Search

This multicentre trial was undertaken to confirm previous results indicating that long-term treatment with oral acetylcysteine reduces the exacerbation rate in patients with chronic bronchitis. Two hundred and eighty-five patients, smokers or ex-smokers, with chronic bronchitis started a pre-trial placebo-period of 1 month. After this run-in period 259 patients were included in the trial and randomized into two parallel groups. The patients were treated in a double-blind way either with acetylcysteine 200 mg b.i.d. or placebo b.i.d. for 6 months. The trial was completed by 98 patients in the acetylcysteine group and by 105 patients in the placebo group. Initially, there were no significant differences between the groups. Twice weekly, the patients filled in a diary card concerning symptoms. The number of exacerbations was assessed from these cards and at visits 2, 4 and 6 months after institution of therapy. The exacerbation rate was significantly lower in the acetylcysteine group in which 40% of the patients remained free from exacerbations compared to 19% in the placebo group. Sick-leave due to acute exacerbation was significantly less common in the acetylcysteine group. The drug was well tolerated.

We briefly review bronchial mucociliary clearance: one of the non-specific host defence mechanisms operating in the lungs, helping to maintain cleanliness and sterility. We describe in detail the measurement in man of bronchial mucociliary clearance by means of the radioaerosol technique used in our laboratory. We report the use of the technique for detecting impairment of tracheobronchial clearance in patients with chronic bronchitis compared with healthy control subjects. We illustrate whole lung and tracheobronchial retention curves in a patient with Kartagener's syndrome - and also preliminary results on the inter-subject variability of clearance in a small group of patients (n = 5) with this syndrome. In 24 chronic bronchitics studied on three separate occasions intra-subject variability of 6 hr tracheobronchial clearance was 17%, inter-subject variability was 25% - figures commensurate with those reported by other authors.

Pulmonary wedge angiograms were compared with haemodynamic measurements at rest and during light exercise in 47 patients with chronic bronchopulmonary disease. The patients were divided into two groups on the basis of the angiograms. In group I (26 patients) less than 50% of the angiograms were abnormal, whilst in group II (21 patients) more than 50% of angiograms were abnormal. Pulmonary artery pressure and pulmonary vascular resistance were lower in group I than in group II and these differences became more marked during exercise. The pulmonary wedge pressure increased significantly on exercise in group II. Similarly, driving pressure in relation to cardiac output increased more from rest to exercise in group II than in group I. We conclude that wedge angiograms are one way to estimate the reduction in the pulmonary vascular bed.

Respiratory cycle time components during rest and graded exercise were measured in 18 patients with chronic obstructive lung disease, and compared with controls matched for sex and age. For a given exercise level (50 W) increased minute ventilation was present in the patients. This was due to shorter cycle time. Both inspiratory and expiratory time shortened to the same degree rendering the ratio inspiratory time/total respiratory cycle time similar in the two groups. At maximal exercise total respiratory cycle time and inspiratory time was shorter in the patients than in the control group, but the ratio between them was still similar. However, for a given total cycle time during maximal exercise inspiratory time was shorter. Inspiratory time and the ratio inspiratory time/total cycle time as measured during 50 W exercise, were positively correlated with the patient's exercise capacity, but not of sufficient accuracy for useful prediction of the latter. The difference in concomitant variation of tidal volume and inspiratory time during exercise ventilation between the patients and the control subjects seemed satisfactorily explained by the different lung volumes at which the two groups were breathing.

The mucolytic activity of acetylcysteine (NAC) was evaluated in a double-blind, placebo controlled, clinical trial performed in three pneumology centres and involving a total of 215 patients with the following diagnoses: 84 acute bronchitis, 95 superinfections of chronic bronchitis, 36 complicated bronchitis in patients with severe chronic respiratory insufficiency. Treatment consisted of 1 sachet of 200 mg NAC t.i.d. for 10 days. Standard antibiotic therapy (amoxycillin 1.5 g/day) was concurrently administered for 7 days. Statistical analysis comparing sputum volume and viscosity, sedation of cough and improvement of PEFR in 108 NAC and in 107 placebo treated patients, showed that NAC was very significantly more effective than placebo. The effect of NAC was negligible in the 36 patients with complicated bronchitis, whereas it was evident and remarkable in patients with acute and chronic bronchitis.

