Showing papers in "Thorax in 2000"

Family size, infection and atopy: the first decade of the "hygiene hypothesis".

Abstract: Background. Declining family size is one factor that has been proposed to contribute to increasing asthma and hay fever prevalence, but its relative importance has not been quantified. Objective. Our purpose was to determine the change in asthma and hay fever prevalence that would be expected from the reduction in family size that has occurred in England/Wales and New Zealand over recent decades. Methods. The relative change in family size between 1961 and 1991 in England/Wales and New Zealand was determined from census data for these years. Summary weighted odds ratios were calculated for the associations among birth order, family size, and asthma and hay fever prevalence. The expected increase in the prevalence of asthma and hay fever between 1961 and 1991 resulting from changes in family size was then calculated. Results. The expected relative increase in the prevalence of asthma between 1961 and 1991 as a result of the smaller family size was 1% and 5% for England/ Wales and New Zealand, respectively; smaller family size would be expected to increase the prevalence of hay fever prevalence in England/Wales by 4%. Conclusions. Changes in family size over the last 30 years do not appear to explain much of the reported increase in asthma or hay fever prevalence. The contribution that other risk factors have made to these increases could be assessed with use of a similar approach. (J Allergy Clin Immunol 1999;104:554–8)

Smoking cessation guidelines for health professionals: an update

Abstract: This paper updates the evidence base and key recommendations of the Health Education Authority (HEA) smoking cessation guidelines for health professionals published in Thorax in 1998. The strategy for updating the evidence base makes use of updated Cochrane reviews supplemented by individual studies where appropriate. This update contains additional detail concerning the effectiveness of interventions as well as comments on issues relating to implementation. The recommendations include clarification of some important issues addressed only in general terms in the original guidelines. The conclusion that smoking cessation interventions delivered through the National Health Service are an extremely cost effective way of preserving life and reducing ill health remains unchanged. The strategy recommended by the guidelines involves: (1) GPs opportunistically advising smokers to stop during routine consultations, giving advice on and/or prescribing effective medications to help them and referring them to specialist cessation services; (2) specialist smokers' services providing behavioural support (in groups or individually) for smokers who want help with stopping and using effective medications wherever possible; (3) specialist cessation counsellors providing behavioural support for hospital patients and pregnant smokers who want help with stopping; (4) all health professionals involved in smoking cessation encouraging and assisting smokers in use of nicotine replacement therapies (NRT) or bupropion where appropriate. The key points of clarification of the previous guidelines include: (1) primary health care teams and hospitals should create and maintain readily accessible records on the current smoking status of patients; (2) GPs should aim to advise smokers to stop, and record having done so, at least once a year; (3) inpatient, outpatient, and pregnant smokers should be advised to stop as early as possible and the advice recorded in the notes in a readily accessible form; (4) there is currently little scientific basis for matching individual smokers to particular forms of NRT; (5) NHS specialist smokers' clinics should be the first point of referral for smokers wanting help beyond what can be provided through brief advice from the GP; (6) help from trained health care professionals specialising in smoking cessation such as practice nurses should be available for smokers who do not have access to specialist clinics; (7) the provision of specialist NHS smokers' clinics should be commensurate with demand; this is currently one or two full time clinics or their equivalent per average sized health authority, but demand may rise as publicity surrounding the services increases.

Indoor air pollution in developing countries and acute lower respiratory infections in children

Abstract: BACKGROUND A critical review was conducted of the quantitative literature linking indoor air pollution from household use of biomass fuels with acute respiratory infections in young children, which is focused on, but not confined to, acute lower respiratory infection and pneumonia in children under two years in less developed countries. Biomass in the form of wood, crop residues, and animal dung is used in more than two fifths of the world9s households as the principal fuel. METHODS Medline and other electronic databases were used, but it was also necessary to secure literature from colleagues in less developed countries where not all publications are yet internationally indexed. RESULTS The studies of indoor air pollution from household biomass fuels are reasonably consistent and, as a group, show a strong significant increase in risk for exposed young children compared with those living in households using cleaner fuels or being otherwise less exposed. Not all studies were able to adjust for confounders, but most of those that did so found that strong and significant risks remained. CONCLUSIONS It seems that the relative risks are likely to be significant for the exposures considered here. Since acute lower respiratory infection is the chief cause of death in children in less developed countries, and exacts a larger burden of disease than any other disease category for the world population, even small additional risks due to such a ubiquitous exposure as air pollution have important public health implications. In the case of indoor air pollution in households using biomass fuels, the risks also seem to be fairly strong, presumably because of the high daily concentrations of pollutants found in such settings and the large amount of time young children spend with their mothers doing household cooking. Given the large vulnerable populations at risk, there is an urgent need to conduct randomised trials to increase confidence in the cause-effect relationship, to quantify the risk more precisely, to determine the degree of reduction in exposure required to significantly improve health, and to establish the effectiveness of interventions.

Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations

Abstract: BACKGROUND Although it is presumed that exacerbations of chronic obstructive pulmonary disease (COPD) are associated with increased airway inflammation, there is little information available on inflammatory markers during an exacerbation and the relationship with severity or time course of recovery. A study was undertaken to investigate the sputum cell and cytokine characteristics of COPD when stable and during an exacerbation. METHODS Induced sputum samples from 57 patients with moderate to severe COPD were analysed (44 samples were taken during a stable period and 37 during an exacerbation). The patients recorded daily symptoms on diary cards. Cell counts and sputum levels of interleukin (IL)-6 and IL-8 were measured. RESULTS Patients with ⩾3 exacerbations/year had higher median stable sputum levels of IL-6 (110 (95% CI 11 to 215) pg/ml) and IL-8 (6694 (95% CI 3120 to 11995) pg/ml) than those with ⩽2 exacerbations/year (22 (95% CI 12 to 93) and 1628 (95% CI 607 to 4812) pg/ml, respectively). Median IL-6 levels were increased during exacerbations compared with stable conditions. The levels of IL-6 during exacerbations were related to the presence of a cold and to the total cell count and eosinophil and lymphocyte numbers, while IL-8 was positively correlated with all sputum cell counts. Sputum cell counts and cytokine levels during an exacerbation did not predict the size and duration of lung function changes in the exacerbation. CONCLUSIONS Patients with more frequent exacerbations have higher baseline sputum cytokine levels, which may predict the frequency of future exacerbations.

