Contributions of loss of lung recoil and of enhanced airways collapsibility to the airflow obstruction of chronic bronchitis and emphysema.

We investigated the contributions of intrinsic disease of the airways, loss of lung recoil and enhanced airway collapsibility to the airflow obstruction of 17 patients with chronic bronchitis and emphysema. Airways conductance at low flow (G(aw)), maximum expiratory flow (V(E, MAX)) and static lung recoil pressure [P(st) (l)] were measured at different lung volumes, and conductance-static recoil pressure and maximum flow-static recoil pressure curves constructed. Low values of DeltaG(aw)/DeltaP(st) (l) and DeltaV(E), max/DeltaP(st) (l) were attributed to intrinsic airways disease. Airway collapsibility was assessed by comparing G(aw) with upstream conductance on forced expiration and by the intercept of the maximum flow-static recoil curve on the static recoil pressure axis (P(tm)'). All patients had reduced G(aw) at all volumes but in seven DeltaG(aw)/DeltaP(st) (l) was normal. On forced expiration, maximum flow in all patients was reduced more than could be accounted for by loss of lung recoil. DeltaV(E, MAX)/DeltaP(st) (l) was reduced in the patients in whom DeltaG(aw)/P(st) (l) was low. In contrast DeltaV(E, MAX)/DeltaP(st) (l) was normal in three and only slightly reduced in another three of the seven patients with normal DeltaG(aw)/DeltaP(st) (l). In these patients G(aw) greatly exceeded upstream conductance and P(tm)' was increased.We conclude that loss of lung recoil could account for the reduction in resting airways dimensions in 7 of the 17 patients. Enhanced airway collapsibility commonly contributed to reduction in maximum flow. In three patients the airflow obstruction could be entirely accounted for by loss of lung recoil and enhanced airway collapsibility.

Predictors of lung function and its decline in mild to moderate COPD in association with gender: results from the Euroscop study.

BACKGROUND: There is increasing appreciation of gender differences in COPD but scant data whether risk factors for low lung function differ in men and women. We analysed data from 3 years follow-up in 178 women and 464 men with COPD, participants in the Euroscop Study who were smokers unexposed to inhaled corticosteroids. METHODS: Explanatory variables of gender, age, starting age and pack-years smoking, respiratory symptoms, FEV(1)%FVC and FEV(1)%IVC (clinically important measures of airway obstruction), body mass index (BMI), and change in smoking were included in multiple linear regression models with baseline and change in post-bronchodilator FEV(1) as dependent variables. RESULTS: Reduced baseline FEV(1) was associated with respiratory symptoms in men only. Annual decline in FEV(1) was not associated with respiratory symptoms in either men or women, and was 55 ml less in obese men (BMI 30 kg/m(2)) than men having normal BMI, an effect not seen in women. It was 32 ml faster in women with FEV(1)%FVC

Postural changes in lung volumes and respiratory resistance in subjects with obesity.

Reduced functional residual capacity (FRC) is consistently found in obese subjects. In 10 obese subjects (mean +/- SE age 49.0 +/- 6 yr, weight 128.4 +/- 8 kg, body mass index 44 +/- 3 kg/m2) without respiratory disease, we examined 1) supine changes in total lung capacity (TLC) and subdivisions, 2) whether values of total respiratory resistance (Rrs) are appropriate for mid-tidal lung volume (MTLV), and 3) estimated resistance of the nasopharyngeal airway (Rnp) in both sitting and supine postures. The results were compared with those of 13 control subjects with body mass indexes of <27 kg/m2. Rrs at 6 Hz was measured by applying forced oscillation at the mouth (Rrs,mo) or the nose (Rrs,na); Rnp was estimated from the difference between sequential measurements of Rrs,mo and Rrs,na. All measurements were made when subjects were seated and when supine. Obese subjects when seated had a restrictive defect with low TLC and FRC-to-TLC ratio; when supine, TLC fell 80 ml and FRC fell only 70 ml compared with a mean supine fall of FRC of 730 ml in control subjects. Values of Rrs,mo and Rrs,na at resting MTLV in obese subjects were about twice those in control subjects in both postures. Relating total respiratory conductance (1/Rrs) to MTLV, the increase in Rrs,mo in obese subjects was only partly explained by their reduced MTLV. Rnp was increased in some obese subjects in both postures. Despite the increased extrapulmonary mass load in obese subjects, further falls in TLC and FRC when supine were negligible. Rrs,mo at isovolume was increased. Further studies are needed to examine the causes of reduced TLC and increases in Rrs,mo and sometimes in Rnp in obese subjects.

