Year in Review Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 MARTIN J. TOBIN Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois
CONTENTS Chronic Obstructive Pulmonary Disease (80) Genetics (3) Epidemiology (3) 1-Antrypsin Deficiency (1) Risk Factors (7) Cellular, Molecular, and Anatomic Abnormalities (7) Lung Inflammation (7) Exhaled Markers (2) Nitric Oxide (1) Other Markers (1) Pathophysiology, Radiology, and Airway Narrowing (8) Pulmonary Vasculature (1) Control of Breathing and Exercise (9) Respiratory Muscles (3) Peripheral Muscles (3) Nutritional Status (3) Health Care Delivery (2) Drug Therapy (9) -Agonists (3) Glucocorticoids (5) Smoking Cessation (1) Other Therapies (9) Lung Volume Reduction Surgery (8) Expectorants and Mucociliary Clearance (1) Rehabilitation and Oxygen Therapy (1) Outcome (2) Air Pollution (19) General (11) Ozone (5) Diesel Exhaust (2) Environmental Tobacco Smoke (1) Pulmonary Vascular and Related Disorders (24) Pulmonary Hypertension (18) Secondary Pulmonary Hypertension (3) Molecular and Pathophysiologic Mechanisms (11) Treatment (4) Thromboembolic Disorders (2) Diagnostic Studies (1) Molecular and Pathophysiologic Mechanisms (1) High Altitude (1) Sickle Cell Disease (3)
Supported by a Merit Review grant from the Veterans Affairs Research Service. Correspondence and requests for reprints should be addressed to Martin J. Tobin, M.D., Division of Pulmonary and Critical Care Medicine, Hines Veterans Affairs Hospital, Route 111N, Hines, IL 60141. E-mail:
[email protected] Am J Respir Crit Care Med Vol 165. pp 642–662, 2002 DOI: 10.1164/rccm.2201065 Internet address: www.atsjournals.org
Lung Transplantation (13) Lung Preservation (2) Patient Selection (1) Obliterative Bronchiolitis (4) Animal Models (2) Cellular and Molecular Mechanisms (1) Early Detection (1) Rejection (3) Immunology and Biochemistry (1) In Cystic Fibrosis (2) Pleural Disorders (2) Diagnostic Techniques (1) Pleurodesis (1) Lung Cancer (4) Diagnosis (3) Molecular Mechanisms (1)
CHRONIC OBSTRUCTIVE PULMONARY DISEASE Genetics
To investigate the familial risk for chronic obstructive pulmonary disease (COPD) among siblings of probands with severe COPD, McCloskey and coworkers (1) enrolled 150 subjects with airway obstruction and low diffusing capacity (but without PiZ 1-antitrypsin deficiency). Complete data were obtained on 173 of 221 (70%) siblings. Of 126 current or exsmoking siblings, 44 (35%) had airway obstruction (ratio of forced expiratory volume in one second to forced vital capacity [FEV1/FVC] of less than 70%). The prevalence of airway obstruction in 419 subjects without a family history of COPD was lower as compared with the siblings (9 versus 32%), with an odds ratio of 4.7 for airway obstruction among the siblings. The authors conclude that the risk of airway obstruction is increased among smoking siblings of patients with COPD. A polymorphism at position 308 of the promoter region of the gene for tumor necrosis factor- is associated with altered secretion of the cytokine. When guanine is present at this position, the allele is denoted as TNF-–308*1. When guanine is replaced by adenine, the rarer allele, TNF-–308*2, occurs and the level of tumor necrosis factor- is higher. To determine whether this polymorphism is associated with the development of COPD, Sakao and coworkers (2) studied 106 patients with COPD, 110 asymptomatic smokers or ex-smokers, and 129 blood donors. The frequency of the TNF-–308*2 allele was 17% in the patients with COPD and 8% in each of the two control groups. The authors conclude that a polymorphism in the promoter region of the tumor necrosis factor- gene (designated TNF-–308*1/2) is associated with the presence of COPD. To determine which genes contribute to the severity of COPD, Sandford and coworkers (3) genotyped two subsets of
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subjects from the Lung Health Study: the 283 subjects with the fastest rate of decline in FEV1 (154 ml per year) and the 308 subjects with no decline (15 ml per year). MZ heterozygosity for the 1-antitrypsin Z allele was associated with a rapid decline in FEV1 (odds ratio, 2.8), and the association was stronger when combined with a family history (odds ratio, 9.7). Homozygosity for the His113/His139 haplotype of the gene for microsomal epoxide hydrolase, an enzyme in the bronchial epithelium that metabolizes epoxides in cigarette smoke, was associated with rapid decline in FEV1 (odds ratio, 2.4). The rate of decline was not associated with isoforms of vitamin D–binding protein and tumor necrosis factor polymorphisms. The authors conclude that the MZ genotype for 1-antitrypsin and the His113/His139 haplotype for microsomal epoxide hydrolase are associated with an increased rate of decline in lung function. Epidemiology
To project the future burden of COPD in the Netherlands, Feenstra and coworkers (4) used a dynamic life table model that takes into account disease duration, aging, population growth, smoking behavior, and comorbidity. Between 1994 and 2015, the prevalence of COPD (per 1,000 of the population) is estimated to increase from 21 to 33 in men and from 10 to 23 in women. Expected changes in smoking behavior will reduce the projected prevalence to 29 in men but will increase the projected prevalence to 25 in women. Loss of life years will increase by more than 60%, and loss of disability-adjusted life years will increase by 75%. Health care costs are projected to rise by 90% over the 21 years, with smoking accounting for 90% of the costs. Most of the increased prevalence of COPD will result from past smoking behavior and aging. The authors conclude that a marked increase in the prevalence and burden of COPD is unavoidable. To determine the influence of potential factors on the risk for hospitalization because of an exacerbation of COPD, Garcia-Aymerich and coworkers (5) did a case-control study. The cases were patients admitted to hospital with an exacerbation of COPD. The control subjects were stable at the time that the referent case was hospitalized but they had previously experienced an exacerbation at the same time as the case. Multiple logistic regression revealed four factors that influenced the risk of hospitalization: three or more admissions for COPD in the preceding years (odds ratio, 6.21); low value of FEV1 (odds ratio, 0.96 for each percentage point); under-prescription of oxygen therapy (odds ratio, 22.6); and current smoking, which had a beneficial effect (odds ratio, 0.30). The authors conclude that a limited number of factors—the number of previous hospital admissions, a lower FEV1, and under-use of oxygen therapy—are independent predictors of admission to hospital for an exacerbation of COPD. Fibrinogen is an acute phase reactant, and it may reflect inflammation in the airways and lung. To determine whether plasma fibrinogen is associated with lung function and the rate of hospital admission for COPD, Dahl and coworkers (6) analyzed data on 8,955 adults from the Danish general population. Serum fibrinogen was categorized into three tertiles: less than 2.7, 2.7 to 3.3, and greater than 3.3 g per liter. Compared with smokers in the lowest fibrinogen tertile, predicted FEV1 was 7% lower in the smokers in the upper tertile and 2% lower in the smokers in the middle tertile. Nonsmokers in the upper fibrinogen tertile also had a 6% lower predicted FEV1 as compared with nonsmokers in the other two tertiles. The rate of hospital admission for COPD (per 10,000 personyears) was 93 in the upper plasma fibrinogen tertile, 60 in the middle tertile, and 52 in the lower tertile. After adjusting for
confounding factors, the relative risks of admission were 1.7 for subjects in the upper tertile and 1.4 for subjects in the middle tertile, as compared with subjects in the lower tertile of plasma fibrinogen. The authors conclude that increased levels of plasma fibrinogen were associated with impaired lung function and increased risk of hospital admission for COPD, and that the risks could not be explained by smoking alone. 1-Antrypsin Deficiency
