Airway smooth muscle thickness in asthma is related to severity but not duration of asthma.

Asthma is characterised by an increased airway smooth muscle (ASM) area (ASM(area)) within the airway wall. The present study examined the relationship of factors including severity and duration of asthma to ASM(area). The perimeter of the basement membrane (PBM) and ASM(area) were measured on transverse sections of large and small airways from post mortem cases of fatal (n = 107) and nonfatal asthma (n = 37) and from control subjects (n = 69). The thickness of ASM (ASM(area)/PBM) was compared between asthma groups using multivariate linear regression. When all airways were considered together, ASM(area)/PBM (in millimetres) was increased in nonfatal (median 0.04; interquartile range 0.013-0.051; p = 0.034) and fatal cases of asthma (0.048; 0.025-0.078; p<0.001) compared with controls (0.036; 0.024-0.042). Compared with cases of nonfatal asthma, ASM(area)/PBM was greater in cases of fatal asthma in large (p<0.001) and medium (p<0.001), but not small, airways. ASM(area)/PBM was not related to duration of asthma, age of onset of asthma, sex or smoking. No effect due to study centre, other than that due to sampling strategy, was found. The thickness of the ASM layer is increased in asthma and is related to the severity of asthma but not its duration.

Budesonide/formoterol maintenance and reliever therapy: impact on airway inflammation in asthma.

The aim of the present study was to compare the effectiveness, safety and health economics of budesonide/formoterol maintenance and a novel reliever therapy with conventional best practice in patients with persistent asthma in Canada. After 2 weeks of usual therapy, 1,538 patients were randomised for 6 months to open-label budesonide/formoterol maintenance and reliever therapy 160/4.5 microg twice daily and as needed, or to guideline-based conventional best practice. Severe asthma exacerbations, reliever medication use and total inhaled corticosteroid dose were analysed in all patients and airway inflammation was assessed in a sub-study of 115 patients. No differences were seen in time to first severe exacerbation and severe asthma exacerbation rate. There were numerically fewer emergency room visits or hospitalisations with budesonide/formoterol maintenance and reliever therapy (4.4 versus 7.5 events per 100 patients x yr(-1), 41% reduction); however, this did not reach statistical significance. Mean total inhaled corticosteroid dose, reliever use, asthma medication costs and total annual costs per patient were all significantly lower with budesonide/formoterol maintenance and reliever therapy. Mean sputum eosinophil cell counts remained in the range for controlled inflammation in both groups. In conclusion, budesonide/formoterol maintenance and reliever therapy achieved similar or improved clinical control compared with conventional best practice, with significantly lower total inhaled corticosteroid dose and lower cost, while maintaining similar control of eosinophilic inflammation.

Utility of lactate dehydrogenase vs radiographic severity in the differential diagnosis of Pneumocystis carinii pneumonia.

STUDY OBJECTIVES: In patients with HIV infection, serum lactate dehydrogenase (LDH) level is commonly stated to be more elevated in Pneumocystis carinii pneumonia (PCP) than in non-PCP. We hypothesized that LDH level reflects radiographic extent and severity of pneumonia rather than P carinii infection specifically and therefore is not useful in the differential diagnosis of lung infections in AIDS. DESIGN: We compared radiographic features and LDH values in 93 sequential patients with HIV infection and a new hospital admission for pneumonia (53 PCP and 40 non-PCP) after excluding all patients with other potential causes for elevated LDH levels. The chest radiograph was graded using a quantitative scale (0 to 24) to assess radiographic extent and severity of pneumonia by two independent observers in blinded fashion. The relationship between radiographic score and hospital admission LDH level was analyzed by linear regression and Bayesian analysis was applied to different LDH ranges to calculate the clinical value of LDH measurements. SETTING: Tertiary care teaching hospital and regional AIDS referral center. RESULTS: Mean LDH level was higher in the PCP group (1.217 +/- 88 U/L compared with 776 +/- 55 U/L; p < 0.001), as was mean radiographic score (12.4 +/- 0.6 for PCP compared with 6.3 +/- 0.5 for non-PCP; p < 0.001). For the whole sample of 93, LDH level was significantly related to chest radiographic score (r = 0.43, p < 0.0001). Significant overlap occurred between the two groups at all levels of LDH such that no cutoff level could be established that impacted significantly on posttest probability of PCP, whereas a radiographic score of > 12 yielded a 96% posttest probability of PCP. CONCLUSIONS: Serum LDH level reflects the degree of radiographic abnormality and is elevated in both PCP and non-PCP pneumonia to an extent that limits its utility in differentiating the two processes in hospitalized patients. The extent of radiographic involvement more clearly distinguishes the two conditions.