Evolution of changes in carbon monoxide transfer factor in men with chronic obstructive pulmonary disease.

Progression of chronic obstructive pulmonary disease (COPD) has been studied predominantly by following change in forced expiratory volume in 1s (FEV1) which reflects both primary airway disease and associated alveolar disease. Carbon monoxide transfer (Tlco) (the product of the transfer coefficient Kco and alveolar volume Va) is the only simple, widely available test of alveolar function, but few studies have followed long-term changes in an individual. Seventeen middle-aged men with moderate chronic airflow obstruction (mean FEV1 56% of predicted values) were observed with yearly measurements of FEV1, Tlco and Kco over a mean of 18.9 yr. At the end of follow-up FEV1 had fallen to 29% of predicted values. Va, measured by single breath dilution, fell in each man. Kco at recruitment ranged from 41% to 110% predicted and remained >75% predicted in eight men at the end of follow-up supporting a phenotype of COPD with predominant airway disease and little emphysema. Fall in FEV1 was faster (2.03% predicted FEV1/yr) in seven men with low initial Kco<75% pred. than in men with initial Kco>75% pred. (1.14% predicted FEV1/yr, P=0.006). Repeated measurements of CO transfer in an individual should increase the present poor knowledge of the contribution of alveolar disease to the progression of chronic airflow obstruction.

Failure of inhaled corticosteroids to modify bronchoconstrictor or bronchodilator responsiveness in middle-aged smokers with mild airflow obstruction.

We have compared the effects of three-month periods of treatment with an inhaled corticosteroid, budesonide 600 micrograms twice daily and with placebo on bronchial responses to inhaled histamine and to bronchodilators in a double-blind crossover trial in 14 middle-aged male smokers (mean age, 59.6 years) with mild airways obstruction (mean FEV1 2.42 L, 80 percent predicted [range, 48 to 110 percent]). Responsiveness to inhaled histamine was assessed monthly by the provocative concentration (mg/ml) reducing FEV1 by 20 percent (PC20). Bronchodilator response to a combination of inhaled salbutamol (5 mg) and ipratropium (0.5 mg) was assessed before and after three months' treatment. Compliance with treatment was checked by weighing aerosol canisters, and by measuring plasma budesonide and metabolites. There was no significant change in FEV1 (budesonide mean 2.38 L [SEM 0.17] vs placebo 2.40 L [0.17]), vital capacity (budesonide mean 3.69 L [0.17] vs placebo 3.81 L [0.17]) or in bronchodilator responsiveness (mean increase over baseline FEV1, budesonide 11.6 [2.7] percent vs placebo 10.5 [3.2] percent). There was a small overall reduction in bronchoconstrictor responsiveness over the period of the trial, but there was no effect of 12 weeks of budesonide treatment compared with 12 weeks of placebo treatment (mean log PC20 during budesonide 0.595 [SEM 0.063], placebo 0.591 [SEM 0.055]). Following the three-month crossover trial, six men continued for nine more months to receive budesonide in a single-blind trial and the results were compared with those in six men who took no active treatment for the subsequent nine months. No improvements in baseline spirometry, home peak flow measurements, bronchoconstrictor or bronchodilator responsiveness were observed after 12 months of budesonide treatment. Thus, a regimen of budesonide treatment that consistently attenuates bronchial responsiveness in asthmatic subjects had no effect in these men; larger and longer trials will be required to establish whether a subgroup of smokers shows a favorable response.

