Bronchoalveolar cellularity and interleukin-8 levels in measles bronchiolitis obliterans

BACKGROUND: Measles virus infection may progress to a chronic obstructive process including bronchiolitis obliterans (BO). This study investigates pulmonary cellular profiles and interleukin (IL)-8 levels in patients with BO following the measles. METHODS: BAL fluid was obtained from 12 children with BO who had a history of measles pneumonia during an outbreak in 2000 and 2001. BAL cell counts and differentials were compared to control patients as well as BAL IL-8 levels, which were measured by enzyme-linked immunosorbent assay. Immunohistochemical staining of BAL cells and three open-lung biopsy specimens were also analyzed for T-cell surface markers CD3, CD4, and CD8. RESULTS: BAL cellular profiles were characterized by a significantly increased percentage of neutrophils in the measles BO group (median, 16.0%) compared to the control group (2.3%) [p < 0.01]. BAL IL-8 levels were also markedly increased in the measles BO group (mean +/- SD, 418.6 +/- 286.0 pg/mL) compared to the control group (92.8 +/- 126.7 pg/mL) [p < 0.01]. BAL IL-8 levels correlated significantly with neutrophil percentages in both the measles BO group (r = 0.86, p = 0.000) and the control group (r = 0.79, p = 0.007). The lymphocyte subsets were characterized by a significantly increased number of CD8+ cells, resulting in a decreased CD4/CD8 ratio in the BAL and the biopsy specimens. CONCLUSION: These results suggest that pulmonary neutrophils and IL-8, along with CD8+ T lymphocytes may play an important role in the pathogenesis of BO after measles virus infection.     

Small airways dysfunction and neutrophilic inflammation in bronchial biopsies and BAL in COPD

BACKGROUND: The single-breath N(2) test (sbN(2)-test) is closely related to small airways pathology in resected lung specimens of smokers. We investigated whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, BAL, and induced sputum in patients with manifest COPD. METHODS: Fifty-one patients with stable COPD not receiving corticosteroids were examined in a cross-sectional study (43 men; mean [SD] age, 63 +/- 8 years; exsmokers and smokers; median pack-years, 41 [interquartile range, 31 to 51 pack-years]). Postbronchodilator spirometry (FEV(1), 63 +/- 8% of predicted) and sbN(2)-test (slope of phase III [DeltaN(2)], closing capacity [CC]/total lung capacity [TLC] percentage of predicted) were performed. Inflammatory cell counts were assessed in bronchial biopsies, BAL (only in the first half of patients), and induced sputum. Neutrophil elastase (NE), secretory leukocyte proteinase inhibitor (SLPI), and interleukin-8 levels were determined in BAL fluid. RESULTS: DeltaN(2) increased with subepithelial neutrophil numbers in bronchial biopsies (rs = 0.337, p = 0.017) and with NE levels (rs = 0.443, p = 0.039), NE/neutrophil ratio (rs = 0.575, p = 0.005) and SLPI levels (rs = 0.484, p = 0.022) in BAL. CC/TLC was associated with BAL neutrophil numbers (rs = 0.448, p = 0.048). The sbN(2)-test was not associated with any other inflammatory cell type in BAL or biopsies, nor with inflammatory cell counts in sputum. Of importance, the correlations between DeltaN(2) and BAL NE/neutrophil ratio, and between CC/TLC and BAL neutrophil numbers remained significant when adjusting for FEV(1) percentage of predicted. CONCLUSIONS: The results of the sbN(2)-test are associated with neutrophilic inflammation in bronchial biopsies and BAL in patients with COPD. Our findings support a role of neutrophilic inflammation in the pathogenesis of small airways dysfunction in COPD.     

Normal bronchial blood flow in COPD is unaffected by inhaled corticosteroids and correlates with exhaled nitric oxide

