Early History of Chronic Obstructive Pulmonary Disease 1808-1980.

COPD has become a more popular research area in the last 3 decades, yet the first clear descriptions of acute and chronic bronchitis were in 1808. This brief history, comprehensively referenced, leads us through the early developments in respiratory physiology and their applications. It emphasises the early history of chronic bronchitis and emphysema in the 19(th) and early 20(th) centuries, long before the dominant effects of cigarette smoking emerged. This remains relevant to developing countries today.

Glottal Aperture and Buccal Airflow Leaks Critically Affect Forced Oscillometry Measurements.

BACKGROUND: The forced oscillation technique (FOT) measures respiratory resistance and reactance; however, the upper airways may affect the results. We quantified the impact of glottal aperture and buccal air leaks. METHODS: In the glottal aperture study (1) 10 healthy subjects (aged 34 ± 2 years) performed a total lung capacity maneuver followed by 10-s breath-hold with and without total glottal closure and (2) the effects of humming (incomplete glottal narrowing) on FOT measurements were studied in six healthy subjects. Glottal narrowing was confirmed by direct rhinolaryngoscopy. In the air leak study, holes of increasing diameter (3.5, 6.0, and 8.5 mm) were made to the breathing filters. Eleven healthy subjects (aged 33 ± 2 years) and five patients with COPD (aged 69 ± 3 years) performed baseline FOT measurements with the three modified filters. RESULTS: Narrow glottal apertures and humming generated whole-breath resistance at 5 Hz (R5) peaks, increased R5 (1.49 ± 0.37 kPa/L/s vs 0.34 ± 0.01 kPa/L/s, P < .001), and decreased whole-breath reactance at 5 Hz (X5) values (-2.10 ± 0.51 kPa/L/s vs -0.09 ± 0.01 kPa/L/s, P < .001). The frequency dependency of resistance was increased. Holes in the breathing filters produced indentations on the breathing trace. Even the smaller holes reduced R5 in healthy subjects (0.33 ± 0.02 to 0.24 ± 0.02 kPa/L/s, P < .01) and patients with COPD (0.50 ± 0.04 to 0.41 ± 0.04 kPa/L/s, P < .05), whereas X5 became less negative (from -0.09 ± 0.01 to -0.05 ± 0.01 in healthy subjects, P < .01; from -0.22 ± 0.06 to -0.11 ± 0.03 kPa/L/s in patients with COPD, P < .05). CONCLUSIONS: Visual inspection of the data is required to exclude glottal narrowing and buccal air leaks identified as R5 peaks and volume indentations, respectively, because these significantly affect FOT measurements.

Smoking cessation in COPD causes a transient improvement in spirometry and decreases micronodules on high-resolution CT imaging.

BACKGROUND: Smoking cessation is of major importance for all smokers; however, in patients with COPD, little information exists on how smoking cessation influences lung function and high-resolution CT (HRCT) scan appearances. METHODS: In this single-center study, we performed screening spirometry in a group of heavy smokers aged 40 to 80 years (N = 358). We then studied the effects of smoking cessation in two groups of selected subjects: smokers with COPD (n = 38) and smokers with normal spirometry (n = 55). In parallel to subjects undergoing smoking cessation, we studied a control group of nonsmokers (n = 19). RESULTS: Subjects with COPD who quit smoking had a marked, but transient improvement in FEV1 at 6 weeks (184 mL, n = 17, P < .01) that was still present at 12 weeks (81 mL, n = 17, P < .05) and only partially maintained at 1 year. In contrast, we saw improvement in the transfer factor of lung for carbon monoxide at 6 weeks in both subjects with COPD who quit smoking (0.47 mmol/min/kPa, n = 17, P < .01) and subjects who quit smoking with normal spirometry (0.40 mmol/min/kPa, n = 35, P < .01). An upper-zone single HRCT image slice reliably identified emphysema at baseline in 74% of smokers with COPD (28 of 38) and 29% of healthy smokers (16 of 55). Smoking cessation had no significant effect on the appearances of emphysema but decreased the presence of micronodules on HRCT imaging. CONCLUSIONS: Cigarette smoking causes extensive lung function and HRCT image abnormalities, even in patients with normal spirometry. Smoking cessation has differential effects on lung function (FEV1 and gas transfer) and features on HRCT images (emphysema and micronodules). Cessation of smoking in patients with COPD causes a transient improvement in FEV1 and decreases the presence of micronodules, offering an opportunity for concomitant therapy during smoking cessation to augment these effects. Smoking cessation at the earliest possible opportunity is vital to minimize permanent damage to the lungs.