Plasma leucocyte elastase concentrations in smokers.

The associations between cigarette smoking, plasma leucocyte elastase concentration, peripheral leucocyte count and FEV1 were examined in 148 men, 72 of whom were current cigarette smokers, 40 of whom were ex-smokers, and 36 who had never smoked. All men were part of a long-term survey. Smokers had significantly higher plasma leucocyte elastase concentrations than ex-smokers or those who had never smoked. Mean current FEV1 was lower, and the annual decline in FEV1 in the preceding 10 years was faster in smokers than the other two groups. A few smokers had slight increases in serum C-reactive protein concentrations. Although peripheral blood leucocyte counts were higher in smokers than in non-smokers or ex-smokers, no association was found in any of the three groups of men between plasma elastase concentration and peripheral leucocyte count, nor between either of these two variables and annual decline in FEV1 or current level of FEV1. There was also no relation between plasma elastase concentration and reported daily cigarette consumption or mixed expired carbon monoxide in smokers. The results indicate that some male smokers have increased in vivo release of elastase from peripheral blood neutrophils at a time when there is no evidence of acute infection. Because leucocyte elastase is a strong candidate for pulmonary tissue damage, further studies of the mechanisms that increase plasma concentrations are indicated.

Maximum airflow through the nose in humans.

Inspiratory and expiratory flow via the nose and via the mouth during maximum-effort vital capacity (VC) maneuvers have been compared in 10 healthy subjects. Under baseline conditions maximum flow via the nose was lower than that via the mouth in the upper 50-60% of the VC on expiration and throughout the VC on inspiration. The mean ratio of maximum inspiratory to maximum expiratory flow at mid-VC was 1.38 during mouth breathing and 0.62 during nasal breathing. Inspiratory flow limitation with no increase in flow through the nose as driving pressure was increased above a critical value (usually between 12 and 30 cmH2O) was found in all six subjects studied. Stenting the alae nasi in seven subjects increased peak flow via the nose from a mean of 3.49 to 4.32 l/s on inspiration and from 4.83 to 5.61 l/s on expiration. Topical application of an alpha-adrenergic agonist in seven subjects increased mean peak nasal flow on inspiration from 3.25 to 3.89 l/s and on expiration from 5.03 to 7.09 l/s. Further increases in peak flow occurred with subsequent alan stenting. With the combination of stenting and topical mucosal vasoconstriction, nasal peak flow on expiration reached 81% and, on inspiration, 79% of corresponding peak flows via the mouth. The results demonstrate that narrowing of the alar vestibule and the state of the mucosal vasculature both influence maximum flow through the nose; under optimal conditions, nasal flow capacity is close to that via the mouth.

Airway caliber and the work of breathing in humans.

Mechanical work rate of breathing was measured in five normal subjects during voluntary eucapnic hyperventilation at rates of approximately 10, 20, 40, 60, and 80 l/min before and after inhalation of 1 mg of ipratropium bromide, an anticholinergic agent. Chest wall recoil pressure was measured over a range of lung volumes in each subject and was used as the reference pressure in the calculation of work rate. There was little change in elastic or resistive work rate at rest when vagal tone was reduced by ipratropium. The mean work at 40, 60, and 80 l/min was 8.9, 17.2, and 34.0 cmH2O.l-1.s before and 5.6, 12.4 and 25.8 cmH2O.l-1.s after ipratropium. This suggests that vagal tone significantly influences the work of breathing at high ventilatory rates, such as occur during strenuous exercise.

Comparison of four methods of assessing airflow resistance before and after induced airway narrowing in normal subjects.