BACKGROUND: In COPD patients, there is reduced vascularity and inflammation of the bronchi, which may have opposite effects on bronchial blood flow (QAW). We studied the relationship of QAW with the fraction of exhaled nitric oxide (FENO), which is a potent vasodilator. We also investigated the vascular response to budesonide and a beta(2)-agonist. METHODS: We measured QAW in 17 patients with COPD (mean [+/- SEM] age, 67 +/- 3 years; 10 male patients; mean FEV(1), 57 +/- 3% predicted; mean FEV(1)/FVC ratio, 54 +/- 4%), all of whom were ex-smokers, and in 16 age-matched nonsmoking volunteers (mean age, 64 +/- 4 years) and compared this to FENO. QAW was measured using the acetylene dilution method. RESULTS: Mean QAW was similar in patients with COPD (34.29 +/- 1.09 microL/mL/min) compared to healthy subjects (35.50 +/- 1.74 microL/mL/min; p > 0.05) and was not affected by long-term treatment (35.89 +/- 1.63 microL/mL/min) or short-term treatment (32.50 +/- 1.24 microL/mL/min; p < 0.05) with inhaled budesonide. QAW positively correlated with the diffusion of carbon monoxide (ie, carbon monoxide transfer coefficient: r = 0.74; p < 0.05). FENO levels were mildly elevated in steroid-treated patients (10.89 +/- 0.87 parts per billion [ppb]) and untreated patients (9.40 +/- 0.86 ppb) compared to the control group (8.22 +/- 0.57 ppb; p < 0.05) and were correlated with QAW (r = 0.6; p < 0.05). Ten minutes after the inhalation of 200 microg of albuterol, QAW was more elevated in healthy control subjects (59.33 +/- 2.40 microL/mL/min) compared to COPD patients (38.00 +/- 0.58 microL/mL/min; p < 0.05), indicating that COPD patients may have a reduced bronchial vascular reactivity. CONCLUSIONS: QAW is normal in COPD patients and is not affected by therapy with inhaled corticosteroids or beta(2)-agonists. In addition, QAW correlates with levels of FENO, which may have a regulatory role.     

CXCR3 and CCR5 chemokines in induced sputum from patients with COPD

BACKGROUND: COPD is associated with increased numbers of CD4(+) and CD8(+) lymphocytes and macrophages in the small airways and lung parenchyma. The chemokines regulating T-cell recruitment into the lung are unknown but may involve CXCR3 and CCR5 chemoattractants. The aims of this study were to determine the concentrations of CXCR3 chemokines CXCL9, CXCL10, CXCL11, and the CCR5 chemokine CCL5 in induced sputum from patients with COPD, smokers, and nonsmokers, and to examine the relationship between chemokine expression, inflammatory cells, and airway obstruction. METHODS: Differential cell counts were performed and concentrations of CXCL9, CXCL10, CXCL11, and CCL5 were measured in induced sputum from nonsmokers (n = 18), smokers (n = 20), and COPD patients (n = 35) using an enzyme-linked immunosorbent assay. RESULTS: Concentrations of CXCL9, CXCL10, CXCL11, and CCL5 were significantly increased in the sputum of patients with COPD when compared with nonsmokers but not smokers without obstruction: CXCL9 (median, 14.3 pg/mL; interquartile range [IQR], 6.5 to 99.3; vs median, 1.4 pg/mL; IQR, 0 to 10.4 [p < 0.001]; vs 8.5 pg/mL; IQR, 0 to 16.0, respectively); CXCL10 (16.9 pg/mL; IQR, 6.2 to 148.8; vs 3.7 pg/mL; IQR, 0 to 18.8 [p < 0.05]; vs 11.3 pg/mL; IQR, 3.7 to 46.7); CXCL11 (58.1 pg/mL; IQR, 34.5 to 85.3; vs 33.5 pg/mL; IQR, 23.2 to 49.7 [p < 0.05]; vs 49.8 pg/mL; IQR, 32.6 to 105.6); and CCL5 (59.9 pg/mL; IQR, 57.1 to 67.8; vs 33.5 pg/mL; IQR, 31.6 to 36.9 [p < 0.001]). CCL5 in sputum from smokers was also significantly increased compared with that from nonsmokers (median, 63.0 pg/mL; IQR, 60.8 to70.2; p < 0.001). There was a negative correlation between FEV(1) percentage of predicted, FEV(1)/FVC ratio, and percentage of macrophages, and all the chemokines analyzed. Neutrophil numbers correlated positively with the concentrations of chemokines. CONCLUSIONS: CXCR3 chemokines and CCL5 are increased in sputum from COPD patients compared with nonsmokers, and may be important in COPD pathogenesis.     

Does Endothelin Play a Role in Chemoreception During Acute Hypoxia in Normal Men?

BACKGROUND: The peripheral chemoreceptors are the dominant reflex mechanism responsible for the rise in ventilation and muscle sympathetic nerve activity (MSNA) in response to hypoxia. Animal studies have suggested that endothelin (ET) plays an important role in chemosensitivity. Moreover, several human clinical conditions in which circulating ET levels are increased are accompanied by enhanced chemoreflex sensitivity. Whether ET plays a role in normal human chemosensitivity is unknown. METHODS: We determined whether bosentan, a nonspecific ET receptor antagonist, would decrease chemoreflex sensitivity in 14 healthy subjects. We assessed the effects of bosentan on the response to isocapnic hypoxia, using a randomized, crossover, double-blinded study design. RESULTS: Bosentan increased mean (+/- SEM) plasma ET levels from 1.97 +/- 0.28 to 2.53 +/- 0.23 pg/mL (p = 0.01). Hypoxia increased mean minute ventilation from 6.7 +/- 0.3 to 8+/0.4 L/min (p < 0.01), mean MSNA from 100 to 111 +/- 5% (p < 0.01), mean heart rate from 67 +/- 3 to 86 +/- 3 beats/min (p < 0.01), and mean systolic BP from 116 +/- 3 to 122 +/- 3 mm Hg (p < 0.01). However, none of these responses differed between therapy with bosentan and therapy with placebo (p = 0.26). Bosentan did not affect the mean MSNA responses to the apneas, during normoxia (change from baseline: placebo, 259 +/- 58%; bosentan, 201 +/- 28%; p = 0.17) or during hypoxia (change from baseline: placebo, 469 +/- 139%; bosentan, 329 +/- 46%; p = 0.24). The durations of the voluntary end-expiratory apneas in normoxia and hypoxia, and the subsequent reductions in oxygen saturation, were also similar with therapy using bosentan and placebo (p = 0.42). CONCLUSION: In healthy men, ET does not play an important role in peripheral chemoreceptor activation by acute hypoxia.     

