported ASC agents and 23 did not. The patients with ASC were older (P<0.01) and coughed significantly more on capsaicin provocation (P<0.001), but did not differ from them with respect to the allergic disease or its treatment or to smoking habits. Patients with atopy but without ASC did not differ from healthy controls with regard to sensitivity to capsaicin inhalation. The scored degree of ASC was directly related to the number of coughs during the capsaicin provocation. CONCLUSION: ASC in atopic patients are related to increased airway sensory nerve reactivity. There is still no explanation for this in certain patients with atopy, but age may be a confounding factor.     

Elevated substance P levels in nasal lavage fluids from patients with chronic nonproductive cough and increased cough sensitivity to inhaled capsaicin

BACKGROUND: The exact mechanism of a chronic nonproductive cough is sometimes unclear when patients who are without symptoms or signs indicating the major causes of chronic cough remain undiagnosed. OBJECTIVE: We hypothesized that some neurochemical alterations in the sensory nerves in the cough reflex may occur in the upper airway of chronic nonproductive cough patients. METHODS: We took nasal lavage fluid (NLF) specimens from 38 patients with a chronic nonproductive cough as the sole presenting symptom. All 38 had normal chest radiography, spirometry, and bronchial responsiveness. We likewise took NLF specimens from 14 healthy control subjects. We used a capsaicin cough provocation test to determine cough sensitivity and considered the value of C5 (the lowest capsaicin concentration inducing 5 consecutive coughs) as an index of cough sensitivity. We measured levels of substance P of NLF specimens by using ELISA. In addition, we evaluated the clinical response of each patient after subsequent therapeutic trials with an antihistamine and decongestant for 2 weeks. RESULTS: By using capsaicin cough sensitivity as the basis for grouping the study subjects, we divided the patients into 2 groups: an increased cough sensitivity group (ICS, C5 <32 mumol/L) and a normal cough sensitivity (NCS) group. Patients with ICS showed an elevated SP concentration in NLF (median value, 408 pg/mL) compared with that of the NCS group (237 pg/mL) and the control subjects (138 pg/mL) (P <.01). The median value of the percentage of remnant cough after therapeutic trial compared with the cough status before treatment was significantly higher in the ICS subgroup (70%) than that of NCS (25%) (P <.05). CONCLUSIONS: Elevated substance P contents in NLF specimens were associated with ICS in patients with chronic nonproductive cough, suggesting a neurochemical abnormality in the upper airway.     

Sensitivity to methacholine and capsaicin in patients with unclear respiratory symptoms

BACKGROUND: Capsaicin, the pungent ingredient in red pepper, is known to stimulate coughing via the sensory nervous system. Earlier studies showed that patients with airway symptoms induced by chemicals and strong scents cough more after inhalation of capsaicin than healthy control subjects and this has been interpreted as a hyperreactivity of airway sensory nerves. Our aim was to study airway sensitivity to inhaled capsaicin and the occurrence of airway symptoms induced by strong scents in patients who underwent a bronchial methacholine test, primarily because of suspected asthma. METHODS: Fifty-two consecutive patients referred for testing with methacholine were also provoked with inhaled capsaicin in increasing concentrations. Cough sensitivity to capsaicin was compared with that in 40 healthy control subjects. RESULTS: The patients coughed significantly more compared with the healthy control subjects with each dose of capsaicin (P < 0.0001). Twelve patients (23%) had a positive methacholine test, and of these, nine were diagnosed with asthma. There was no difference in capsaicin sensitivity between patients sensitive or insensitive to methacholine. CONCLUSIONS: The majority of the patients had no increased sensitivity to methacholine but did demonstrate sensory hyperreactivity (SHR). SHR appears to be a common diagnosis in investigations of patients with obscure airway symptoms.     