Four methods for assessing airflow resistance were compared in seven normal adults at baseline and after inducing airway narrowing with inhaled methacholine. Airway resistance (Raw) was measured during panting at 1-2 Hz within a body plethysmograph; total lung resistance was measured by using an esophageal balloon during quiet breathing (RLq) and with doubling of frequency while maintaining the original tidal volume; total respiratory resistance (Rrs) was measured at 6 Hz during forced oscillation applied at the airway opening, and interruption resistance (Rint) was measured at midtidal expiratory flow. Three methods of obtaining Rint after airflow interruption were compared [smooth curve fit of mouth pressure (Pm) back extrapolated to valve closure; two-point linear fit of Pm back extrapolated to 15 ms after closure; and Pm at 100 ms after valve closure]. We found similar basal median values (cmH2O.l-1.s) of Raw (1.3), RLq (1.4), RL of double resting frequency (1.9), Rrs (1.7), and smooth curve fit of Pm back extrapolated to valve closure (1.5); basal values of two-point linear fit of Pm back extrapolated to 15 ms after closure (2.4) and Pm at 100 ms after valve closure (4.4) were considerably larger. After induced airway narrowing, all methods of measuring resistance showed significant increases; these were largest with RLq (median %change of 265) and smallest with the three Rint methods (median %change of 62-72). Rint and Rrs methods had poorer sensitivity for detecting bronchoconstriction than lung resistance of Raw. Of the Rint methods, end interruption pressure was the most sensitive.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of posture on respiratory mechanics in obesity.

Increased abdominal mass in obesity should enhance normal gravitational effects on supine respiratory mechanics. We have examined respiratory impedance (forced oscillation over 4-26 Hz applied at the mouth during tidal breathing), maximum inspiratory and expiratory mouth pressures (MIP and MEP), and maximum effort flow-volume curves seated and supine in seven obese subjects (O) (mean age 51 yr, body mass index 43.6 kg/m2) and seven control subjects (C) (mean age 50 yr, body mass index 21.8 kg/m2). Seated mean total lung capacity was smaller in O than in C (82 vs. 100% of predicted); ratio of functional residual capacity (FRC) to total lung capacity averaged 43% in O and 61% in C (P < 0.01). Total respiratory resistance (Rrs) at 6 Hz seated was higher in O (4.6 cmH2O.l-1.s) than in C (2.2 cmH2O.l-1.s; P < 0.001); total respiratory reactance (Xrs) at 6 Hz was lower in O than in C. In C, on changing to the supine posture, mean Rrs at 6 Hz rose to 2.9 cmH2O.l-1.s, FRC fell by 0.68 liter, and Xrs at 6 Hz showed a small fall. In O, despite no further fall in FRC, supine Rrs at 6 Hz increased to 7.3 cmH2O.l-1.s, and marked frequency dependency of Rrs and falls in Xrs developed. Seated, MIP and MEP in C and O were similar; supine there were small falls in MEP and maximum expiratory flow in O. The site and mechanism of the increase in supine Rrs and reduction in supine Xrs and the mechanism maintaining supine FRC in obesity all need further investigation.

Effect of inhaled and systemic opiates on responses to inhaled capsaicin in humans.

To determine the site of action of opiates in humans, we have studied the effect of systemic and inhaled opiates on cough and increase in respiratory resistance (Rrs) caused by inhaled capsaicin. In 13 subjects, a range of doses of capsaicin inhaled in single breaths given in random order produced a reproducible dose-cough response. Inhalation of a dose of capsaicin that caused fewer than two coughs increased Rrs by 28% (21-35, mean 95% confidence interval). Inhaled codeine (50 mg) and morphine (10 mg) did not alter the cough response. In contrast, both drugs increased base-line Rrs by 24% (16-44) and 13% (3-23), respectively, and significantly reduced the increase in Rrs after inhaled capsaicin (P less than 0.05). Oral codeine (60 mg) significantly (P less than 0.05) reduced the number of coughs at 1 and 2 h but did not alter base-line Rrs or its increase after capsaicin. Intravenous morphine (0.15 mg/kg) significantly reduced the sensitivity of the cough response (P less than 0.05), which was reversed by naloxone. However, there was no significant drug effect on either the base-line Rrs or its increase after capsaicin. Systemic dosing of opiates is therefore required to reduce the cough reflex, whereas inhaled opiates may reduce the increase in Rrs after inhaled capsaicin.

