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In vitro and in vivo studies have shown that carbon monoxide (CO) has both anti-inflammatory and anti-oxidant capacities. Since chronic obstructive pulmonary disease (COPD) is characterised by inflammation and oxidative stress, low-dose CO could be of therapeutic use. The aim of the present study was to investigate the feasibility and anti-inflammatory effects of 100-125 ppm CO inhalation in patients with stable COPD. In total, 20 ex-smoking COPD patients with post-bronchodilator forced expiratory volume in one second (FEV(1)) >1.20 L and FEV(1)/forced vital capacity

Height is used in allocation of donor lungs as an indirect estimate of thoracic size. Total lung capacity (TLC), determined by both height and sex, could be a more accurate functional estimation of thoracic size. Size-matching criteria based on height versus predicted TLC was retrospectively evaluated, and, furthermore, whether a TLC mismatch was related to clinical and functional complications.The ratio of donor and recipient height, as well as the ratio of predicted TLC in donors and recipients, were calculated in 80 patients after bilateral lung transplantation. Complications evaluated included persistent atelectasis, persistent pneumothorax and increased number of days in intensive care, occurrence of bronchiolitis obliterans syndrome and limitation of exercise capacity.Median height donor/recipient ratio was 1.01 (0.93-1.12). Median predicted TLC donor/recipient ratio was 1.01 (with a clearly broader range 0.72-1.41). Neither sex mismatch nor TLC mismatch were related to clinical or functional complications.Allocation of donor lungs based upon height alone leads to a substantial mismatch in total lung capacity caused by sex mismatch. The absence of complications suggests that a greater height donor/recipient discrepancy can be accepted for allocation than previously assumed.

Background. The immunosuppressive effects of cyclosporine (CsA), tacrolimus (FK506), mycophenolate mofetil (MMF), and prednisolone in cells from the immunological compartment are well documented. In contrast, limited information is available with respect to the effects of these immunosuppressive drugs on airway-epithelial cells, although these cells may contribute to the development of obliterative bronchiolitis (OB) through the production of interleukin (IL)-6 and IL-8. Methods. We studied the production of IL-6 and IL-8 proteins by airway-derived epithelial cell lines and primary epithelial cell cultures obtained from lung brushings. Transcriptional mechanisms were detected by transient transfections. Results. We demonstrate that CsA dose dependently induces the production of the proinflammatory cytokines IL-6 and IL-8 in both cell lines and primary epithelial cells. FK506 and MMF were also able to upregulate IL-8, although the effect was less dramatic than observed for CsA. Low concentrations of prednisolone (0.01 and 0.001 mu g/ml) enhanced IL-6 and IL-8 secretion, whereas concentrations greater than or equal to 0.01 mu g/ml significantly diminished IL-6 secretion. Furthermore, we showed that CsA and prednisolone mediate their effects at the transcriptional level. Conclusions. The data provide evidence that relevant concentrations of CsA and MMF in vivo may enhance the inflammatory processes in the lower airways of patients after lung transplantation.

Background Airways hyperresponsiveness (AHR) is an important feature of patients with chronic obstructive pulmonary disease (COPD). Little is known about factors that modulate AHR in COPD. Objective To study these factors, we performed a long-term, double-blind, parallel intervention study in 58 male, non-allergic patients with COPD. Methods During a period of 2 years, patients were treated with inhaled budesonide (1600 mu g/day), inhaled budesonide (1600 mu g/day) plus oral prednisolone (5 mg/day), or placebo. PC20 histamine was measured at 4-monthly intervals. The influence of treatment, smoking, age, level of lung function, initial serum IgE level and peripheral blood eosinophils on level and longitudinal change of PC20 histamine was analysed. Results During follow-up, PC20 decreased in our group, and this decrease was not influenced by treatment. PC20 tended to decrease faster in current smokers than in ex-smokers. PC20 was significantly associated with pre-challenge FEV1 at each time point. Level nor decline of PC20 were significantly related to age. A higher initial serum IgE level was independently associated with a lower PC20 Moreover, a higher initial serum IgE level was associated with a slower annual decline of PC20, regardless of treatment, pre-challenge FEV1, and other modulating factors. No significant associations were found between initial blood eosinophils and level or decline of PC20. Conclusion We conclude that AHR increases over time in non-allergic patients with COPD. Treatment with an inhaled corticosteroid alone or in combination with oral prednisolone does not change this increase. Our study suggests an important role for IgE in the course of the disease, since a higher initial serum IgE level predicts a more favourable course with regard to annual decline of PC20 histamine.

Patients with chronic illnesses, such as chronic obstructive pulmonary disease (COPD), report an increase in the perception of fatigue in the clinical setting. Subjective fatigue associated with physiological factors has not been reported. The purpose of this study was to determine the relationship between subjective fatigue and pulmonary function, respiratory and peripheral muscle force and exercise capacity in patients with COPD. Nineteen patients with COPD participated in the study [mean (SD) FEV 1 38% (17%) predicted]. Fatigue was measured with the Multidimensional Fatigue Inventory 20 (MFI-20) that includes the following subscale dimensions: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. The following physical variables were measured: forced expiratory volume in 1 s (FEV 1 ), vital capacity (VC), maximal inspiratory peak pressure ( P imax), symptom-limited bicycle exercise capacity (maximum workload) and maximal voluntary isometric muscle force of both left and right quadriceps (Qu), hamstrings (Ha), biceps (Bi) and triceps (Tr). The MFI-20 fatigue dimensions, reduced activity and reduced Motivation, are significantly correlated with FEV 1 (% predicted) ( r = −0·62, r = −0·55 respectively). No significant correlation was found between the dimensions of fatigue and maximum workload. In contrast the fatigue dimension, physical fatigue, shows significant correlations with seven of eight muscle forces measured (Qu left r − =0·49, right r = −0·54; Ha left r = −0·49, right r − 0·38; Tr left r = −0·61, right r = −0·45; Bi left r = −0·46, right r = −0·48). Data from this study show that activity and physical dimensions of subjective fatigue are related to pulmonary function and skeletal muscle force in COPD patients. Interventions to improve skeletal muscle force might improve subjective fatigue in patients with COPD.

This study is a result of two consecutive double-blind, placebo-controlled, cross-over studies. In the first study, we evaluated therapeutic effects of a single transdermal scopolamine patch (Scopoderm(R) TTS, size 2.5 cm(2), Ciba Geigy) on forced expiratory volume in one second (FEV1), reversibility, peak expiratory flow (PEF) and symptoms in ten patients with reversible airways disease (Delta FEV1 greater than or equal to 9% predicted). During the study, blood and urine samples were taken from the patients and analysed for scopolamine levels. The drug was adequately taken up from the patch into the systemic circulation. However, no significant clinical effects, nor correlations between the scopolamine levels and the outcome parameters were observed. Because of the possibility of sub-therapeutic doses in the first study, a second study with two transdermal scopolamine patches was performed in ten patients with bronchial hyperresponsiveness to methacholine. The blood and urine concentrations of free scopolamine were doubled compared to the first study. There were still no statistically significant effects on FEV1, PEF, symptoms, and bronchial hyperresponsiveness, yet most of the patients now reported adverse side effects. We conclude that transdermal administration of scopolamine is not clinically useful in asthma and chronic obstructive pulmonary disease. Even application of two patches does not result in therapeutically effective levels at the muscarinic receptors in the lung, yet causes several side effects. (C) 1997 Elsevier Science B.V.