To determine the relative power of spirometry, exercise capacity, and quantification of emphysema on computed tomography (CT) in predicting health status, Dowson and coworkers (7) studied 29 patients with 1-antitrypsin deficiency (PiZ). Peak oxygen consumption during exercise was predicted by both FEV1 (r 0.64) and the extent of lower-zone emphysema on CT (r 0.64). Health status, as measured by St. George’s respiratory questionnaire, was related to FEV1 (r 0.43) and to the extent of emphysema on high-resolution CT (r 0.37). Exercise capacity was the best predictor of health status: performance on an incremental shuttle walking test accounted for up to 55% of the variability in the respiratory questionnaire and for up to 53% of the variability for physical function on SF-36 generic questionnaire. The authors conclude that exercise testing provides the best estimate of the limitations in health status in patients with lower zone emphysema. Risk Factors
To determine the role of viral infection in exacerbations of COPD, Seemungal and coworkers (8) studied 83 patients with COPD (FEV1, 42% of predicted). Over 16 months, the patients experienced 321 exacerbations (2.9 exacerbations per patient per year). Exacerbations were associated with increased dyspnea (76%), increased sputum volume (62%), increased wheeze (49%), increased cough (48%), increased sputum purulence (39%), and sore throat (18%). In 64% of exacerbations, a cold occurred in the preceding 18 days. Of 168 reported exacerbations in 53 patients, viruses or atypical bacteria were present in 66 (39%) of nasal aspirates. Of viruses found, rhinovirus accounted for 58% of viral exacerbations. Compared with nonviral exacerbations, viral exacerbations were associated with a higher symptom score and a longer time to recovery (13 versus 6 days). The authors conclude that almost 40% of exacerbations in patients with COPD are associated with a viral infection, and that exacerbations associated with viruses are more severe as compared with nonviral exacerbations. An editorial commentary by Hogg (9) accompanies this article. The frequency of colonization of the lower respiratory tract with nontypeable Haemophilus influenzae is not well defined. In washes or brush specimens on bronchoscopy, Bandi and coworkers (10) found nontypeable H. influenzae in 6 of 23 (26%) patients with stable chronic bronchitis, in 1 of 15 (7%) patients with an acute exacerbation of chronic bronchitis, and in 0 of 26 healthy subjects undergoing elective surgery. The low recovery in the patients with an acute exacerbation probably resulted from the use of parenteral antibiotics. In five of the nine patients with stable chronic bronchitis, molecular typing revealed different strains of nontypeable H. influenzae in the upper and lower respiratory tract. Intracellular nontypeable H. influenzae were found in bronchial biopsy specimens from 13 of the 15 (87%) patients with an exacerbation, 8 of the 24 (33%) stable patients, and 0 of 7 healthy subjects. The authors conclude that the lower airways of patients with stable chronic bronchitis are frequently colonized with multiple strains of nontypeable Haemophilus influenzae, that cultures obtained from the upper airways differ from cultures from the lower airways, and that intracellular infection with H. influenzae
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contributes to the pathogenesis of acute exacerbations of chronic bronchitis. To determine the effect of self-reported lower respiratory illnesses on lung function, Kanner and coworkers (11) analyzed data from 5,887 smokers participating in the Lung Health Study. Individuals entered into an intensive program for smoking cessation had a higher rate of quitting smoking and fewer lower respiratory illnesses as compared with the persons who were simply advised to quit smoking. Sustained quitters had fewer lower respiratory illnesses as compared with persons who continued to smoke. Lower respiratory illnesses accelerated the rate of decline in FEV1 only in persons who continued to smoke. Smokers experiencing one lower respiratory illness a year had an accelerated decline in FEV1, averaging 7 ml per year over 5 years. Smokers with more than one lower respiratory illness a year had greater declines in lung function. Chronic bronchitis was associated with an increased frequency of lower respiratory illnesses, but it did not influence the effect of these illnesses on lung function. The authors conclude that lower respiratory illnesses and smoking have interactive effects on FEV1 in people with mild COPD, and that frequent lower respiratory illnesses in smokers may influence the long-term course of the disease. To determine whether a diet rich in flavonoids protects against the development of COPD, Tabak and coworkers (12) studied 13,651 subjects participating in the MORGEN Study (the monitoring project on risk factors and health in the Netherlands). The average daily intake of catechins, flavonols, and flavones was 58 mg, with tea and apples being the main source. A higher intake of these three flavonoids (expressed as the difference between the fifth and the first quintile of intake) was associated with an increase in FEV1 of 44 ml and inversely associated with chronic cough (odds ratio, 0.80) and breathlessness (odds ratio, 0.74). The intake of solid fruit (apples, pears), but not tea, was associated with fewer clinical manifestations of COPD. The beneficial effect was stronger for catechins as compared with flavonols or flavones. The authors conclude that a high intake of catechins and solid fruit is protective against the manifestations of COPD. The role of airway infection in accelerating the decline of lung function in patients with COPD is debated by Wedzicha (13) and MacNee (14), with rebuttals from each (15, 16). Cellular, Molecular, and Anatomic Abnormalities
The adenovirus targets lung epithelium, and adenoviral transactivating protein (E1A) fosters an exaggerated inflammatory response. To determine whether lung inflammation is increased in patients with emphysema, Retamales and coworkers (17) obtained lung tissue from seven patients with severe emphysema, seven patients with mild emphysema, and seven smokers without emphysema. On CT, the proportion of the lung taken up by emphysema was 43% in the patients with severe emphysema, 13% in the patients with mild emphysema, and 2% in the smokers with normal lung function. The patients with severe emphysema had increased numbers of neutrophils, macrophages, eosinophils, CD4 cells, and CD8 cells in lung tissue and airspaces. The extent of emphysema on CT was correlated with the number of inflammatory cells per surface area; for example, r2 0.86 for CD8 cells in lung tissue and r2 0.63 for CD4 cells in the airspace. The number of alveolar epithelial cells containing adenoviral transactivating protein was increased 5-fold in the patients with mild emphysema and 41-fold in the patients with severe emphysema. The authors conclude that lung inflammation is increased in patients with severe emphysema and that latent expression of adenoviral transactivating protein by alveolar epithelial cells