儿童血清特异性IgE水平与哮喘临床及气道反应性之间的关系

目的:为了探讨儿童血清特异性免疫球蛋白(SIgE)同哮喘临床(喘息、咳嗽)及气道反应性(BHR)的关系方法:对4000例学龄儿童(10—11岁)作哮喘调查,并随机抽查了其中64例有哮喘症状者(Ⅰ组)和60例无症状者(Ⅱ组)用荧光酶联免疫法测定其血清SIgE,和采用乙酰甲胆碱激发试验测定BHR结果:SIgE的阳性率在Ⅰ组58例(90.6%),在Ⅱ组17例(28.3%).而其中气道高反应(BHR)58例中SIgE的阳性56例(96.6%),正常BHR66例SIgE的阳性19例(28.8%).Ⅰ组中且具备BHR者,SIgE的阳性率呈现100%.3者分别作卡方检验p<0.001.说明儿童血清SIgE与哮喘临床症状及气道反应性有显著相关.结论:Ⅰ.吸入性变应原与儿童哮喘及气道高反应性具有密切相关.2.SIgE检测可作为哮喘诊断的重要参考指标,尤适用于不能完成气道激发试验的幼儿.     

Effects of suplatast tosilate, a new type of anti-allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea-pigs

BACKGROUND: Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non-productive cough. Suplatast tosilate, an anti-allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)-4, IL-5, immunoglobulin (Ig)E production, and local eosinophil accumulation. OBJECTIVE: The purpose of this study was to investigate the effect of suplatast on antigen-induced airway cough hypersensitivity and eosinophil infiltration into the airway. METHODS: Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10-8, 10-6 and 10-4 M) was counted 24 h after an antigen challenge in conscious guinea-pigs and then bronchoalveolar lavage was performed. We investigated the effect of single (before antigen challenge or capsaicin provocation) or repetitive treatment with intraperitoneal suplatast at a dose of 10 or 30 mg/kg on antigen-induced cough hypersensitivity. RESULTS: Twenty-four hours after antigen challenge, guinea-pigs developed an increase in cough receptor sensitivity to inhaled capsaicin and eosinophil infiltration in the airways. After a 2-week treatment with suplatast, but not after only a single treatment before antigen challenge or capsaicin provocation, the antigen-induced early phase bronchoconstriction, cough hypersensitivity, and airway eosinophilia were inhibited in a dose-dependent manner. CONCLUSION: These results indicate that suplatast inhibits airway cough hypersensitivity underlying allergic eosinophilic inflammation.     

Quality of life and capsaicin sensitivity in patients with sensory airway hyperreactivity

BACKGROUND: A group of patients with asthma-like symptoms and sensitivity to chemical irritants has shown an increased cough sensitivity to inhaled capsaicin compared to patients with asthma and to healthy controls. The condition is called sensory hyperreactivity (SHR), and the patients often feel that they are socially handicapped because of the risk of exposure to chemical irritants in daily life. METHODS: Twenty-six patients with asthma-like symptoms after exposure to nonspecific irritating stimuli, but without IgE-mediated allergy or demonstrable bronchial obstruction, were selected for a study of the response to a capsaicin test and measurement of quality of life by a general health profile (the Nottingham Health Profile [NHP]). We also investigated whether there was a correlation between quality of life and sensitivity to capsaicin. RESULTS: The patients demonstrated a dose-dependent response to the capsaicin provocation, with coughing and respiratory and other symptoms, that significantly differed from 12 healthy controls. The health profile showed that patients with SHR had a significantly reduced quality of life compared to reference values, and there was a significant correlation between the health profile and sensitivity to capsaicin. CONCLUSIONS: Patients with asthma-like symptoms verified by the capsaicin inhalation test for sensory hyperreactivity have a poor quality of life. The correlation between quality of life and sensitivity to capsaicin objectively demonstrates the validity of this general health profile study.     