Measurement of nitric oxide levels in exhaled air is commonly performed using a chemiluminescence detector. However, water vapour and carbon dioxide affect the chemiluminescence process. The influence of these gases at the concentrations present in exhaled air, has not yet been studied. For this in vitro study, mixtures of 50, 100 and 200 parts per billion (ppb) NO in air were prepared and fed into the NO analyser either directly or bubbled through water. Mixtures with CO2 were prepared by adding 0-10% CO2 to the diluent air. We found a significant decrease in NO readings in the water-saturated samples compared to the dry gas (p < 0.001), strongly dependent on the partial pressure of water. NO levels in exhaled air (mean 10 +/- 2 ppb) showed a decrease of 17 +/- 3% when water vapour was not absorbed. From the experiments with CO2 we found a decrease in NO reading of 1.04 +/- 0.07% per volume CO2 (%). Presence of water vapour, thus, leads to a systematic underestimation of NO levels. Insertion of a water absorber might, therefore, be advantageous. The influence of CO2 concentrations in the normal respiratory range is negligible. With high expiratory CO2 levels as applied in permissive hypercapnia, the effects may be substantial.

In contrast to the numerous studies which show that lymphocytes play an important role in the pathogenesis of asthma, few studies have investigated the role of lymphocytes in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of the present study was to investigate lymphocyte subsets in peripheral venous blood of smoking and non-smoking COPD patients and healthy controls. The interaction of smoking and IgE has also been assessed, and it was investigated whether a lower level of FEV1 was associated with changes in lymphocyte subsets. In the present study, peripheral venous blood lymphocyte subsets were investigated in 42 smoking and non-smoking, non-atopic subjects with a clear diagnosis of COPD (43-74 years) who all used bronchodilator therapy only, and in 24 normal, healthy control subjects (40-72 years). No significant differences in lymphocyte subsets were found when either total groups or smoking subjects of both groups were compared. However, the percentage of CD8+ lymphocytes (suppressor/ cytotoxic T-cells) was significantly higher in the non-smoking COPD subjects compared with the non-smoking, healthy control subjects (P0.05). In addition, within the group of non-smoking COPD subjects, a higher CD4:CD8 ratio was associated with a higher FEV1 as a percentage of predicted (% pred.) (r = 0.55, P = 0.01) and a lower total serum IgE (r = -0.45, P = 0.04). Within the group of smoking COPD subjects, a higher FEV1 % pred. was associated with a higher percentage of CD19+ lymphocytes (B-cells) (r = 0.65, P0.01). The present study provides further evidence that the changes in the balance of T-cell subsets and IgE synthesis possibly plays a role in the pathogenesis of COPD.

The median age of survival in patients with cystic fibrosis (CF) has improved considerably. Despite this improvement, deterioration of pulmonary function and decrease in exercise capacity are still the main problems for many patients. Although dyspnoea is a common complaint in CF patients, relatively little regard has been paid to this symptom. This study examined the relationship between dyspnoea, bicycle exercise capacity and pulmonary function in patients with CF. In 14 patients in a stable clinical condition, pulmonary function [forced expiratory volume in 1 s (FEV1), inspiratory vital capacity (IVC)], bicycle exercise capacity [maximum exercise capacity (Wmax)], subjective degree of dyspnoea during daily living [Medical Research Council (MRC) dyspnoea scale], and during exercise (Borg scale) were assessed. The mean (SD) age of the patients was 25 (6.8) years, FEV1 was 41 (19)% predicted, IVC was 63 (17)% predicted and FEV1/IVC ratio was 47 (10)%; median (range) Wmax was 55 (0-79)% predicted. Bicycle exercise test performance appeared to be mainly determined by pulmonary function and MRC dyspnoea grade; multiple regression equation containing FEV1 and dyspnoea accounted for 76% of the variance in Wmax (% predicted) (Wmax = -7.9 dysp + 1.1 FEV1, +24). Exercise dyspnoea, assessed by the Borg scale, showed a significant linear correlation with minute ventilation. (VE), maximal voluntary ventilation (MVV) (%) (r = 0.76; P < 0.001). Medical Research Council dyspnoea score correlated relatively poorly with FEV1 (% predicted) (r = -0.17; n.s.) and IVC (% predicted) (r = -0.48; n.s.). Borg score at maximal exercise did not correlate with MRC dyspnoea score (r = -0.07). Borg50% score correlated significantly with MRC dyspnoea score (r = 0.61; P < 0.05). These results show that dyspnoea has an influence on exercise capacity. Dyspnoea score showed a large inter-individual variation, not strongly related to pulmonary function. It is concluded that dyspnoea deserves more attention in CF patients and needs to be assessed in rehabilitation programmes and other intervention studies in these patients.

The majority of patients with cystic fibrosis (CF) will grow into adulthood. Despite this improvement in survival, the disease is progressive, especially with respect to the decline in pulmonary function, which in turn may have an impact on a patient's quality of life. In this study we evaluated the quality of life in CF adults and examined the relationship between quality of life and pulmonary function, exercise capacity, and dyspnea. We assessed in 15 patients in stable clinical condition their forced expired volume in the first second (FEV1) inspiratory vital capacity (IVC), cycle exercise capacity (Wmax), and subjective degrees of dyspnea during daily living (MRC dyspnea scale). Quality of life was assessed with the Sickness Impact Profile (SIP). A sample of 100 healthy individuals, ranging in age from 18 to 30 years, served as the control group. Mean (SD) age of the patients was 25.9 (7.3) years, FEV1 was 38 (16)% predicted, IVC was 65 (17)% predicted, FEV1 IVC ratio was 46 (10)%, and Wmax was 90 (54) W. The overall SIP and physical SIP scores in CF patients were significantly higher than in the controls, indicating more impairment in overall and physical functioning in the patients than in the control group (P < 0.001). The psychosocial SIP score did not differ significantly between the two groups. Overall SIP score correlated poorly with FEV1 % predicted (r = -0.33; n.s) and IVC % predicted (r = -0.36; n.s.) but showed a better and significant relationship to the maximal exercise capacity (r = -0.57; P < 0.05). MRC dyspnea scores showed a strong correlation with overall SIP scores (r = 0.75; P < 0.001). These results show that CF affects quality of life in adults primarily due to a limitation in physical functioning. Psychosocial functioning did not differ from that of healthy controls. Exercise capacity and dyspnea scores were related to the impairment in the quality of life. Therefore, the effects of programs aimed to improve exercise capacity and reduce dyspnea on CF patients' quality of life need to be evaluated.