Elevation of interleukin-15 protein expression in bronchoalveolar fluid in acute lung allograft rejection

BACKGROUND: Acute rejection remains a major source of morbidity in lung transplantation. Although interleukin (IL)-2 has been the principal T-cell growth factor implicated in acute rejection, IL-2 blockade does not prevent acute rejection completely. Recently, IL-15, a stromal cell-derived cytokine, has been found to share a similar biological function with IL-2. We hypothesized that IL-15 levels may be elevated in acute lung rejection in the presence of IL-2 blockade. METHODS: Acute allograft rejection developed in 21 of 42 lung transplant recipients. BAL fluid (BALF) was analyzed for IL-2 and IL-15 protein expression by standard enzyme-linked immunosorbent assay. RESULTS: The average (+/- SD) BALF IL-15 level was higher in lung transplant recipients with acute rejection compared to those without rejection (25 +/- 25 pg/mL vs 4.5 +/- 1.5 pg/mL, respectively; p < 0.0001). In addition, there appeared to be a bimodal distribution of BALF IL-15 levels in lung transplant recipients with acute rejection. BALF IL-2 levels were not associated with acute rejection. BALF IL-15 levels were not associated with bacterial, fungal, or cytomegalovirus infection. CONCLUSION: These data show that BALF IL-15 levels are elevated in acute lung allograft rejection in the presence of IL-2 receptor blockade and may be an important mediator for acute rejection in lung transplantation.     

Tiotropium and simplified detection of dynamic hyperinflation

STUDY OBJECTIVE: To detect dynamic hyperinflation (DH) by evaluating reduction in inspiratory capacity (IC) during metronome-paced hyperventilation (MPH) in patients with moderate-to-severe COPD, studied before and after treatment with tiotropium. METHODS: IC and FEV(1) were measured before and immediately after MPH at two times resting the respiratory rate for 20 s in 60 COPD patients (28 men; mean age, 66 +/- 10 years [+/- SD]) before and after 30 days of treatment with tiotropium bromide, 18 mug. Patients were encouraged to maintain a constant tidal volume during MPH. RESULTS: At baseline, mean FEV(1) was 1.5 +/- 0.1 L (+/- SE) [57 +/- 1.6% of predicted], mean FVC was 2.6 +/- 0.1L (77 +/- 1.8% of predicted), and mean FEV(1)/FVC was 56 +/- 1%. After 180 mug of aerosolized albuterol sulfate, mean FEV(1) was 1.7 +/- 0.1 L (63 +/- 1.5% of predicted) [p < 0.001] and mean FEV(1)/FVC was 58 +/- 1%. Compared to baseline, after 30 days and 1.5 h after tiotropium there was an increase in IC of 0.18 +/- 0.04L (p < 0.0001); FEV(1) of 0.13 +/- 0.03 L (5.6 +/- 0.8% of predicted; p = 0.0002); FVC of 0.22 +/- 0.05 L (6.5 +/- 1.3% of predicted; p < 0.001); and decrease in end-expiratory lung volume (EELV)/total lung capacity (TLC) of - 3.1 +/- 0.6% (p = 0.0001); a decrease in end-inspiratory lung volume (EILV)/TLC of - 2.9 +/- 1.3% (p = 0.03); and no change in TLC (- 0.06 +/- 0.05 L). Results following MPH-induced DH at baseline and after 30 days of tiotropium were similar, with decreases in IC (- 0.35 +/- 0.03 L; p < 0.001); FEV(1) (- 0.05 +/- 0.04 L; p = 0.2); and FVC (- 0.22 +/- 0.03 L; p < 0.0001); no change in TLC; and increases in EELV/TLC (11.8 +/- 1.0% of predicted; p < 0.0001) and EILV/TLC (4.0 +/- 1.3% of predicted, p < 0.003). CONCLUSION: In patients with moderate-to-severe COPD, tiotropium did not reduce MPH-induced DH and reduction in IC, compared to baseline. However, because tiotropium induced bronchodilation and increased baseline IC, lower operational lung volumes may blunt the effect of MPH-induced DH. The noninvasive simplicity of MPH-induced DH provides a clinically useful screening surrogate to monitor changes in IC following treatment with tiotropium.     