Cough provocation with capsaicin is an objective way to test sensory hyperreactivity in patients with asthma-like symptoms

BACKGROUND: A group of patients with asthma-like symptoms and sensitivity to chemical irritants, but without bronchial obstruction, has been found among subjects referred for suspected asthma. They have no well-defined diagnosis, and no objective diagnostic method has previously been available. These patients are more sensitive to inhaled capsaicin than are patients with asthma or healthy controls. The aim was to study cough and other capsaicin-induced symptoms and to test the effect of a drug (lidocaine) that inhibits nerve transmission in sensory nerves. METHODS: Twelve patients were provoked with three different concentrations of inhaled capsaicin solutions in a randomized, double-blind order. They all had asthma-like symptoms and were sensitive to chemical irritants, but had no IgE-mediated allergy or demonstrable bronchial obstruction. Before the provocations, the patients inhaled lidocaine or placebo (saline), also in a double-blind, randomized order. The results were expressed as the number of coughs and scores of various symptoms. RESULTS: The patients reacted in a dose-dependent way with cough, airway, and eye symptoms, which were significantly reduced after preinhalation of lidocaine. CONCLUSIONS: A drug that inhibits transmission in sensory nerves successfully blocked the number of coughs and other symptoms provoked by inhalation of capsaicin. This indicates that the mechanisms underlying chemical sensitivity in these patients may originate in the sensory nervous system, and we call this condition "sensory hyperreactivity".     

Enhanced cough response to hyperpnea with cold air challenge in chronic cough patients showing increased cough sensitivity to inhaled capsaicin

BACKGROUND: Although many chronic cough patients have complained of an induced cough by cold air contact, the clinical relevance of cold air to inducing a cough and the diagnostic value of a hyperpnea with cold air (HCA) challenge to detect a hyperreactive cough reflex have not yet been investigated. METHODS: Recordings of cough counts after a 2-min HCA challenge were performed in 49 chronic cough patients and 15 healthy controls. Capsaicin cough provocation tests, which determine the threshold concentration of capsaicin that induces five or more consecutive coughs (C5), were also administered. RESULTS: After comparing the results from the capsaicin cough provocation tests of the patients and the controls, the chronic cough patients were divided into two groups: an increased cough sensitivity (ICS) group (n = 28) (C5 < 32 micromol/l) and a normal cough sensitivity (NCS) group (n = 21) (C5 >or= 32 micromol/l). The median value of induced cough counts after a HCA challenge was 11 coughs in patients with ICS and was a significantly enhanced cough response compared to that of the patients with NCS and healthy controls (four coughs, respectively). CONCLUSIONS: A simple cough provocation test using a HCA challenge may be useful for detecting ICS. It also suggests that hyperreactive cough reflexes may be one of the mechanisms of inducing chronic cough.     

Bronchial hyperresponsiveness and airway wall remodelling induced by exposure to allergen for 9 weeks.

Prolonged exposure to allergen has been proposed to be important for the development of bronchial hyperresponsiveness and airway remodelling in asthma. The present study was designed to examine the effect of chronic allergen exposure on bronchial responsiveness, eosinophil infiltration, and airway remodelling. We sensitized brown Norway rats with the occupational allergen trimellitic anhydride (TMA) and exposed the animals to TMA conjugated to rat serum albumin (TMA-RSA) on 5 consecutive days each week for 9 weeks, starting 4 weeks after sensitization. IgE and IgG anti-TMA antibodies in serum and bronchial responsiveness to acetylcholine were evaluated before and at weeks 3, 6, and 9 of allergen exposure. Thickness of the airway wall, airway luminal narrowing, and the number of goblet cells and eosinophils in the airway wall were evaluated with an image analysis system in lungs resected after the last assessment of bronchial responsiveness, at the end of the 9-week allergen exposure. All rats developed IgE and IgG anti-TMA antibodies after sensitization. The levels of antibodies increased with allergen exposure until week 6, and then declined. Bronchial hyperresponsiveness to acetylcholine was induced in allergen-exposed rats without ongoing airway eosinophilia. Bronchial hyperresponsiveness induced by chronic allergen exposure via inhalation was accompanied by significantly increased thickness of smooth muscle and airway narrowing in the small airways, and goblet cell hyperplasia in the large airways. We conclude that chronic exposure to allergen can induce bronchial hyperresponsiveness and airway wall remodelling. Airway wall remodelling may contribute to bronchial hyperresponsiveness.     