A pilot study was set up to assess the long-term effects of once weekly versus once monthly follow-up of pulmonary rehabilitation after a comprehensive home rehabilitation program on physical performance in patients with chronic obstructive pulmonary disease (COPD) during an 18-mo period. Thirty-six patients with a mean FEV(1) of 1.3 +/- 0.4 L (43% pred) were included in the study. Groups A and B (n = 23) visited the physical therapist twice weekly for 3 mo. Thereafter, 11 patients (Group A) had a follow-up of pulmonary rehabilitation once a week, and 12 patients (Group B) had a follow-up once a month. Thirteen patients received no rehabilitation at all (Group C). Long-term home rehabilitation does not appear to improve exercise tolerance; however, on the other hand, there is a deterioration in vital capacity (p

The aim of the study was to investigate whether seasonal differences in house dust mite (HDM) allergen exposure influence the circadian peak expiratory flow (PEF) amplitude in asthmatic children. Asthmatic children (n = 25) with a solitary allergy to HDM were studied in spring and in autumn. All used inhaled corticosteroids (ICS) regularly. Six days after withdrawal of ICS, PEF amplitude (every 4 h during 24 h, highest-lowest/percentage of mean value) was assessed. HDM allergen (HDMA) in living rooms, bedrooms, and mattresses was collected. HDMA levels were not always highest in autumn. PEF amplitudes in spring and autumn did not correlate with HDMA levels in the same season. However, the seasonal difference in PEF amplitude (autumn value - spring value) correlated positively and significantly with the seasonal difference in HDMA exposure levels from the mattresses (rho = 0.34, p

The influence of exogenous factors in the home on the circadian variation of airway obstruction has not been fully assessed in children with asthma. The aim of the present study was to investigate the contribution of exogenous stimuli to the degree of peak expiratory flow (PEF) variability during 24 h. Fifty-five children (33 boys and 22 girls; mean age, 9.3 +/- 1.7 yr) with symptoms of asthma, increased bronchial responsiveness, and a solitary allergy to house dust mite (HDM) participated. Their asthma symptoms were well-controlled for at least 4 mo with daily inhaled corticosteroids (ICS) and beta 2-adrenergic drugs if needed. Symptoms, peripheral blood eosinophils, total IgE, and specific IgE to HDM were assessed. Spirometry and PC20 histamine were performed. PEF amplitudes during 24 h (highest minus lowest as a percentage of the day's mean value) were obtained at home during and 6 d after withdrawal of ICS. Dust samples were collected from the total area of the living rooms, bedrooms, mattresses (n = 25), and classrooms to obtain the HDM allergen (HDMA) exposure to Der p I and Der p II. Family smoking habits, presence of pets, and types of floor-covering were recorded on a checklist. Mean PEF amplitude did not increase after withdrawal of ICS, but absolute PEF values were significantly lower (p = 0.05) at midnight and 4:00 A.M. Twenty-six children (47%) were exposed to environmental tobacco smoke (ETS), and 23 (42%) kept pets. Mattresses contained significantly higher amounts of HDMA compared with other locations. PEF amplitude after withdrawal of ICS was significantly higher in children exposed to ETS, a pet, or a high HDMA level in their mattress than in children who were not exposed (ETS: 29.7% [3.9 to 56.6] versus 19.4% [0.0 to 56.6], p

Aim - To determine whether house dust mite (HDM) exposure in living rooms and bedrooms is higher in asthmatic children than in those of age and sex matched healthy children, living in the same area. Methods - Types of floor-coverings were recorded and dust samples were collected by vacuum cleaning the total area of living rooms and bedrooms; Der p I and Del p II per gram fine dust concentrations were assessed. Twenty-five asthmatic children (RAST HDM greater than or equal to class 3, age 6-12 years) and 25 healthy children participated in the study. Results - The frequency of cleaning and prevalence of smooth floor-coverings in bedrooms of asthmatic children were significantly higher. There were no differences in living rooms in this respect. The amount of fine dust/m(2) floor space was significantly lower in bedrooms of asthmatic children, Concentrations of HDM were low and no differences in Del p I and Del p II concentrations were observed between the two groups (asthmatic children: Der p I living room: 1.1 (0.04 - 59.4 mu g/ g), bedroom: 0.5 (below detection - 19.3 mu g/g); nonasthmatic children: Der p I living room: 1.4 (below detection - 27.5 mu g/g), bedroom: 0.9 (below de tection - 68.8 mu g/g. Smooth floor coverings contained significantly less fine dust, Der p I, and Der p II than carpeted floors. Conclusion - Low HDM concentrations are a general finding in Dutch dwellings in the present generation of children. We observed a higher cleaning frequency, and more smooth floor coverings in bedrooms of asthmatic children than of healthy children, yet HDM concentrations were not significantly different. The latter can be explained by the observation that only 40% of the asthmatic children had smooth floor coverings in their bedrooms. Smooth floor coverings contain less fine dust and lower concentrations of Der p I and Der p LI than carpeted floors

BACKGROUND--Pulmonary rehabilitation has been shown to have short term subjective and objective benefits for patients with chronic obstructive pulmonary disease (COPD). However, appropriately controlled studies have not previously been performed, nor have the benefits of different types of continuation programme for rehabilitation been investigated. Both these problems have been addressed in a single study of the long term effects of once monthly physiotherapy versus once weekly physiotherapy at home after a comprehensive home rehabilitation programme on quality of life and exercise tolerance in patients with COPD. METHODS--Thirty six patients with severe airways obstruction (mean SD) forced expiratory volume in one second (FEV1) 1.3(0.4) 1, FEV1/inspiratory vital capacity (IVC) 37.2(7.9)%) were studied. Twenty three patients followed a rehabilitation programme at home for 18 months consisting of physiotherapy and supervision by a nurse and general practitioner. During the first three months all 23 patients visited the physiotherapist twice a week for a 0.5 hour session. Thereafter, 11 patients (group A) received a session of physiotherapy once weekly while 12 patients (group B) received a session of physiotherapy once a month. The control group C (13 patients) received no rehabilitation at all. Quality of life was assessed by the Chronic Respiratory Questionnaire, exercise tolerance by the six minute walking distance, and lung function by FEV1 and IVC. Outcome measures were assessed at baseline and at three, six, 12, and 18 months. RESULTS--Long term improvements in quality of life were found in patients in groups A and B, but not in those in group C compared with baseline, but these only reached significance in group B at all time points. Patients in group B had a higher quality of life than those in group C only at three and 12 months. There was a decrease in both six minute walking distance (at 12 and 18 months) and IVC (at three, 12, and 18 months) in patients in group C compared with the baseline measurement. Between groups analysis showed no differences for six minute walking distance, FEV1, and IVC. CONCLUSIONS--This study is the first to show that rehabilitation at home for three months followed by once monthly physiotherapy sessions improves quality of life over 18 months. The change in quality of life was not associated with a change in exercise tolerance.

Background - In addition to bronchodilator and anti-inflammatory therapy, exacerbations in patients with chronic obstructive pulmonary disease (COPD) are often treated with antibiotics. Haemophilus influenzae and Moraxella (Branhamella) catarrhalis, two important respiratory pathogens, may produce beta-lactamase which makes them resistant to ampicillin. Surveillance studies conducted in various countries have shown an increasing incidence of these beta-lactamase producing bacteria. Although this may simply be a consequence of the increasing use of antibiotics, it is possible that other factors are important. A study was undertaken to investigate whether clinical factors are related to the presence of beta-lactamase forming bacteria in the sputum of patients with COPD.Methods - One hundred patients with COPD aged over 40 years were sequentially selected from an outpatient clinic on the basis of sputum culture results. Fifty had beta-lactamase positive (beta L +) and 50 had beta-lactamase negative (beta L +) bacteria in their sputum. Patients were included only if sputum culture results yielded one pathogen. The files of these patients were investigated for possible causative factors present during the two preceding years.Results - Both groups were almost identical in terms of lung function, maintenance medication, and smoking history. The total number of antibiotic courses in the beta L + group was higher, as were individual courses of cephalosporins, tetracyclines, and macrolides. The number of patients admitted to hospital was higher in the beta L + group, but admissions were of equal duration in both groups. Patients admitted to hospital had poorer lung function. Risk factors for beta-lactamase producing bacteria were identified by logistic regression analysis which revealed an odds ratio for one course of antibiotics of 1.15 (95% CI 1.04 to 1.28).Conclusions - An increased number of antibiotic courses is related to a higher incidence of beta-lactamase producing bacteria and more patients had hospital admissions in the beta L + group. beta-lactamase stable antibiotics were used more frequently in the beta L + group, probably because prescribing was adapted to the presence of beta-lactamase producing bacteria. No other differences were found between the beta L + and beta L - groups.