Twentyfour adults, aged 19-47 years, with congenitally nonfunctioning cilia were investigated by clinical examination, radiography, spirometry, and in most cases by tracheobronchial clearance measurements and ultrastructural examination of respiratory tract cilia and/or sperm tails. They all suffered from chronic bronchitis, rhinitis and sinusitis, and most of them had bronchiectasis and a history of otitis. Most had spirometrically overt obstructive lung disease and four radiological signs of emphysema. Clinical profile, lung function and mucociliary clearance data were compared to corresponding data from samples of patients with other obstructive lung diseases. These comparisons indicate that a long-standing impairment of mucociliary clearance is of pathogenetic importance in common chronic obstructive lung disease associated with chronic bronchitis, but not in emphysema associated with severe alpha 1-antitrypsin deficiency without chronic bronchitis, and not in asthma. In cystic fibrosis and in hypogammaglobulinemia an impaired clearance is not of primary pathogenetic significance but may contribute to the development of obstructive lung disease.

Tracheobronchial clearance was studied in five patients who had emphysema associated with deficiency of serum alpha1-antitrypsin but no history of chronic bronchitis. After the patients had inhaled an aerosol of 6 micrometer teflon particles tagged with 99mTc, the radioactivity in the lungs was followed externally during 2 h. Clearance in the emphysematous patients was normal or even rapid as compared with clearance in healthy subjects, and was significantly more rapid than clearance in patients with a history of chronic bronchitis. The results indicate that emphysema can develop in patients with alpha1-antitrypsin deficiency without their having an impairment of mucociliary transport.

The effects on respiratory regulation of giving almitrine bismesylate (100 mg daily) orally for four weeks in twelve patients with chronic airflow obstruction were assessed in a double-blind placebo-controlled study. The drug caused significant increases in ventilation and the ventilatory response to hypoxia, associated with partial relief of arterial hypoxaemia and a fall in arterial CO2 tension. No consistent changes occurred with placebo. The results are in accord with a sustained action of almitrine bismesylates sensitising peripheral chemoreception.

A placebo controlled, double-blind, cross-over study was carried out to examine both the bronchodilator properties and the effect on lung mucociliary clearance of terbutaline (Bricanyl), a beta agonist, and ipratropium (Atrovent), a synthetic anticholinergic drug. Both were given regularly (two puffs four times a day for 1 week) from pressurised metered dose inhalers to patients with chronic obstructive bronchitis. A total of 10 patients completed the terbutaline study and 12 patients the ipratropium study; of these, seven patients were common to both studies. Measurements of the pulmonary function indices, forced expiratory volume in 1 s, forced vital capacity (FVC), peak expiratory flow rate and the flow rate at 50% of FVC measured from maximal expiratory flow-volume curves, confirmed the bronchodilator action of both drugs in these patients. Clearance of lung secretions was measured by the non-invasive, radioaerosol technique. No evidence was found that either drug had any effect on the rate of mucociliary clearance. The radioaerosol tracer particles used for measuring lung clearance, although inhaled under strictly controlled conditions, were deposited significantly more towards the lung periphery after treatment with ipratropium only. This suggested that ipratropium reduced the resistance to the entry of inhaled aerosols in the small airways.

Thirty-four patients with chronic obstructive lung disease were exercised stepwise up to maximal work load. V02 at maximal work load showed a slightly significant correlation to FEV1, while a closer association with VC as well as Ve and Vt was noted. In most patients Vt during maximal exercise was around 50% of VC, while no such limit was present when Vt was related to FEV1. These patterns were independent of the clinical type of obstructive lung disease. At 300 kpm/min (50 W) Vt/VC% as well as heart rate was negatively correlated to V02 max, but not to FEV1. No significant relationship was seen between V02 or Ve at this exercise level and V02 max, as well as FEV1. The ventilatory pattern during exercise seemed to reflect the patients' ventilatory strain more adequately than pre-exercise FEV1. The negative relationship between heart rate during moderate exercise and V02 max might further reflect this strain.

