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Biomedical subjects

P M Calverley

Publications and source records attributed to P M Calverley.

At least 19 recordsLinked to original sources

Overview of current therapies.

The therapy of chronic obstructive pulmonary disease has been comprehensively reviewed in a number of international treatment guidelines. There is consensus about what elements should be included, but the purposes of therapy and the timing of its introduction remain poorly defined. Major factors limiting effective treatment beyond those associated with the biology of the condition itself are poor diagnostic methodology, failure to identify relevant co-morbidities and reluctance to devote appropriate resources to maximizing patient gain. Too many patients are identified at the end-stages of their illness when treatment is relatively limited. Most therapy is directed at reducing the impact of the disease in terms of symptoms, exercise performance and exacerbations on the individual and only smoking cessation modifies the evolution of the disease. Treatment of hypoxaemic patients with domiciliary oxygen improves mortality and slows the development of pulmonary hypertension. Effective smoking cessation is relevant at all stages of the disease. It depends on the willingness of the individual to participate, and quit rates can be improved by the use of nicotine replacement therapy and possibly bupropion. Inhaled bronchodilator drugs palliate symptoms and improve exercise performance in pharmacologically predictable ways. In patients with severe disease, reduction in operating lung volumes is more important than 'bronchodilitation' and is better sustained by long acting beta agonists and anticholinergics. Inhaled corticosteroids reduce exacerbation rates and improve health status in established disease but do not modify disease evolution. Pulmonary rehabilitation improves exercise performance and health status without changing underlying pulmonary mechanics. Whether hospitalizations and exacerbations can be modified is still to be established. Nutritional therapy is in its infancy but calorie supplementation alone is insufficient to improve patient well being. Selected individuals can undergo lung volume reduction surgery with benefits extending up to two years but the risks are dependent on the skill of the operators and the appropriateness of patient selection. Lung transplantation is symptomatically helpful but does not modify the natural history of the disease. Hospitalization due to exacerbations of disease is frequent and their treatment with bronchodilators, antibiotics and corticosteroids now have a basis in randomized trial data. Mortality reflects the incidence of respiratory acidosis and noninvasive ventilation has a role in safely managing patients outside of the intensive care unit. Effective prevention of exacerbation should be possible with newer antiviral agents but data are presently lacking.

Administration, Inhalation↗

Alternative methods for assessing bronchodilator reversibility in chronic obstructive pulmonary disease.

BACKGROUND: Bronchodilator reversibility testing is recommended in all patients with chronic obstructive pulmonary disease (COPD) but does not predict improvements in breathlessness or exercise performance. Two alternative ways of assessing lung mechanics-measurement of end expiratory lung volume (EELV) using the inspiratory capacity manoeuvre and application of negative expiratory pressure (NEP) during tidal breathing to detect tidal airflow limitation-do relate to the degree of breathlessness in COPD. Their usefulness as end points in bronchodilator reversibility testing has not been examined. METHODS: We studied 20 patients with clinically stable COPD (mean age 69.9 (1.5) years, 15 men, forced expiratory volume in one second (FEV(1)) 29.5 (1.6)% predicted) with tidal flow limitation as assessed by their maximum flow-volume loop. Spirometric parameters, slow vital capacity (SVC), inspiratory capacity (IC), and NEP were measured seated, before and after nebulised saline, and at intervals after 5 mg nebulised salbutamol and 500 microg nebulised ipratropium bromide. The patients attended twice and the treatment order was randomised. RESULTS: Mean FEV(1), FVC, SVC, and IC were unchanged after saline but the degree of tidal flow limitation varied. FEV(1) improved significantly after salbutamol and ipratropium (0.11 (0.02) l and 0.09 (0.02) l, respectively) as did the other lung volumes with further significant increases after the combination. Tidal volume and mean expiratory flow increased significantly after all bronchodilators but breathlessness fell significantly only after the combination treatment. The initial NEP score was unrelated to subsequent changes in lung volume. CONCLUSIONS: NEP is not an appropriate measurement of acute bronchodilator responsiveness. Changes in IC were significantly larger than those in FEV(1) and may be more easily detected. However, our data showed no evidence for separation of "reversible" and "irreversible" groups whatever outcome measure was adopted.

Aged↗

Health status deterioration in patients with chronic obstructive pulmonary disease.