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amplifies this process. An editorial commentary by Shapiro (18) accompanies this article. Transforming growth factor-1 induces fibroblast proliferation, increased production of extracellular matrix proteins, and decreased collagen degradation. To study the gene expression levels of this growth factor, Takizawa and coworkers (19) used an ultrathin fiberscope (biopsy channel 0.8 mm) to do bronchoscopy. In epithelial cells from the small airways, messenger RNA levels of transforming growth factor-1 were higher in 17 patients with COPD (FEV1, 65% of predicted) and in 18 smokers as compared with 15 nonsmokers. The levels were correlated with the pack-years of smoking in both the patients with COPD (r 0.65) and the smokers (r 0.62), and with the degree of small airway obstruction on flow–volume curves in both the patients (r 0.76) and the smokers (r 0.67). The epithelial cells of the patients and the smokers showed more intense staining for protein of the growth factor and increased spontaneous release of the protein as compared with cells from the control subjects. The authors conclude that the expression of transforming growth factor-1 is increased in the epithelial cells of the small airways of patients with COPD and healthy smokers, and that these cells may be involved in the remodeling and obstruction of the small airways. Kasahara and coworkers (20) determined whether apoptosis contributes to the loss of alveolar structure in emphysema. The number of apoptotic events in epithelial and endothelial cells of the alveolar septa in the lungs of seven patients with emphysema were twofold higher as compared with the lungs of seven subjects with normal lungs and sixfold higher as compared with the lungs of five patients with primary pulmonary hypertension. Apoptotic events did not differ between the healthy nonsmokers and smokers. Emphysematous lungs had increased levels of oligonucleosomal-length DNA fragmentation, and decreased amounts of vascular endothelial growth factor and of its receptor 2. The authors conclude that the death of epithelial and endothelial cells secondary to a decrease of endothelial cell maintenance factors may be part of the pathogenesis of emphysema. Because emphysema is believed to result from an imbalance between proteolytic enzymes and their inhibitors, Imai and colleagues (21) examined the lung parenchyma of 23 patients with emphysema and eight normal subjects for metalloelastases. Matrix metalloproteinase-1 (a collagenase) was expressed in type II pneumocytes in all of the patients with emphysema (despite them having stopped smoking for at least three months), but in none of the control subjects. Matrix metalloproteinase 12 was not expressed in the samples. The authors conclude that the secretion of matrix metalloproteinase-1 by type II pneumocytes may contribute to the alveolar destruction in emphysema. Cavarra and coworkers (22) studied the response to cigarette smoking in mice of differing susceptibility. Acute exposure to cigarette smoke caused a decrease in the antioxidant defenses in the bronchoalveolar fluid of a strain of mice (C57BL/6J) that has a mild deficiency in its antielastase screen and also in a strain of mice (DBA/2) that is sensitive to oxidants. Acute smoke exposure caused an increase in the antioxidant defenses in a strain of mice (ICR) that has a normal antielastase screen and is not sensitive to oxidants. More chronic exposure to cigarette smoke (three cigarettes a day, five days a week for seven months) produced a decrease in lung elastin content and emphysema in the C57BL/6J and DBA/2 mice, but not in the ICR mice. Exposing pallid mice, which have a severe deficiency of 1-proteinase inhibitor and develop emphysema spontaneously, to cigarette smoke over four months accelerated the development of emphysema. The authors conclude
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that the sensitivity of mice to cigarette smoke depends on the sensitivity to oxidants and the elastase inhibiting capacity of the strain. In a pulmonary perspective, Saetta and colleagues (23) discuss the cellular and structural bases of COPD. Lung Inflammation
Because eosinophilia occurs in nonasthmatic patients experiencing an acute exacerbation of bronchitis, Zhu and coworkers (24) determined which of three eosinophil chemoattractants—eotaxin, monocyte chemoattractant protein, or RANTES (regulated on activation, normal T cell expressed and secreted)—is upregulated in this condition. Nine patients with an exacerbation of chronic bronchitis (FEV1 61% predicted) had six times the number of activated (that is, EG2-positive) tissue eosinophils as compared with 11 patients with stable chronic bronchitis (FEV1 75% predicted) or seven healthy nonsmokers. The number of lymphomononuclear cells expressing messenger RNA for eotaxin was higher in the patients with chronic bronchitis as compared with the healthy subjects. RANTES was upregulated during an exacerbation, and it was expressed strongly in both the surface epithelium and in subepithelial lymphomononuclear cells. Only RANTES was correlated with the increased number of EG2-positive cells (r 0.51). The authors conclude that the recruitment of tissue eosinophils during an acute exacerbation of chronic bronchitis results primarily from a marked upregulation of epithelial RANTES. An editorial commentary by Costabel (25) accompanies this article. To determine whether the inflammatory cells surrounding the mucus-secreting glands of the airways are associated with the expression of the regulatory cytokines, interleukin-4 and interleukin-5, Zhu and coworkers (26) studied tissue surgically resected from 11 asymptomatic smokers, 10 smokers with chronic bronchitis who had normal lung function, and 10 smokers with chronic bronchitis who had COPD (FEV1 65% of predicted). Cells containing messenger RNA for interleukin-4 were three times more plentiful as compared with cells containing messenger RNA for interleukin-5. Cells of the submucosal glands containing messenger RNA for interleukin-4 were 3.4-fold more common in the patients with chronic bronchitis who had normal lung function as compared with the asymptomatic smokers and 2.5-fold more common as compared with the patients with COPD. The number of cells containing messenger RNA for interleukin-4 was correlated with the total number of inflammatory cells in both the subepithelium (r 0.60) and in the glandular compartment (r 0.70). The number of CD8 cells was not correlated with the number of cells containing messenger RNA for either interleukin4 or interleukin-5. The authors conclude that gene expression for interleukin-4 is increased in the mucus-secreting glands and airway mucosa of smokers with chronic bronchitis, whereas patients with COPD have fewer inflammatory cells and less gene expression for interleukin-4. Transport of polymeric IgA, the first line of defense in the respiratory tract, into the mucosal lumen requires the expression of the polymeric immunoglobulin receptor (pIgR) on epithelial cells. The extracellular part of this receptor is released after cleavage as secretory component. Compared with a control group of six nonsmokers who had pulmonary hypertension, Pilette and coworkers (27) found that epithelial expression of the secretory component was decreased by 45% in the large airways and by 26% in the small airways of eight patients with COPD. Reduced expression of secretory component in the small airways was correlated with both FEV1 and FVC, and reduced expression in the large airways was correlated
with neutrophil infiltration in submucosal glands. Expression of Clara cell protein (CC 16), which has anti-inflammatory actions, was decreased by 38% in the bronchial epithelium of patients with COPD, although it did not correlate with lung function. The authors conclude that reduced expression of secretory protein in the airway epithelium is associated with airway obstruction and neutrophil infiltration in patients with severe COPD. To determine the role of airway inflammation and infection in an exacerbation of COPD, Aaron and coworkers (28) enrolled 50 patients with COPD (FEV1 39% predicted) in a 15-month follow-up study. Fourteen patients met predetermined criteria for an acute exacerbation. During an exacerbation, the patients developed a 4-fold increase in tumor necrosis factor- and a 1.8-fold increase in interleukin-8 in their sputum. Over the subsequent month, the cytokines declined. Bacterial or viral infection was confirmed in three of the 14 patients (21%), and these patients did not display higher levels of cytokines in their sputum. The authors conclude that markers of neutrophilic inflammation increase in the airways of patients with COPD at the time of an acute exacerbation and that the response occurs independently of a demonstrable viral or bacterial infection. In 60 patients with COPD (FEV1, 52% predicted), Prieto and coworkers (29) studied alterations in innate (natural) immunity and they also did a double-blind trial of glycophosphopeptical (inmunoferon). Compared with 56 healthy subjects, the patients had decreased cytotoxic activity of natural killer cells in their peripheral blood. The patients also had decreases in phagocytic activity: 60% less for peripheral blood monocytes and 77% less for neutrophils. Treatment with glycophosphopeptical increased the cytotoxic activity of the natural killer cells to a level seen in the healthy subjects, and it produced an 87% increase in the phagocytic activity of monocytes and a 44% increase in the phagocytic activity of neutrophils. The authors conclude that the peripheral blood cells of patients with COPD show deficits in natural immunity that are partially reversed by glycophosphopeptical. In a state of the art review article, D’Ambrosio and colleagues (30) discuss the role of cytokines and their receptors in guiding the recruitment of T lymphocytes in lung inflammation. Exhaled Markers