How well do we care for patients with end stage chronic obstructive pulmonary disease (COPD)? A comparison of palliative care and quality of life in COPD and lung cancer

Abstract: BACKGROUND—Patients with severe chronic obstructive pulmonary disease (COPD) have a poor quality of life and limited life expectancy. This study examined whether these patients were relatively disadvantaged in terms of medical and social care compared with a group with inoperable lung cancer. METHODS—An open two group comparison was made of 50 patients with severe COPD (forced expiratory volume in one second (FEV1) <0.75 l and at least one admission for hypercapnic respiratory failure) and 50 patients with unresectable non-small cell lung cancer (NSCLC). A multi-method design was used involving standardised quality of life tools, semi-structured interviews, and review of documentation. RESULTS—The patients with COPD had significantly worse activities of daily living and physical, social, and emotional functioning than the patients with NSCLC (p<0.05). The Hospital Anxiety and Depression Scale (HADS) scores suggested that 90% of patients with COPD suffered clinically relevant anxiety or depression compared with 52% of patients with NSCLC. Patients were generally satisfied with the medical care received, but only 4% in each group were formally assessed or treated for mental health problems. With regard to social support, the main difference between the groups was that, while 30% of patients with NSCLC received help from specialist palliative care services, none of the patients with COPD had access to a similar system of specialist care. Finally, patients in both groups reported a lack of information from professionals regarding diagnosis, prognosis and social support, although patients' information needs were disparate and often conflicting. CONCLUSION—This study suggests that patients with end stage COPD have significantly impaired quality of life and emotional well being which may not be as well met as those of patients with lung cancer, nor do they receive holistic care appropriate to their needs.

Molecular mechanisms of glucocorticoid action: what is important?

Abstract: Inflammatory diseases such as asthma and rheumatoid arthritis are characterised at the molecular level by chronically increased expression of multiple cytokines, chemokines, kinins and their receptors, adhesion molecules, and inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and the inducible cyclooxygenase (COX-2).1 At the cellular level, inflamed regions show a substantial influx of various inflammatory cells, arterial dilation, increased blood flow, plasma protein leakage, and oedema whilst, in the case of chronic asthma, substantial remodelling of the airways is observed involving excessive smooth muscle proliferation. However, these parameters of inflammation are effectively reduced by treatment with glucocorticoids by both direct and indirect mechanisms.2 3 For example, the reduced eosinophilia following glucocorticoid treatment in asthmatic subjects arises by direct promotion of eosinophil apoptosis and indirectly by suppressing receptor expression and production of cytokines or growth factors.4 These include factors such as interleukin (IL)-3, IL-5, granulocyte-macrophage colony stimulating factor (GM-CSF), and eotaxin which are involved in eosinophil maturation, recruitment, and survival. Similarly, glucocorticoids reduce T cell proliferation and increase T cell apoptosis via mechanisms that are at least partly the result of inhibition of the T cell growth factor, IL-2.5-8 Likewise, monocyte apoptosis is increased and influx of other infiltrating inflammatory cells is also repressed.2 9 Again, this is partly caused by reduced expression of adhesion molecules, both on migrating and target cells, as well as reduced expression of cytokines and chemokines from sites of inflammation. Therapeutically, the ability to suppress a number of inflammatory indices makes glucocorticoids among the most potent anti-inflammatory agents currently available for the treatment of chronic inflammatory diseases such as asthma.2 3 The clinical efficacy of synthetic glucocorticoids such as prednisolone or dexamethasone stems from their ability to mimic natural glucocorticosteroids. Bodily insults, including inflammation, pain, infection or even mental …

Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families.

Abstract: BACKGROUND—Respiratory syncytial virus (RSV) infects nearly all children by the end of their second winter. Why some develop bronchiolitis is poorly understood; it is not known whether there is a genetic component. The pathological features include neutrophil infiltration and high levels of interleukin 8 (IL-8), a potent neutrophil chemoattractant. METHODS—Common genetic variants of the promoter region of the IL-8 gene were identified by sequencing DNA from 36 healthy individuals. Genetic correlates of IL-8 production were assessed using whole blood from 50 healthy subjects. To investigate genetic correlates of disease severity 117 nuclear families were recruited in which a child had required hospital admission for RSV bronchiolitis. RESULTS—A common single nucleotide polymorphism (allele frequency 0.44) was identified 251 bp upstream of the IL-8 transcription start site. The IL8-251A allele tended to be associated with increased IL-8 production by lipopolysaccharide stimulated whole blood (p=0.07). Using the transmission disequilibrium test, the frequency of this allele was significantly increased in infants with bronchiolitis (transmission = 62% (95% confidence interval (CI) 53 to 71), p=0.014) and particularly in those without known risk factors (transmission= 78% (95% CI 62 to 93), p=0.004). CONCLUSION—Disease severity following RSV infection appears to be determined by a genetic factor close to the IL-8 gene. Further analysis of this effect may elucidate causal processes in the pathogenesis of RSV bronchiolitis.

Ongoing airway inflammation in patients with COPD who do not currently smoke

Abstract: BACKGROUND—Inflammatory changes in the airways in chronic obstructive pulmonary disease (COPD) are largely attributed to smoking, yet they may be present even if patients do not currently smoke. The differences in inflammatory cells and the factors contributing to these differences were examined in the airways of patients with COPD who do not currently smoke. METHODS—Eighteen non-atopic subjects with COPD (14 men) of mean (SD) age 62 (8) years and forced expiratory volume in one second (FEV1) 59 (13)% predicted and 11 non-atopic healthy subjects (eight men) of mean (SD) age 58 (8) years, FEV1 104 (11)% predicted were studied. Sputum induction and bronchoscopy with bronchoalveolar lavage (BAL) and biopsies were performed. RESULTS—Patients with COPD had more mucosal EG2+ cells (eosinophils) (median (range) 40 (0-190) versus 5 (0-40) cells/mm2, p = 0.049) and CD68+ cells (1115 (330-2920) versus 590 (450-1580) cells/mm2, p = 0.03), and a tendency towards more CD4+ but not CD8+ lymphocytes than healthy controls. Furthermore, patients with COPD had higher percentages of sputum neutrophils (77 (29-94) versus 36 (18-60)%, p = 0.001) and eosinophils (1.2 (0-8.5) versus 0.2 (0-3.1)%, p= 0.008), BAL fluid eosinophils (0.4 (0-1.7) versus 0.2 (0-0.5)%, p = 0.03), and higher concentrations of sputum eosinophilic cationic protein (ECP) (838 (115-23 760) versus 121 (35-218) ng/ml, p<0.001). Concentrations of ECP expressed per eosinophil were not higher. Patients with COPD with high mucosal EG2+ cell numbers also had high mucosal CD4+ cell numbers. Sputum eosinophilia was associated with a decrease in FEV1/VC and BAL fluid eosinophilia with a decrease in mucosal NP57+ cells (neutrophils). CONCLUSIONS—Subjects with COPD who do not currently smoke have increased numbers of inflammatory cells. Eosinophils are increased in number in the airways in COPD but do not seem to be activated. The increased eosinophil numbers are probably due to recruitment as a result of ongoing inflammation. Macrophages and lymphocytes may play a part in this inflammation.

Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function

Abstract: Background—Exposure to environmental tobacco smoke (ETS) during childhood and in utero exposure to maternal smoking are associated with adverse eVects on lung growth and development. Methods—A study was undertaken of the associations between maternal smoking during pregnancy, exposure to ETS, and pulmonary function in 3357 school children residing in 12 Southern California communities. Current and past exposure to household ETS and exposure to maternal smoking in utero were assessed by a self-administered questionnaire completed by parents of 4th, 7th, and 10th grade students in 1993. Standard linear regression techniques were used to estimate the eVects of in utero and ETS exposure on lung function, adjusting for age, sex, race, Hispanic ethnicity, height, weight, asthma, personal smoking, and selected household characteristics. Results—In utero exposure to maternal smoking was associated with reduced peak expiratory flow rate (PEFR) (‐3.0%, 95% CI ‐4.4 to ‐1.4), mean mid expiratory flow (MMEF) (‐4.6%, 95% CI ‐7.0 to ‐2.3), and forced expiratory flow (FEF75) (‐6.2%,95% CI ‐9.1 to ‐3.1), but not forced expiratory volume in one second (FEV1). Adjusting for household ETS exposure did not substantially change these estimates. The reductions in flows associated with in utero exposure did not significantly vary with sex, race, grade, income, parental education, or personal smoking. Exposure to two or more current household smokers was associated with reduced MMEF (‐4.1%, 95% CI ‐7.6 to ‐0.4) and FEF75 (‐4.4%, 95% CI ‐9.0 to 0.4). Current or past maternal smoking was associated with reductions in PEFR and MMEF; however, after adjustment for in utero exposure, deficits in MMEF and FEF75 associated with all measurements of ETS were substantially reduced and were not statistically significant. Conclusions—In utero exposure to maternal smoking is independently associated with decreased lung function in children of school age, especially for small airway flows. (Thorax 2000;55:271‐276)

Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism

Abstract: BACKGROUND—Polymorphisms of the β2 adrenoceptor influence receptor function in vitro and asthma phenotypes in vivo. However, their importance in determining responses to inhaled β agonist treatment has not been clearly defined. METHODS—In a retrospective analysis of previously published data we have examined relationships between polymorphisms at codons 16and 27 of the β2 adrenoceptor and clinical outcomes in a randomised, placebo controlled, crossover trial of regularly scheduled salbutamol and salmeterol in 115 patients with mild to moderate asthma. Genotyping was obtained for positions 16 and 27 in 108 and 107 patients, respectively. For position 16, 17 patients (16%) were homozygous Arg-Arg, 40 (37%) were heterozygous Arg-Gly, and 51 (47%) were homozygous Gly-Gly. RESULTS—Within the homozygous Arg-16 group major exacerbations were more frequent during salbutamol treatment than with placebo (1.91(95% CI 1.07 to 3.12) per year versus 0.81 (95% CI 0.28 to 1.66) per year; p = 0.005). No significant treatment related differences occurred for heterozygous Arg-Gly patients (salbutamol 0.11 (95% CI 0.01 to 0.40), placebo 0.54 (95% CI 0.26 to 1.00) exacerbations per year) or homozygous Gly-16 patients (salbutamol 0.38 (95% CI 0.17 to 0.73), placebo 0.30 (95% CI 0.12 to 0.61) exacerbations per year). No adverse changes occurred for any position 16 subgroup with salmeterol. There was no significant relationship between position 27 genotypes and treatment related outcomes. CONCLUSION—Homozygous Arg-16 patients are susceptible to clinically important increases in asthma exacerbations during chronic dosing with the short acting β2 agonist salbutamol.

Epidemiology of pneumothorax in England

Abstract: BACKGROUND Little is known of the epidemiology of pneumothorax. Routinely available data on pneumothorax in England are described. METHODS Patients consulting in primary care with a diagnosis of pneumothorax in each year from 1991 to 1995 inclusive were identified from the General Practice Research Database (GPRD). Emergency hospital admissions for pneumothorax were identified for the years 1991–4 from the Hospital Episode Statistics (HES) data. Mortality data for England & Wales were obtained for 1950–97. Analyses of pneumothorax rates by age and sex were performed for all data sources. Seasonal and geographical analyses were carried out for the HES data. RESULTS The overall person consulting rate for pneumothorax (primary and secondary combined) in the GPRD was 24.0/100 000 each year for men and 9.8/100 000 each year for women. Hospital admissions for pneumothorax as a primary diagnosis occurred at an overall incidence of 16.7/100 000 per year and 5.8/100 000 per year for men and women, respectively. Mortality rates were 1.26/million per year for men and 0.62/million per year for women. The age distribution in both men and women showed a biphasic distribution for both GP consultations and hospital admissions. Deaths showed a single peak with highest rates in the elderly. There was an urban-rural trend observed for hospital admissions in the older age group (55+ years) with admission rates in the conurbations significantly higher than in the rural areas. Analysis for trends in mortality data for 1950–97 showed a striking increase in the death rate for pneumothorax in those aged 55+ years between 1960 and 1990, with a steep decline in the 1990s. Mortality in the younger age group (15–34 years) remained low and constant. CONCLUSION There is evidence of two epidemiologically distinct forms of spontaneous pneumothorax in England. The explanation for the rise and fall in mortality for secondary pneumothorax is obscure.