This study examined health status decline in patients with chronic obstructive pulmonary disease (COPD). Data are from the Inhaled Steroids in Obstructive Lung Disease (ISOLDE) trial. After an 8-wk run-in, 751 patients (566 male), mean age 64 yr, were randomized to receive fluticasone propionate (FP) 500 microg twice daily (376 patients) or placebo (375 patients). Mean baseline postbronchodilator FEV1 was 50 +/- 15% predicted. Patients completed the St George's Respiratory Questionnaire (SGRQ) and the Short-Form 36 (SF-36) at baseline and every 6 mo for 3 yr. FEV1 and smoking status were assessed at baseline and at 3-mo intervals. A total of 387 (212 FP) patients completed the trial. All SGRQ components (p = 0.03 to 0.004) and Physical Function, Mental Health, Energy/ Vitality, and Physical Role Limitation scales of the SF-36 (p = 0.05 to 0.005) deteriorated faster in the placebo group. FEV1 and SGRQ scores correlated at baseline values (r = -0.25, p < 0.0001), as did change in FEV1 and change in SGRQ (Delta r = -0.24, p < 0.0001). At baseline values smokers had worse SGRQ Total, Symptoms, and Impacts scores than ex-smokers. This difference was maintained throughout the study. Smoking status did not influence the rate of decline in health status. The SGRQ Total scores of FP-treated patients took 59% longer than placebo to deteriorate by a clinically significant amount. We conclude that health status decline in moderate to severe COPD can be reduced by high-dose fluticasone.

Adult↗

Function of pulmonary neuronal M(2) muscarinic receptors in stable chronic obstructive pulmonary disease.

Anticholinergic drugs often cause a considerable degree of bronchodilation in patients with chronic obstructive pulmonary disease (COPD). Pulmonary neuronal M(2) muscarinic receptors function to limit the magnitude of vagally induced bronchoconstriction. We hypothesized that the effectiveness of anticholinergic agents in patients with COPD may reflect increased vagal reactivity due to dysfunction of M(2) muscarinic receptors. The function of M(2) receptors and the magnitude of vagally induced bronchoconstriction were assessed in subjects with normal lung function and in subjects with COPD. A nasal cold dry air challenge was used to induce a bronchoconstriction, measured as a change in airway resistance (Raw) at 5 Hz (R5) using impulse oscillometry. In subjects with COPD R5 rose from 0.68 +/- 0.06 to 0.74 +/- 0.07 kPa/L/s after the cold dry air challenge (p < 0.01) and in the control subjects R5 rose from 0.34 +/- 0.03 to 0.39 +/- 0.03 kPa/L/s (p < 0.01). The bronchoconstriction was inhibited by pretreatment with ipratropium bromide, indicating that it was vagally mediated. In both groups of subjects pretreatment with the selective M(2) muscarinic receptor agonist pilocarpine (5 mg/ml) prevented the cold air-induced bronchoconstriction, indicating normal function of M(2) receptors. These studies indicate that M(2) muscarinic receptors are functional in subjects with stable COPD.

Aged↗

"Hospital at home" versus hospital care in patients with exacerbations of chronic obstructive pulmonary disease: prospective randomised controlled trial.

OBJECTIVES: To compare "hospital at home" and hospital care as an inpatient in acute exacerbations of chronic obstructive pulmonary disease. DESIGN: Prospective randomised controlled trial with three months' follow up. SETTING: University teaching hospital offering secondary care service to 350 000 patients. PATIENTS: Selected patients with an exacerbation of chronic obstructive pulmonary disease where hospital admission had been recommended after medical assessment. INTERVENTIONS: Nurse administered home care was provided as an alternative to inpatient admission. MAIN OUTCOME MEASURES: Readmission rates at two weeks and three months, changes in forced expiratory volume in one second (FEV(1)) from baseline at these times and mortality. RESULTS: 583 patients with chronic obstructive pulmonary disease referred for admission were assessed. 192 met the criteria for home care, and 42 refused to enter the trial. 100 were randomised to home care and 50 to hospital care. On admission, FEV(1) after use of a bronchodilator was 36.1% (95% confidence interval 2.4% to 69.8%) predicted in home care and 35.1% (6.3% to 63. 9%) predicted in hospital care. No significant difference was found in FEV(1 )after use of a bronchodilator at two weeks (42.6%, 3.4% to 81.8% versus 42.1%, 5.1% to 79.1%) or three months (41.5%, 8.2% to 74.8% versus 41.9%, 6.2% to 77.6%) between the groups. 37% of patients receiving home care and 34% receiving hospital care were readmitted at three months. No significant difference was found in mortality between the groups at three months (9% versus 8%). CONCLUSIONS: Hospital at home care is a practical alternative to emergency admission in selected patients with exacerbations of chronic obstructive pulmonary disease.