Leukotriene B4 in exhaled breath condensate and sputum supernatant in patients with COPD and asthma

STUDY OBJECTIVES: Some patients with COPD present with significant reversibility of airflow limitation after receiving bronchodilation therapy. Leukotriene B(4) (LTB(4)) has been implicated in the pathophysiology of both COPD and asthma. We tested the hypothesis that COPD patients with airflow reversibility and asthmatic patients who smoke might have similar levels of LTB(4) in exhaled breath condensate (EBC) and sputum supernatant. The repeatability and stability of LTB(4) measurements were additionally studied. DESIGN: Prospective, cross-sectional study. PATIENTS OR PARTICIPANTS: We studied 30 patients with COPD (15 smokers [FEV(1), 56% predicted; SD, 6% predicted]; 15 patients with significant reversibility in airway obstruction after bronchodilation [FEV(1), 14% predicted; SD, 2% predicted]). Fifteen asthmatic patients who smoked, with similar FEV(1) and reversibility were also studied. Ten healthy smokers served as control subjects. SETTING: A hospital research laboratory. INTERVENTIONS: Spirometry and reversibility testing were performed on the first visit. On the following day, EBC was collected for the measurement of LTB(4), and induced sputum was collected for differential cell counts and LTB(4) measurement in the sputum supernatant. MEASUREMENTS AND RESULTS: LTB(4) levels in EBC [mean (SD)] were increased in COPD patients (mean, 86.7 pg/mL; SD, 19 pg/mL) and asthmatic patients (mean, 97.5 pg/mL; SD, 15 pg/mL) compared to control subjects (mean, 32.3 pg/mL; SD, 10 pg/mL; p < 0.0001 for both groups). COPD patients with airflow reversibility (mean, 99.8 pg/mL; SD, 12 pg/mL) had values similar to those of asthmatic patients (mean, 97.5 pg/mL; SD, 15 pg/mL; p = 0.2) and higher than those of COPD patients without airflow reversibility (mean, 73.7 pg/mL; SD, 17 pg/mL; p = 0.002). Similar results were observed in the sputum supernatant. Measurements of LTB(4) in EBC and sputum were repeatable on two consecutive days, but measurements in the frozen samples of EBC and sputum were not stable after 3 weeks. CONCLUSIONS: Patients with asthma and reversible COPD presented with higher LTB(4) values compared to patients with nonreversible COPD and healthy smokers. This difference may be mainly attributed to the presence of reversibility in airway obstruction, probably as part of a common underlying inflammatory process.     

The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function

BACKGROUND: Obstructive sleep apnea (OSA) is associated with endothelial dysfunction. In the current study, we assessed the effect of long-term modified Herbst mandibular advancement splint (MAS) treatment on OSA, oxidative stress markers, and on endothelial function (EF). METHODS: A total of 16 subjects participated (11 men and 5 women; mean [+/- SD] age, 54.0 +/- 8.3 years; mean body mass index, 28.0 +/- 3.1 kg/m(2)), 12 of whom completed the 1-year evaluation. Apnea severity, levels of oxidative stress markers, and EF were assessed after 3 months and 1 year of receiving treatment. For comparison, 6 untreated patients underwent two evaluations 9 months apart, and 10 non-OSA individuals were assessed once as a reference group. The results are presented as the mean +/- SD. RESULTS: The mean apnea-hypopnea index (AHI) decreased significantly from 29.7 +/- 18.5 events/h before treatment to 17.7 +/- 11.1 events/h after 3 months of treatment and 19.6 +/- 11.5 events/h after 1 year of treatment (p < 0.005 for both). The mean Epworth sleepiness scale score decreased significantly from 12.4 +/- 6.0 before treatment to 10.2 +/- 6.6 after 3 months of treatment and 7.8 +/- 3.8 after 1 year of treatment (p < 0.001 for both). The mean EF improved significantly from 1.77 +/- 0.4 before treatment to 2.1 +/- 0.4 after 3 months of treatment (p < 0.05) and 2.0 +/- 0.3 after 1 year of treatment (p = 0.055), which were similar to the values of the reference group. Thiobarbituric acid-reactive substance (TBARS) levels decreased from 18.8 +/- 6.2 nmol malondialdehyde (MDA)/mL before treatment to 15.8 +/- 3.9 MDA/mL after 3 months of treatment (p = 0.09) and 15.5 +/- 3.2 nmol MDA/mL after 1 year of treatment (p < 0.05). There was a correlation between the improvement in AHI and in EF or TBARS levels (r = 0.55; p = 0.05). The untreated control group remained unchanged. CONCLUSIONS: The Herbst MAS may be a moderately effective long-term treatment for patients with OSA. EF improved to levels that were not significantly different than reference levels, even though apneic events were not completely eliminated. We think that these data are encouraging and that they justify the performance of larger randomized controlled studies.     