This study was based on a sample of 1,831 farmers with no symptoms of the lower respiratory tract, which was taken from a larger survey population of 12,056 farmers. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were determined cross-sectionally in connection with health examinations at local health centres. Background data, which included age, sex, height, presence of atopic symptoms, and smoking habits, were gathered in a postal survey conducted by the Social Insurance Institution of Finland. Mean FEV1 and mean FVC were adjusted for age, sex, and height; FEV1 was also adjusted for FVC. Although atopy (defined on the basis of past or present atopic dermatitis, including infantile eczema, and/or hay fever or other allergic rhinitis) had no effect on mean FEV1, mean FVC was lower in atopic than in non-atopic subjects. Both mean FEV1 and mean FVC were lower in smokers than in non-smokers. Smoking thus influenced both FEV1 and FVC, but affected FEV1 slightly more. The effects of atopy and smoking on FVC seemed to be additive. These results, which imply that atopy may predispose obstruction of small airways, match our previous finding that atopy and smoking increase the occurrence of chronic bronchitis additively.

The mucociliary clearance characteristics and the correlation between the extent of smoking and bronchial mucociliary dysfunction were studied in 71 smokers (15 without chronic bronchitis, 16 with simple and 40 with obstructive chronic bronchitis). Mucociliary clearance (MC) was measured with 99mTc-tagged human erythrocytes. Lung function values were determined by whole body plethysmography. All three smoking groups had significantly (p less than 0.001) lower TMC60.min rates (total MC in 60 min) on the average than the predicted values. The mean TMC60.min rates of heavy smokers with simple and obstructive chronic bronchitis were significantly (p less than 0.001) lower than that of light smokers without chronic bronchitis. There was no significant difference between the TMC60.min rates of smokers with simple and obstructive chronic bronchitis. The decrease in the MC rates was more pronounced in the central than in the peripheral airways. A significant (p less than 0.001) correlation was found between the extent of smoking (pack years) and the decrease of MC. The results suggest that the decrease of MC is an early functional abnormality in smokers, which precedes the development of symptoms of chronic bronchitis as well as functional detectability of airways obstruction.

We have studied a representative population sample comprising 185 persons, aged 35-54 years, having certain respiratory symptoms and considered to have chronic bronchitis and/or bronchial asthma. There were 86 with bronchial asthma (without chronic bronchitis), 69 with chronic bronchitis (without asthma) and 30 with both chronic bronchitis and bronchial asthma. Fifty-one of the 116 asthmatics had reaginic bronchial allergy. In the groups with chronic bronchitis or bronchial asthma, the mean ventilatory capacities were slightly below the normal, being 89 and 91%, respectively, of the predicted values for FEV1 and 85 and 87% of those for MVV40. In the group of persons with both diseases, the mean FEV1 was 77% and the mean MVV40 84% of that predicted. Of the 21 persons with a mean FEV1 below 70% of that predicted 10 had both asthma and bronchitis. Exercise-induced bronchoconstriction, defined as a 15% fall of PEF after exercise, occurred in 22 of the 116 asthmatics and in one of the 69 persons with chronic bronchitis without bronchial asthma. In the asthmatics there was a significant correlation between resting PEF or the difference in PEF before and after orciprenaline inhalation on the one hand, and exercise-induced bronchoconstriction on the other hand. This was taken as an indication of increased bronchial hyperreactivity.