Airway smooth muscle shortening in excised canine lung lobes.

To estimate the importance of lung parenchymal airway interdependence in attenuating airway narrowing, airway smooth muscle shortening in response to nebulized carbachol was measured in excised canine lung lobes and compared with the calculated load applied by lung elastic recoil. Pulmonary resistance of matched right and left upper lobes of five dogs was measured in a pressure-compensated volume plethysmograph by forced oscillation (6 Hz) before and after administration of an aerosol of carbachol (250 mg/ml) or saline. Matched lobes were studied at transpulmonary pressures (PL) of 5, 7, 10, 12, and 15 cmH2O. The lungs were then fixed at that PL by pulmonary arterial perfusion with formaldehyde, and cross sections of multiple airways from each lobe (n = 275) were examined by use of morphometric techniques to measure luminal area and smooth muscle length. By use of the saline lobe as a control, percentage of muscle shortening and decrease in airway lumen area caused by carbachol could be calculated. Passive and active smooth muscle stresses in each airway were calculated from PL and the calculated change in peribronchial pressure for a given change in airway diameter. The increase in pulmonary resistance and average smooth muscle shortening after administration of carbachol was greater in lobes held at lower PL. There was marked variation in narrowing between airways within a lobe: smooth muscle shortening ranged between 0 and 65% but averaged < 45% at all levels of PL.(ABSTRACT TRUNCATED AT 250 WORDS)

NO does not mediate inhibitory neural responses in sheep airway and bronchial vascular smooth muscle.

Endogenous nitric oxide (NO) influences acetylcholine-induced bronchovascular dilation in sheep and is a mediator of the airway smooth muscle inhibitory nonadrenergic, noncholinergic neural response in several species. This study was designed to determine the importance of NO as a neurally derived modulator of ovine airway and bronchial vascular smooth muscle. We measured the response of pulmonary resistance (RL) and bronchial blood flow (Qbr) to vagal stimulation in 14 anesthetized, ventilated, open-chest sheep during the following conditions: 1) control; 2) infusion of the alpha-agonist phenylephrine to reduce baseline Qbr by the same amount as would be produced by infusion of Nomega-nitro-L-arginine (L-NNA), a NO synthase inhibitor; 3) infusion of L-NNA (10(-2) M); and 4) after administration of atropine (1.5 mg/kg). The results showed that vagal stimulation produced an increase in RL and Qbr in periods 1, 2, and 3 (P < 0.01) that was not affected by L-NNA. After atropine was administered, there was no increase in Qbr or RL. In vitro experiments on trachealis smooth muscle contracted with carbachol showed no effect of L-NNA on neural relaxation but showed a complete blockade with propranolol (P < 0.01). In conclusion, the vagally induced airway smooth muscle contraction and bronchial vascular dilation are not influenced by NO, and the sheep's trachealis muscle, unlike that in several other species, does not have inhibitory nonadrenergic, noncholinergic innervation.

Central and local cholinergic components of histamine-induced bronchoconstriction in dogs.

To determine the importance of central and local reflexes in the bronchoconstriction produced by inhaled aerosolized histamine, chloralose-urethan-anesthetized dogs were intubated with a double-lumen catheter, ventilated with a dual cylinder respirator, and instrumented for the measurements of pulmonary conductance (GL) and dynamic compliance (Cdyn) in each lung. In each dog, dose-response curves to inhaled aerosolized histamine were obtained in both lungs separately but synchronously. Four series of experiments were performed. In the first series (n = 10) the responses of the right and left lungs were compared and found to be approximately equal, indicating that one lung could be used as a control for the other. In the second and third series the dose-response curve of one lung that had either been treated with inhaled atropine sulfate (n = 6) (4 mg/ml) or vagotomized (n = 4) was compared with the contralateral control lung. At low concentrations of histamine, GL and Cdyn decreased more in the control lungs than in their atropine-treated or vagotomized counterparts, and approximately 40% of the bronchoconstriction induced was reflex in origin. At higher concentrations of histamine the responses of the control and atropine-treated or vagotomized lungs were not significantly different. In the fourth series of experiments (n = 6) histamine dose-response curves were obtained following combined bilateral vagotomy and unilateral delivery of inhaled aerosolized atropine. In these dogs GL, but not Cdyn, fell to a greater extent in the control than in the atropine-treated lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchial arterial response to contrast medium.