Nitric oxide. To determine the effect of inhaled beclomethasone (500 g twice daily) on markers of airway inflammation, Ferreira and coworkers (31) did a double-blind crossover study in 20 stable patients with COPD (FEV1, 55% of predicted). Median exhaled nitric oxide was 26.2 ppb at baseline, and the concentration fell by 10.6 ppb after one week and by 6.3 ppb after two weeks of inhaled beclomethasone. The concentration did not change with placebo. The change in exhaled nitric oxide was inversely related to the change in FEV1 (r 0.50). The concentration of hydrogen peroxide in the breath condensate did not change with beclomethasone or placebo. The authors conclude that inhaled beclomethasone decreases the level of exhaled nitric oxide in stable patients with COPD. Other markers. Heme oxygenases catalyze the degradation of heme to biliverdin, producing free iron and carbon monoxide, and the heme degradation products may protect against oxidant-mediated injury. Maestrelli and coworkers (32) studied the expression of heme oxygenases in lung specimens obtained at surgery. Immunoreactivity for the inducible isoform, heme oxygenase-1 (also termed heat shock protein), was mainly seen in alveolar macrophages. The percentage of macrophages positive for heme oxygenase-1 was 36% in 10 smokers with COPD, 34% in 6 smokers without lung disease, and
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13% in 10 nonsmoking subjects. Immunoreactivity for the constitutive isoform, heme oxygenase-2, was distributed more widely, involving the alveolar walls, the adventitia of the pulmonary arteries, and vascular smooth muscle. Cells positive for heme oxygenase-2 were greater in the smokers as compared with the nonsmokers. The authors conclude that lung tissue of smokers has increased expression of inducible heme oxygenase-1 and constitutive heme oxygenase-2, and that the increases may be the result of oxidative stress associated with cigarette smoking. Pathophysiology, Radiology, and Airway Narrowing
The protease–antiprotease theory for the development of emphysema ignores the contribution of mechanical forces to the destruction of the alveolar walls. To investigate the latter aspect, Kononov and coworkers (33) studied rats with elastaseinduced emphysema. In the elastase-treated rats, remodeling produced thickening of the elastin and collagen fibers. Compared with tissue from healthy rats, macroscopic stretching of tissue from elastase-treated rats caused substantially greater distortions of the newly deposited elastin and collagen fibers. The threshold for mechanical failure of collagen was also reduced in the elastase-treated rats. The authors conclude that mechanical forces during breathing are capable of causing failure of the remodeled collagen network at points of stress and may contribute to the progression of emphysema. An editorial commentary by Fessler (34) accompanies this article. Ninane and coworkers (35) developed a new approach for detecting airflow limitation. They reasoned that manual compression of the abdomen during expiration would not produce an increase in airflow in a patient with flow limitation. In seven healthy seated subjects, manual compression caused a 27% decrease in the anteroposterior dimension of the abdomen, a 15 cm H2O increase in gastric pressure, and a 6 cm H2O increase in esophageal pressure. Expiratory flow was increased over the entire range of expiration as compared with the preceding spontaneous expiration. In 12 seated patients with COPD, compression caused similar changes in abdominal dimensions and pressures, but half of the patients showed no increase in expiratory flow. In the supine posture, abdominal compression failed to increase expiratory flow in 10 of the 12 patients with COPD. In another seven patients with obstructive sleep apnea who had collapsible upper airways, applying negative pressure to the upper airway produced a pattern of airflow limitation in three patients, whereas compressing the abdomen elicited a normal response. The authors conclude that measuring the change in expiratory flow after manually compressing the abdomen is a simple method for detecting airflow limitation. Stimulation of the M2 muscarinic receptors on postganglionic cholinergic nerves limits the magnitude of bronchoconstriction that results from stimulation of the vagus nerve. On and coworkers (36) assessed the function of the M2 muscarinic receptors in 22 patients with COPD (FEV1 49% of predicted) and 13 control subjects. A cold dry air challenge to the nose, which is known to produce vagally mediated bronchoconstriction, caused airway resistance to increase by 14% in the control subjects and by 9% in the patients with COPD. Pretreatment with ipratropium bromide prevented the bronchoconstriction, indicating that it was vagally mediated. Pretreatment with pilocarpine, a selective agonist of the M2 muscarinic receptor, prevented the bronchoconstriction in both groups, indicating normal function of the M2 receptors. The authors conclude that stable patients with COPD have normal function of the M2 muscarinic receptors.
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To determine the relationship between the extent of pulmonary emphysema, assessed by high-resolution CT, and lung mechanics, Baldi and coworkers (37) studied 24 patients with COPD (FEV1, 17 to 72% of predicted). The extent of emphysema, defined as areas with Hounsfield Units more negative than 950, was 21% of total area (range, 1 to 38%). Maximum static recoil pressure was 54% of predicted (range, 20 to 128%). The extent of emphysema on CT was inversely related to diffusing capacity corrected for alveolar volume (r 0.84), but not to either maximal static elastic recoil pressure or to the exponential constant of the pressure–volume curve. A measure of the heterogeneity of lung density on CT was related to the exponential constant of the pressure–volume curve (r 0.68). The authors conclude that the extent of emphysema on highresolution CT is correlated with the reduction in diffusing capacity but not with the elastic properties of lung tissue. In 43 patients with 1-antitrypsin deficiency of the PiZ phenotype who had never received augmentation therapy, Dowson and coworkers (38) studied the longitudinal changes in physiologic, radiologic, and health status. Over 2 years, FEV1 decreased by 10% (67 ml per year), diffusing capacity decreased by 12%, and upper zone emphysema on high-resolution CT (voxels with a density below 910 Hounsfield units) increased by 15%. Health status, measured by the St. George’s respiratory questionnaire, did not change. The decline in FEV1 was related to baseline FEV1 (r 0.56), reversibility with a bronchodilator (r 0.52), and the frequency of exacerbations (r 0.38). The authors conclude that the decline in FEV1 in patients with emphysema caused by 1-antitrypsin deficiency is dependent on baseline physiology and the frequency of exacerbations, and that high-resolution CT and diffusing capacity are the most sensitive measures of the deterioration. To determine whether chronic hypoxemia produces increased sympathetic nerve activity, Heindl and coworkers (39) studied 11 patients with PO2 of less than 60 mm Hg (6 had COPD and 5 had lung fibrosis) and 11 healthy subjects. Microneurographic recordings of efferent sympathetic activity in the peroneal nerve revealed 64 bursts per minute in the patients and 34 bursts per minute in the control subjects. Inspiring oxygen at 4 liters per minute caused an 11% decrease in the number of bursts in the patients, and had no effect in the control subjects. The authors conclude that sympathetic activity is increased in patients with chronic respiratory failure and hypoxemia. To elucidate the mechanisms underlying the adverse response to inhaled hypertonic saline in patients with COPD, Taube and coworkers (40) studied 20 patients (FEV1, 42% of predicted). A concentration of 0.9% saline produced a decrease in FEV1 of 202 ml, a concentration of 3% saline produced a decrease in FEV1 of 363 ml, and albuterol produced an increase in FEV1 of 138 ml. The increase in dyspnea after inhaled saline was correlated with FEV1 (r 0.62), FIV1 (forced inspired volume in one second; r 0.73), and inspiratory capacity (r 0.67). The concentration of histamine in induced sputum was higher with 3% as compared with 0.9% saline: 39 versus 30 ng per ml. The authors conclude that inhaled hypertonic saline causes a deterioration in lung function of patients with COPD and that the deterioration appears to be mediated by activation of mast cells. Pulmonary Vasculature