Control and prevention of tuberculosis in the United Kingdom:Code of Practice 2000

Abstract: BACKGROUND—The guidelines on control and prevention of tuberculosis in the United Kingdom have been reviewed and updated. METHODS—A subcommittee was appointed by the Joint Tuberculosis Committee (JTC) of the British Thoracic Society to revise the guidelines published in 1994 by the JTC, including representatives of the Royal College of Nursing, Public Health Medicine Environmental Group, and Medical Society for Study of Venereal Diseases. In preparing the revised guidelines the authors took account of new published evidence and graded the strength of evidence for their recommendations. The guidelines have been approved by the JTC and the Standards of Care Committee of the British Thoracic Society. RECOMMENDATIONS—Tuberculosis services in each district should have staffing and resources to fulfil both the control and prevention recommendations in this document and to ensure adequate treatment monitoring. Notification of tuberculosis is required for surveillance and to initiate contact tracing (where appropriate). The following areas are discussed and recommendations made where appropriate: (1) public health law in relation to tuberculosis; (2) the organisational requirements for tuberculosis services; (3) measures for control of tuberculosis in hospitals, including segregation of patients; (4) the requirements for health care worker protection, including HIV infected health care workers; (5) measures for control of tuberculosis in prisons; (6) protection for other groups with potential exposure to tuberculosis; (7) awareness of the high rates of tuberculosis in the homeless together with local plans for detection and action; (8) detailed advice on contact tracing; (9) contact tracing required for close contacts of bovine tuberculosis; (10) management of tuberculosis in schools; (11) screening of new immigrants and how this should be performed; (12) outbreak contingency investigation; and (13) BCG vaccination and the management of positive reactors found in the schools programme.

Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care

Abstract: BACKGROUND Chronic obstructive pulmonary disease (COPD) is common although often poorly characterised, particularly in primary care. However, application of guidelines to the management of such patients needs a clear understanding of the phenotype. In particular, the British guidelines for the management of COPD recommend that the diagnosis is based on appropriate symptoms and evidence of airflow obstruction as determined by a forced expiratory volume in one second (FEV 1 ) of 1 /VC ratio of METHODS A study was undertaken of 110 patients aged 40–80 years who had presented to their general practitioner with an acute exacerbation of COPD. The episode was treated at home and, when patients had recovered to the stable state (two months later), they were characterised by full lung function tests and a high resolution computed tomographic (HRCT) scan of the chest. RESULTS There was a wide range of impairment of FEV 1 which was in the normal range (⩾80%) in 30%, mildly impaired (60–79%) in 18%, moderately impaired (40–59%) in 33%, and severely impaired ( 1 /VC ratio was present in all patients with an FEV 1 of 1 of ⩾80% predicted. Only 5% of patients had a substantial bronchodilator response suggesting a diagnosis of asthma. Emphysema was present in 51% of patients and confined to the upper lobes in most (73% of these patients). HRCT evidence of bronchiectasis was noted in 29% of patients and was predominantly tubular; most (81%) were current or ex-smokers. A solitary pulmonary nodule was seen on 9% of scans and unsuspected lung malignancy was diagnosed in two patients. CONCLUSIONS This study confirms that COPD in primary care is a heterogeneous condition. Some patients do not fulfil the proposed diagnostic criteria with FEV 1 of ⩾80% predicted but they may nevertheless have airflow obstruction. Bronchiectasis is common in this group of patients, as is unsuspected malignancy. These findings should be considered when developing recommendations for the investigation and management of COPD in the community.

Recent trends in physician diagnosed COPD in women and men in the UK

Abstract: Background—Recent trends in physician diagnosed chronic obstructive pulmonary disease (COPD) in the UK were estimated, with a particular focus on women. Methods—A retrospective cohort of British patients with COPD was constructed from the General Practice Research Database (GPRD), a large automated database of UK general practice data. Prevalence and all-cause mortality rates by sex, calendar year, and severity of COPD, based on treatment only, were estimated from January 1990 to December 1997. Results—A total of 50 714 incident COPD patients were studied, 23 277 (45.9%) of whom were women. From 1990 to 1997 the annual prevalence rates of physician diagnosed COPD in women rose continuously from 0.80% (95% CI 0.75 to 0.83) to 1.36% (95% CI 1.34 to 1.39), (p for trend <0.01), rising to the rate observed in men in 1990. Increases in the prevalence of COPD were observed in women of all ages; in contrast, a plateau was observed in the prevalence of COPD in men from the mid 1990s. Allcause mortality rates were higher in men than in women (106.8 versus 82.2 per 1000 person-years), with a consistently increased relative risk in men of 1.3 even after controlling for the severity of COPD. Significantly increased mortality rates were also observed in adults aged less than 65 years. The mean age at death was 76.5 years; patients with severe COPD died an average of three years before those with mild disease (p<0.01) and four years before the age and sex matched reference population. Conclusions—While prevalence rates of COPD in the UK seem to have peaked in men, they are continuing to rise in women. This trend, together with the ageing of the population and the long term cumulative eVect of pack-years of smoking in women, is likely to increase the present burden of COPD in the UK. (Thorax 2000;55:789‐794)

Diet and childhood asthma in a society in transition: a study in urban and rural Saudi Arabia.

Abstract: BACKGROUND—The causes of the worldwide increases in asthma and allergic diseases in childhood, which seem to relate to increasing prosperity, are unknown. We have previously hypothesised that a reduction in the antioxidant component of the diet is an important factor. An investigation was undertaken of dietary and other risk factors for asthma in Saudi Arabia where major lifestyle differences and prevalences of allergic disease are found in different communities. METHODS—From a cross sectional study of 1444 children with a mean age of 12 (SD 1) years in Jeddah and a group of rural Saudi villages, we selected 114 cases with a history of asthma and wheeze in the last 12 months and 202 controls who had never complained of wheeze or asthma, as recorded on the ISAAC questionnaire. Risk factors for asthma and allergies (family history, social class, infections, immunisations, family size, and diet) were ascertained by questionnaire. Atopy was assessed by skin prick testing. RESULTS—In univariate analyses, family history, atopy, and eating at fast food outlets were significant risk factors for wheezy illness, as were the lowest intakes of milk and vegetables and of fibre, vitamin E, calcium, magnesium, sodium, and potassium. These differences were present also in the urban children considered separately. Sex, family size, social class, infections, and parental smoking showed no relationship to risk. In multiple logistic regression analysis, urban residence, positive skin tests, family history of allergic disease, and the lowest intakes of vitamin E, magnesium and sodium related significantly and independently to risk. The lowest tertile of intake of vitamin E was associated with a threefold (95% CI 1.38 to 6.50) increase in risk when adjusted for the other factors. Intake of milk and vegetables both showed inverse linear relationships to being a case. CONCLUSIONS—This study suggests that dietary factors during childhood are an important influence in determining the expression of wheezy illness, after allowing for urban/rural residence, sex, family history, and atopy. The findings are consistent with previous studies in adults and with the hypothesis that change in diet has been a determinant of the worldwide increases in asthma and allergies.