Breathing with positive expiratory pressure (PEP), such as pursed lip breathing (PLB), is a therapeutic intervention for patients with obstructive lung disease. The effects of PEP breathing are thought to be based on the amount of the applied oral pressure. The purpose of this study was to compare oral pressures during PLB with those during other forms of PEP breathing, in order to establish the best artificial replacement for the expiratory pressures reached during PLB.Oral pressure was measured during PLB, during breathing with an expiratory threshold valve of 5 cm H2O (PEP5) and during expiration through tubes of diameter 2, 3 and 5 mm. The study group comprised 16 healthy subjects and 8 patients with chronic obstructive pulmonary disease. We found that during PLB, a peak expiratory pressure of about 5 cm H2O is reached. This is comparable to breathing with a PEP threshold valve of 5 cm H2O. Based on these results, we recommend a flow-independent threshold valve in order to simulate the expiratory pres...

BACKGROUND--Several studies have shown that both objective and subjective measurements are related to exercise capacity in patients with chronic obstructive pulmonary disease (COPD). In this study the relative contribution of lung function, maximal inspiratory pressure, dyspnoea, and quality of life to the performance in a walking distance test and a bicycle ergometer test was investigated. METHODS--Static lung volumes, forced expiratory volume in one second (FEV1), inspiratory slow vital capacity (IVC), transfer factor for carbon monoxide (TLCO) divided by the alveolar volume (TLCO/VA), static compliance (Cst), and maximal inspiratory peak pressure (PImaxPOES) were measured in 40 patients with COPD with severe airways obstruction (mean FEV1 44% predicted, mean FEV1/IVC 37% predicted). Quality of life was assessed by the Chronic Respiratory Questionnaire (CRQ) and dyspnoea by the Borg category scale. Exercise capacity was measured by both a six minute walking distance (test) and a maximal work load of the bicycle ergometer test (Wmax). RESULTS--Spirometric values and maximal inspiratory pressure were modestly correlated with both the six minute walking test and Wmax, r values ranging from 0.50 to 0.58. The TLCO was strongly correlated with the six minute walking test (r = 0.62) and with Wmax (r = 0.78). Quality of life showed no correlation with exercise capacity, while there was a correlation between dyspnoea and the six minute walking test (r = -0.41). Backward linear regression analysis selected TLCO and PImaxPOES as the most significant determinants for exercise performance. They explained 54% and 69% of the variance in the six minute walking test and Wmax, respectively. CONCLUSIONS--The results show that exercise capacity in patients with COPD with severe airways obstruction is more strongly related to inspiratory muscle strength and lung function than to dyspnoea and quality of life. The significant correlation between dyspnoea and the six minute walking test suggests that subjective variables are more strongly related to walking tests than to bicycle ergometer tests.

A beta-lactamase-stable antibiotic, the oral penem FCE 22891 (ritipenem acoxil), was investigated for use in exacerbations of chronic obstructive pulmonary disease (COPD). Thirteen of the 15 COPD patients had a proven lower respiratory tract infection. Symptom scores and forced expiratory volumes in 1 s significantly improved during therapy with FCE 22891 in combination with bronchodilators and intravenous corticosteroids. Conversion of representative sputum to nonrepresentative sputum or eradication of the original pathogen in representative sputum was effected in 12 patients. Resistance to FCE 22891 was observed in three cases with Haemophilus influenzae. Gastrointestinal disturbances, of which one was severe, were experienced by eight patients. Although FCE 22891 has some beneficial effect in exacerbations of COPD, there are reservations about its use because of adverse effects and potential inefficacy in the treatment of infection with H. influenzae.

The purpose of this study was to investigate the relationship between bronchoalveolar lavage (BAL)-derived parameters of interstitial lung disease and clinical and lung function parameters in 34 patients with sarcoidosis and 23 patients with idiopathic pulmonary fibrosis (IPF). BAL findings of healthy individuals served as controls. Cell content and differentiation of BAL fluid were determined. Oxygen radical (O2-) production of BAL cells and of blood polymorphonuclear (PMN) cells was measured. Phenotypes of lung and blood lymphocytes were determined by immunoperoxidase staining. In addition, lung function was assessed, chest X-rays were made and serum ACE was measured. Lymphocyte alveolitis in sarcoidosis was associated with increased alveolar macrophage (AM) O2- production (P < 0.025 vs. sarcoidosis with normal lymphocyte counts). Patients with extrapulmonary sarcoidosis had higher CD4/CD8 ratios in BAL (P < 0.025) and shorter disease duration (P < 0.01) than those with strictly pulmonary sarcoidosis. Disease duration in sarcoidosis correlated inversely with the number of BAL cells (r = -0.38, P < 0.05), the relative and absolute number of lymphocytes in BAL fluid (r = -0.34, P < 0.05 and r = -0.44, P < 0.01, respectively) and the percentage of CD4-positive cells and the CD4/CD8 ratio (r = -0.43, P < 0.05 and r = -0.48, P < 0.025, respectively). Although significant increases in O2- production by BAL cells were observed in both IPF and sarcoidosis, only in sarcoidosis was a higher AM O2- production associated with a significantly lower total lung capacity (r = -0.67, P < 0.005) and pulmonary diffusing capacity TLCO (r = -0.50, P < 0.05). In conclusion, our findings show that lung lymphocyte phenotypes differ among patients with pulmonary and extrapulmonary sarcoidosis and that O2- production is upregulated in active sarcoidosis. In addition, our findings suggest that different relationships between BAL data and lung function in patients with sarcoidosis and IPF may be explained by differences in disease duration. In IPF, disease duration is likely to be underestimated because of its insidious onset. In sarcoidosis, the presence of extrapulmonary symptoms, helpful to establish an early diagnosis, is associated with significant BAL lymphocytosis.

Inhaled corticosteroid has been shown to be effective in the management of asthma. However, there is a lack of studies that assess the effect of cessation after long-term treatment with inhaled corticosteroid. This question was addressed in 28 children with stable asthma, aged 11 to 18 yr of age, who had completed 28 to 36 months of treatment with inhaled corticosteroid (budesonide 200 µg 3 times/day) and inhaled β-2-agonist (salbutamol 200 µg 3 times/day). The children were randomized in a 1:2 ratio in a double-blind study either to continue budesonide (n = 8) during a period of 6 months or to decrease the dose of budesonide (n = 20) within 2 months, followed by placebo for 4 months. Treatment with salbutamol 600 µg daily was continued in both groups. Eight children from the tapering-off group withdrew, mainly due to symptoms of asthma, compared with none in the continuous treatment group. Five patients in the tapering-off group experienced exacerbations for which prednisolone was given, compared with no...