Examination of the carbon monoxide diffusing capacity (DL(CO)) in relation to its KCO and VA components.

The single-breath carbon monoxide diffusing capacity (DL(CO)) is the product of two measurements during breath holding at full inflation: (1) the rate constant for carbon monoxide uptake from alveolar gas (kco [minute(-1)]) and (2) the "accessible" alveolar volume (Va). kco expressed per mm Hg alveolar dry gas pressure (Pb*) as kco/Pb*, and then multiplied by Va, equals Dl(CO); thus, Dl(CO) divided by Va (DL(CO)/Va, also called Kco) is only kco/Pb* in different units, remaining, essentially, a rate constant. The notion that DL(CO)/Va "corrects" DL(CO) for reduced Va is physiologically incorrect, because DL(CO)/Va is not constant as Va changes; thus, the term Kco reflects the physiology more appropriately. Crucially, the same DL(CO) may occur with various combinations of Kco and Va, each suggesting different pathologies. Decreased Kco occurs in alveolar-capillary damage, microvascular pathology, or anemia. Increased Kco occurs with (1) failure to expand normal lungs to predicted full inflation (extrapulmonary restriction); or (2) increased capillary volume and flow, either globally (left-to-right intracardiac shunting) or from flow and volume diversion from lost or damaged units to surviving normal units (e.g., pneumonectomy). Decreased Va occurs in (1) reduced alveolar expansion, (2) alveolar damage or loss, or (3) maldistribution of inspired gases with airflow obstruction. Kco will be greater than 120% predicted in case 1, 100-120% in case 2, and 40-120% in case 3, depending on pathology. Kco and Va values should be available to clinicians, as fundamental to understanding the clinical implications of DL(CO). The diffusing capacity for nitric oxide (DL(NO)), and the DL(NO)/DL(CO) ratio, provide additional insights.

Comparison of inspiratory and expiratory resistance and reactance in patients with asthma and chronic obstructive pulmonary disease.

BACKGROUND: The usual analysis of forced oscillometry measures respiratory resistance (Rrs) and reactance (Xrs) averaged over several tidal breaths (whole-breath analysis). Recent within-breath analyses have separated Rrs and Xrs into their mean inspiratory and mean expiratory components (inspiratory-expiratory breath analysis) but these have not been used to compare patients with asthma and those with chronic obstructive pulmonary disease (COPD). Large inspiratory-expiratory variations in Xrs at 5 Hz (DeltaX5) in an individual have been used as a surrogate marker of expiratory flow limitation. METHODS: Whole-breath and inspiratory-expiratory impulse oscillometry was assessed in 34 patients with asthma (49 + or - 3 years; 15 male, forced expiratory volume in 1 s (FEV(1)) 69 + or - 4% predicted), 48 patients with COPD (64 + or - 2 years; 32 male, FEV(1) 59 + or - 3% predicted) and 18 normal subjects (37 + or - 2 years; 8 male). RESULTS: Whole-breath analysis failed to discriminate between patients with asthma and patients with COPD either for all patients or for patients with FEV(1) <60% predicted. Inspiratory-expiratory analysis in patients with FEV(1) <60% predicted showed that in the COPD group mean expiratory X5 (-0.44 + or - 0.04 kPa/l/s) was greater than inspiratory X5 (-0.23 + or - 0.02 kPa/l/s, p<0.001) whereas patients with asthma did not show such changes (-0.36 + or - 0.07 kPa/l/s vs -0.26 + or - 0.03 kPa/l/s, p=0.23). Even though DeltaX5 was larger in patients with COPD (0.21 + or - 0.03 kPa/l/s) than in patients with asthma (0.10 + or - 0.07 kPa/l/s), this was not significant (p=0.15). CONCLUSIONS: Whole-breath impulse oscillation system analysis failed to discriminate between patients with asthma and those with COPD. Inspiratory-expiratory X5 analysis differentiated patients with asthma from those with COPD presumably reflecting enhanced dynamic airway narrowing on expiration in COPD. Further studies are needed to confirm these differences and investigate their cause.

Effects of repeated deep inspirations on recovery from methacholine-induced airway narrowing in normal subjects.