Incidence and causes of non-invasive mechanical ventilation failure after initial success

Abstract: BACKGROUND The rate of failure of non-invasive mechanical ventilation (NIMV) in patients with chronic obstructive pulmonary disease (COPD) with acute respiratory insufficiency ranges from 5% to 40%. Most of the studies report an incidence of “late failure” (after >48 hours of NIMV) of about 10–20%. The recognition of this subset of patients is critical because prolonged application of NIMV may unduly delay the time of intubation. METHODS In this multicentre study the primary aims were to assess the rate of “late NIMV failure” and possible associated predictive factors; secondary aims of the study were evaluation of the best ventilatory strategy in this subset of patients and their outcomes in and out of hospital. The study was performed in two respiratory intensive care units (ICUs) on patients with COPD admitted with an episode of hypercapnic respiratory failure (mean (SD) pH 7.23 (0.07), Paco 2 85.3 (15.8) mm Hg). RESULTS One hundred and thirty seven patients initially responded to NIMV in terms of objective (arterial blood gas tensions) and subjective improvement. After 8.4 (2.8) days of NIMV 31 patients (23%; 95% confidence interval (CI) 18 to 33) experienced a new episode of acute respiratory failure while still ventilated. The occurrence of “late NIMV failure” was significantly associated with functional limitations (ADL scale) before admission to the respiratory ICU, the presence of medical complications (particularly hyperglycaemia), and a lower pH on admission. Depending on their willingness or not to be intubated, the patients received invasive ventilation (n=19) or “more aggressive” (more hours/day) NIMV (n=12). Eleven (92%) of those in this latter subgroup died while in the respiratory ICU compared with 10 (53%) of the patients receiving invasive ventilation. The overall 90 day mortality was 21% and, after discharge from hospital, was similar in the “late NIMV failure” group and in patients who did not experience a second episode of acute respiratory failure. CONCLUSIONS The chance of COPD patients with acute respiratory failure having a second episode of acute respiratory failure after an initial (first 48 hours) successful response to NIMV is about 20%. This event is more likely to occur in patients with more severe functional and clinical disease who have more complications at the time of admission to the ICU. These patients have a very poor in-hospital prognosis, especially if NIMV is continued rather than prompt initiation of invasive ventilation.

Automated analysis of digital oximetry in the diagnosis of obstructive sleep apnoea

Abstract: Background—The gold standard diagnostic test for obstructive sleep apnoea (OSA) is overnight polysomnography (PSG) which is costly in terms of time and money. Consequently, a number of alternatives to PSG have been proposed. Oximetry is appealing because of its widespread availability and ease of application. The diagnostic performance of an automated analysis algorithm based on falls and recovery of digitally recorded oxygen saturation was compared with PSG. Methods—Two hundred and forty six patients with suspected OSA were randomly selected for PSG and automated oV line analysis of the digitally recorded oximeter signal. Results—The PSG derived apnoea hypopnoea index (AHI) and oximeter derived respiratory disturbance index (RDI) were highly correlated (R = 0.97). The mean (2SD) of the diVerences between AHI and RDI was 2.18 (12.34)/h. The sensitivity and specificity of the algorithm depended on the AHI and RDI criteria selected for OSA case designation. Using case designation criteria of 15/h for AHI and RDI, the sensitivity and specificity were 98% and 88%, respectively. If the PSG derived AHI included EEG based arousals as part of the hypopnoea definition, the mean (2SD) of the diVerences between RDI and AHI was ‐0.12 (15.62)/h and the sensitivity and specificity profile did not change significantly. Conclusions—In a population of patients suspected of having OSA, oV line automated analysis of the oximetry signal provides a close estimate of AHI as well as excellent diagnostic sensitivity and specificity for OSA. (Thorax 2000;55:302‐307)

Decreased plasma levels of nitric oxide derivatives in obstructive sleep apnoea: response to CPAP therapy

Abstract: BACKGROUND Reduced endothelium dependent vasodilation has been reported in patients with obstructive sleep apnoea (OSA) but direct measurements of the most potent naturally occurring vasodilator, nitric oxide (NO) or its derivatives (nitrate and nitrite, NO x ), have not yet been performed in these patients. METHODS In 21 patients with OSA of mean (SE) age 54 (2) years, body mass index (BMI) 30.9 (1.1) kg/m 2 , and apnoea-hypopnoea index (AHI) 37 (4)/h, NO x levels were measured in peripheral venous blood samples by chemiluminescence. Blood samples were obtained before and after two nights of continuous positive airway pressure (CPAP) and after 5.5 (1.5) months of follow up. Thirteen age matched, healthy volunteers and 18 patients without OSA but with a similar spectrum of comorbidity served as controls (control groups 1 and 2). RESULTS Before CPAP NO x levels were 21.7 (1.5) μM in patients with OSA compared with 42.6 (2.2) μM and 36.7 (1.7) μM in control groups 1 and 2, respectively (p x concentrations increased to 32.1 (2.7) μM after two nights of CPAP and remained constant at 32.9 (2.3) μM at follow up (p CONCLUSIONS Plasma NO x levels are reduced in OSA and can be increased by short and long term CPAP therapy. Although the precise mechanism underlying this observation remains to be clarified, it may have important implications for the development of cardiovascular disease in patients with OSA and for the life saving effect of CPAP.