To determine the natural history of pulmonary hypertension in patients with mild-to-moderate hypoxemia, Kessler and coworkers (41) prospectively followed 131 patients with COPD (mean PO2, 67 mm Hg) who did not have resting pulmonary hypertension. After 6 years, 25% of the patients developed resting pulmonary hypertension (mean pulmonary artery pressure
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exceeding 20 mm Hg); the increase in pressure was mild (20 to 43 mm Hg). The patients who developed resting pulmonary hypertension had initially a 13% higher pulmonary artery pressure at rest and an 11% higher pulmonary artery pressure during exercise as compared with the patients who did not develop pulmonary hypertension. The patients who developed pulmonary hypertension also experienced a fall in resting PO2 (64 to 60 mm Hg), whereas PO2 remained constant (69 mm Hg) in the patients who did not develop pulmonary hypertension. On logistic regression, baseline pulmonary artery pressures both at rest and during exercise were independently associated with the subsequent development of pulmonary hypertension. The authors conclude that only about 25% of patients with COPD with mild-to-moderate hypoxemia develop pulmonary hypertension over 6 years of follow-up, and that the risk is associated with pulmonary artery pressure during rest and exercise at baseline. Control of Breathing and Exercise
To determine to what extent dynamic hyperinflation impairs exercise performance, O’Donnell and coworkers (42) studied 105 patients with COPD (FEV1, 37% of predicted) and 25 healthy subjects. During incremental exercise on a cycle, 80% of the patients developed an increase in dynamic hyperinflation (measured as a fall in inspiratory capacity). The mean decrease in inspiratory capacity was 0.37 liters, but it ranged from 1.42 to 0.77 liters. The change in inspiratory capacity was inversely related to the resting inspiratory capacity (r 0.50). The peak oxygen consumption during exercise was correlated with the peak tidal volume during exercise (r 0.68), which, in turn, was correlated with inspiratory capacity both at peak exercise (r 0.79) and at rest (r 0.75). The authors conclude that dynamic hyperinflation curtails the ability to increase tidal volume during exercise in patients with COPD, and that this curtailment contributes to exercise intolerance. To determine the effect of hyperoxia on exercise performance, O’Donnell and colleagues (43) did a double-blind crossover trial in 11 patients with severe COPD (FEV1 31% of predicted, PO2 52 mm Hg, PCO2 48 mm Hg). After exercise at 50% of maximal capacity, the patients had a PO2 of 46 mm Hg when breathing air and 245 mm Hg when breathing 60% oxygen. Hyperoxia caused endurance time to increase from 4.1 to 8.8 minutes, and it decreased the slopes on plots of dyspnea, minute ventilation, CO2 production and lactate against time. At a fixed time near the end of exercise, hyperoxia caused dyspnea to decrease by 41%, CO2 production to decrease by 12%, minute ventilation to decrease by 13%, and respiratory frequency to decrease by 15%, and it produced a 27% increase in inspiratory capacity. The authors conclude that the improvement in exercise endurance with hyperoxia was explained by decrease in ventilatory demands, a decrease in endexpiratory volume, and the relief of dyspnea. The antioxidant, reduced glutathione, inactivates reactive oxygen species by forming oxidized glutathione disulfide as the oxidation byproduct. The balance between reduced glutathione and oxidized glutathione can be used to assess the overall redox environment of the cell. In 17 patients with COPD (FEV1, 38% of predicted; PO2, 69 mm Hg), Rabinovich and coworkers (44) did needle biopsies of the vastus lateralis before and after endurance training (5 days a week for 8 weeks). Before training, the levels of reduced and oxidized glutathione were equivalent in the patients and the control subjects both at rest and after 11 minutes of exercise. Training produced an 89% increase in reduced glutathione in healthy subjects but not in the patients. Training produced a 43% in-
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crease in oxidized glutathione in the patients but not in the control subjects. The increase in peak work rate induced by training was correlated with the rise in oxidized glutathione in the patients (r 0.55) and with the rise in reduced glutathione in the control subjects (r 0.83). Concentrations of messenger RNA for -glutamyl cysteine synthetase, a key enzyme in glutathione synthesis, tended to fall in the healthy subjects and tended to rise in the patients. The authors conclude that exercise training induces an increase in the antioxidant, reduced glutathione, in the limb muscle of healthy subjects but not in the muscles of patients with COPD, and that training produces an increase of oxidized glutathione in the muscles of patients with COPD but not in the muscles of healthy subjects. An editorial commentary by Reid (45) accompanies this article. To determine the effect of resistive unloading in subjects with mild COPD, Babb (46) studied 10 patients, aged 70 years, with an FEV1/FVC ratio of 61%. The subjects performed graded cycle ergometry to exhaustion, once while breathing air and once while breathing a mixture of helium (79%) and oxygen (21%). While breathing the helium-oxygen mixture, minute ventilation was 12% greater at the ventilatory threshold and 22% greater at maximal exercise. End-tidal PCO2 fell at all levels. The total work done against the lung did not change. The author concludes that a helium–oxygen mixture increases minute ventilation during exercise in patients with COPD because of resistive unloading and the unchanged work of breathing. To determine whether patients with respiratory disease develop central inhibition of the diaphragm while exercising to exhaustion, Sinderby and coworkers (47) studied 10 patients with COPD (FEV1, 33% predicted). Incremental exercise to exhaustion caused an increase in minute ventilation from 12 to 31 liters per minute. Transdiaphragmatic pressure increased from 9 to 13 cm H2O during early exercise, but it did not change thereafter. Electrical activity of the diaphragm was 24% of maximum at rest, and it increased progressively to 81% of maximum at the end of exercise. Lung volume at the end of inspiration was 86% of total lung capacity at rest and 97% of total lung capacity at the end of exercise. The authors conclude that transdiaphragmatic pressure increases only modestly during maximum exercise in patients with COPD, and that the minor nature of the increase is secondary to the development of dynamic hyperinflation rather than to an inhibition of central drive. To determine whether measurements other than distance help in assessing patient performance during the six-minute walk test, van Stel and coworkers (48) studied 83 patients with COPD. Of 15 variables, four independent factors accounted for 78% of the variance: endurance capacity, the pattern of heart rate, perceived symptoms, and impairment of oxygen transport. Pulmonary rehabilitation produced an improvement in self-perceived exercise tolerance in 84% of 53 patients, and 29 patients showed improvements in three or four factors. The improvement was explained by a change in walking distance, less desaturation, and less dyspnea (r2 0.55). The authors conclude that assessing patient performance during a six-minute walk test is improved when factors other than the distance walked are also measured. To determine the mechanism for dyspnea during the sixminute walk test, Marin and coworkers (49) studied 72 men with COPD (FEV1, 45% of predicted). The distance walked in six minutes was 439 m. The inspiratory capacity decreased from 29% of total lung capacity before the test to 24% after its completion. Dyspnea on exertion was correlated with the change in inspiratory capacity (r 0.49) and with baseline dyspnea (r 0.59). The authors conclude that dynamic hyperinflation contributes