Effect of clonidine on induced cough and bronchoconstriction in guinea pigs and healthy humans.

We examined the effects of the alpha 2-receptor agonist clonidine, administered orally and by inhalation, on citric acid- and capsaicin-induced reflexes in guinea pigs and healthy human subjects. In groups (n = 8-10) of conscious guinea pigs, oral clonidine (10 and 100 micrograms/kg) was without effects, whereas inhaled clonidine (10-1,000 microM) caused a concentration-dependent inhibition of citric acid-induced cough (coughs during 3 min: control, 6.5 +/- 0.9; 1,000 microM clonidine, 1.7 +/- 1.0; P < 0.05) and reflex bronchoconstriction (time to onset of bronchoconstriction: control, 191 +/- 24 s; 1,000 microM clonidine, 317 +/- 33 s; P < 0.05). The inhibitory effect of inhaled clonidine on both reflexes was completely reversed by pretreatment with yohimbine but not with prazosin. In 12 healthy human volunteers, oral clonidine (150 mg) caused a significant fall in supine and erect systolic blood pressure and a significant increase in drowsiness as measured on a visual analogue scale 1 and 2 h after administration. Despite these effects, oral clonidine had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. In contrast to the effects in guinea pigs, inhaled clonidine (281 microM) had no effect on capsaicin-induced cough or reflex bronchoconstriction in humans. These data suggest that peripheral alpha 2-receptors exert an inhibitory effect on sensory neurotransmission in the guinea pig but not in the healthy human airway, indicating an important difference between the two species.

Urinary N tau-methylimidazole acetic acid excretion in respiratory disease.

N tau-methylimidazole acetic acid (N tau-MIAA) is the principal urinary metabolite of histamine. The basal urinary excretion rate of N tau-MIAA was determined as 0.117 +/- 0.008 (SE) mg/h, with a renal clearance for N tau-MIAA of 273 +/- 27 ml/min implying active secretion. After subpharmacological infusion of histamine (50 ng.kg-1.min-1 over 2 h) in five volunteers that increased plasma histamine from 0.28 +/- 0.04 to 0.71 +/- 0.15 ng/ml, urinary excretion of N tau-MIAA over 8 h was increased by less than 17% compared with a control saline infusion. Urinary N tau-MIAA excretion in normal controls (273 +/- 14 micrograms/mmol creatinine) was similar to that observed in patients with severe acute asthma (253 +/- 22 micrograms/mmol), antigen-induced bronchoconstriction (269 +/- 21 micrograms/mmol), seasonal allergic rhinitis (304 +/- 31 micrograms/mmol), and clinically stable bronchiectasis (270 +/- 22 micrograms/mmol). In contrast, large increases in metabolite excretion (greater than 7,000 micrograms/mmol creatinine) were observed in a patient with systemic mastocytosis where very high plasma histamine levels were recorded (greater than 500 ng/ml) and marked systemic hemodynamic effects occurred. We conclude that urinary N tau-MIAA will only be increased in pathologies where sustained hyperhistaminemia occurs and that increased local histamine production in the lung or the upper airway does not cause a measurable change in the basal urinary excretion of this metabolite.

Tests of forced expiration and inspiration.

Analysis of the volume versus time curve during a maximum effort forced expiratory vital capacity maneuver started from total lung capacity (TLC) is by far the most performed test of respiratory mechanics, having spread from the laboratory to the wards and outpatient clinics and gradually into the offices of general practitioners. In particular, forced expiratory volume in 1 second (FEV1) is the best characterized test of respiratorv function; information on changes with age, gender, ethnic group, growth and disease is more developed than for any other test, repeatability is good, and it provides useful information across the whole range from normal to advanced disease.

Inspiratory flow reserve in boys with Duchenne muscular dystrophy.