Chronic pulmonary function impairment caused by initial and recurrent pulmonary tuberculosis following treatment

Abstract: BACKGROUND—A study was undertaken to establish the chronic effect of initial and recurrent treated pulmonary tuberculosis on impairment of lung function. METHODS—A total of 27 660 black South African gold miners who had reliable pulmonary function tests from January 1995 to August 1996were retrospectively followed for the incidence of pulmonary tuberculosis to 1970. The lung function measurements in 1995-6 were related to the number of previous episodes of tuberculosis and to the time that had lapsed from the diagnosis of the last episode of tuberculosis to the lung function test. Miners without tuberculosis or pneumoconiosis served as a comparison group. RESULTS—There were 2137 miners who had one episode of tuberculosis, 366 who had two, and 96 who had three or more episodes. The average time between the diagnosis of the last episode of tuberculosis and the lung function test was 4.6 years (range one month to 31years). The loss of lung function was highest within six months of the diagnosis of tuberculosis and stabilised after 12 months when the loss was considered to be chronic. The estimated average chronic deficit in forced expiratory volume in one second (FEV1) after one, two, and three or more episodes of tuberculosis was 153 ml, 326 ml, and 410 ml, respectively. The corresponding deficits for forced vital capacity (FVC) were 96 ml, 286 ml, and 345 ml. The loss of function due to tuberculosis was not biased by the presence of HIV as HIV positive and HIV negative subjects had similar losses. The percentage of subjects with chronic airflow impairment (FEV1 <80% predicted) was 18.4% in those with one episode, 27.1% in those with two, and 35.2% in those with three or more episodes of tuberculosis. CONCLUSIONS—Tuberculosis can cause chronic impairment of lung function which increases incrementally with the number of episodes of tuberculosis. Clearly, prevention of tuberculosis and its effect on lung function is important and can be achieved by early detection and by reduction of the risk of tuberculosis through intervention on risk factors such as HIV, silica dust exposure, silicosis, and socioeconomic factors.

Oxidative enzyme activities of the vastus lateralis muscle and the functional status in patients with COPD

Abstract: BACKGROUND Enzymatic and histochemical abnormalities of the peripheral muscle may play a role in exercise intolerance in patients with chronic obstructive pulmonary disease (COPD). A study was undertaken to measure the mitochondrial enzyme activity of the vastus lateralis muscle in patients with COPD and to evaluate the relationship between enzyme activities and functional status. METHODS Fifty seven patients with COPD of mean (SD) age 66 (7) years with forced expiratory volume in one second (FEV1) 39 (15)% predicted and peak oxygen uptake (V˙o 2) of 14 (4) ml/min/kg and 15 normal subjects of similar age were included in the study. Each subject performed a stepwise exercise test up to maximal capacity during which five-breath averages of V˙o 2were measured. Muscle specimens were obtained by percutaneous needle biopsy of the vastus lateralis muscle and the activity of two mitochondrial enzymes (citrate synthase (CS) and 3-hydroxyacyl CoA dehydrogenase (HADH)) was measured. The functional status of the patients was classified according to peakV˙o 2. RESULTS CS and HADH activities were markedly reduced in patients with COPD compared with normal subjects (22.3 (2.7) versus 29.5 (7.3) μmol/min/g muscle (p<0.0001) and 5.1 (2.0) versus 6.7 (1.9) μmol/min/g muscle (p<0.005), respectively). The activity of CS decreased progressively with the deterioration in the functional status while that of HADH was not related to functional status. Using a stepwise regression analysis, percentage predicted functional residual capacity (FRC), the activity of CS, oxygen desaturation during exercise, age, and inspiratory capacity (% pred) were found to be significant determinants of peakV˙o 2. The regression model explained 59% of the variance in peak V˙o 2 (p<0.0001). CONCLUSIONS The oxidative capacity of the vastus lateralis muscle is reduced in patients with moderate to severe COPD compared with normal subjects of similar age. In these individuals the activity of CS correlated significantly with peak exercise capacity and independently of lung function impairment.

Factors associated with hospital admissions and repeat emergency department visits for adults with asthma

Abstract: BACKGROUND—A small proportion of patients with asthma account for a disproportionate number of acute health service events. To identify whether factors other than severity and low socioeconomic status were associated with this disproportionate use, a prospective study was undertaken to examine management and psychosocial factors associated with increased risk for admission to hospital with asthma and repeat visits to the emergency department over a 12month period. METHODS—A total of 293 patients with moderate or severe asthma managed at least in part at two teaching hospitals completed surveys of clinical status, acute events, sociodemographic, and psychological variables. RESULTS—Twenty three percent had a single admission to hospital and 16% had two or more hospital admissions. Twenty six percent had one emergency department visit and 32% had two or more visits to the emergency department. In a multiple logistic regression model, adjusted for age, sex, education and income, odds ratios (95% CI) for baseline factors associated with hospital admissions over the next 12 months were: moderate severity compared with severe asthma 0.6 (0.2 to 0.9); no hospital admissions in the past 12 months 0.1 (0.01 to 0.2); not possessing a written asthma action plan 4.0 (1.5 to 10.7); less use of an avoidance coping style 0.4 (0.3 to 0.7); lower preferences for autonomy in asthma management decisions 1.4 (0.96 to 2.0). Adjusted odds ratios (95% CI) for repeat emergency department visits were: moderate asthma severity 0.3 (0.1 to 0.8); current regular use of oral corticosteroids 10.0 (3.1 to 32.4); a hospital admission in the past 12 months 2.9 (1.8 to 4.8); not possessing a written asthma action plan 2.2 (1.1 to 5.6); less dislike of asthma medications 0.7 (0.5to 0.9). CONCLUSIONS—In addition to factors relating to severity, not possessing a written asthma action plan, avoidance coping, and attitudes to self-management were related to acute use of health services in this at risk group. Interventions need to address or take these factors into account to reduce asthma morbidity.

One year period prevalence study of respiratory acidosis in acute exacerbations of COPD: implications for the provision of non-invasive ventilation and oxygen administration