Aged↗

Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.

OBJECTIVES: To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. DESIGN: Double blind, placebo controlled study. SETTING: Eighteen UK hospitals. PARTICIPANTS: 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV(1)) 50% of predicted normal. INTERVENTIONS: Inhaled fluticasone propionate 500 microgram twice daily from a metered dose inhaler or identical placebo. MAIN OUTCOME MEASURES: Efficacy measures: rate of decline in FEV(1) after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. RESULTS: There was no significant difference in the annual rate of decline in FEV(1 )(P=0.16). Mean FEV(1) after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P<0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P=0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v 19%, P=0.034). CONCLUSIONS: Fluticasone propionate 500 microgram twice daily did not affect the rate of decline in FEV(1) but did produce a small increase in FEV(1). Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease.

Administration, Inhalation↗

Capsaicin induced cough in cryptogenic fibrosing alveolitis.

BACKGROUND: Cough is a common and troublesome symptom in cryptogenic fibrosing alveolitis (CFA) but the mechanisms responsible are not known. The cough threshold to inhaled capsaicin is increased in asthma and chronic obstructive pulmonary disease (COPD) where lung volumes are increased, but the relationship between cough response and symptom intensity has not been studied in CFA where lung volumes are reduced. METHODS: Capsaicin challenge tests were performed on 15 subjects with proven CFA and 96 healthy controls. Symptoms, as assessed by daily diary card cough score and by visual analogue scale (VAS), were related to the capsaicin sensitivity (C5) and compared with lung volumes. Volume restriction was produced in a group of 12 normal healthy subjects by a plastic shell tightly strapped to the chest wall. Capsaicin challenge tests were performed in these subjects, both strapped and unstrapped, to determine whether volume restriction altered the cough reflex. RESULTS: The median C5 response in normal subjects was more than 500 microM compared with 15.6 microM in those with CFA (p<0.001). The C5 response of the CFA patients was not related to symptoms of cough (whether measured by diary card or by VAS), nor was it related to percentage predicted total lung capacity (TLC) or forced vital capacity (FVC). Volume restriction of normal subjects with chest strapping successfully restricted lung volumes to levels similar to that of the CFA patients but did not change the sensitivity to capsaicin. CONCLUSIONS: The cough reflex measured using capsaicin is markedly increased in patients with CFA. This increase is not the result of alterations in the deposition of inhaled particles of capsaicin brought about by volume restriction. It could be related to reduced lung compliance leading to sensitisation of rapidly adapting receptors, other mechanical changes, or to destruction of pulmonary C fibres secondary to interstitial inflammation. The capsaicin test may be a useful method of objectively monitoring cough propensity in CFA.

Adult↗

Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease.

BACKGROUND: Chronic cough is associated with an increased sensitivity to inhaled capsaicin in a number of conditions but there are no data for patients with more severe asthma or chronic obstructive pulmonary disease (COPD). Moreover, the relationships between the capsaicin response (expressed as the concentration of capsaicin provoking five coughs, C5), self-reported cough, and routine medication is not known. METHODS: The cough response to capsaicin in 53 subjects with asthma, 56 subjects with COPD, and 96 healthy individuals was recorded and compared with a number of subjective measures of self-reported cough, measures of airway obstruction, and prescribed medication. In asthmatic subjects the relationships between the cough response to capsaicin and mean daily peak flow variability and non-specific bronchial hyperresponsiveness to histamine were also examined. RESULTS: Subjects with asthma (median C5 = 62 mM) and COPD (median C5 = 31 mM) were similarly sensitive to capsaicin and both were more reactive than normal subjects (median C5 >500 mM). Capsaicin sensitivity was related to symptomatic cough as measured by the diary card score in both asthma and COPD (r = -0.38 and r = -0.44, respectively), but only in asthma and not COPD when measured using a visual analogue score (r = -0.32 and r = -0.05, respectively). Capsaicin sensitivity was independent of the degree of airway obstruction and in asthmatics was not related to PEF variability or PC(20) for histamine. The response to capsaicin was not related to treatment with inhaled corticosteroids but was increased in those using anticholinergic agents in both conditions. CONCLUSIONS: These data suggest that an increased cough reflex, as measured by capsaicin responsiveness, is an important contributor to the presence of cough in asthma and COPD, rather than cough being simply secondary to excessive airway secretions. The lack of any relationship between capsaicin responsiveness and airflow limitation as measured by the FEV(1) suggests that the mechanisms producing cough are likely to be different from those causing airways obstruction, at least in patients with COPD.