RATIONALE AND OBJECTIVES: Contrast agents have been shown to produce vasodilatory responses in several vascular beds. To our knowledge, however, their effect on the bronchial vasculature has not been examined. Clinically, contrast-induced bronchial vasodilation could potentially exacerbate life-threatening pulmonary hemorrhage during bronchial angiography for hemoptysis. In the current study, we systematically measured the bronchial vasodilatory response to diatrizoate meglumine 66% and diatrizoate sodium 10% (MD-76) and examined whether vasodilation would be mediated by nitric oxide (NO). METHODS: We measured bronchial blood flow in seven anesthetized, ventilated, open-chested sheep using an ultrasonic flow probe placed around the bronchial artery. Bronchial blood flow was recorded before and after injection of 2 ml MD-76 into the bronchial artery. The protocol was repeated after 20 min infusion of N omega-nitro-L-arginine (L-NA; 10(-2) mol/l), an NO-synthase inhibitor, into the bronchial artery. RESULTS: There was a 45 +/- 8 ml/min increase (p < .01) in bronchial blood flow after injection of MD-76, which was reduced to 20 +/- 6 ml/min (p < .01) after infusion of L-NA. CONCLUSION: Bronchial arterial injection of MD-76 results in a consistent increase in bronchial blood flow that is mediated partly by NO.

Respiratory failure associated with the lipodystrophy syndrome in an HIV-positive patient with compromised lung function.

Protease inhibitors, used as treatment in human immunodeficiency virus (HIV) infection, are associated with a syndrome of peripheral lipodystrophy, central adiposity, hyperlipidemia and insulin resistance. An HIV-positive patient with chronic obstructive pulmonary disease is presented who developed the lipodystrophy syndrome that is associated with the use of protease inhibitors. It is postulated that the lipodystrophy syndrome further compromised his lung function, leading to respiratory failure. Patients who have pulmonary disease and are taking protease inhibitors require monitoring of clinical status and pulmonary function tests.

Bullae, bronchiectasis and nutritional emphysema in severe anorexia nervosa.

STUDY OBJECTIVES: Pulmonary complications of anorexia nervosa are rarely documented. The case of a patient with anorexia nervosa and pulmonary disease is presented, a new quantitative computed tomography (CT) method for the detection of emphysema is employed, the literature is reviewed and the concept of 'nutritional' emphysema is discussed. RESULTS: The case of a 34-year-old, nonsmoking woman with long-standing severe anorexia nervosa who was evaluated for cough and progressive shortness of breath is reported. Pulmonary function testing showed a predominant restrictive pattern with a marked reduction in carbon monoxide transfer and respiratory muscle strength, and an elevated residual volume. Imaging revealed bullae and bronchiectasis, and quantitative analysis of the CT scan was consistent with mild, generalized emphysema. Bronchial washings grew Pseudomonas aeruginosa. Known causes for bronchiectasis were excluded. A literature review disclosed few reported noninfectious pulmonary complications of anorexia nervosa. CONCLUSIONS: To the authors' knowledge, this is the first report of bullae and bronchiectasis in a patient with anorexia nervosa, and the CT analysis was consistent with mild emphysema. Malnutrition has been associated with emphysematous changes in animals and may be the primary insult in the development of emphysema, bullae and bronchiectasis in the present patient.

What is new since the last (1999) Canadian Asthma Consensus Guidelines?

