Tw van der Mark

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

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

Relation of lung function, maximal inspiratory pressure, dyspnoea, and quality of life with exercise capacity in patients with chronic obstructive pulmonary disease.

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.

Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD

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 mL for bronchial wash (BW) and the subsequent 150 mL 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 (p=0.66, p=0.007) and sputum interleukin-8 (IL-8) concentration with BAL fluid IL-8 concentration (p= 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.

Markers of nitric oxide metabolism in sputum and exhaled air are not increased in chronic obstructive pulmonary disease

BACKGROUND Nitric oxide (NO) is involved in inflammation and host defence of the lung. It has been found in increased concentrations in the airways in asthmatic subjects but its levels in patients with chronic obstructive pulmonary disease (COPD) have not been investigated. A study was undertaken to determine whether markers of NO metabolism (NO in exhaled air, iNOS expression in sputum cells, and nitrite + nitrate (NO2 –/NO3 –) in sputum supernatant) are increased in subjects with COPD, and whether they correlate with inflammatory indices in induced sputum. The associations of these markers with smoking were also assessed. METHODS Sixteen subjects with COPD (median age 66 years, median forced expiratory volume in one second (FEV1) 63% predicted, eight current smokers) and 16 healthy subjects (median age 63 years, median FEV1 113% predicted, eight current smokers) participated in the study. NO was measured during tidal breathing and sputum was induced by inhalation of hypertonic saline. RESULTS No differences were observed between subjects with COPD and healthy controls in exhaled NO excretion rate (median 5.15 and 6.25 nmol/min), sputum macrophage iNOS expression (14% and 12%), and sputum supernatant NO2 –/NO3 – (46 and 73 μM). NO in exhaled air correlated with the percentage of sputum eosinophils in patients with COPD (rho = 0.65, p = 0.009) but not in healthy individuals. Exhaled NO and supernatant NO2 –/NO3 – levels were lower in healthy smokers than in healthy non/ex-smokers. CONCLUSIONS Our findings indicate that NO metabolism is not increased in patients with stable COPD. The close association between exhaled NO levels and sputum eosinophils suggests a role for NO in airway inflammation in COPD. Studies performed during exacerbations may clarify this role.

Effects of home rehabilitation on physical performance in patients with chronic obstructive pulmonary disease (COPD)

We investigated whether 12 weeks of rehabilitation at home in patients with chronic obstructive pulmonary disease (COPD) had a beneficial effect on lactate production, metabolic gas exchange data, workload of the inspiratory muscles, and dyspnoea during a maximal bicycle ergometer test. A second aim was to assess whether a change in dyspnoea was related to a change of inspiratory muscle workload. Forty three COPD patients with severe airways obstruction were included in the study: mean forced expiratory volume in one second (FEV1) 1.3 +/- 0.4 L (44% predicted), mean FEV1/inspiratory vital capacity (IVC) 37 +/- 8%. Twenty eight patients started a rehabilitation programme, whilst 15 patients received no rehabilitation. Rehabilitation was carried out at home; patients were supervised by a general practitioner, a physiotherapist and a nurse. Exercise tolerance was measured by means of a 6 min walking distance test (6MWD) and maximal workload (Wmax) during an incremental symptom-limited cycle ergometer test. Inspiratory muscle workload at Wmax was assessed with the Tension Time Index (TTI), and dyspnoea at Wmax with the Borg scale. After 12 weeks, the rehabilitation group showed a significantly larger increase in 6MWD (from 438 to 447 m) and in Wmax (from 70 to 78 W) compared with the control group. A significant improvement in oxygen consumption (V1O2) (from 1.0 to 1.1 L), lactate level (from 3.7 to 3.1 mEq.L(-1)), dyspnoea (from 6.0 to 4.5) and TTI (from 0.10 to 0.08) at Wmax occurred in the rehabilitation group during the programme. The reduction in TTI was not significantly correlated with the fall in dyspnoea, as assessed by the Borg scale. We conclude that 12 weeks of rehabilitation at home in COPD patients increases symptom-limited V1O2 in combination with an increased Wmax. At this significantly higher Wmax, there was a reduction in dyspnoea, lactate level and inspiratory muscle workload. The reduction in dyspnoea was not related to a decreased inspiratory muscle workload. This study shows that rehabilitation at home can produce beneficial physiological improvements during exercise in patients with chronic obstructive pulmonary disease.

Airway inflammation and hyperresponsiveness to adenosine 5'-monophosphate in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is often accompanied by bronchial hyperresponsiveness (BHR). Measurement of BHR may give information about airway inflammation.

Nitric oxide measured with single-breath and tidal-breathing methods in asthma and COPD

Nitric oxide (NO) can be measured in exhaled air with the single-breath (SB) and tidal-breathing (TB) methods. To allow comparison between different laboratories, a European Respiratory Society task force recently reported guidelines for standardization of both methods. To facilitate comparison between laboratories further, this study investigated whether there is a difference between NO values measured with SB and TB methods in subjects with asthma or chronic obstructive pulmonary disease (COPD), and in healthy subjects. Moreover, the differences between groups were studied and the influence of smoking in asthma was assessed. Sixteen atopic nonsmoking asthmatics, 16 atopic currently smoking asthmatics, 16 nonatopic nonsmoking healthy controls, 16 nonatopic exsmokers with COPD and 16 nonatopic exsmoking healthy controls were studied. NO concentrations differed substantially between both methods. Mean NO concentrations were higher with the SB than with the TB method in nonsmoking and in smoking asthmatics and especially so with the higher NO values. Furthermore, NO values with both methods were higher in nonsmoking asthmatics than in nonsmoking healthy subjects. NO was not significantly different between exsmokers with COPD and healthy exsmokers. In conclusion nitric oxide values of the single-breath and tidal-breathing methods are not interchangeable. Both methods can be used to measure differences between groups.

Size matching in lung transplantation using predicted total lung 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.

Effect of forced expirations on mucus clearance in patients with chronic airflow obstruction : effect of lung recoil pressure

Spontaneous mucus clearance and the effect of forced expirations and coughing on mucus clearance were investigated in eight patients with chronic airflow obstruction and low elastic recoil pressure (emphysema group: mean FEV1 45% predicted) and in seven patients with chronic airflow obstruction and normal elastic recoil pressure (chronic bronchitis group: mean FEV1 57% predicted). Mucus clearance was measured in a central and a peripheral lung region by a radioactive aerosol tracer technique. Spontaneous mucus clearance from the peripheral lung region was higher in the patients with emphysema than in those with chronic bronchitis. There was no difference in central mucus clearance between the two groups. Mucus clearance from the peripheral lung region increased significantly during forced expirations and coughing in the patients with chronic bronchitis but not in those with emphysema. It is concluded that in patients with chronic airflow obstruction and regular sputum production spontaneous peripheral mucus clearance is greater in those with decreased elastic recoil pressure. Physiotherapy that includes forced expirations and coughing can enhance mucus clearance in such patients when elastic recoil pressure is normal but is unlikely to be effective when elastic recoil pressure is decreased.

Effects of corticosteroids on bronchodilator action in chronic obstructive lung disease.

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.