BACKGROUND: A single deep inspiration (DI) is known to be a potent bronchodilator but it is not known if repeated DI can accelerate sustained recovery from bronchoconstriction. METHODS: We induced sustained bronchoconstriction using increasing concentrations of nebulized methacholine (Mch) during tidal breathing and assessed airway narrowing by measuring respiratory resistance (Rrs) using forced oscillation in six healthy subjects. On separate days we examined the effects of DI every 3 minutes and of prohibition of DI on recovery of Rrs for 30 minutes after the end of Mch nebulization. RESULTS: Bronchoconstriction (Rrs approximately 150% above baseline) was induced. DI during recovery had a transient bronchodilator effect but no cumulative effect. At 30 minutes after end of nebulization (and 2 minutes after the last DI) Rrs was 87% above baseline compared to 93% above baseline when DI was prohibited. CONCLUSION: Recovery from induced bronchoconstriction with methacholine was slow (approximately 2%/min) and not accelerated by frequent DI.

Proposal for a multidimensional staging system for chronic obstructive pulmonary disease.

The severity of chronic obstructive pulmonary disease (COPD) is currently assessed using a single physiological measurement, the forced expiratory volume in 1s (FEV1). COPD, however, has complex effects on other aspects of respiratory function, and in many patients is associated with important systemic changes. We hypothesized that a multidimensional staging system for COPD could provide a more complete assessment of the disease's impact. We considered over 40 potential staging variables, evaluating them according to sensitivity to change, measured reproducibly, independence of the information they provide and prognostic value. We finally selected three: FEV1 (including arterial blood gas measurements when FEV1 falls below 35% predicted), Medical Research Council dyspnea scale and body mass index (BMI). Each measure correlates independently with prognosis in COPD, is supported by a significant body of literature and serves as a surrogate for other potentially important variables. We then used principal components analysis (PCA) to determine the degree of association between 30 of the potential variables measured in 813 stable COPD patients. Using PCA, six groups of measurements defined independent categories of patient information: pulmonary function (including FEV1), symptoms of cough and sputum, dyspnea, health status, bronchodilator reversibility and BMI. These include the three principal variables selected for the staging system. Although the staging boundaries were based on existing literature, they have proven useful in predicting survival. We conclude that a multidimensional grading system is useful to assess the impact of COPD.

Inhaled corticosteroids in chronic obstructive pulmonary disease: results from two observational designs free of immortal time bias.

RATIONALE: Recent cohort studies in chronic obstructive pulmonary disease (COPD) have questioned the validity of previously reported associations between inhaled corticosteroids (ICS) and reductions in mortality and rehospitalization in observational studies. Using time-dependent versions of statistical survival models, these studies have suggested immortal time bias as responsible for the proposed beneficial association. OBJECTIVES: We explored the extent of this bias in a study of patients with COPD monitored for a year from COPD discharge with two designs free of any immortal time bias in the General Practice Research Database in the United Kingdom. METHODS: In Design 1, we used only patients whose treatment status was defined on the same day of discharge to obtain a matched cohort based on propensity scores, which were derived from the patient-level baseline characteristics. In Design 2, we identified all in the study cohort who experienced death or rehospitalization and then matched each case to up to four noncases by randomly sampling from the cohort risk sets without regard to treatment status. MEASUREMENTS AND MAIN RESULTS: The propensity scores matched cohort analysis of 786 patients without a wait time found a significant risk reduction associated with use of ICS: hazard ratio, 0.69 (95% confidence interval, 0.52-0.93). The matched nested case-control analysis of 2,222 patients, designed without regard to exposure status and hence free of immortal time bias, gave a similar association with exposure to ICS in the last 6-month period: hazard ratio, 0.71 (0.56-0.90). CONCLUSIONS: We conclude that immortal time bias cannot account for the risk reduction associated with ICS exposure in observational studies.

Flow dependence and repeatability of interrupter resistance in lower airways and nose.