Bronchial responsiveness to methacholine during airway cooling in normal subjects

In order to investigate the effects of airway cooling on bronchial responsiveness in normal subjects, we measured bronchial responsiveness to inhaled methacholine with and without the inhalation of cold air. Two out of seven subjects showed an increase in baseline respiratory resistance (Rrs) during cooling of the airway but the other five subjects showed little change in their baseline Rrs. All subjects increased bronchial responsiveness to methacholine. Additionally, the threshold dose of methacholine decreased to one-third of the control dose with cooling of the airway. We speculate that airway cooling increased bronchial responsiveness to methacholine in normal subjects presumably due to increased vagal tone, increased alpha-adrenergic activity and/or a release of chemical mediators.     

Chronic cough with eosinophilic bronchitis: examination for variable airflow obstruction and response to corticosteroid

The purpose of this study was to examine airway responsiveness, sputum cells and the effects of inhaled corticosteroid in the chronic cough syndrome associated with eosinophilic bronchitis. We studied nine consecutive referrals with chronic cough, sputum with >10% eosinophils, normal spirometry, and normal methacholine airway responsiveness. Clinical assessment, sputum analysis, allergy skin tests and a methacholine inhalation test were performed at the first visit. Peak expiratory flow (PEF) was measured twice daily for 1 week followed by an adenosine monophosphate (AMP) inhalation test. Subjects were then treated with inhaled beclomethasone 0.4 mg twice daily for 7 days. Sputum analysis and measurement of methacholine responsiveness were then repeated. Excessive airway narrowing to methacholine was not present in any of the subjects. A methacholine plateau response was present in five subjects. Hyperresponsiveness to AMP was absent in six of the nine subjects, and PEF variability was not increased for eight subjects. Corticosteroid therapy led to a reduction in sputum eosinophil counts from 40.1 (so 21.4)% to 4.0 (4.5)% but there was no significant change in metachromatic cell counts (0.8 so 0.5% vs 0.6 sd 0.6%) or total cell counts. Methacholine responsiveness improved within the normal range in the three subjects in whom it could be determined. Chronic cough associated with eosinophilic airway inflammation can occur in the absence of variable airflow obstruction (asthma) and can improve after treatment with inhaled corticosteroid. This treatment can reduce the level of methacholine responsiveness within the normal range and reduces sputum eosinophils but not mast cells. These results suggest that the occurrence of variable airflow obstruction depends on the baseline level of methacholine responsiveness, the degree of eosinophilic infiltration and the degree to which methacholine responsiveness becomes heightened.     

In vivo airway eosinophil accumulation induced by polymyxin-B reduces bronchial responsiveness in guinea pigs

BACKGROUND: Chronic desquamative eosinophilic bronchitis and bronchial hyperresponsiveness have been considered essential for bronchial asthma. However, it has not been studied whether airway eosinophils enhance or inhibit bronchial responsiveness in vivo. OBJECTIVE: This study was conducted to elucidate the influence of airway eosinophil accumulation on bronchial responsiveness in vivo. MATERIALS AND METHODS: Guinea pigs were transnasally treated with 75 microg/kg of polymyxin-B or vehicle twice a week for a total of 3 weeks. Guinea pigs were surgically cannulated and artificially ventilated 24 h after the last administration of polymyxin-B or vehicle. Ten minutes after the installation of artificial ventilation, ascending doses of methacholine, acetylcholine or histamine were inhaled for 20 s at intervals of 5 min. Subsequent study was conducted 20 min after treatment of 60 mg/kg of indomethacin in the same manner. Final study was conducted in naive guinea pigs after single inhalation of 75 microg/mL of polymyxin B. RESULTS: The proportion of eosinophils in bronchoalveolar lavage fluid significantly increased in guinea pigs treated with polymyxin-B compared with vehicle. Bronchial responsiveness to inhaled methacholine, acetylcholine and histamine was significantly decreased by the polymyxin-B treatment. This protective effect induced by polymyxin B was abolished by pretreatment of indomethacin. A significant increase in bronchial responsiveness was observed after a single inhalation of polymyxin B. CONCLUSION: These results suggest that in vivo airway eosinophils may reduce non-specific bronchial responsiveness through inhibitory or bronchoprotective prostanoids.     