Since mononuclear phagocytes are crucial in resisting microbial challenge in the lung, selected functions of blood monocytes were studied in 27 patients with chronic bronchitis (19 with hypersecretory symptoms and many acute infectious exacerbations and eight with obstructive symptoms without recurrent infections), and compared with 82 healthy controls. While monocytes from patients with solely obstructive symptoms had a normal migratory function, both spontaneous and chemotactic migration were depressed in the patients with hypersecretory symptoms. Phagocytic activity of the blood monocytes was equally depressed in both subgroups. Intracellular killing of Candida albicans was normal in all patients when compared with smoking control subjects. Chemotactic responsiveness was thus decreased only in patients with hypersecretory symptoms, suggesting that a defect in monocyte migration in these patients might contribute to the high incidence of acute bronchial exacerbations.

A first survey has been conducted on 1179 iron-ore mine workers, 35-55 years old, who were randomly selected from 5900 at work with normal chest roentgenograms. Five years later, 871 of them were re-examined. Both surveys included a standard respiratory symptoms questionnaire (British MRC), a physical examination of the chest, and measurement of pulmonary function (vital capacity - VC; forced expiratory volume during 1 s - FEV1.0; residual volume - R.V. by helium dilution: carbon monoxide uptake - FuCO by the steady-state method). Both surveys were done by the same research team under identical conditions, using the same equipment. The mine technical services determined the dust and noxious gas concentrations at work places. No evidence of worsening of respiratory health status was observed overall. Symptoms of chronic bronchitis and asthma were recorded with a similar prevalence in both surveys; the decline in lung function was minimal for the total sample. However, our aim was to compare changes that were observed in groups differing by work place (surface or underground) or by activity (active or retired). Analysis showed that development of respiratory symptoms was more frequent and decline in lung function accelerated in the 5-year interval among underground workers who were still active as compared to those retired. In all subgroups (surface or underground workers, active or retired), decline of lung function values was more marked in smokers compared to non-smokers.

Extensive physiological evaluation of lung function were conducted in two groups of asymptomatic individuals with deficiencies of alpha1-antitrypsin: seven subjects with phenotype Pi SZ and six subjects with phenotype Pi Z. Four symptomatic individuals of Pi Z type were also investigated. The asymptomatic individuals of both SZ and Z phenotypes revealed reduction of elastic recoil, hypoventilation and hypoperfusion of the lung bases with increased closing and nitogen wash-out volumes. No signs of bronchial obstruction were observed. The asymptomatic Pi SZ subjects revealed as many signs of subclinical disease as did the asymptomatic Pi Z subjects. These data suggest that Pi SZ subjects are at increased risk of emphysema similar to Pi Z subjects.

The effect of manual chest percussion was studied in 10 patients recovering from an acute exacerbation of chronic bronchitis. All patients were studied on 2 consecutive days. Physiotherapy consisting of postural drainage and instructed coughing was given on both days. Chest percussion was included in a randomized way on either day. Percussion was associated with a small but statistically significant increase in airflow obstruction, measured as a reduction in FEV1 after the treatment. There were no differences in the deposition or clearance of inhaled radiolabelled particles between the 2 forms of treatment. Changes in oxygen saturation were small and insignificant during both forms of treatment. The study indicates that manual chest percussion is of little value as an adjunct to postural drainage and instructed coughing in the treatment of patients with chronic bronchitis.

We describe seven entities which could be comprised under the heading of "chronic Bronchiolitis in adults". In particular clinical, radiological and functional details are described. In a graphic presentation we tried to give a synopsis of morphological and clinical entities under the three morphologic notions bronchiolitis, alveolitis and bronchitis and emphysema.