Increased airway hyperresponsiveness is thought to be one of the phenomena underlying nocturnal airway obstruction in asthma. To investigate the mechanisms that influence and modulate this phenomenon, we compared circadian variations in airway responsiveness with AMP and propranolol with the circadian variation in airway responsiveness to methacholine. Inhalation provocation tests were performed at 16.00 and 04.00 h in 16 nonsmoking atopic asthmatic subjects (18 to 42 yr of age), prospectively assigned to Group 1 (mean circadian peak expiratory flow rate [PEFR] variation greater-than-or-equal-to 15%) and Group 2 (

Background: The relationships between allergic symptoms after exposure to house dust, allergy parameters (skin test to house dust mite [HDM], total IgE, HDM-specific IgE, and blood eosinophil counts), and several confounding variables (age, sex, smoking habits, and airway hyperresponsiveness) were evaluated in 235 patients with asthma and chronic obstructive pulmonary disease (COPD). Results: Skin tests had higher diagnostic value (sensitivity plus specificity) for symptomatic allergy than specific IgE (1.45 versus 1.36) or total IgE (1.16). The other allergy parameters gave no additional information on symptoms once the skin test was known. Expressing the skin test relative to the histamine control proved slightly better than uncorrected wheal size, but this probably has limited clinical value. The best cutoff level for a positive skin test was 0.7 when the histamine wheal size was accounted for by division, −6 mm when subtraction was used, and 7 mm for absolute wheal size. These cutoff levels proved equally applicable in various subgroups of patients with asthma and COPD. Only the skin test and female sex were independent predictors of allergic symptoms. Conclusion: We conclude that skin tests to HDM are better predictors for clinical allergy than total or specific IgE levels and eosinophil count, and that they are applicable in most patients with asthma and with COPD.

Previous studies have reported a familial predisposition for the development of atopy, bronchial hyperresponsiveness and clinical asthma, and therefore have suggested the presence of a heritable component to these disorders. The specific contributions of genetic and environmental factors in the pathogenesis of allergic disease and asthma have not been determined although Cookson et al. [1] have postulated linkage between atopy and chromosome 11q. We have studied 20 families (two and three generations) ascertained through a proband identified as having asthma (90% were also allergic) during the period of time between 1962 and 1970. Of those who were originally skin test positive, 82% remained positive. All probands whose pulmonary function allowed retesting (FEV1 > 1.2 l) remained hyperresponsive to histamine. The children of these probands are now in the same age range as their parents when they were originally evaluated; 66% are atopic using criteria described by Cookson et al. (one or more positive skin tests > or = 2 mm, an elevated total serum IgE or a positive specific IgE) and 22% demonstrate bronchial hyperresponsiveness (PC20 FEV1) to histamine. Using the highly polymorphic marker INT2 (which maps 2 cM from p lambda MS.5 l on chromosome 11q) and atopy, we obtained a lod score of -2.00 at a recombination fraction of 0.12. In addition, because many studies have suggested an association between atopy and certain HLA antigens, we investigated the possibility of linkage between atopy and bronchial hyperresponsiveness and D6S105, a polymorphic marker on chromosome 6p, located 7 cM from HLA-DR. For this marker and atopy, we observed a lod score of -2.00 with a recombination fraction of 0.07.(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND: Short term treatment with corticosteroids does not usually reduce airflow limitation and airway responsiveness in patients with chronic obstructive lung disease. We investigated whether corticosteroids modulate the effects of inhaled salbutamol and ipratropium bromide. METHODS: Ten non-allergic subjects with stable disease were investigated; eight completed the randomised, double blind, three period cross over study. Treatment regimens consisted of 1.6 mg inhaled budesonide a day for three weeks, 40 mg oral prednisone a day for eight days, and placebo. After each period cumulative doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo were administered on separate days until a plateau in FEV1 was reached. A histamine challenge was then performed. RESULTS: At the end of placebo treatment mean FEV1 was 55.5% predicted after inhaled placebo, 67.9% predicted after salbutamol and 64.0% predicted after ipratropium. Compared with the results after the placebo period the FEV1 with salbutamol increased by 0.7% predicted after treatment with budesonide and by 0.7% predicted after treatment with prednisone; the FEV1 with ipratropium increased by 0.7% predicted after budesonide and by 4.8% predicted after prednisone; none of these changes was significant. After placebo treatment the geometric mean PC20 was 0.55 mg/ml after placebo, 1.71 mg/ml after salbutamol and 0.97 mg/ml after ipratropium. Compared with the placebo period the PC20 with salbutamol was increased by 0.86 doubling concentrations after treatment with budesonide, and by 0.67 doubling concentrations after prednisone; the PC20 with ipratropium increased by 0.03 and 0.34 doubling concentrations after budesonide and after prednisone respectively compared with placebo; none of these changes was significant. CONCLUSIONS: In non-allergic subjects with chronic obstructive lung disease short term treatment with high doses of inhaled or oral corticosteroids does not modify the bronchodilator response to salbutamol or ipratropium or the protection provided by either drug against histamine. Salbutamol produces greater protection from histamine induced bronchoconstriction than ipratropium.

We have investigated separate and interactive effects of corticosteroids and bronchodilators on airflow obstruction and airway hyperresponsiveness. Twelve allergic subjects with asthma were treated in a double-blind, crossover, randomized study with budesonide, 1.6 mg daily for 3 weeks, prednisone, 40 mg daily, for 8 days, and placebo. After each period, dose-response curves were measured on 4 study days with doubling doses of salbutamol, ipratropium, a combination of salbutamol and ipratropium, and placebo until a plateau in FEV1 was reached. A histamine challenge was then performed, and the provocation concentration causing a 20% fall in FEV1 (PC20) was calculated. The budesonide and prednisone regimens were equipotent. FEV1 was 81.2% of predicted after budesonide, 81.0% predicted after prednisone, and 67.5% predicted after placebo, bronchodilatation thus being 13.7% predicted (budesonide) and 13.5% predicted (prednisone). PC20 improved with 2.17 doubling concentrations (DCs) after budesonide, and 1.86 DCs after prednisone, compared with that of placebo. Salbutamol caused stronger bronchodilatation than ipratropium (26.2% versus 14.7% predicted) and a better protection against histamine challenge (3.95 versus 1.12 DC). The effects of corticosteroids and bronchodilators on FEV1 and PC20 were, in general, additive. This study emphasizes different modes of action on both airflow obstruction and airway hyperresponsiveness by corticosteroids and bronchodilators, and it demonstrates no enhancement of bronchodilator action by corticosteroids.

Bronchial hyperresponsiveness (BHR) to methacholine and adenosine 5'-monophosphate (AMP) was studied in 15 allergic asthmatic patients before and 3 and 24 h after allergen challenge with house dust mite (HDM). Subjects attended the clinic on 3 consecutive days. On the first day a control solution was inhaled, and methacholine or AMP challenge was performed 3 h later. The next day HDM was inhaled, and 3 and 24 h later methacholine or AMP challenge was performed again. There were no significant difference in FEV1 baseline value between any of the study days. PD20 HDM, percentage decrease in FEV1, and AUC for both the EAR and LAR were not significantly different in the methacholine and AMP studies. After HDM challenge, PC20 methacholine decreased significantly from a geometric mean (+/- SEM) starting value of 1.39 +/- 0.63 mg/ml to 0.30 +/- 0.78 mg/ml (p less than 0.001) at 3 h and to 0.22 +/- 0.75 mg/ml (p less than 0.001) at 24 h. The magnitude of the decrease in PC20 methacholine at 3 h correlated with the severity of the late asthmatic reaction (LAR) as measured by the percentage fall in FEV1 and area under the curve (AUC) (r = -0.60 and r = 0.55; p less than 0.05). A significant decrease was observed in the PC20 AMP at 3 h, from a geometric mean value of 12.2 +/- 0.96 mg/ml after challenge with the control solution to 4.47 +/- 0.99 mg/ml (p less than 0.05) after HDM challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

