Biomedical subjects
Publications and source records attributed to P V Gardiner.
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We report a patient with chronic bronchiectasis who developed systemic vasculitis. The patient was initially treated with immunosuppression; however, the addition of antibiotic therapy improved control of her vasculitis and the need for immunosuppression was reduced. Chronic bronchial suppuration may have an aetiological role in the pathogenesis of this condition.
Inhaled corticosteroids are now first-line therapy for most patients with asthma. However, it has been shown that there is ongoing airway inflammation and airway hyperresponsiveness even in the presence of low dose inhaled corticosteroids. To ensure a maximal therapeutic potential we investigated the effect of 3 mo of a very high dose of a new inhaled corticosteroid, fluticasone propionate (FP) (equivalent to 4,000 micrograms daily of beclomethasone dipropionate [BDP]. Twenty asthmatics with mild-to-moderate disease were recruited into this single-blind study. Baseline data were compared with those from 26 normal subjects. Differences in inflammatory indices between asthmatics and normal subjects were detected in both BAL and endobronchial biopsies. After the FP treatment period there was a significant improvement in symptom scores, lung function, and airway responsiveness by a mean 2.8 doubling dilutions of methacholine. Reduction in the airway lymphocyte load and lymphocyte activation was demonstrated and is likely to be an important mechanism mediating the effects of inhaled corticosteroids. Decreased mast cell numbers and activity in atopic asthma suggest that corticosteroids may have additional targets in different types of asthma. Reduced lymphocyte and mast cell activity was found with high dose FP even in those receiving low dose maintenance BDP prior to the study, suggesting a dose-response effect of inhaled corticosteroids on airway inflammation. BAL eosinophilia was still present after FP, indicative of a component of asthmatic airway inflammation that is relatively resistant to corticosteroid therapy.
Despite the increasing complexity of bronchoalveolar lavage (BAL) studies in asthmatics there are few published data concerning the variability of inflammatory parameters measured using this technique. We studied the intrasubject variability of cellular and solute parameters in 20 clinically stable, symptomatic, mild-to-moderate asthmatics, in repeat 180 mL BAL procedures performed 1 month apart. During the study, there was no change in disease activity or medication. Mean (SD) forced expiratory volume in one second (FEV1) was 3.2 (1.09) L at the first BAL and 3.05 (0.98) L at the second. The geometric mean dose of methacholine provoking a 20% decrease in FEV1 (PD20) was 23 micrograms (range 2-1,170 micrograms) at the first BAL and 28 micrograms (range 2-400 micrograms) at the second. There was considerable variability in the BAL cellular and solute parameters measured over the two procedures. Estimates of power calculated for subsequent studies involving this type of subject group were made from the observed variability. Sample sizes of less than 15 mean that differences have to be large in order to be detected in repeat BAL samples. However, there is little improvement in the power of BAL studies for sample sizes greater than 20, indicating that there is little gain in recruiting more than this number of subjects. Thus, our study indicates that although studies of the pathophysiology underlying asthma using BAL require considerable commitment, they are practicable.
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Using BAL, we studied the effects of 8 wk of treatment with salmeterol on airway inflammation in nine asthmatic subjects in a double-blind crossover placebo-controlled protocol. The study patients were all receiving regular inhaled corticosteroid therapy (400 to 1,000 micrograms beclomethasone dipropionate per day) and inhaled albuterol for symptomatic relief, i.e., subjects who might be considered suitable for treatment with salmeterol. The asthmatic group had significant differences in numbers of epithelial cells and eosinophils in BAL compared with a group of 15 normal control subjects (p < 0.01). During salmeterol treatment mean morning and evening peak flow rates were increased (p < 0.05). There was no significant change in BAL cell profile and no change in percentages of CD4 and CD8 lymphocytes or proportion of lymphocytes expressing HLA-DR after salmeterol. In conclusion, we were unable to demonstrate any significant anti-inflammatory effect of regular salmeterol therapy on airway inflammation using BAL in these asthmatic patients. At the same time, there was equally no evidence of a deterioration in the underlying inflammatory disease process.
It has been suggested that the new long-acting beta 2-agonist, salmeterol, has anti-inflammatory properties--properties which should improve airway responsiveness (AR). Conversely, several recent studies have suggested that regular beta 2-agonist treatment may worsen asthma and AR. Furthermore, a short-lived rebound increase in AR has been described following cessation of regular treatment with these agents. We have consequently assessed the effects on AR of regular treatment with either salmeterol or salbutamol at conventional doses over 6 weeks. FEV1 and AR were measured five times in 20 asthmatic subjects randomly allocated to one or other treatment regimen; twice during a 2-week run-in period; and 24 h, 72 h, and 2 weeks after the last dose of the study medication. Peak expiratory flow rate (PEFR) was also recorded throughout the study period. There were no statistically significant changes in FEV1 or AR between the run-in period and any of the post treatment measurements for either of the treatments used. Mean PEFR was significantly higher during the treatment period than the run-in period for the salmeterol group, but not the salbutamol group, confirming that therapeutically adequate doses of salmeterol had been given. We conclude that if the regular use of salmeterol is associated with beneficial or adverse effects on AR, this is not apparent after a treatment period of 6 weeks.