Patients with advanced muscular dystrophy frequently develop ventilatory failure. Currently respiratory impairment usually is assessed by measuring vital capacity and the mouth pressure generated during a maximal inspiratory maneuver (PI,max), neither of which directly measures ventilatory capacity. We assessed inspiratory flow reserve in 26 boys [mean (SD) age 12.8 (3.8) years] with Duchenne muscular dystrophy (DMD) without ventilatory failure and in 28 normal boys [mean (SD) age 12.6 (1.9) years] by analyzing the ratio between the largest inspiratory flow during tidal breathing (V'I,max(t)) and during a forced vital capacity maneuver (V'I,max(FVC), (V'I,max(t)/V'I,maxFVC). We have compared this ratio with the forced vital capacity FVC and PI,max measured at functional residual capacity. Mean PI,max was -90(30)cmH2O, average 112% (range 57-179%) of predicted values in control boys and -31(11)cmH2O, average 40% predicted values in DMD boys (control vs DMD, P < 0.001). FVC was reduced in DMD boys [59(20)% predicted values vs 86(10)% predicted values in controls, P < 0.01]. Absolute V'I,max(FVC) was strongly related to FVC in both control and DMD boys; V'I,max(FVC) (expressed as FVC. s(-1)) was not related to PI,max in either group. The mean V'I,max(t)/V'I,max(FVC); ratio was higher in DMD 0.22 (0.08) than in controls 0.12 (0.03) (P < 0.001) indicating a reduction in inspiratory flow reserve in DMD. Inspiratory flow reserve was within the normal range in 8 of 19 DMD patients with PI,max less than 50% of predicted values. We conclude that measurement of inspiratory flow reserve (V'I,max(t)/V'I,maxFVC ratio) provides a simple and direct assessment of dynamic inspiratory muscle function which is not replicated by static measurement of PI,max or vital capacity and might be useful in assessment of respiratory impairment in boys with Duchenne muscular dystrophy. Follow-up studies are required to establish whether measures of inspiratory flow reserve are of clinical value in predicting subsequent ventilatory failure.

Changes in carbon monoxide transfer over 22 years in middle-aged men.

We measured single breath CO transfer (T(LCO)), single breath alveolar volume (VA), CO transfer coefficient (K(CO)) and forced expiratory volume in 1 sec (FEV1) in 84 men, mean age 40.5 years at recruitment, in 1975 and in 1997. At recruitment, 42 men were cigarette smokers and 42 were not smoking. Mean annual decline in FEV1 was similar in never- (34.2 ml yr(-1)) and ex- (33.1 ml yr(-1)) smokers and faster (51.0 ml yr(-1)) in continuing smokers. In contrast to predictions from cross-sectional reference values, there was no fall in T(LCO) or K(CO) in men who did not smoke over the period of follow-up. In the 16 men who smoked throughout follow-up there was a 10% fall in T(LCO) (P = 0.043) but most of this was due to a significant fall in VA (P = 0.017), presumably reflecting uneven gas mixing. These results indicate the need for population-based longitudinal studies of T(LCO) and K(CO). If single breath estimates of VA are used in subjects with even mild airflow obstruction, K(CO) rather than T(LCO) should be used to assess alveolar function.

Capsaicin cough sensitivity increases during upper respiratory infection.

The mechanism of cough associated with upper respiratory infection (URI) is poorly understood. This paper reports a study of the role of altered sensitivity of capsaicin-sensitive airway nerves. In a prospective study, baseline (B) capsaicin-induced cough and methacholine-induced airway responsiveness were measured in 103 healthy volunteers. During the following year, 31 subjects reattended for challenge testing during URI (I) and after recovery (R). The log concentration of capsaicin required to elicit two coughs (C2) was significantly lower during infection than recovery but not baseline [median (interquartile range) B = 0.59 (0.28-1.20), I = 0.27 (0-0.89), R = 0.89 (0.28-1.49)]. Log C5 (concentration causing five coughs) was lower during infection than baseline and recovery [B = 1.79 (1.20-2.70), I = 1.49 (0.89-2.08), R = 1.79 (1.20-2.40)]. FEV1 and PC15 methacholine values were unchanged during infection compared to baseline. Subjects with dry cough (n = 14) had lower C5 values during infection than both baseline and recovery, and lower C2 values during infection than recovery; in these subjects, increase in capsaicin sensitivity correlated with cough severity score. Subjects with productive cough or no cough showed no consistent changes during infection. Twenty-six control subjects who reattended without URI showed no change in capsaicin sensitivity. Upper respiratory infection may cause cough as a result of increased sensitivity of capsaicin-sensitive afferent airway nerves without affecting airway calibre or responsiveness.