The objective of the present document is to review the impact of new information on the recommendations made in the last (1999) Canadian Asthma Consensus Guidelines. It includes relevant published studies and observations or comments regarding what are considered to be the main issues in asthma management in children and adults in office, emergency department, hospital and clinical settings. Asthma is still insufficiently controlled in a large number of patients, and practice guidelines need to be integrated better with current care. This report re-emphasises the need for the following: objective measures of airflow obstruction to confirm the diagnosis of asthma suggested by the clinical evaluation; identification of contributing factors; and the establishment of a treatment plan to rapidly obtain and maintain optimal asthma control according to specific criteria. Recent publications support the essential role of asthma education and environmental control in asthma management. They further support the role of inhaled corticosteroids as the mainstay of anti-inflammatory therapy of asthma, and of both long acting beta2-agonists and leukotriene antagonists as effective means to improve asthma control when inhaled corticosteroids are insufficient. New developments, such as combination therapy, and recent major trials, such as the Children's Asthma Management Project (CAMP) study, are discussed.

The basidiomycete ganoderma and asthma: collection, quantitation and immunogenicity of the spores.

Ganoderma fungal spores are a major component of the Auckland air-spora. Previous studies of ganoderma involvement in allergic asthma and rhinitis were extended by locating the sporophores (fruiting bodies) in the Auckland area and systematically collecting the ejected spores. Maximum production by one sporophore was 5 gram dry weight of spores in one week, equivalent to 11 billion spores. We have estimated that between 400 and 1200 sporophores would account for previously reported levels of ganoderma spores collected from the air by Burkhard spore traps. Both whole spores and extracts of spores were strongly immunogenic in rabbits. Of the 115 asthma patients who were skin prick tested with a variety of fungal extracts, 32 (28%) were positive to one or more fungi. Of these, 18 (16%) reacted positively to ganoderma extracts. A theory proposing how ganoderma might contribute to allergic hyperreactivity in susceptible patients is developed.

The functional consequences of airway remodeling in asthma.

Structural changes in the airway walls involving extracellular matrix remodelling are prominent features of asthma. These changes are probably driven by mediators released as a consequence of chronic allergic inflammation. It is clear that changes in the extracellular matrix have the capacity to influence airway function in asthma. However, it is not clear how each of the many changes that occur in the airway wall contribute to altered airway function in asthma. Collagen deposition in the subepithelial matrix, and hyaluronan and versican deposition around and internal to the smooth muscle would be expected to oppose the effect of smooth muscle contraction. Conversely, geometric considerations would result in exaggerated airway narrowing for a given degree of smooth muscle shortening, as the airway wall is thickened by the deposition of these molecules internal to the smooth muscle. Elastin and cartilage reorganization and degradation in the airway walls would be expected to result in decreased airway wall stiffness and increased airway narrowing for a given amount of force generated by the smooth muscle. Degradation of matrix associated with the smooth muscle may both decrease the stiffness of the parallel elastic component and uncouple smooth muscle from the load provided by lung recoil, allowing exaggerated smooth muscle shortening. Increase in muscle mass may be associated with an increase, a decrease or no change in smooth muscle contractility. If an increase in muscle mass was associated with preservation of its contractile capacity modelling studies suggest that it could be the most important contributor to exaggerated airway narrowing. Modelling studies also suggest that the pattern of mucosal folding during smooth muscle contraction may be an important determinant of airway narrowing. The greater the number of folds, and the stiffer the subepithelial collagenous layer the more resistant the airway will be to narrowing.

Severe exacerbations predict excess lung function decline in asthma.

Severe asthma exacerbations are periods of intense airway inflammation that have been hypothesised to contribute to structural changes in the airways. If so, accelerated lung function decline over time should be more prevalent in adult patients with asthma who have frequent exacerbations than those without, but to date this has not been demonstrated. A cohort study was performed in order to investigate the effect of severe exacerbations on the progression of airway obstruction in 93 nonsmoking asthmatics with moderate-to-severe disease prior to treatment with inhaled corticosteroids. Subjects were followed for > or =5 yrs (median follow-up 11 yrs). In total, 56 (60.2%) subjects experienced at least one severe exacerbation (median rate 0.10.yr(-1)). Oral corticosteroid use and more severe airway obstruction at baseline were associated with a higher exacerbation rate. Independent of these variables, asthma patients with frequent exacerbations had a significantly larger annual decline in forced expiratory volume in one second (FEV(1); median difference (95% confidence interval) 16.9 (1.5-32.2) mL.yr(-1)). Exacerbation rate significantly predicted an excess decline in FEV(1), such that one severe exacerbation per year was associated with a 30.2 mL greater annual decline in FEV(1). These data support the hypothesis that exacerbations, indicating intermittent periods of worsening airway inflammation, are associated with excess lung function decline in asthma.