Abstract: Background—Non-invasive ventilation (NIV) reduces mortality and intubation rates in patients with chronic obstructive pulmonary disease (COPD) admitted to hospital with respiratory acidosis This study aimed to determine the prevalence of respiratory acidosis in patients admitted with COPD, to draw inferences about oxygen therapy, and to determine the need for NIV services for acute COPD in typical UK hospitals Methods—This one year prospective prevalence study identified patients with COPD aged 45‐79 years inclusive who were admitted to Leeds General Infirmary, St James’s University, and Killingbeck Hospitals, Leeds between 1 March 1997 and 28 February 1998 The prevalence of respiratory acidosis and the relationship with oxygenation are described Other outcomes included intensive care use and in hospital mortality From this data population prevalence estimates were determined for respiratory acidosis, from which the need for NIV in a typical district general hospital was modelled Results—983 patients were admitted, 11 of whom required immediate intubation 20% of the remaining 972 had a respiratory acidosisAcidosis was associated with subsequent admission to the intensive care unit (ICU): pH 10 kPa being associated with acidosis in most hypercapnic patients 80% remained acidotic after initial treatment, giving an age/sex specific prevalence for England and Wales of 75 (95% CI 61 to 90)/ 100 000/year for men aged 45‐79 years and 57 (95% CI 46 to 69)/100 000/year for women Modelling the need for NIV for all COPD patients indicates that a typical UK hospital will admit 90 patients per year with acidosis of which 72 will require NIV Conclusions—In patients with acute COPD the PaO2 should be maintained at 73‐10 kPa (SaO2 85‐92%) to avoid the dangers of hypoxia and acidosis If all COPD patients with a respiratory acidosis (pH<735) after initial treatment are offered NIV, a typical UK hospital will treat 72 patients per year (Thorax 2000;55:550‐554)

Rare diseases bullet 8: Organising pneumonia

Abstract: Organising pneumonia is defined pathologically by the presence in the distal air spaces of buds of granulation tissue progressing from fibrin exudates to loose collagen containing fibroblasts (fig 1). 2 The lesions occur predominantly within the alveolar spaces but are often associated with buds of granulation tissue occupying the bronchiolar lumen (bronchiolitis obliterans). This pathological pattern is not specific for any disorder or cause, but reflects one type of inflammatory process resulting from lung injury. It may also be a feature of the organising stage of adult respiratory distress syndrome and may be an accessory finding in other inflammatory disorders such as vasculitis. However, organising pneumonia is the particular pathological hallmark of a characteristic clinicoradiological entity called cryptogenic organising pneumonia. This terminology is preferred to the other name used for this condition—namely, idiopathic bronchiolitis obliterans with organising pneumonia (BOOP)—which may be confused with other types of bronchiolar disorders, particularly constrictive bronchiolitis obliterans which is mainly characterised by airflow obstruction.

Pulmonary alveolar proteinosis: clinical aspects and current concepts on pathogenesis

Abstract: Pulmonary alveolar proteinosis was first described by Rosen et al in 1958.1 It is an unusual diffuse lung disease characterised by the accumulation of large amounts of a phospholipoproteinaceous material in the alveoli. It has a variable clinical presentation and course. Most cases are primary but occasionally the condition is secondary to other conditions or inhalation of chemicals. Whole lung lavage remains the most effective treatment and the overall prognosis is good. Surfactant homeostasis is abnormal and animal experiments suggest that this may relate, in some instances at least, to defects in GM-CSF signalling. There are at least two congenital forms of the disease and several different animal models suggesting that pulmonary alveolar proteinosis is unlikely to be a single disease entity and more likely to represent a clinical syndrome. Pulmonary alveolar proteinosis is a rare lung disease and accurate estimates of incidence are not available. Current estimates suggest an incidence of one in two million people. The series reported in the literature suggest a male preponderance (male:female ratio 3:1).1-11 Peak onset is in the third or fourth decade of life with over 80% of reported cases occurring in this age group.1-9 However, there are reports of the disease occurring in neonates,12 children,13-15 and the elderly.11 ### CLINICAL PRESENTATION Dyspnoea is the most common presenting symptom. It usually occurs on moderate exertion but in a few patients occurs at rest.1-11 Cough is the other common symptom. These symptoms are often trivial and some patients do not present until they develop a supervening infection. This may explain the acute onset of symptoms and fever observed in some patients. A low grade fever may also occur as a consequence of pulmonary alveolar proteinosis in the absence of secondary infection.6 Physical examination is often normal and inspiratory crackles …

Capsaicin responsiveness and cough in asthma and chronic obstructive pulmonary disease

Abstract: 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.

Airflow obstruction in bronchiectasis: correlation between computed tomography features and pulmonary function tests

Abstract: Background—An obstructive defect is usual in bronchiectasis, but the pathophysiological basis of airflow obstruction remains uncertain. High resolution computed tomographic (CT) scanning now allows quantitation of static morphological abnormalities, as well as dynamic changes shown on expiratory CT scans. The aim of this study was to determine which static and dynamic structural abnormalities on the CT scan are associated with airflow obstruction in bronchiectasis. Methods—The inspiratory and expiratory features on the CT scan of 100 patients with bronchiectasis undergoing concurrent lung function tests were scored semiquantitatively by three observers. Results—On univariate analysis the extent and severity of bronchiectasis, the severity of bronchial wall thickening, and the extent of decreased attenuation on the expiratory CT scan correlated strongly with the severity of airflow obstruction; the closest relationship was seen between decreased forced expiratory volume in one second (FEV1) and the extent of decreased attenuation on the expiratory CT scan (Rs = ‐0.55, p<0.00005). On multivariate analysis bronchial wall thickness and decreased attenuation were consistently the strongest independent determinants of airflow obstruction. The extent of decreased attenuation was positively associated with the severity of bronchial wall thickness, but was not independently linked to gas transfer levels. Endobronchial secretions seen on CT scanning had no functional significance; the severity of bronchial dilatation was negatively associated with airflow obstruction after adjustment for other morphological features. Conclusions—These findings indicate that airflow obstruction in bronchiectasis is primarily linked to evidence of intrinsic disease of small and medium airways on CT scanning and not to bronchiectatic abnormalities in large airways, emphysema, or retained endobronchial secretions. (Thorax 2000;55:198‐204)

Analysis of ciliary beat pattern and beat frequency using digital high speed imaging: comparison with the photomultiplier and photodiode methods

Abstract: BACKGROUND—The aim of this study was to determine the relationship of the power and recovery stroke of respiratory cilia using digital high speed video imaging. Beat frequency measurements made using digital high speed video were also compared with those obtained using the photomultiplier and modified photodiode techniques. METHOD—Ciliated epithelium was obtained by brushing the inferior nasal turbinate of 20 healthy subjects. Ciliated edges were observed by microscopy and the deviation of cilia during their recovery stroke relative to the path travelled during their power stroke was measured. Beat frequency measurements made by digital high speed video analysis were compared with those obtained using the photomultiplier and modified photodiode. RESULTS—Cilia were found to beat with a forward power stroke and a backward recovery stroke within the same plane. The mean angular deviation of the cilia during the recovery stroke from the plane of the forward power stroke was only 3.6°(95% CI 3.1 to 4.1). There was a significant difference in beat frequency measurement between the digital high speed video (13.2 Hz (95% CI 11.8 to 14.6)) and both photomultiplier (12.0 Hz (95% CI 10.8 to 13.1), p = 0.01) and photodiode (11.2 Hz (95% CI 9.9 to 12.5), p<0.001) techniques. The Bland-Altman limits of agreement for the digital high speed video were -2.75 to 5.15 Hz with the photomultiplier and -2.30 to 6.06 Hz with the photodiode. CONCLUSION—Respiratory cilia beat forwards and backwards within the same plane without a classical sideways recovery sweep. Digital high speed video imaging allows both ciliary beat frequency and beat pattern to be evaluated.