The interrupter technique, the simplest method for measuring airflow resistance (R(int)) is particularly valuable under field conditions. We investigate whether during tidal breathing, variations in the flow at which interruption occurs contribute to variability of results. Using a portable device with mouthpiece, sets of 10 measurements of R(int) (R(int,mo)) were made in inspiration and expiration at 0.05 l s(-1) intervals from 0.1 up to 0.9 l s(-1) flow in 22 normal adults, 11 children (5-9 years) and 12 COPD patients. R(int) was also measured via nasal-mask in normal adults (R(int,na)). Intra-subject coefficient of variation was obtained at each flow and flow-dependence of R(int) was assessed. In normal subjects, R(int)-flow relationships were consistent, with a narrow range of absolute values. R(int,na), but not R(int,mo), rose with increasing flow, especially >0.4 l s(-1). Repeatability was poor at flows <0.3 l s(-1) but improved with increasing flow and was better in inspiration than expiration. In children, repeatability was better than in adults and R(int,mo) was not flow dependent at < or =0.4 l s(-1). By contrast, in COPD patients repeatability was less good and R(int,mo) increased with increasing flows. R(int,mo) and R(int,na) should be measured at fixed inspiratory flows. The best signal-to-noise ratios were obtained at 0.4 l s(-1) for R(int) in normal adults and COPD patients and at 0.3 l s(-1) in children.

The proportional Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom.

STUDY OBJECTIVES: The nonproportional Venn diagram of obstructive lung disease (OLD) produced for the 1995 American Thoracic Society guidelines has not been quantified. We aim to quantify the proportion of the general population with OLD and the intersections of physician-diagnosed asthma, chronic bronchitis, and emphysema in the United States and the United Kingdom, and to examine the relationship to obstructive spirometry. DESIGN AND PARTICIPANTS: We analyzed data from the US National Health and Nutrition Examination (NHANES) III survey (1988 to 1994) and the UK General Practice Research Database for the year 1998. RESULTS: The areas of intersection among the three OLD conditions produced seven mutually exclusive disease groups. The asthma-only group was the largest proportion of OLD patients, accounting for 50.3% and 79.4% of all OLD patients in the United States and the United Kingdom, respectively, and decreased with increasing age. Overall, 17% and 19% of OLD patients in the United States and in the United Kingdom, respectively, reported more than one OLD condition, and this percentage increased with age. According to the spirometry data from NHANES III, only 37.4% of emphysema-only patients had objective airflow obstruction. The prevalence of airflow obstruction was significantly higher among participants with combinations of emphysema and chronic bronchitis (57.7%), with emphysema and asthma (51.9%), and with all three OLD diseases concomitantly (52.0%). CONCLUSION: Concomitant diagnosis of asthma, chronic bronchitis, or emphysema is common among OLD patients from the general population, particularly in adults aged > or = 50 years.

Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease (COPD), whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status. We postulated that a combination of these treatments would be better than each component used alone. METHODS: 1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, double-blind, parallel-group, placebo-controlled study with either 50 microg salmeterol twice daily (n=372), 500 microg fluticasone twice daily (n=374), 50 microg salmeterol and 500 microg fluticasone twice daily (n=358), or placebo (n=361) for 12 months. The primary outcome was the pretreatment forced expiratory volume in 1s (FEV1) after 12 months treatment' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h. Secondary outcomes were other lung function measurements, symptoms and rescue treatment use, the number of exacerbations, patient withdrawals, and disease-specific health status. We assessed adverse events, serum cortisol concentrations, skin bruising, and electrocardiograms. Analysis was as predefined in the study protocol. FINDINGS: All active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV1 significantly more than did placebo (treatment difference 133 mL, 95% CI 105-161, p<0.0001), salmeterol (73 mL, 46-101, p<0.0001), or fluticasone alone (95 mL, 67-122, p<0.0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration. INTERPRETATION: Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function, with no greater risk of side-effects than that with use of either component alone, this combination treatment should be considered for patients with COPD.

Inhaled corticosteroids with/without long-acting beta-agonists reduce the risk of rehospitalization and death in COPD patients.