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to dyspnea during a six-minute walk test, and that it can be easily detected by measuring inspiratory capacity. To determine the effect of an acute episode of exercise on cognitive function in patients with COPD, Emery and coworkers (50) studied 29 patients with COPD (FEV1, 43% of predicted) and 29 healthy subjects. Compared with watching a video, exercising to a peak level produced an 8% increase in verbal fluency in the patients but not in the control subjects. Other tests of cognitive performance were not altered. The authors conclude that an acute episode of exercise improves some measures of cognitive performance in patients with COPD. Respiratory Muscles
To determine whether the diaphragm of patients with COPD displays ultrastructural evidence of injury and to determine whether acute loading induces diaphragmatic injury, OrozcoLevi and coworkers (51) obtained biopsies from the costal diaphragm in 18 patients with COPD and 11 healthy subjects during surgery. Electron microscopy revealed sarcomere disruptions in all samples, and the density and area of disruptions in the patients were twice that seen in control subjects. The density of sarcomere disruptions was correlated with FEV1 (r 0.59) and with the ratio of residual volume to total lung capacity (r 0.80). Before the surgery, a subset of seven patients with COPD and five control subjects breathed through a threshold resistor until task failure. Compared with the unloaded state, the density of sarcomere disruptions increased by 89% in the loaded healthy subjects and by 38% in the loaded patients. The density of disruptions was about three times greater in the patients with COPD after loading, as compared with the unloaded healthy subjects. The authors conclude that sarcomere disruptions are increased in the diaphragm of patients with COPD, and that acute loading causes sarcomere disruption in the diaphragm of both healthy subjects and patients with COPD. To determine whether patients with airflow obstruction experience injury to their diaphragm, MacGowan and coworkers (52) did partial thickness biopsies of the diaphragm in 21 patients undergoing thoracotomy. The FEV1 of the patients ranged from 16 to 122% of predicted, mean 74%. The contributions to the cross-sectional area were: normal diaphragm, 66%; abnormal muscle, 18%; and connective tissue, 16%. The abnormal tissue included fibers with internally located nuclei, lipofuscin pigmentation, small angulated fibers, and some inflammation. The percent predicted FEV1 was inversely related to the area of abnormal muscle (r 0.53), but not to the number of macrophages present. The authors conclude that patients with increasing severity of airway obstruction have a proportional increase in abnormal tissue in their diaphragm. Because diaphragmatic dysfunction in emphysema has been attributed to an imbalance between oxygen supply and demand, Poole and coworkers (53) measured oxygen within the diaphragm in hamsters. Microvascular PO2 within the costal diaphragm of hamsters with elastase-induced emphysema was about half the value found in control animals. The value was substantially decreased across inspired oxygen concentrations between 10 and 100%. Decreases in mean arterial pressure from 115 to 40 mm Hg caused proportional decreases in diaphragmatic PO2 (r 0.98). The authors conclude that microvascular oxygen tension is decreased in the diaphragm of emphysematous hamsters. Peripheral Muscles
To determine the effect of exercise on amino acid metabolism, Engelen and coworkers (54) obtained arterialized venous blood and quadriceps biopsies before and after 20 minutes of
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exercise in 14 patients with COPD and eight healthy subjects. In the muscle, the sum of amino acids fell by 20% after exercise in the patients, but it did not change in the healthy subjects. In the plasma, the sum of amino acids rose by 16% after exercise in the patients, and the increases in plasma alanine (61%) and glutamine (21%) were even greater. The authors conclude that patients with COPD experience an increased release of amino acids from the quadriceps muscle during exercise. Patients with COPD develop fatigue of the quadriceps muscle after exercising to the limits of tolerance. To determine whether a rehabilitation program would increase resistance to muscle fatigue, Mador and coworkers (55) entered 21 patients with COPD (FEV1, 45% of predicted) into a program of supervised exercise training (50% of maximum work was performed three times a week for eight weeks). The program produced a 34% increase in maximum exercise capacity. Before rehabilitation, exercise caused fatigue of the quadriceps as reflected by an 18% decrease in the twitch pressure that resulted from stimulation of the femoral nerve. After completing the rehabilitation program, exercise no longer caused a fall in the twitch pressure of the quadriceps. The authors conclude that supervised rehabilitation increases the resistance of the quadriceps muscle to fatigue in patients with COPD. In a pulmonary perspective, Debigaré and colleagues (56) discuss wasting of the peripheral muscles in patients with COPD. Nutritional Status
Leptin, an adipocyte-derived hormone involved in the control of body weight, is decreased in patients with COPD. To determine the circadian rhythm of leptin, Takabatake and coworkers (57) measured serum leptin on eight occasions over 24 hours in nine patients with COPD and cachexia, in eight patients with COPD without cachexia, and in seven healthy subjects. The leptin levels had a diurnal pattern in the control subjects and in the patients without cachexia, but the circadian pattern was blunted, with marked attenuation of the nocturnal peak, in the patients with cachexia. In all three groups, the 24-hour fluctuations in leptin were identical to the fluctuations of heart-rate variability in the very low-frequency band, a measure of autonomic and neuroendocrine control. The authors conclude that patients with COPD free of cachexia have a normal circadian rhythm in serum leptin, which is under autonomic and neuroendocrine regulation, and that the rhythm is lost in patients with COPD who have cachexia. An editorial commentary by Goldberger (58) accompanies this article. To determine the role of systemic inflammation on body composition, Eid and coworkers (59) studied 80 stable patients with COPD. Body mass index was normal (greater than 20 kg per m2) in 55 patients (69%). Among the patients with a normal body mass index, 17 (31%) had a decrease in skeletal muscle mass, as reflected by a creatinine-height index of less than 80% of predicted. A low creatinine-height index was associated with increased levels of circulating interleukin-6 (r 0.40), tumor necrosis factor- (r 0.30), soluble receptor for interleukin-6 (r 0.30), and soluble receptor 2 for tumornecrosis factor- (r 0.40). Patients with a normal body mass index and low creatinine-height index had equivalent levels of inflammatory mediators as compared with patients with a low body mass index and low creatinine-height index. Urinary excretion of nitrogen was 94% higher in patients with a low versus a normal creatinine-height index, although nitrogen balance was equivalent in the two groups. The authors conclude that weight loss, particularly of skeletal muscle mass, in patients with COPD is associated with the host inflammatory response.