Safety of sputum induction during exacerbations of COPD

Sputum induction (SI) is considered to be a safe tool for assessing airway inflammation in stable patients with COPD, but little is known about its safety during exacerbations. We therefore assessed the safety of SI during COPD exacerbations. SI data from 44 COPD patients were assessed both in the stable phase and during exacerbation. The median FEV1 for the stable phase and exacerbation were 61% predicted (interquartile range [IQR], 49 to 74% predicted) and 51% predicted (IQR, 45 to 60% predicted), respectively. The median decrease in FEV(1) with SI during an exacerbation was 0.27 L (IQR, 0.17 to 0.40 L) vs 0.28 L (IQR, 0.22 to 0.44 L) during the stable phase (p = 0.03). The patients experienced the associated dyspnea well; no other adverse events occurred. All FEV1 values returned to within 90% of their initial value within 30 min. A larger decrease in FEV1 due to SI during an exacerbation was associated with the following parameters in the stable phase of disease: lower total sputum cell count (r = -0.37; p = 0.01); higher percentage of eosinophils (r = 0.33; p = 0.04); and a larger decrease in FEV1 after SI (r = 0.39; p = 0.03). In a multivariate analysis, the only independent association was with the larger decrease in FEV1 in the stable phase. We concluded that SI can be safely carried out in patients with mild-to-moderate COPD who experience an exacerbation, and this occurs with no greater risk than in stable patients with COPD.     

Atrial septostomy in treatment of end-stage right heart failure in patients with pulmonary hypertension

BACKGROUND: Right ventricular (RV) failure is the main cause of death in patients with pulmonary hypertension (PH). Balloon atrial septostomy (BAS) is believed to relieve symptoms of PH by increasing systemic flow and reducing RV preload. METHODS: Fourteen BAS procedures were performed in 11 patients (5 men and 6 women; mean [+/- SD] age, 33 +/- 12 years) with RV failure in the course of PH that was refractory to conventional treatment. BAS consisted of a puncture of the interatrial septum and subsequent dilatations with balloons of increasing diameter in a step-by-step manner. RESULTS: After BAS, the mean oxygen saturation of aortic blood decreased (before, 93 +/- 4%; after, 84 +/- 4%; p = 0.001), while mean cardiac index increased (before, 1.54 +/- 0.34 L/min/m(2); after, 1.78 +/- 0.35 L/min/m(2); p = 0.001), resulting in a positive trend for mean systemic oxygen transport (before, 270 +/- 64 mL/min; after, 286 +/- 81 mL/min; p = 0.08). Pulmonary vascular resistance (PVR) slightly increased immediately after the procedure, and this rise inversely correlated with mixed venous blood partial oxygen pressure both before BAS (r = -0.69; p = 0.009) and after BAS (r = -0.64; p = 0.018). Mean functional class improved from 3.2 +/- 0.4 to 2.6 +/- 0.7 (p = 0.03) after 1 month. At follow-up (mean time to follow-up, 8.1 +/- 6.2 months; range, 0.8 to 20.2 months), seven patients died and two underwent lung transplantation. There was no difference in the survival rate compared to that obtained from National Institutes of Health equation. A significant size reduction in the created defect was observed in six patients, requiring repeat BAS procedures in three cases. CONCLUSIONS: The current BAS technique improves cardiac index and functional class without significant periprocedural complications, except for a transient increase in PVR related to acute desaturation of mixed venous blood. At long-term follow-up, a high incidence of spontaneous decrease in orifice size has been observed.     

Diagnostic and prognostic utility of brain natriuretic Peptide in subjects admitted to the ICU with hypoxic respiratory failure due to noncardiogenic and cardiogenic pulmonary edema

BACKGROUND: Brain natriuretic peptide (BNP) is useful in diagnosing congestive heart failure (CHF) in patients presenting in the emergency department with acute dyspnea. We prospectively tested the utility of BNP for discriminating ARDS vs cardiogenic pulmonary edema (CPE). METHODS: We enrolled ICU patients with acute hypoxemic respiratory failure and bilateral pulmonary infiltrates who were undergoing right-heart catheterization (RHC) to aid in diagnosis. Patients with acute coronary syndrome, end-stage renal disease, recent coronary artery bypass graft surgery, or preexisting left ventricular ejection fraction /= 1,200 pg/mL, BNP had a specificity of 92% for CPE. Higher levels of BNP were associated with a decreased odds for ARDS (odds ratio, 0.4 per log increase; p = 0.007) after adjustment for age, history of CHF, and right atrial pressure. BNP was associated with in-hospital mortality (p = 0.03) irrespective of the final diagnosis and independent of APACHE (acute physiology and chronic health evaluation) II score. CONCLUSION: In ICU patients with hypoxemic respiratory failure, BNP appears useful in excluding CPE and identifying patients with a high probability of ARDS, and was associated with mortality in patients with both ARDS and CPE. Larger studies are necessary to validate these findings.     