Eosinophil infiltration and enhancement of airway reactivity by leukocyte chemotactic factor, formyl-methionyl-leucyl-phenylalanine (fMLP), in guinea pigs.

N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) is a bacterial-derived chemotactic factor for eosinophils and neutrophils. This study is aimed to examine whether or not eosinophil infiltration induced by intra-airway administration of fMLP causes the damage of the bronchial epithelium and results in airway hyperresponsiveness in normal non-sensitized guinea pigs. In normal guinea pigs fMLP administered by aerosol inhalation or intratracheal injection caused significant infiltration of eosinophils in the tracheal mucosa and enhanced bronchial reactivity to inhaled histamine 6 and 24 hours after exposure. Electron microscopic examination showed damage of the alignment of the epithelial cells in the bronchial mucosa in fMLP-treated guinea pigs. PAF antagonists CV3988 and WEB2086 and a 5-lipoxygenase inhibitor (AA-861) did not prevent fMLP induced eosinophil infiltration, which suggests that fMLP caused eosinophil infiltration mainly by its chemotactic activity, not by the release of platelet activating factor (PAF) or leukotrienes in this experimental condition. These results showed that in normal guinea pigs a bacteria-derived chemoattractant of fMLP could reproduce a sequence of eosinophil infiltration and airway hyperresponsiveness, similar to the inflammatory pathophysiology after antigen challenge in sensitized animals. We concluded that eosinophil infiltration induced by either immunological or non-immunological mechanisms can cause airway damage and airway hyperresponsiveness.     

The role of fungi in the airway of chronic rhinosinusitis patients

PURPOSE OF REVIEW: To analyze the role of fungi in the upper and lower airway in chronic rhinosinusitis patients. RECENT FINDINGS: Recently, the involvement of the lower airway (as asthma, small airway disease and bronchial hyperresponsiveness) in chronic rhinosinusitis patients had been documented. Fungal spores after inhalation are submerged in the aqueous lining layers of the airway. The site depends on the size of the inhaled spores. The process of inhalation, retention and clearance of fungal spores may explain the positive culture results in both normal subjects and in most chronic rhinosinusitis patients. Fungal culture of different parts of the upper and lower airway in chronic rhinosinusitis patients had no correlation with cellular changes (local eosinophilia) and other clinical parameters. In chronic rhinosinusitis, with persistence of the chronic inflammatory process, the cells may be activated nonspecifically. SUMMARY: The role played by fungi in most chronic rhinosinusitis patients as the target antigen of initiation of such chronic inflammation is still debated. With the presence of chronic eosinophilic inflammation in chronic rhinosinusitis, an exaggerated reaction to various inhaled antigens is anticipated. The role of fungi will be confirmed only when T cells within the sinuses are shown to be actively responding to fungal antigens cultured from the sinus and with the demonstration that their elimination will stop the disease.     