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We have used the Health Assessment Questionnaire (HAQ) to follow changes in disability in an unselected group of 245 patients with RA. The HAQ has been widely used in cross-sectional studies of disability in RA, but little is known about the dynamics of the change in HAQ score with long term follow-up. If it is to prove useful as a measure of health outcome it must not only be able to accommodate a wide range of disability but also show adequate sensitivity to change in disability. We administered the HAQ to 245 RA inpatients and outpatients at the beginning and end of a 5-yr period to address this important question. The mean change in individual HAQ score in the 175 patients for whom complete data was available was +0.18 (SD 0.66) over 5 yr, i.e. 0.03 units per year. It is likely that the observed rate of change in HAQ score is an under-estimate of the true rate of progression of disability, as the scale failed to accommodate change in disability toward its upper limit. The inherent design of the HAQ creates several 'ceilings' in functional subcategories (such as lower limb function) which may be masked by the overall HAQ score. Longitudinal studies of disability using the HAQ as outcome measure should therefore be interpreted with caution, and close attention paid to the baseline HAQ score.
BACKGROUND: Standardised expression of results of bronchoalveolar lavage (BAL) is problematical in the absence of a validated "denominator" of epithelial lining fluid dilution. The suitability of albumin in BAL fluid has been investigated in groups of clinically stable asthmatic and control subjects. METHODS: Absolute levels of albumin in BAL fluid were measured in a preliminary study of 21 asthmatic and 10 control subjects. In a more complex study designed to investigate the origin of albumin sampled at BAL in nine asthmatic and seven control subjects, radiolabelled albumin was injected intravenously five minutes before BAL. RESULTS: In the preliminary study levels of albumin in BAL fluid were very similar, with a geometric mean value of 44 (95% CI 35-54) micrograms/ml BAL supernatant for the asthmatic subjects and 41 (95% CI 33-52) micrograms/ml for the controls. The majority of control and asthmatic subjects in the radiolabel study exhibited minimal flux of albumin from the circulation into the BAL aspirate. This finding was not uniform, however, and in a third of the asthmatic subjects an albumin flux equivalent to > 20% of the measurable albumin was found in two or more aliquots of a 3 x 60 ml lavage. CONCLUSIONS: The results of this investigation into the source of albumin sampled at BAL suggest that, in general, albumin would be a reasonable reference solute for normalising the degree of dilution of BAL fluid in the groups studied. The origin of albumin was not always restricted to the bronchopulmonary segment under investigation, however, with significant leakage from the blood compartment in some individuals despite the consistency of absolute levels observed in the preliminary study.
Previous open studies have suggested that thromboxane receptor antagonists or synthesis inhibitors lower airway hyperresponsiveness in human subjects. This would indicate a role of thromboxane A2 in the development or maintenance of hyperresponsiveness in asthma. Ten nonsmoking asthmatics (aged 23-64 yrs, 9 male) were included in a randomized, double-blind, placebo-controlled, cross-over study of the effect of one week of treatment with a potent selective thromboxane synthetase inhibitor (UK-38,485, 600 mg daily) on airway responsiveness. The study was preceded by a two week run-in period, and two weeks were used for wash-out between the two trial periods. Adequacy of dosage and patient compliance was confirmed by a reduction in the ex vivo formation of thromboxane B2 (median concentration 3.22 micrograms.ml-1 after placebo, 0.10 microgram.ml-1 after UK-38,485, p < 0.05). The mean forced expiratory volume in one second (FEV1) after UK-38,485 was 2.55 l, compared to 2.56 l after treatment with placebo (p = 0.74). The geometric mean provocative dose of methacholine producing a 20% fall in FEV1 (PD20) before and after UK-38,485 was 23.9 and 32.2 micrograms, respectively, compared to 25.1 and 26.3 micrograms respectively, before and after placebo (p = 0.31). The results of this study suggest that thromboxane A2 does not play an important role in the maintenance of increased airway responsiveness in moderately severe asthmatics treated with low doses of inhaled steroids.
Different technical aspects concerning bronchoalveolar lavage (BAL) are still controversial: optimal instillation volume for airway sampling, processing of lavage cells and measurement of solutes are all matter of debate. Data from BAL must then be interpreted cautiously. In asthma and bronchial hyperresponsiveness different studies with BAL seem to agree on a few points such as the presence in the airways of inflammatory cells, predominantly eosinophils and mononuclear cells, and epithelial cells. Macrophages and polymorphs from asthmatic airways are more active in terms of oxygen radical release, this activity being correlated with methacholine responsiveness. In our studies we found a positive correlation between PD20 and lymphocyte numbers. Inflammatory mediators such as arachidonic acid derivatives and PAF have been assessed in BAL fluids in different studies but the precise meaning of those data still remains to be clarified. Corticosteroid treatment can significantly modify the cellular profile in BAL: eosinophils, epithelial cells and mast cells decrease, but lymphocyte numbers increase. Though in its infancy, direct sampling of airways fluids is likely to lead to a much greater understanding of pathophysiological mechanisms in asthma with important therapeutic implications.
Bronchoalveolar lavage (BAL) urea has been advocated as a denominator that might allow for the dilution of the pulmonary epithelial lining fluid sampled at BAL, and so provide a meaningful method of expressing BAL data. We investigated the origin of water and urea sampled at BAL in five asthmatic and five control subjects using radiolabeled urea injected intravenously 5 min before BAL. Labeled BAL urea was found to be fully equilibrated with that in the bloodstream. A strong relationship was found between influx of radiolabeled water and radiolabeled urea from blood to BAL fluid, suggesting that urea sampled at BAL may be derived predominantly from an acute movement from the bloodstream into the BAL aspirate. We conclude that urea is an inappropriate denominator for the expression of BAL results, and that the fluid and solute dynamics that occur during BAL are both complex and variable.
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