Use of B-type natriuretic peptide in the risk stratification of acute exacerbations of COPD

BACKGROUND: In patients with COPD, prognosis might be determined at least in part by the extent of cardiac stress induced by hypoxia and pulmonary arterial hypertension. METHODS: B-type natriuretic peptide (BNP), a quantitative marker of cardiac stress, was determined in 208 consecutive patients presenting to the emergency department with an acute exacerbation of COPD (AECOPD). The accuracy of BNP to predict death at a 2-year follow-up was evaluated as the primary end point. The need for intensive care and in-hospital mortality were determined as secondary end points. RESULTS: BNP levels were significantly elevated during the acute exacerbation compared to recovery (65 pg/mL; interquartile range [IQR], 34 to 189 pg/mL; vs 45 pg/mL; IQR, 25 to 85 pg/mL; p < 0.001), particularly in those patients requiring ICU treatment (105 pg/mL; IQR, 66 to 553 pg/mL; vs 60 pg/mL; IQR, 31 to 169 pg/mL; p = 0.007). In multivariate Cox regression analysis, BNP accurately predicted the need for ICU care (hazard ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.24 for an increase in BNP of 100 pg/mL; p = 0.008). In a receiver operating characteristic analysis to evaluate the potential of BNP levels to predict short-term and long-term mortality rates, areas under the curve were 0.55 (SD, 0.71; 95% CI, 0.41 to 0.68) and 0.56 (SD, 0.53; 95% CI, 0.45 to 0.66, respectively). CONCLUSIONS: In patients with AECOPD, BNP levels independently predict the need for intensive care. However, BNP levels failed to adequately predict short-term and long-term mortality rates in AECOPD patients.     

Relationship between serum substance P levels and daytime sleepiness in obstructive sleep apnea syndrome

OBJECTIVE: We hypothesized that intermittent hypoxia might influence serum substance P levels, and that this effect might in turn contribute in excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea syndrome (OSAS). PATIENTS AND METHODS: Fifty-five patients with newly diagnosed OSAS and 15 age-matched nonapneic control subjects were enrolled in this study. Full polysomnography was performed in all patients. Single blood samples were drawn between 8:00 am and 9:00 am after the sleep study. Substance P levels were analyzed with a competitive enzyme immunoassay (substance P EIA kit; Cayman Chemical; Ann Arbor, MI). RESULTS: There were no significant differences in age, gender, body mass index, smoking habit, and snoring between the two groups. Serum substance P levels in the OSAS group were significantly lower than that in the control group (p < 0.0001). Serum substance P levels were positively correlated with rapid eye movement sleep (r = 0.330, p = 0.049) and slow-wave sleep (r = 0.324, p = 0.049) phases. Serum substance P levels were negatively correlated with Epworth sleepiness scale score (r = - 0.253, p = 0.048), number of total apneas during the night (r = - 0.247, p = 0.036), number of respiratory events during the night (r = - 0.266, p = 0.024), apnea-hypopnea index (r = - 0.287, p = 0.015), respiratory arousal index (r = - 0.267, p = 0.026), time spent in apnea and hypopnea (r = - 0.307, p = 0.01), average oxygen desaturation (r = - 0.265, p = 0.026), and oxygen desaturation index (r = - 0.254, p = 0.031). CONCLUSION: We concluded that EDS seen in some of the OSAS patients might be associated with various pathophysiologic mechanisms including substance P levels.     

Prognostic value of circulating levels of endothelin-1 in patients after acute myocardial infarction undergoing primary coronary angioplasty

BACKGROUND: The link between increased circulating level of endothelin (ET)-1 and adverse clinical outcomes after acute myocardial infarction (AMI) has been established. Current studies demonstrate that reperfusion therapy by either thrombolysis or primary percutaneous coronary intervention (PCI) can salvage myocardium, improving survival of AMI patients. However, whether reperfusion therapy by primary PCI can prevent the adverse effect of ET-1 on clinical outcomes in patients after AMI remains unclear. Therefore, this study examined the predictive value of circulating ET-1 levels on 30-day outcomes in ST-segment elevated AMI treated with primary PCI. METHODS AND RESULTS: We conducted a prospective cohort study of 186 consecutive patients with ST-segment elevated AMI of onset < 12 h who underwent primary PCI. Blood samples for plasma concentration of ET-1 were collected in the catheterization laboratory following vascular puncture. Patients were classified into a high group (group 1, ET-1 level >or= 0.632 pg/mL, n = 93) and a low group (group 2, ET-1 level < 0.632 pg/mL, n = 93) according to the median value of ET-1 after AMI. Univariate analysis demonstrated that the 30-day composite major adverse clinical outcomes (MACO) [advanced Killip score >or= 3], severe congestive heart failure (CHF) [New York Heart Association functional class 4], and 30-day mortality were strongly associated with high ET-1 level (>or= 0.632 pg/mL; p < 0.0001), unsuccessful reperfusion (final Thrombolysis in Myocardial Infarction flow 相似文献   