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Year in Review Health Care Delivery
In an executive summary from an NHLBI/WHO workshop on a Global Initiative for Chronic Obstructive Lung Disease (GOLD), Pauwels and colleagues (60) outline a challenge to increase the awareness of COPD, to improve its prevention and management, and to encourage renewed research on this subject. An editorial commentary by Gross (61) accompanies this article. Drug Therapy
-Agonists. In a double-blind study in 780 patients with COPD (FEV1, 45% of predicted), Dahl and coworkers (62) compared formoterol (12 or 24 g twice daily), ipratropium bromide (40 g four times daily), and placebo. After 12 weeks of treatment, the area under the curve for FEV1 measured over 12 hours was greater for formoterol, 12 g twice daily (0.223 liter), formoterol, 24 g twice daily (0.194 liter), and ipratropium (0.137 liter) as compared with placebo. The area under the curve for both doses of formoterol was greater as compared with ipratropium. Compared with placebo, both doses of formoterol improved symptoms and the quality of life, whereas ipratropium did not have a beneficial effect. The authors conclude that formoterol, a long-acting 2-adrenergic agonist, is more effective than ipratropium bromide in the treatment of patients with COPD. In 405 patients with COPD, Rennard and coworkers (63) did a randomized double-blind comparison of salmeterol (42 g twice daily), ipratropium bromide (36 g four times daily), and placebo. The bronchodilator effects were compared over a 12-hour interval before, during, and after 12 weeks of therapy. Salmeterol produced similar bronchodilation as compared with ipratropium. The response was more prolonged with salmeterol, and tachyphylaxis was not observed. The authors conclude that the long-acting -agonist, salmeterol, produces bronchodilation in patients with COPD. In a double-blind, crossover study in 53 patients with COPD (FEV1 34% predicted), Cook and coworkers (64) asked the question “Is the scheduled use of an inhaled -agonist superior to use on an as-needed basis?” All patients received inhaled ipratropium bromide (40 g four times daily), beclomethasone (500 g twice daily), and albuterol as needed. The intervention consisted of scheduled albuterol (200 g four times daily) or placebo, each for three months. Consumption of albuterol was twice as high when patients took it on a scheduled basis as compared with using it on an as-needed basis (12.8 versus 6.3 puffs per day). The groups showed no differences in FEV1, six-minute walking distance, and health status on a questionnaire. The authors conclude that patients with COPD consume twice as much of an inhaled -agonist when instructed to use it on a scheduled basis as compared with using it on an as-needed basis. Glucocorticoids. To determine whether inhaled glucocorticoids influence repeat hospitalization and mortality in elderly patients with COPD, Sin and Tu (65) studied a cohort of 22,620 patients with COPD who were 65 years of age or older. At 1-year follow-up, 25% of the patients had undergone repeat hospitalization and 11% had died. In the 90 days after the first discharge, 51% of the patients received inhaled glucocorticoids. During follow-up, the patients receiving inhaled glucocorticoids had 24% fewer hospitalizations for COPD and a 29% lower mortality. The authors conclude that use of inhaled glucocorticoids is associated with decreased morbidity and mortality in elderly patients with COPD. An editorial commentary by Vestbo (66) accompanies this article. To determine the cost effectiveness of early treatment with an inhaled glucocorticoid in subjects with previously undiag-
nosed obstructive airway disease, van den Boom and coworkers (67) entered 82 subjects from a random sample of the general population into a one-year double-blind study of inhaled fluticasone proprionate (250 g twice daily) versus placebo. Compared with placebo, the group treated with fluticasone developed a 90-ml increase in post-bronchodilator FEV1. At 12 months, subjects with reversible airway obstruction showed an improvement in airway hyperresponsiveness (1.4 steps in the dose of histamine producing a 20% decrease in FEV1). Early treatment resulted in a gain of 2.7 QALYs (quality-adjusted life years) per 100 subjects treated and an improvement in dyspnea. The incremental cost effectiveness ratio was $13,016 per QALY for early treatment and $33,921 per QALY for detection combined with treatment. The mean incremental cost for achieving a relevant decrease in dyspnea in one additional subject was $1,674. The authors conclude that early intervention with fluticasone improves lung function and the quality of life at relatively low financial cost in subjects with manifestations of obstructive airway disease. To determine whether withdrawal of inhaled glucocorticoids would lead to a worsening of lung function, O’Brien and coworkers (68) did a double-blind crossover study in 24 men with COPD (age, 67 years; FEV1, 47% of predicted). After discontinuing inhaled glucocorticoids, the patients were randomized to either six weeks of placebo followed by six weeks of beclomethasone diproprionate (336 g daily) or the reverse sequence. The patients experienced a 2.4% increase in FEV1 while taking beclomethasone, as compared with a 5.9% decrease in FEV1 while taking placebo. Patients experienced less dyspnea during walking when they were taking beclomethasone. The distance walked during six minutes, sputum cell counts, and subjective assessment on a chronic respiratory disease questionnaire did not differ between the two arms of the study. The authors conclude that the withdrawal of inhaled glucocorticoids in elderly patients with COPD leads to a deterioration in lung function and to an increase in dyspnea while walking. To determine whether change in health status is detectable over time, Spencer and coworkers (69) analyzed data on 387 patients with COPD (FEV1, 50% of predicted) participating in the ISOLDE (inhaled steroids in obstructive lung disease) study. Health status was measured using a generic instrument, the SF-36, and a disease-specific instrument, the St George’s respiratory questionnaire, at baseline and every six months for three years. Progressive deterioration in all domains of health (symptoms, physical activity, and psychosocial function) was detectable using either instrument. Deterioration was slower in the patients receiving fluticasone (1,000 g daily) as compared with the patients receiving placebo. FEV1 was correlated with scores on the respiratory questionnaire at baseline (r 0.25), and the changes in the scores and in FEV1 over time were correlated (r 0.24). At baseline, smokers had poorer scores on the respiratory questionnaire as compared with the ex-smokers; although this difference was maintained throughout the study, smoking did not influence the rate of decline in health status. The authors conclude that measuring health status is valuable in assessing the effect of a long-term therapy in COPD, and that inhaled fluticasone reduces the decline in health status. Smoking cessation. In a pulmonary perspective, Britton and colleagues (70) discuss the challenges of treating nicotine addiction. Other Therapies
Lung volume reduction surgery. On CT scan, emphysema appears to be more extensive in the inner region (core) as compared
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with the outer region (rind) of the lung. Because a predominance of emphysema in the outer region may be more accessible during lung volume reduction surgery, Nakano and coworkers (71) determined whether quantifying the distribution of emphysema would predict outcome in 21 patients undergoing surgery. The peripheral 50% of the lung area on CT scan was defined as the rind, and remainder as the core. (Areas of lung expansion exceeding 10.2 ml per gram of tissue [equivalent to Hounsfield units more negative than –910] are associated with emphysematous lesions exceeding 5 mm in diameter; areas of lung expansion between 6.0 and 10.2 ml per gram of tissue [equivalent to 910 to 856 Hounsfield units] are associated with emphysematous lesions of less than 5 mm in diameter; and areas of expansion of less than 6 ml per gram of tissue are associated with normal lung tissue.) Surgery produced an increase in FEV1 from 29 to 40% of predicted and an increase in exercise performance from 26 to 44 watts. The amount of lung displaying severe emphysema (expansion beyond 10.2 ml per gram) in the rind of the upper lung predicted a greater increase in FEV1 and an increase in maximal exercise capacity after surgery. The authors conclude that patients who have more emphysema in the surgically accessible rind area of the upper lung show the greatest benefit after lung volume reduction surgery. An editorial commentary by Gevenois and Estenne (72) accompanies this article. Because improvement after lung volume reduction surgery has been attributed to changes in dimensions and configuration of the diaphragm, Cassart and coworkers (73) did threedimensional reconstructions of the diaphragm with spiral CT in 11 patients with emphysema. Surgery produced a 51% increase in FEV1 and a 30% decrease in functional residual capacity. Surgery produced a 17% increase in total surface area of the diaphragm and a 43% increase in the area of the zone of apposition; both areas, however, were still 11 and 24%, respectively, smaller as compared with the areas in 11 healthy subjects. The proportion of the diaphragmatic area apposed to the rib cage increased from 40 to 49% after surgery, and the change was related to the fall in functional residual capacity (r 0.47). Surgery did not change the area of the dome. The authors conclude that the decrease in lung volume after lung volume reduction surgery causes the dome of the diaphragm to move upwards, and thus it increases the area of the diaphragm that is apposed to the rib cage. An editorial commentary by Hoppin (74) accompanies this article. To determine whether radiologic and physiologic measurements can predict benefit from lung volume reduction surgery, Ingenito and coworkers (75) studied 48 patients with emphysema (FEV1, 23% of predicted). Patients were classified as having homogenous emphysema when the ratio of perfusion to the upper and lower zones on a radioisotope scan was between 0.75 and 1.25. At six months after surgery, 27 patients with heterogeneous disease experienced a greater increase in FEV1 as compared with 21 patients with homogenous disease (increases of 41 versus 22%). Good airflow on inspiration, as reflected by a high inspiratory conductance, was correlated with the improvement in FEV1 at six months (r 0.53). Conductance identified 11 patients who had a good response to surgery but were missed by the radiologic criteria. On multiple regression analysis, the combination of inspiratory conductance and the radiologic pattern explained 33% of the improvement in FEV1. The authors conclude that radiologic and physiologic measurements are additive in their ability to predict patients who are likely to benefit from lung volume reduction surgery. To elucidate the mechanism of improvement in lung function after lung volume reduction surgery, Ingenito and coworkers (76) studied 37 patients. Surgery produced an overall