A better outcome of patients with chronic obstructive pulmonary disease (COPD) appears to be determined by higher FEV1, smoking cessation, lower airway hyperresponsiveness, and, at least in the presence of therapy, with a higher reversibility of airflow obstruction. In our opinion, these findings provide a firm ground for smoking cessation and most likely for institution of early treatment directed at both the reversible part of airflow obstruction and airway hyperresponsiveness in patients with COPD. But there are large gaps in our understanding of the effects of bronchodilator and antiinflammatory drugs on airway hyperresponsiveness. After acute administration, sympathomimetics cause a larger reduction of airway hyperresponsiveness than do anticholinergics, both in asthma and in COPD. What happens after longer periods of treatment is not yet clear in COPD, whereas in asthma there may occur a deterioration of airway responsiveness. Corticosteroids appear to have a beneficial effect on lung function and the severity of airway hyperresponsiveness in asthma. In COPD, however, no definite conclusion can be drawn as to the beneficial effect of corticosteroids, but short-term effects are not promising.The available data from the literature strongly suggest the need for long-term studies with large groups of patients in order to assess a potential treatment effect. In this way, also, a subgroup of patients with COPD who improve with corticosteroids and/or bronchodilators may be found. It seems advisable to include both subjective (i.e., quality of life, complaints, symptoms) and objective (i.e., hospitalization, survival, FEV1, PEFR, PC20, and reversibility) data as investigational tools for outcome analysis.

Between 1966 and 1969, housedust (HD) inhalation provocation tests were performed in 119 children with asthma. Between 1984 and 1987, 101 of the 119 subjects (85%) were reinvestigated. Thirty-one of these 101 adults who participated in a study on the outcome of childhood asthma were rechallenged with HD after a mean interval of 16 years to establish the change in airway responsiveness to HD from childhood to adult life. In the childhood study in these 31 subjects, six had no response (NAR); six, an early response (EAR); eight, a late (LAR); and eleven subjects, an EAR followed by an LAR (dual asthmatic response [DAR]) to the inhalation of HD. In the second survey, two of the subjects with NAR in the first study had a bronchoconstrictor response to HD. Five subjects with an EAR or an LAR response in childhood had NAR as an adult. The eleven subjects with a DAR during childhood also had a response to HD as an adult; five had an EAR, and six adults again had a DAR. Eleven of the 13 adults (85%) with current respiratory symptoms had a response to HD during the second survey. Although they were symptom free, 11 of the other 18 adults (61%) responded on inhalation of HD. One of the 18 subjects without (6%), and six of the 13 subjects (46%) with current respiratory symptoms, had a provocative concentration of histamine in FEV1 10% of baseline less than or equal to 16 mg/ml. We conclude that, although respiratory symptoms disappear in one half the children with asthma and although adults may believe that they have outgrown their disease, adults still have the potency to respond to inhaled allergens. Most children do outgrow their respiratory symptoms but not the susceptibility of their airways to allergens.

Patienten met astma of COPD worden gekenmerkt door een aanvalsgewijze of chronisch optredende kortademigheid, hoest en/of sputumproductie. De kortademigheidsklachten worden veroorzaakt door een bronchusobstructie, die het gevolg kan zijn van contractie van glad spierweefsel rond de luchtwegen, microvasculaire lekkage (oedeem) of afzetting van taai slijm op de bronchuswand. Hieraan kunnen zowel allergische als niet-allergische ontstekingsmechanismen ten grondslag liggen (zie figuren 16.1 en 16.2). Daarnaast worden astma- en in veel gevallen ook COPD-patienten gekarakteriseerd door het optreden van bronchiale hyperreactiviteit, gedefinieerd als een toegenomen gevoeligheid van de luchtwegen voor aspecifieke (niet-allergene) prikkels. De mechanismen van bronchiale hyperreactiviteit zijn slechts ten dele bekend, maar hangen voor een belangrijk deel samen met ontsteking van de luchtwegen. Met name bij astma is bronchiale hyperreactiviteit sterk gerelateerd aan de ernst van de ziekte en de noodzaak van medicatie. Vandaar dat farmacotherapie bij astma zoveel mogelijk gericht dient te zijn op zowel het voorkomen en verminderen van de bronchusobstructie als op het voorkomen en verminderen van bronchiale hyperreactiviteit. Hierbij speelt onderhoudstherapie met anti-inflammatoire geneesmiddelen een grote rol. Bij COPD staat de luchtwegverwijding centraal en staat de effectiviteit van onderhoudstherapie met anti-inflammatoire middelen (inhalatiecorticosteroi- den) nog ter discussie.

Secretory leukoprotease inhibitor (SLPI) is a low molecular weight serine protease inhibitor found on various mucosal surfaces and has been ascribed an important role in maintaining the protease-anti-protease balance of the airways. Recent scientific evidence has suggested that SLPI may also have a broad spectrum antibiotic activity that includes antiretroviral, bactericidal, and antifungal activity. Given the unpropitious development of drug resistance to infectious micro-organisms in the human population, the need for therapeutic alternatives in the treatment of infectious diseases has become clear. SLPI may prove valuable in the prophylaxis and future treatment of infectious diseases, yet the clinical efficacy of SLPI remains largely to be elucidated.

BACKGROUND: Factors contributing to either "complete" or "clinical" remission of asthma are important to know since there is no cure for the disease.METHODS: A cohort of 119 allergic asthmatic children was examined three times with a mean follow up of 30 years. They were aged 5-14 years at visit 1 (1966-9), 21-33 years at visit 2 (1983-6), and 32-42 years at visit 3 (1995-6). Complete remission of asthma at visit 3 was defined as no asthma symptoms, no use of inhaled corticosteroids, normal lung function (FEV1 >90% predicted), and no bronchial hyperresponsiveness (PC10 >16 mg/ml). Clinical remission was defined as no asthma symptoms and no use of inhaled corticosteroids.RESULTS: 22% of the group was in complete remission of asthma at visit 3 and a further 30% was in clinical remission (total 52%); 57% of subjects in clinical remission had bronchial hyperresponsiveness and/or a low lung function. Logistic regression analyses showed that a higher FEV1 in childhood and more improvement in FEV1 from age 5-14 to 21-33 were associated with both complete and clinical asthma remission at age 32-42.CONCLUSIONS: Complete remission of asthma was present in a small subset of asthmatics while half the subjects showed clinical remission. Both complete and clinical remission were associated with a higher lung function level in childhood and a higher subsequent increase in FEV1. These results support the view that defining remission only on the basis of symptoms and medication use will overlook subjects with subclinical active disease and possibly associated airway remodelling.

The purpose of this study was to explore the relationship between diagnosis and the cost-effectiveness and cost-utility of lung transplantation.A microsimulation model was used, based on empirical data from the Dutch lung transplantation program, collected between 1991 and 1999. We assessed life-years, quality-adjusted life-years, and costs with and without transplantation for the diagnostic categories alfa-1 antitrypsin deficiency, COPD/emphysema, bronchiectasis, primary and secondary pulmonary hypertension, cystic fibrosis, and pulmonary fibrosis.Alfa-1 antitrypsin deficiency and bronchiectasis had the highest survival gain. Secondary pulmonary hypertension and pulmonary fibrosis had the lowest survival gain and the lowest gain of quality-adjusted life-years. As compared with COPD/emphysema, alfa-1 antitrypsin deficiency, bronchiectasis, and CF had 25%, 40% and 19% more favorable cost-effectiveness ratios, respectively. Cost-utility ratios varied less, with values of -7%, -14% and -11% for alfa-1 antitrypsin deficiency, bronchiectasis, and primary pulmonary hypertension, respectively, compared with COPD.In conclusion, our model suggests that there is considerable variation in cost-effectiveness and, to a lesser degree, in cost-utility between the different diagnostic categories. These variations are the result of differences in survival and in quality of life with and without lung transplantation.