Administration, Inhalation↗

The future for tiotropium.

In spite of growing interest in and knowledge about the causes and progression of COPD, neither the assessment nor pharmacologic treatment of this condition is currently ideal. Tiotropium is the first new treatment for COPD in many years. Tiotropium is a long-acting anticholinergic agent that has a potential role as a once-daily maintenance treatment, and a picture of its effectiveness is gradually emerging. Spirometry data from clinical studies demonstrate that it is a potent bronchodilator in patients with COPD and it is very well tolerated. Further data on health status and quality of life are awaited.

Bronchodilator Agents↗

COPD: early detection and intervention.

The compelling evidence for the increasing economic and social burden of COPD, resulting from its rising prevalence and significant morbidity, has been reviewed in other sections of this supplement. The impact of this disease within the United States and globally is projected to increase irrespective of short-term medical action, but developing successful strategies to identify the illness and reduce its impact is essential if this growing problem is to be managed successfully. In this article, some of the important concepts relevant to this process are considered, and some of the present techniques used to intervene in established COPD are reviewed.

Anti-Inflammatory Agents↗

Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial.

BACKGROUND: The role of oral corticosteroids in treating patients with exacerbations of chronic obstructive pulmonary disease (COPD) remains contentious. We assessed in a prospective, randomised, double-blind, placebo-controlled trial the effects of oral corticosteroid therapy in patients with exacerbations of COPD requiring hospital admission. METHODS: We recruited patients with non-acidotic exacerbations of COPD who were randomly assigned oral prednisolone 30 mg once daily (n=29) or identical placebo (n=27) for 14 days, in addition to standard treatment with nebulised bronchodilators, antibiotics, and oxygen. We did spirometry and recorded symptom scores daily in inpatients. Time to discharge and withdrawals were noted in each group. We recalled patients at 6 weeks to repeat spirometry and collect data on subsequent exacerbations and treatment. Hospital stay was analysed by intention to treat and forced expiratory volume in 1 s (FEV1) according to protocol. FINDINGS: FEV1 after bronchodilation increased more rapidly and to a greater extent in the corticosteroid-treated group: percentage predicted FEV1 after bronchodilation rose from 25.7% (95% CI 21.0-30.4) to 32.2% (27.3-27.1) in the placebo group (p<0.0001) compared with 28.2% (23.5-32.9) to 41.5% (35.8-47.2) in the corticosteroid-treated group (p<0.0001). Up to day 5 of hospital stay, FEV1 after bronchodilation increased by 90 mL daily (50.8-129.2) and by 30 mL daily (10.4-49.6) in the placebo group (p=0.039). Hospital stays were shorter in the corticosteroid-treated group. Groups did not differ at 6-week follow-up. INTERPRETATION: These data provide evidence to support the current practice of prescribing low-dose oral corticosteroids to all patients with non-acidotic exacerbations of COPD requiring hospital admission.

Aged↗

An observational study of inhaled corticosteroid withdrawal in stable chronic obstructive pulmonary disease. ISOLDE Study Group.

Withdrawal of inhaled corticosteroids is known to worsen disease control in bronchial asthma but similar data are lacking in chronic obstructive pulmonary disease (COPD). We hypothesized that clinical exacerbations requiring treatment would occur more often in patients whose inhaled corticosteroids were stopped than in other patients not treated with these agents. We studied 272 patients in mean age 65 (SD 0.8) years, mean FEV1 42.8 (SD 12.6)% predicted, entering the run-in phase of the Inhaled Steroids in Obstructive Lung Disease (ISOLDE) trial. All had been clinically stable for at least 6 weeks and there were no differences in the degree of bronchodilator reversibility, baseline lung function or pack-years of smoking between the 160 patients receiving inhaled corticosteroids and those not so treated. Inhaled corticosteroids were withdrawn in the first week of the study and during the remaining 7 weeks of the study 38% of those previously treated with these drugs had an exacerbation compared to 6% of the chronically untreated group. Patients receiving inhaled corticosteroids reported a longer duration of symptoms but neither this or any other recorded variable predicted the risk of exacerbation. These data suggest that abrupt withdrawal of inhaled corticosteroids should be monitored carefully even in patients with apparently irreversible COPD.

Administration, Inhalation↗