Management of opportunist mycobacterial infections: Joint Tuberculosis Committee guidelines 1999

Abstract: Guidelines have been produced for tuberculosis by the British Thoracic Society (BTS), 2 the American Thoracic Society (ATS), the International Union Against Tuberculosis and Lung Disease, and the World Health Organisation. These, however, deal mainly with Mycobacterium tuberculosis complex infections (M tuberculosis, M africanum, and M bovis). With the exception of the ATS guidelines on non-tuberculous mycobacteria, these do not address the opportunist mycobacteria (also called atypical mycobacteria, mycobacteria other than tuberculosis (MOTT), nontuberculous mycobacteria (NTM), or environmental mycobacteria). The number of isolates of such opportunist mycobacteria has been increasing, both in HIV negative and HIV positive individuals. Because of the growing numbers of patients with disease due to infection by these mycobacteria, the wide range of species, the diYculties in both diagnosis and management, and in response to increasing requests for advice on management, the BTS Joint Tuberculosis Committee has reviewed the evidence on management of these infections. On the whole the evidence is not derived from controlled clinical trials as very few have been reported but, where possible, we have graded the evidence according to the criteria in table 1. Sections cover epidemiology, bacteriological aspects, diagnosis and treatment in adults and children, separated where appropriate into sections according to their HIV infection status.

Case-control study of 24 hour ambulatory blood pressure in patients with obstructive sleep apnoea and normal matched control subjects

Abstract: BACKGROUND There is considerable debate regarding the relationship between obstructive sleep apnoea (OSA) and hypertension. It is unclear whether OSA is an independent vascular risk factor as studies attempting to assess this association have produced conflicting results because of confounding variables such as upper body obesity, alcohol, and smoking. A case-control study of 24 hour ambulatory blood pressure was undertaken in patients with OSA and matched controls to assess whether OSA is an independent correlate of diurnal hypertension. METHODS Forty five patients with moderate to severe OSA and excessive daytime sleepiness were matched with 45 controls without OSA in a sleep study. Matched variables included age, body mass index (BMI), alcohol, cigarette usage, treated hypertension, and ischaemic heart disease. Upper body obesity was compared by waist:hip and waist:height ratios; 24 hour ambulatory blood pressure recordings were performed (before treatment for OSA) in all subjects. RESULTS Patients with OSA had significantly increased mean (SD) diastolic blood pressure (mm Hg) during both daytime (87.4 (10.2) versus 82.8 (9.1); p=0.03, mean difference 4.6 (95% CI 0.7 to 8.6) and night time (78.6 (9.3) versus 71.4 (8.0); p CONCLUSIONS Compared with closely matched control subjects, patients with OSA have increased ambulatory diastolic blood pressure during both day and night, and increased systolic blood pressure at night. The magnitude of these differences is sufficient to carry an increased risk of cardiovascular morbidity. The slight excess of upper body fat deposition in the controls may make these results conservative.

A randomised controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease

Abstract: BACKGROUND A study was undertaken to evaluate and compare the efficacy and safety of tiotropium and ipratropium during long term treatment in patients with stable chronic obstructive pulmonary disease (COPD). METHODS 288 patients of mean (SD) age 65 (8) years and forced expiratory volume in one second (FEV1) 41 (12)% predicted participated in a 14 centre, double blind, double dummy, parallel group study and were randomised after a run in period of two weeks to receive either tiotropium 18 μg once daily from a dry powder inhaler (HandiHaler; two thirds of patients) or ipratropium 40 μg four times daily from a metered dose inhaler (one third of patients) for a period of 13 weeks. Outcome measures were lung function, daily records of peak expiratory flow (PEF), and the use of concomitant salbutamol. FEV1and forced vital capacity (FVC) were measured one hour before and immediately before inhalation (mean value of the two measurements on test day 1 was the baseline value while on all other test days it was known as the trough FEV1 and FVC), and 0.5, 1, 2, 3, 4, 5, and 6 hours after inhalation of the study drug on days 1, 8, 50, and 92. RESULTS During treatment tiotropium achieved a significantly greater improvement than ipratropium (p<0.05) in trough, average, and peak FEV1levels and in trough and average FVC levels. The trough FEV1 response on days 8, 50, and 92 ranged between 0.15 l (95% CI 0.11 to 0.19) and 0.16 l (95% CI 0.12 to 0.20) for tiotropium and between 0.01 l (95% CI –0.03 to 0.05) and 0.03 l (95% CI 0.01 to 0.07) for ipratropium. The trough FVC response on days 8, 50, and 92 ranged between 0.34 l (95% CI 0.28 to 0.40) and 0.39 l (95% CI 0.31 to 0.47) for tiotropium and between 0.08 l (95% CI 0.00 to 0.16) and 0.18 l (95% CI 0.08 to 0.28) for ipratropium. On all test days tiotropium produced a greater improvement in FEV1than ipratropium starting three hours after inhalation (p<0.05). During treatment weekly mean morning and evening peak expiratory flow (PEF) was consistently better in the tiotropium group than in the ipratropium group, the difference in morning PEF being significant up through week 10 and in evening PEF up through week 7 of treatment (p<0.05). The use of concomitant salbutamol was also lower in the tiotropium group (p<0.05). The only drug related adverse event was dry mouth (tiotropium 14.7%, ipratropium 10.3% of patients). CONCLUSIONS Tiotropium in a dose of 18 μg inhaled once daily using the HandiHaler was significantly more effective than 40 μg ipratropium four times daily in improving trough, average, and peak lung function over the 13 week period. The safety profile of tiotropium was similar to ipratropium. These data support the use of tiotropium as first line treatment for the long term maintenance treatment of patients with airflow obstruction due to COPD.