Summary Introduction Bronchial hyper-responsiveness is usually measured with direct stimuli such as methacholine (MCh) or histamine. Adenosine 5′-monophosphate (AMP), which acts indirectly via the secondary release of mediators, is another stimulus to measure bronchial hyper-responsiveness. Aim To investigate whether provocation with inhaled AMP itself initiates an inflammatory response resulting in an influx of eosinophils into the airway lumen. Methods We have included 21 non-smoking atopic asthmatic subjects (mean FEV1 101% predicted, mean age 34 years). Each subject performed three sputum inductions on different days, at least seven days apart: one without previous provocation, one hour after PC20 methacholine, and one hour after PC20 AMP. Results After provocation with AMP, but not methacholine, the percentage of sputum eosinophils increased significantly (from 1.9±0.5% to 4.5±1% (P

Background: In lung transplantation (LTx), allocation of donor lungs is usually based on blood group, height and waiting time. Long waiting times favor patients with a slowly progressive end-stage lung disease and make the current allocation system the subject of discussion. In an attempt to equalize the chances for transplantation for every patient, irrespective of diagnosis, we investigated the effect of diagnosis-dependent prioritization on the waiting list, using a simulation model. Methods: For the main disease categories on the waiting list, the relative risks of dying while on the waiting list were calculated using empirical data from the Dutch LTx program gathered over a period of 10 years. In a microsimulation model of the Dutch LTx program based on data from the actual situation, patients with diagnoses associated with a statistically significant increased risk of death while on the waiting list were prioritized by multiplying the time on the waiting list by the relative risk. Results: Relative risks of death on the waiting list were increased significantly in patients with cystic fibrosis, primary pulmonary hypertension and pulmonary fibrosis. Prioritization resulted in an increased chance of transplantation for the prioritized diagnoses and a decreased chance for the non-prioritized diagnoses. The distribution of diagnoses after LTx was almost equal to the distribution of diagnoses on the waiting list. Conclusion: The simulated method of prioritization on the waiting list is a step forward to a more equitable allocation of donor lungs. Moreover, this method is clinically feasible, as long as the waiting list is updated frequently.

There is a large variability in clinical response to corticosteroid treatment in patients with asthma. Several markers of inflammation like eosinophils and eosinophil cationic protein (ECP), as well as exhaled nitric oxide (NO), are good candidates to predict clinical response.We wanted to determine whether we could actually predict a favourable response to inhaled corticosteroids in individual patients.One hundred and twenty patients with unstable asthma were treated with either prednisolone 30 mg/day, fluticasone propionate 1000 microg/day b.i.d. or fluticasone propionate 250 microg/day b.i.d., both via Diskhaler. They were treated during 2 weeks, in a double-blind, parallel group, double dummy design. We measured eosinophils and ECP in blood and sputum, and exhaled nitric oxide as inflammatory parameters before and after 2 weeks in order to predict the changes in forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% fall in FEV1 (PC20 Mch), and asthma quality of life (QOL). Secondly, to test whether these results were applicable in clinical practice we determined the individual prediction of corticosteroid response.We found that changes in FEV1, PC20 Mch and QOL with corticosteroids were predominantly predicted by their respective baseline value and to a smaller extent by eosinophils in blood or sputum. ECP, measured in blood or sputum, was certainly not better than eosinophils in predicting clinical response to corticosteroids. Smoking status was an additional predictor for change in FEV1, but not for change in PC20 Mch or QOL. Prediction of a good clinical response was poor. For instance, high sputum eosinophils (or = 3%) correctly predicted an improvement in PC20 Mch in only 65% of the patients.Our findings show that baseline values of the clinical parameters used as outcome parameters are the major predictors of clinical response to corticosteroids. Eosinophil percentage in blood or sputum adds to this, whereas ECP provides no additional information. Correct prediction of clinical response in an individual patient, however, remains poor with our currently used clinical and inflammatory parameters.

Background: The adhesion of lymphocytes to the epithelium and the release of proinflammatory cytokines are important features observed during acute and chronic allograft rejection. Development of chronic rejection in lung-transplantation patients is preceded by high levels of interleukin (IL)-6 and IL-8 protein in the bronchoalveolar lavage. Therefore, we studied the expression of IL-6 and IL-8 in cocultures of epithelial cells and allogeneic lymphocytes. Methods: IL-6 and IL-8 protein levels were determined in supernatants of the airway-derived epithelial cell line A549 and in primary epithelial cells obtained from lung-brushings after coculturing with autologous and allogeneic lymphocytes. Transcriptional mechanisms were detected by transient transfections. Results: Coculture-supernatants of epithelial cells and allogeneic CD2+ lymphocytes show high levels of IL-6 and IL-8 protein due to transcriptional activation of the respective genes in epithelial cells. Highest productions were measured when the epithelial-cell:lymphocyte ratio was 1:10. Highly purified CD4+ and/or CD8+ cells were unable to induce the same response as observed with the total lymphocyte-population. Depletion of CD4+ and/or CD8+ had no effect on the IL-6 and IL-8 production induced by the total CD2+ lymphocyte-population. However, depletion of CD56+ cells diminished the lymphocyte-induced IL-6 and IL-8 production by > 75%. Conclusion: These data show that allogeneic CD2+ lymphocytes are able to activate lung-derived epithelial cells, resulting in the release of proinflammatory cytokines, which have a prominent role in chronic allograft rejection observed in lung-transplantation patients.

We report a patient who received a single, left lung transplantation for idiopathic pulmonary fibrosis. The effect of the graft on pulmonary improvement was only temporary, because the patient developed obliterative bronchiolitis (OB), resulting in complete destruction of the graft. The patient, however, remains alive 6 years after OB was diagnosed, apparently as a consequence of native lung improvement with triple-immunosuppressive medicine. This case is of interest for several reasons: first, it shows that pulmonary fibrosis may respond to intensive immunosuppressive therapy; second, it demonstrates that ventilation scintigraphy is useful in addition to pulmonary function tests in estimating the actual function of the graft after single lung transplantation; and third, it appears that the gradation of bronchiolitis obliterans syndrome (BOS) after single lung transplantation may overestimate the true function of the transplant.

Little information is available about the effects of inspiratory muscle training in patients with cystic fibrosis (CF). In this study the effects of inspiratory-threshold loading in patients with CF on strength and endurance of the inspiratory muscles, pulmonary function, exercise capacity, dyspnoea and fatigue were evaluated. Sixteen patients were assigned to one of two groups using the minimization method: eight patients in the training group and eight patients in the control group. The training was performed using an inspiratory-threshold loading device. Patients were instructed to use the threshold trainer 20 min a day, 5 days a week for 6 weeks. Patients in the training group trained at inspiratory threshold loads up to 40% of maximal static inspiratory pressure (Pimax) and patients in the control group got 'sham' training at a load of 10% of Pimax. No significant differences were found among the two groups in gender, age, weight, height, pulmonary function, exercise capacity, inspiratory-muscle strength and inspiratory-muscle endurance before starting the training programme. Mean (SD) age in the control group was 19 (5.5) years, mean (SD) age in the training group was 17 (5.2) years. Mean FEV1 in both groups was 70% predicted, mean inspiratory-muscle strength in both groups was above 100% predicted. All patients except one, assigned to the training group, completed the programme. After 6 weeks of training, mean inspiratory-muscle endurance (% Pimax) in the control group increased from 50% to 54% (P = 0.197); in the training group mean inspiratory muscle endurance (% Pimax) increased from 49% to 66% (P = 0.003). Statistical analysis showed that the change in inspiratory-muscle endurance (% Pimax) in the training group was significantly higher than in the control group (P = 0.012). After training, in the training group there was a tendency of improvement in Pimax with an increase from 105 to 123% predicted, which just fell short of statistical significance (P = 0.064). After training no significant differences were found in changes from baseline in pulmonary function, exercise capacity, dyspnoea and fatigue. It is concluded that low-intensity inspiratory-threshold loading at 40% of Pimax was sufficient to elicit an increased inspiratory-muscle endurance in patients with CF.