Predictors of survival in COPD patients with chronic hypercapnic respiratory failure receiving noninvasive home ventilation

BACKGROUND: Patients with COPD and chronic hypercapnic respiratory failure (CHRF) are at high risk, and noninvasive ventilation at home is increasingly being used. Knowledge of prognostic parameters under these conditions is limited but may be clinically helpful and highlight the role of noninvasive ventilation. METHODS: In 188 patients with COPD (mean +/- SD FEV1, 31.0 +/- 9.6% of predicted; PaCo2, 56.3 +/- 9.4 mm Hg) discharged from the hospital receiving NIV between July 1994 and July 2004, the prognostic value of body mass index (BMI), lung function, laboratory parameters, and blood gas levels was assessed by univariate and multivariate Cox regression analyses. Moreover, the impact of changes in risk factors on mortality assessed 6.7 +/- 2.8 months after the initiation of noninvasive ventilation was evaluated. RESULTS: Overall, the mortality rate during follow-up (duration, 32.2 +/- 24.3 months) was 44.7%, with 1-year, 2-year, and 5-year survival rates of 84.0%, 65.3%, and 26.4%. Deaths resulted predominantly from respiratory causes (73.8%). Univariate regression analyses revealed age, BMI, hemoglobin, FEV1, specific airway resistance, residual volume (RV)/total lung capacity (TLC), pH, and base excess (BE) to be associated with prognosis (p < 0.01 each), whereas multivariate analysis identified only age, BMI, RV/TLC, and BE as independent predictors (p < 0.05). In patients at risk (BMI < 25 km/m2, RV/TLC >or= 73%, or BE >or= 9 mmol/L), changes in these predictors were also associated with survival. CONCLUSIONS: In patients with COPD and CHRF, nutritional status, hyperinflation, and BE, which turned out to be reliable and consistent markers in CHRF, were independent prognostic factors for mortality. These data favor a multidimensional approach in these patients, including the use of noninvasive ventilation.     

Impact of COPD exacerbations on patient-centered outcomes

BACKGROUND: Frequent exacerbations are associated with a faster decline in FEV(1), impaired health status, and worse survival. Their impact and temporal relationship with other outcomes such as functional status, dyspnea, and the multidimensional body mass index, obstruction, dyspnea, exercise capacity (BODE) index remain unknown. HYPOTHESIS: We reasoned that exacerbations affect the BODE index and its components, and that changes in the BODE index could be used to monitor the effect of exacerbations on the host. STUDY DESIGN: Prospective observational study in a Veterans Affairs medical center. METHODS: We studied 205 patients with COPD (mean [+/- SD] FEV(1), 43 +/- 15% predicted), and recorded the body mass index, FEV(1) percent predicted, modified Medical Research Council dyspnea scale, 6-min walk distance, and the BODE index at baseline, during the exacerbation, and at 6, 12, and 24 months following the first episode, and documented all exacerbations for 2 years after the first acute exacerbation. RESULTS: From the cohort, 130 patients (63%) experienced 352 exacerbations or (0.85 exacerbations per patient per year); 48 patients (23%), experienced one episode, 82 patients (40%) experienced 2 or more exacerbations, and 50 patients required hospitalization. At study entry, exacerbators had a worse mean baseline BODE index score (4.2 +/- 2.1 vs 3.57 +/- 2.3, respectively; p < 0.03). The BODE index score worsened by 1.38 points during the exacerbation, and remained 0.8 and 1.1 points above baseline at 1 and 2 years, respectively. There was little change in BODE index score at 2 years in nonexacerbators. CONCLUSION: COPD exacerbations negatively impact on the BODE index and its components. The BODE index is a sensitive tool used to assess the impact of exacerbations and to monitor COPD disease progression.     