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma.

Excessive airway obstruction is the cause of symptoms and abnormal lung function in asthma. As airway smooth muscle (ASM) is the effecter controlling airway calibre, it is suspected that dysfunction of ASM contributes to the pathophysiology of asthma. However, the precise role of ASM in the series of events leading to asthmatic symptoms is not clear. It is not certain whether, in asthma, there is a change in the intrinsic properties of ASM, a change in the structure and mechanical properties of the noncontractile components of the airway wall, or a change in the interdependence of the airway wall with the surrounding lung parenchyma. All these potential changes could result from acute or chronic airway inflammation and associated tissue repair and remodelling. Anti-inflammatory therapy, however, does not "cure" asthma, and airway hyperresponsiveness can persist in asthmatics, even in the absence of airway inflammation. This is perhaps because the therapy does not directly address a fundamental abnormality of asthma, that of exaggerated airway narrowing due to excessive shortening of ASM. In the present study, a central role for airway smooth muscle in the pathogenesis of airway hyperresponsiveness in asthma is explored.

Abnormalities in airway smooth muscle in fatal asthma. A comparison between trachea and bronchus.

Tracheal smooth muscle from seven cases of fatal asthma demonstrated an increased contractile response to histamine, acetylcholine, and electrical stimulation of intrinsic cholinergic nerves; impaired relaxation to isoproterenol, and possibly theophylline, was also evident (1). Fourth generation bronchial spirals from the same patients were also studied, and these results were compared with those of the trachea and normal bronchi (n = 5). In contrast to trachea, contractile responses in asthmatic bronchi to acetylcholine, histamine, and cholinergic nerve stimulation were similar to those in control bronchi. The potency of isoprenaline (IC50) was reduced 9.4-fold (p less than 0.003), similar to trachea (4.5-fold), whereas theophylline responses were normal. The discrepant results obtained may reflect differences in the disease process, including rates of postmortem change, at the two anatomic sites.

Abnormalities in airway smooth muscle in fatal asthma.

The characteristics of asthmatic airway smooth muscle are poorly described. Using standard organ bath techniques, the in vitro isometric contractile and relaxant responses of tracheal strips obtained from seven asthmatics (A) (mean age, 48 +/- 6 SEM yr) dying during severe asthma attacks outside hospital were studied 7.6 +/- 1.3 h after death. Drug therapy had varied, but it had always included inhaled beta 2-agonists. Control data (C) were obtained from 31 subjects (54 +/- 2 yr) studied 9.5 +/- 0.4 h after sudden nonrespiratory death. Cholinergic contractile and nonadrenergic noncholinergic inhibitory (NANCI) neural responses were studied with electrical field stimulation (EFS); histamine, isoproterenol (ISO), and theophylline (THEO) responses were studied using cumulative techniques. The maximal response (Tmax, g/g tissue) to histamine, cholinergic EFS (A = 61.3 +/- 13.2, C = 33.6 +/- 3.6, p less than 0.0001), (A = 70.3 +/- 11.8, C = 47.3 +/- 4.5, p = 0.041), and acetylcholine (ACh) (A = 101.9 +/- 17.4, C = 62.7 +/- 7.5, p = 0.012) was greater in the asthmatics but NANCI responses were similar. Cholinergic Tmax (EFS) as a percentage of Tmax (ACh), EC50 (histamine), and EF50 (EFS) were similar in the two groups. With tissues contracted to 60% of maximum with histamine, the concentrations of ISO (A = 60.3 nM, C = 12.7, p = 0.01) and THEO (A = 31.9 microM, C = 5.7, p = 0.041) to reduce tension by 50% (IC50) were greater in asthmatics.(ABSTRACT TRUNCATED AT 250 WORDS)