INTRODUCTION: In patients with COPD who have recently been hospitalized for their disease, we examined whether treatment with inhaled corticosteroids without or with long-acting beta-adrenoceptor agonists (beta-agonists) reduced rehospitalization and mortality. STUDY DESIGN: Retrospective cohort analysis in the UK General Practice Research Database. METHODS: We compared rehospitalization for a COPD-related medical condition or death within 1 year after first hospitalization, in 3636 COPD patients receiving prescriptions for inhaled corticosteroids or long-acting beta-agonists compared with 627 reference patients with COPD who were prescribed short-acting bronchodilators only. RESULTS: Rehospitalization within a year occurred in 13.2% of the reference COPD patients, 14.0% of users of long-acting beta-agonists only, 12.3% of users of inhaled corticosteroids only, and 10.4% of users of inhaled corticosteroids and long-acting beta-agonists. Death within a year occurred in 24.3% of the reference COPD patients, 17.3% of users of long-acting beta-agonists only, 17.1% of users of inhaled corticosteroids only, and in 10.5% of users of inhaled corticosteroids and long-acting beta-agonists. In multivariate analyses the risk of rehospitalization or death was reduced by 10% in users of long-acting beta-agonists only (NS), by 16% in users of inhaled corticosteroids only, and by 41% in users of combined inhaled corticosteroids and long-acting beta-agonists (both p < 0.05). CONCLUSION: Use of inhaled corticosteroids with/without long-acting beta-agonists was associated with a reduction of rehospitalization or death in COPD patients.

Diaphragm length during tidal breathing in patients with chronic obstructive pulmonary disease.

Diaphragm function is compromised in severe chronic obstructive pulmonary disease (COPD) by hyperinflation, but its ability to shorten and contribute to tidal volume is uncertain. We estimated coronal diaphragm length by measuring zone of apposition length with ultrasound and rib cage diameters with magnetometers, in 10 male patients with severe COPD and 10 age- and sex-matched control subjects. Diaphragm length was 20% shorter in patients at residual volume (413 and 536 mm in patients and control subjects, respectively) and FRC (381 and 456 mm, respectively), but was not different at total lung capacity (312 and 336 mm, respectively). Zone of apposition length was reduced 50% at residual volume and FRC in patients, but was larger at a given absolute lung volume than in control subjects. There were no differences in tidal volume (0.8 L), tidal changes in zone of apposition length (20 mm) and diaphragm length (38 and 42 mm), and tidal volume displaced by the diaphragm (0.6 L), even though mean FRC in patients was similar to predicted total lung capacity. Although the diaphragm is shorter at FRC in patients with COPD, its motion and change in length during tidal breathing is similar to that in control subjects.

Effect of severe isolated unilateral and bilateral diaphragm weakness on exercise performance.

Patients with isolated diaphragm paralysis depend on recruitment of extradiaphragmatic respiratory muscles to increase ventilation, but little is known about exercise performance or the response of the inspiratory muscles to loaded breathing. By convention, unilateral diaphragm paralysis is regarded as a trivial condition whereas bilateral paralysis is considered to be potentially life-threatening. In fact, no data exist concerning exercise performance under these conditions. We studied incremental treadmill exercise performed by eight patients with bilateral diaphragm paralysis, eight patients with unilateral diaphragm paralysis, and eight age-matched control subjects. Respiratory muscle endurance (RME) was also measured by an inspiratory threshold loading method. Exercise time, compared with control subjects (671 seconds), was moderately reduced in unilateral diaphragm paralysis (512 seconds, p = 0.07) and further reduced in bilateral diaphragm paralysis (456 seconds, p = 0.02). Similarly, peak minute ventilation was lower in patients with unilateral diaphragm paralysis (84 L x min(-1), p = 0.01) and in patients with bilateral diaphragm paralysis (69 L x min(-1), p = 0.001) compared with control subjects (114 L x min(-1)). However, patients with unilateral diaphragm paralysis and patients with bilateral diaphragm paralysis had increased ratios of peak oxygen consumption to peak minute ventilation compared with control subjects (p = 0.0007 and p < 0.0001, respectively). Nine patients had normal RME; exercise time was moderately increased in these patients (502 seconds) compared with seven patients with reduced RME (461 seconds). In conclusion, although exercise performance is impaired in bilateral diaphragm paralysis, these patients can sustain a reasonable exercise load, particularly if RME is preserved and compensatory mechanisms have developed. In addition, exercise tolerance is diminished in patients with unilateral diaphragm paralysis.

Chronic obstructive pulmonary disease in the United Kingdom: trends in mortality, morbidity, and smoking.

Current trends in chronic obstructive pulmonary disease (COPD) in the UK differ from those in many other countries because, in the past, COPD was much more common than in other countries undergoing a smoking epidemic at the same time, and peak cigarette consumption in men and women occurred more 25 years ago. Male mortality from COPD has been falling for 30 years, while female mortality has risen steadily during the same period. A strong socioeconomic gradient in morbidity and mortality persists. Emergency hospital admissions for exacerbations and home oxygen account for a large proportion of the healthcare costs.