On 17 ex-smokers (7 without chronic bronchitis, 10 with chronic bronchitis) and 48 smokers (13 without chronic bronchitis, 35 with chronic bronchitis) we analyzed the correlation between smoking habits (pack years, smoking and ex-smoking time), mucociliary clearance rate (mC) and airways obstruction. The mC was measured with 99mTc tagged monodisperse erythrocytes. The static and dynamic lung volumes, the maximal expiratory flow volume curve and the airway resistance were measured by whole body plethysmography. The ex-smokers without chronic bronchitis showed the same mucociliary clearance rate (t-mC in 1 h = 38.3 +/- 10.3%) as the 80 control subjects who never smoked (t-mC in 1 h = 36.9 +/- 12.6%). But the subjects who never smoked showed less airway obstruction. The mucociliary clearance rate in normal subjects who never smoked is a function of age: t-mC in 1 h = -0.37 X age + 53; c-mC in 1 h = -0.45 X age + 73; p-mC in 1 h = -0.25 X age + 38. The smokers without chronic bronchitis showed normal ventilatory function tests but a lower mC rate (t-mC in 1 h = 27.8 +/- 12.3%) than the healthy ex-smokers and the control subjects who never smoked (p less than 0.01). The ex-smokers and smokers with chronic bronchitis had a lower mC rate (t-mC in 1 h = 21.2 +/- 11.3% and 18.1 +/- 9.1) and more airway obstruction (p less than 0.001) than the subjects who did not report any symptoms of chronic bronchitis. The ex-smokers with persistent symptoms of chronic bronchitis showed the severest degree of airways obstruction. The smokers with chronic bronchitis showed the most delayed central mC (c-mC) rate, but less airway obstruction than the ex-smokers with persistent symptoms of chronic bronchitis. The smoking habits (pack years) correlated with the decreased mC rate (p less than 0.01) and the degree of airways obstruction (p less than 0.001).

The pressure/flow relationship in the pulmonary circulation has been studied in 43 patients with chronic bronchitis, at rest (R) and during exercise at two levels: 30 or 40 W (E1), and 60 or 80 W (E2), without interruption. For the entire group, pulmonary vascular resistance was 142 +/- 70 dyn X s X cm-5 at rest, 131 +/- 55 at the first exercise level and 118 +/- 60 at the second level. Individual changes were variable, however; a "linearity index" was computed as delta(PPA-PW)/delta Q from the first to the second exercise level divided by the same value from rest to the first exercise level. This index was below 0.75 in 27 patients (i.e. the pressure/flow slope was lower for the second exercise level and the pressure/flow curve was concave to the flow axis), it was above 1.25 in nine patients (i.e. the slope increased with exercise and the pressure/flow curve was convex to the flow axis), and the pressure/flow relationship was close to rectilinear in seven patients. Functional disturbances were mild in these subjects, and in the majority of them pulmonary vascular resistance did not increase with exercise.

Animal studies have suggested that stabilising mast cells may reduce the rise in pulmonary artery pressure which is produced by hypoxia. In six patients with stable hypoxic chronic bronchitis and emphysema, we have compared the pulmonary artery pressure at rest and on exercise before and after inhaling disodium cromoglycate (DSCG). The increase in heart rate was the same after each period of exercise (17 beats/min increase on placebo; 16 beats/min on DSCG), as was fall in arterial oxygen saturation (6% on placebo; 6% on DSCG). The subsequent rise in pulmonary artery pressure (PAP) during exercise was also not significantly different between placebo and DSCG. We conclude that 80 mg of aerosolised DSCG does not modify the pulmonary artery pressure in patients with chronic bronchitis and emphysema either at rest or during exercise.

In vivo and in vitro mucociliary clearance have been investigated in 27 patients with chronic bronchitis with relation to the rheological, cytobacteriological and biochemical characteristics of sputum. In normal subjects, the mean percentage of bronchial radioactivity cleared (PBRC) by mucociliary clearance was 30.1 +/- SD: 12.5. The patients studied were differentiated into two groups: 1) 10 patients showing a PBRC similar to that of the normal subjects (30.6 +/- SD: 14.3), 2) 17 patients with a markedly decreased mucociliary clearance (PBRC: 4.1 +/- SD: 4.2). In the healthy subjects, PBRC by coughing was significantly lower than by mucociliary clearance, while no consistent difference was observed in the patients. A weak but significant positive correlation (r = 0.53, P less than 0.01) was observed between in vivo mucociliary clearance and the relative transport rate of the sputum measured on the ciliated frog palate mucosa. The optimal rheological conditions for mucociliary transport were characterized by an apparent viscosity (eta 0) ranging from 25 to 180 poise, a strain recovery (SR) ranging from 4 to 12 units and an elastic modulus (G) ranging from 4 to 8 dyn/cm-2. The apparent viscosity and the elastic modulus G respectively, were significantly correlated with the concentration of serum albumin and of secretory IgA. Patients with a sputum leukocyte count higher than 3500/mm3 had a significantly decreased mucociliary clearance in comparison with non-purulent sputum patients.