Systemic inflammation and COPD: the Framingham Heart Study

BACKGROUND: The current paradigm for the pathogenesis of COPD includes an ultimately maladaptive local inflammatory response to environmental stimuli. We examined the hypothesis that systemic inflammatory biomarkers are associated with impaired lung function, particularly among those with extensive cigarette smoking. METHODS: Using data from the Framingham Heart Study, we examined cross-sectional associations of systemic inflammatory biomarkers (CD40 ligand [CD40L], intercellular adhesion molecule [ICAM]-1, interleukin [IL]-6, monocyte chemoattractant protein-1, P-selectin, and myeloperoxidase, in addition to C-reactive protein) to impaired lung function. RESULTS: IL-6 was consistently associated with impaired lung function; a 1-SD higher concentration of IL-6 was associated with a 41-mL lower FEV(1) (95% confidence interval [CI], - 61 to - 20) and a borderline 15% higher odds of COPD (odds ratio, 1.15; 95% CI, 0.99 to 1.34). Additionally, P-selectin was associated with lower FEV(1) levels; after adjusting for the other biomarkers, a 1-SD higher concentration of P-selectin predicted an FEV(1) that was on average 19 mL lower (95% CI, - 37 to 0). Including the biomarkers individually as sole exposures in the models generally strengthened the impaired lung function/biomarker association; the relations of ICAM-1 to FEV(1), and ICAM and CD40L to COPD became significant. The observed associations did not vary significantly with smoking history, except that the association between CD40L and COPD appeared greater in individuals with more extensive smoking histories. CONCLUSIONS: Among participants in the Framingham Heart Study, systemic inflammation was associated with lower levels of pulmonary function. Further research into the role of systemic inflammation in the development of pulmonary dysfunction is merited.     

A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo

BACKGROUND: There is controversy about whether therapy with inhaled corticosteroids (ICSs) modifies the natural history of COPD, characterized by an accelerated decline in FEV(1). METHODS: The Inhaled Steroids Effect Evaluation in COPD (ISEEC) study is a pooled study of patient-level data from seven long-term randomized controlled trials of ICS vs placebo lasting >/= 12 months in patients with moderate-to-severe COPD. We have previously reported a survival benefit for ICS therapy in COPD patients using ISEEC data. We aimed to determine whether the regular use of ICSs vs placebo improves FEV(1) decline in COPD patients, and whether this relationship is modified by gender and smoking. RESULTS: There were 3,911 randomized participants (29.2% female) in this analysis. In the first 6 months after randomization, ICS use was associated with a significant mean (+/- SE) relative increase in FEV(1) of 2.42 +/- 0.19% compared with placebo (p < 0.01), which is quantifiable in absolute terms as 42 mL in men and 29 mL in women over 6 months. From 6 to 36 months, there was no significant difference between placebo and ICS therapy in terms of FEV(1) decline (-0.01 +/- 0.09%; p = 0.86). The initial treatment effect was dependent on smoking status and gender. Smokers who continued to smoke had a smaller increase in FEV(1) during the first 6 months than did ex-smokers. Female ex-smokers had a larger increase in FEV(1) with ICS therapy than did male ex-smokers. CONCLUSIONS: We conclude that in COPD in the first 6 months of treatment, ICS therapy is more effective in ex-smokers than in current smokers with COPD in improving lung function, and women may have a bigger response to ICSs than men. However, it seems that after 6 months, ICS therapy does not modify the decline in FEV(1) among those who completed these randomized clinical trials.     

Induced sputum in the very young: a new key to infection and inflammation

BACKGROUND: Chronic inflammation and infection in patients with cystic fibrosis (CF) and other lung diseases begin early, making noninvasive diagnostic techniques vital. As induced sputum (IS) testing is useful in older patients, we investigated its adaptation to young nonexpectorating children. METHODS: Following the inhalation of a 4.5% saline solution, sputum was collected by nasopharyngeal or oropharyngeal suction for culture and testing for inflammatory markers, with paired preceding oropharyngeal cough swabs (OCSs) in a subgroup. Specimens from 48 IS procedures (46 successful) in 20 CF children (median age, 3 years) were compared with 8 specimens from 8 non-CF pulmonary patients (median age, 4.5 years). RESULTS: The procedure was safe, with arterial oxygen saturation remaining at > or = 96%. Cultures from 14 of 46 CF patients (30%) grew Pseudomonas aeruginosa, whereas cultures from 19 of 46 CF patients (41%) had no growth. Cultures from seven of eight non-CF subjects grew bacteria, but none were P aeruginosa. Comparing 29 paired IS and OCS samples, 11 and 5 samples, respectively, cultured P aeruginosa (not significant), whereas 12 and 21 samples, respectively, had no growth (p = 0.02). A correlation was found between the independent inflammatory markers NE and both interleukin (IL)-8 (r = 0.85; p < 0.001) and the percentage of neutrophils (r = 0.35; p < 0.05), confirming the validity of IS samples in evaluating early airway disease. IL-8 levels also increased with age (r = 0.41; p < 0.05). Inflammation was similar in CF and non-CF subjects. CONCLUSIONS: IS testing in the young is feasible, safe, and clinically useful, and could serve as an outcome measure for new therapies.