Comparison of oscillation with three other methods for measuring nasal airways resistance.

In this study we have compared the sensitivity and reproducibility of nasal airways resistance measurements made using an oscillometer, with those made by passive anterior, active anterior and active posterior rhinomanometry. Nasal airways resistance values were compared in 12 patients with rhinitis and 15 normal subjects, of whom ten had additional measurements after a vasoconstrictor spray, oxymetazoline. The coefficients of variation of 6-8 technically satisfactory measurements were 9-19%. The decongestant effect of oxymetazoline was detected by all methods, with no decrease in reproducibility. Post vasoconstrictor nasal airways resistance fell by 28% (passive anterior), 35% (active anterior), 36% (active posterior) and 58% (oscillometry). In conclusion, the oscillation method for deriving nasal airways resistance is a useful, new, simple and noninvasive way of assessing nasal airways patency. Results compare favourably with other, more established techniques.

The European Respiratory Society study on chronic obstructive pulmonary disease (EUROSCOP): recruitment methods and strategies.

The European Respiratory Society's study on chronic obstructive pulmonary disease (EUROSCOP) is a multicentre study performed initially in 12 countries to assess the effect of 3 years' treatment with inhaled corticosteroids on lung function decline in smokers with chronic obstructive pulmonary disease (COPD). It aimed at recruiting 50 subjects in 50 European centres. This study discusses the most successful, countrywise, recruitment strategies, an important issue since many multicentre European studies may follow in the future. The total number of recruited subjects was 2147 in 39 participating centres. In total, at least 25,000 screening spirometries were performed, and about 80,000 hospital records were checked. The most effective way of recruiting subjects was to screen subjects by spirometry after mass media campaigns (eight out of nine countries). Others used workplace screenings and different types of population survey, and only a few centres successfully recruited participants by hospital records. Inclusion criteria were slightly changed upon low initial accrual rate. Initial surveys in one country, where 2405 subjects were screened by spirometry, gave an important indication for the change of the inclusion criteria. Extension of the upper age limit from 60 to 65 yr considerably improved recruitment, as did a change of the upper limit of FEV1 from below 80% predicted normal to below 100% predicted normal, while maintaining the FEV1/VC ratio below 70%. A tremendous effort is needed to recruit individuals with preclinical COPD, but this is certainly feasible with adequate strategies adjusted to each country.

Intranasal histamine challenge in normality and allergic rhinitis.

A series of investigations was performed in which histamine challenge was used to compare nasal responsiveness in 20 normal subjects and 20 with allergic rhinitis. There was found to be a lower threshold of reactivity (D100) to histamine in allergic subjects as measured by resistance changes (geometric mean, 0.53 mg/ml; normal subjects, 2.15: p = 0.022). This may represent increased number or sensitivity of histamine receptors on the nasal capacitance vessels. The loss of a laser Doppler response to a supramaximal histamine stimulus (normal subjects, 102% increase in flux at 3 minutes; p < 0.05) was observed in patients with allergic rhinitis and indicates either a down-regulation of the capillary system or an altered effect of histamine on superficial vessels, perhaps mediated by a shift in histamine receptor type. There was an observed increase in neutrophils at the mucosal surface under baseline conditions (rhinitis median, 49.6%; normal subjects, 32.72%: p < 0.05), which suggests an important primary role in the pathogenesis of this condition for this active cell. The observed increase in secretory volume response to histamine in allergic subjects, which persisted beyond 40 minutes after a single D100 challenge, may be related to an altered sensitivity of glandular tissue. There are important changes in nasal reactivity to histamine challenge in allergic rhinitis that may have implications for its pathogenesis.