Sensory hyperreactivity – a possible mechanism underlying cough and asthma-like symptoms

Background Investigations of patients referred for suspected asthma have revealed a little-known group with symptoms suggesting hyperreactive airways in whom provocation with methacholine does not lead to bronchial obstruction. The underlying mechanisms are not known, and no objective diagnostic method has been available.
Methods Provocations by inhalation of capsaicin solutions in stepwise increasing concentrations were used. Ten patients with asthma-like symptoms after exposure to nonspecific irritating stimuli, but without IgE-mediated allergy or demonstrable bronchial obstruction, were compared to 10 patients with verified bronchial asthma and 28 healthy controls. Results The patients with asthma-like symptoms reacted with cough in a dose-dependent way. The number of coughs was significantly greater than in asthmatic patients and healthy controls. The latter two groups did not differ significantly.
Conclusions The capsaicin provocation test may be a valuable method for showing not only a greater cough sensitivity, but also asthma-like symptoms. The pathophysiology underlying the symptoms may be related to increased sensitivity of free, overactive nerve endings in the respiratory mucosa. Therefore, we suggest that this overreaction in the lower airways be called "sensory hyperreactivity".     

Relationship between atopy and bronchial responsiveness to histamine in a random population

Although there are theoretical reasons to suggest that atopy might predispose to non-allergic bronchial hyperresponsiveness, previous studies have yielded conflicting results. We assessed this by determining the atopic status and bronchial responsiveness to inhaled histamine in 400 randomly selected college students. An atopy score was determined as the number of "+"s from a standard battery of seven allergy prick skin tests each graded from + to +, and the atopic status was graded as non-atopic (no +'s) mildly atopic (1 to 4 +'s), moderately atopic (5 to 8 +'s), or markedly atopic (greater than 8 +'s). Non-allergic bronchial responsiveness to inhaled histamine was measured with a standardized histamine inhalation test from which the histamine provocation concentration producing a 20% FEV1 fall (PC20) was calculated. The prevalence of bronchial hyperresponsiveness to histamine (PC20 less than or equal to 8 mg/ml) was 10.3% in the entire population. There was a progressive increase from 6.1% in the non-atopic group to 33% in the markedly atopic group (p less than 0.001). In 43 subjects with both measurable atopy score (greater than or equal to 1) and PC20 (less than or equal to 16 mg/ml), a regression of atopy score vs. log PC20 produced a small (r = -0.36) but significant (p less than 0.02) correlation. These data indicate a significant relationship exists between atopic status and increased non-allergic bronchial responsiveness to histamine. Although cause and effect cannot be inferred from this study, it is hypothesized that atopy is one factor, among others, which predisposes to non-allergic bronchial hyperresponsiveness.     

The role of intercellular adhesion molecule-1 in chronic airway inflammation

We have examined the role of intercellular adhesion molecule-1 (ICAM-1) in chronic airway inflammation and airway hyperresponsiveness in a primate model of asthma. Airway cellular composition was assessed by bronchoalveolar lavage (BAL) and airway responsiveness was measured as the bronchoconstrictor response to inhaled methacholine. In animals with chronic airway inflammation (increased BAL eosinophils) and sustained airway hyperresponsiveness, a 7 day dosing scheme with a murine anti-human ICAM-1 monoclonal antibody (R6.5, 2 mg/kg/day; i.v.) did not reduce the existing airway inflammation or airway hyperresponsiveness. In contrast, a similar dosing scheme with dexamethasone (0.2 mg/kg/day, i.m.) was found to significantly reduce both the airway eosinophilia and hyperresponsiveness. However, one week after cessation of dexamethasone treatment, the airway inflammation and hyperresponsiveness returned to pre-treatment levels. In further experiments where animals were first treated with dexamethasone (7 days) followed by a 7 day treatment with R6.5, the reoccurrence of airway inflammation and subsequent increase in airway responsiveness was prevented. We conclude that the efficacy of ICAM-1 is primarily associated with inhibition of the influx of inflammatory cells into the airways and subsequent reduction in airway responsiveness. These data suggest that in lungs with pre-existing inflammation the modulation of ICAM-1 following treatment with glucocorticoids may be a novel and more selective long-term treatment for control of the chronic airway inflammation and hyperresponsiveness associated with bronchial asthma.