In a prospective cohort study, we assessed whether changes in total cell counts and differentiation and interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1) concentrations in bronchoalveolar lavage fluid (BALF) are associated with a higher risk to develop obliterative bronchiolitis (OB). We investigated 60 lung transplant patients (follow-up of 2 to 8 yr) with either histologic evidence of OB within 1 yr after lung transplantation (n = 19) or no pathology, good outcome (CO) for at least 24 mo and well-preserved lung function, i.e., FEV greater than or equal to 80% of baseline (n = 41). Median time between lung transplantation and the first BAL was 42 d for the GO group and 41 d for the OB group (p > 0.05). in the bronchial fraction, median total cell counts (0.06 x 10(3)/ml versus 0.04 x 10(3)/ml), lymphocyte (9 x 10(3)/ml versus 2 x 10(3)/ml), and eosinophilic granulocyte counts (1 x 10(3)/ml versus 0) were significantly higher in the OB group than in the CO group (p

Dyspnoea differs between subjects with chronic obstructive pulmonary disease (COPD) and asthma, partly because the underlying mechanisms for bronchoconstriction differ. This study investigated the possible role of inflammation and the contribution of clinical variables on dyspnoea in subjects with COPD and asthma. Forty-eight smoking subjects with COPD and 21 nonsmoking subjects with asthma, were challenged with adenosine 5'-monophosphate (AMP) and methacholine. The Borg score was assessed before and after each challenge. Mean increases in Borg score (per percentage decrease in baseline forced expiratory volume in one second (FEV1)) were significantly smaller in COPD than in asthma (p

It is unclear how cellular and soluble inflammatory markers in induced sputum relate to markers in lavage fluid and biopsies in chronic obstructive pulmonary disease (COPD), This was investigated and also the possible differences between subjects with COPD and healthy controls assessed. Eighteen nonatopic subjects with COPD and 11 healthy controls were studied. Sputum was induced by inhalation of hypertonic saline. The airways were lavaged, using the first 50 mt for bronchial wash (BW) and the subsequent 150 mt for bronchoalveolar lavage (BAL), and biopsies were taken from subsegmental carinae. Neutrophils were the predominant cell type in sputum in COPD (median 77.3%) but not in BW (5.5%) and BAL fluid (1.7%), Differential cell counts in sputum did not correlate with the counts in BW or BAL fluid or biopsies, whereas sputum eosinophil cationic protein (ECP) levels correlated with BW fluid ECP levels (rho=0.66, p=0.007) and sputum interleukin-8 (IL-8) concentration,vith BAL, fluid LL-8 concentration (rho= 0.52, p=0.026), Subjects with COPD had a higher percentage of sputum neutrophils and eosinophils and higher concentrations of ECP and IL-8 than healthy controls. The higher percentages of eosinophils and concentrations of ECP were also seen in BW and BAL fluid. Finally, higher numbers of macrophages and eosinophils were found in biopsies. In conclusion, induced sputum is derived from a different compartment from BW and BAL fluid and biopsies. Induced sputum may be useful for studying the contribution of luminal neutrophils and eosinophils in chronic obstructive pulmonary disease.

Proteases secreted by Aspergillus fumigatus induce the production of cytokines by epithelial cells, including interleukin (IL)-6 and IL-8, In the present study, we focused on the mechanism(s) by which A. fumigatus-derived proteases elicit cytokine production in epithelial cells. In the epithelial cell line A549, IL-6 and IL-8 mRNA levels were enhanced by proteases as a result of transcriptional induction of the respective genes. Transcriptional induction of both genes coincided with enhanced DNA binding of nuclear factor (NF)-kappa B and NF-IL6, whereas activator protein-1 was unlikely to be involved. The enhanced transcriptional activity could be inhibited by the addition of chymostatin, showing serine protease dependency. Posttranscriptional mechanisms affecting the stability of IL-6 and IL-8 mRNAs were not involved in protease-induced IL-6 and IL-8 production. These data show that after exposure to A. fumigatus-derived proteases, IL-6 and IL-8 gene expressions are up-regulated as a result of transcriptional mechanisms.

Cough and expectoration of mucus are the best-known symptoms in patients with pulmonary disease. The most applied intervention for these symptoms is the use of chest physiotherapy to increase bronchial mucus transport and reduce retention of mucus in the airways. Chest physiotherapy interventions can be evaluated using different outcome variables, such as bronchial mucus transport measurement, measurement of the amount of expectorated mucus, pulmonary function, medication use, frequency of exacerbation and quality of life. Measurement of the transport rate of mucus in the airways using a radioactive tracer appears to be an appropriate outcome variable for short-term studies. Evaluation of chest physiotherapy only with pulmonary function tests appears to be inadequate in short-term studies. The popularity of using pulmonary function tests is probably based more on the availability of the instruments than on a theoretical basis related to the question of chest physiotherapy improving mucus transport. Quality of life and progression of the disease are not often used as outcome variables, but it may be worthwhile to use these in the future.

Lung transplantation has become an accepted treatment modality for end stage lung disease.1 Traditionally, immunosuppressive maintenance therapy consists of cyclosporin, azathioprine, and prednisolone in kidney and liver transplantation as well as in lung transplantation. Despite the use of these drugs, acute rejection occurs frequently, especially in the first weeks and months after lung transplantation. Although these periods are now almost never life threatening, they are associated with substantial morbidity. Prevalences of acute rejection ranging from 60% to 100% have been reported, depending on whether acute rejection is based on clinical or histological diagnosis.2-4 The incidence of acute rejection is far higher after lung transplantation than after any other form of solid organ transplantation. This may be due to the fact that the donor lung contains a substantial amount of immunocompetent tissue and because the lungs are constantly exposed to environmental factors.5 Bronchiolitis obliterans syndrome (BOS) is the major cause of morbidity and mortality in long term survivors of lung transplantation.6 7 It occurs in approximately 30–50% of recipients still alive one year after transplantation and is characterised by progressive airway obstruction, usually in the presence of histological evidence of obliterative bronchiolitis (OB).8 Once established it is usually refractory to immunosuppressive treatment,9 thus stressing the importance of preventing this long term complication. As the frequency and severity of periods of acute rejection are the main risk factors for development of BOS,8 it follows that it is of utmost importance to prevent acute rejection. A substantial effort has therefore been made to develop and introduce new immunosuppressant drugs, not only to prevent and treat acute and chronic rejection, but also with the hope of fewer side effects. This review will focus on recently approved immunosuppressant drugs, some of their pharmacological properties, evidence of their effectiveness …