"Sensitive" and "conventional" lung function tests were compared in a group of 114 males, aged 35-55 years, including healthy non-smokers, asymptomatic smokers with normal spirometry, and smokers with chronic bronchitis with or without mild airflow limitation. In non-smokers, with the exception of a MEF vs. FEV1 correlation, "sensitive" and "conventional" tests were independent of each other. In asymptomatic smokers the phase III slope and the closing volume were significantly related to FEV1, RV/TLC and CO transfer factor. In smokers with chronic bronchitis all the "sensitive" tests were related to the "conventional" tests (with the exception of the total lung capacity). Hyperinflation and CO transfer impairment suggest that early emphysema may accompany mucus hypersecretion in smokers.

8 normals, 8 asthmatics and 8 bronchitics inhaled comparable doses of ipratropin and salbutamol. Five different flow-volume parameters were measured before and at intervals from 3 to 360 minutes after inhalation, on a total number of 2880 maximal effort expiratory flow-volume curves. Arterial blood gas tensions were measured before and 60 minutes after inhalation. In all parameters a significant larger effect (p less than 0.05) of ipratropin was found in normals, but in different time intervals. The parameter FEV1 and MEF at 50% of FVC showed the largest effect of salbutamol during the interval from 3 to 60 minutes in the asthma patients. None of the parameters showed significant difference in drug effects in the bronchitis patients. The findings suggested a more peripheral action of ipratropin than of salbutamol in the normals. No significant change in gas tensions were found after inhalation in any of the three groups.

This review examines the effects of tobacco smoke on the production and clearance of lower airway secretions, in healthy smokers and smokers with chronic bronchitis. Cigarette smoke shows to have a profound effect on airway mucociliary function, producing structural and functional changes in the mucosa.

We carried out a randomised, double-blind, two-period crossover study in 15 stable, chronic bronchitics to ascertain the effect on tracheobronchial clearance (TBC) of 1 week's treatment with iodopropylidene glycerol (IPG-Organidin), two tablets four times daily compared to matched placebo. TBC was measured by radioaerosol technique. The drug did not significantly alter TBC in the group as a whole but did significantly enhance TBC in 6 patients who expectorated during both placebo and IPG 6-h observation periods. In 4 patients who did not expectorate in either period no change in TBC occurred. In 10 patients who expectorated in either one or both observation periods, a significant positive correlation was found between an index of the patients' sputum produced and improvement in TBC following IPG treatment. IPG can be an effective expectorant in patients with mucus hypersecretion and particularly so in patients with copious sputum production.

We summarize the findings of 18 clinical studies carried out over a decade to ascertain the effect of 14 pharmacological agents on lung mucociliary clearance. These studies were carried out on a total of 172 subjects/patients and amounted to 443 individual assessments. The objective, in vivo radioaerosol technique was used to measure clearance. Bromhexine, aerosolized hypertonic saline and aminophylline enhanced the clearance of lung secretions. There was some indirect evidence of a speeding up of mucociliary clearance following the administration of prednisolone and the synthetic anticholinergic bronchodilator ipratropium, while hyoscine was found to reduce clearance. There was no effect on clearance of single doses of the beta blockers propranolol and atenolol, the beta 2 adrenergic drug terbutaline, the cholonergic drug bethanecol and the expectorants 2-mercapto-ethane-sulphonate (aerosol) and glycerol guaiacolate. Long term administration (4 - 7 days) of the beta 2 adrenergic drugs terbutaline and clenbuterol also failed to show any effect on lung mucociliary function.