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increase in FEV1 of 28%, and a positive response was defined as an increase in FEV1 of at least 12%. Nineteen responders had a mean increase in FEV1 of 60% and 18 nonresponders had a mean decrease in FEV1 of 6%. The responders experienced a 39% increase in elastic recoil pressure and a 12% decrease in the time-constant for expiration. Conductance, transmural pressure at the site of flow limitation, and lung compliance did not change. An increase in elastic recoil pressure weighted by the preoperative value of conductance upstream of the site of flow limitation accounted for 72% of the improvement in expiratory flow. The only change in the nonresponders was a 13% increase in the expiratory time-constant. In the nonresponders, the change in expiratory flow was correlated with a change in conductance weighted by the preoperative recoil pressure. The authors conclude that the improvement in expiratory flow after lung volume reduction surgery is mainly the result of an increase in elastic recoil pressure. Gelb and coworkers (77) followed 26 patients with emphysema (FEV1 700 ml, 29% of predicted) for 5 years after lung volume reduction surgery. Mortality caused by respiratory failure was 4% in the first year, 31% after three years, and 58% after five years. An increase in FEV1 of more than 200 ml above baseline was noted in 73% of patients at one year, in 35% at three years, and in 8% at five years. Eighteen patients were initially oxygen dependent. This dependence was eliminated in 78% of patients at one year, in 33% at three years, and in 0% at five years. In the 11 patients who survived for five years, the peak increase in FEV1 in the first post-operative year was 438 ml. The fastest decline was over the subsequent year, 149 ml, and a decline of 78 ml per year occurred over the following four years. The authors conclude that lung volume reduction surgery produced significant improvement in 35% of patients at three years and in 8% of patients at five years. In 12 sheep with papain-induced emphysema, Ingenito and coworkers (78) investigated the effect of a less invasive alternative to lung volume reduction surgery. Dysfunctional regions of the lung were obliterated under bronchoscopic control using both a washout solution and a fibrin-based glue to collapse, seal, and scar the region. After 8 to 12 weeks, the bronchoscopic approach produced equivalent decreases in total lung capacity and residual volume as compared with the sheep undergoing lung volume reduction surgery. Histology revealed collapse and scarring in 11 of 20 target areas, and three zones developed sterile abscesses. Complications with the bronchoscopic approach were less common as compared with surgery. The authors conclude that the application of a fibrin-based glue through a bronchoscope can achieve similar reductions in lung volume as those achieved by surgery in sheep with emphysema. Expectorants and mucociliary clearance. Uridine 5 -triphosphate, an agonist of the purinergic receptors, enhances mucociliary clearance in healthy subjects. In 15 patients with chronic bronchitis, Bennett and coworkers (79) did a doubleblind study of the effect of the agonist on the clearance of inhaled technetium particles (99mTc-Fe2O3), which have a mass median aerodynamic diameter of 4 m. Inhaling 20 mg of uridine 5 -triphosphate produced a 46% increase in the clearance rate of the particles. When the dosage was increased fivefold, clearance was no greater. The authors conclude that a small dose of aerosolized uridine 5 -triphosphate increases mucociliary clearance in patients with chronic bronchitis, presumably by stimulating cilia and hydrating airway secretions. Rehabilitation and Oxygen Therapy
The optimal flow rate for use with long-term oxygen therapy has not been standardized. In 88 patients with COPD, Guyatt
Year in Review
and coworkers (80) studied four protocols for selecting the delivered flow: rest, exercise in hospital, exercise during simulation of the home, and exercise at home. For each protocol, the flow of oxygen was adjusted according to explicit criteria. For four testings done at rest, 63% yielded the same prescription and 94% of the prescriptions were within 1 liter per minute of each other. For four testings done during exercise, 27% yielded the same prescription and 73% of the prescriptions were within 1 liter per minute of each other. During exercise, hospital testing produced a higher prescription as compared with the simulated home testing (2.5 versus 2.0 liters per minute). The authors conclude that the use of explicit protocols for selecting a flow of supplemental oxygen that prevents hypoxemia during exercise achieve a moderate degree of reproducibility when done in a hospital setting and less reproducibility in the home setting. Outcome
To determine whether undiagnosed airway obstruction has an impact on health, Coultas and coworkers (81) analyzed data from the National Health and Nutrition Examination Survey (NHANES III). Undiagnosed airway obstruction, based on FEV1 and responses to a questionnaire, was more common (12%) as compared with physician-made diagnoses of COPD (3.1%) or asthma (2.7%). The occurrence of undiagnosed airway obstruction (FEV1 less than 75% of predicted) was equivalent among men (5.7%) and women (4.6%). After adjusting for smoking and co-morbid conditions, the risk of impaired general health and the difficulty in walking were associated with the degree of reduction in FEV1. Among women with airflow obstruction, 12 to 35% had never smoked. The authors conclude that undiagnosed airway obstruction occurs in 5% of the general population and is associated with impaired health and functional status. FEV1 is most accurate in predicting prognosis in patients with COPD when measured after maximal bronchodilation. To assess the power of peak expiratory flow rate (PEFR), after maximizing lung function with bronchodilators and glucocorticoids, in predicting prognosis, Hansen and coworkers (82) studied 491 patients with asthma and 1,095 patients with COPD (baseline FEV1, 49% of predicted). Ten to 15 years after measuring pulmonary function, 26% of the patients with asthma and 66% of the patients with COPD had died. After controlling for age, smoking, sex, and body mass index, the best value of PEFR was at least equally powerful as the best value of FEV1 in predicting prognosis. Despite its close correlation with FEV1, PEFR provided independent information on prognosis. In patients with asthma, the best FEV1 was a better predictor of mortality than the best PEFR. The authors conclude that measurement of PEFR after maximal bronchodilation was at least as powerful as FEV1 in predicting prognosis in patients with moderate-to-severe COPD.
AIR POLLUTION General
Epidemiologic studies done before the closure of a steel mill in the Utah Valley in 1986, during closure of the mill, and after reopening of the mill established that exposure to particulate matter was related to human health. Ghio and Devlin (83) generated aqueous extracts from filters containing particulate matter from the three time periods, and instilled the extracts through a bronchoscope into the lingula of 24 healthy subjects. When the lingula was lavaged 24 hours later, the bronchoalveolar fluid of the subjects exposed to particulate matter from the time when the mill was open contained higher levels of
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neutrophils, protein, fibronectin, -antitrypsin, interleukin-8, interleukin-1, tumor necrosis factor, and oxidized products as compared with the subjects exposed to particulate matter from when the mill was closed. The subjects exposed to particulate matter from when the mill was open also had lower concentrations of tissue factor and fibrinogen. The authors conclude that mass is not the only important variable when assessing health effects of air pollution particles, and that the particle composition also needs to be considered. An editorial commentary by Beckett (84) accompanies this article. Van Eeden and coworkers (85) surveyed the cytokines produced by human alveolar macrophages on exposure to ambient particles of different composition and size. Incubation of macrophages with particle suspensions of latex, inert carbon, or residual oil fly ash produced a 1.5- to 2-fold increase in tumor necrosis factor-, whereas ambient urban particles (EHC 93) produced a 10-fold increase. Macrophages incubated with ambient urban particles also produced interleukin-6, macrophage inflammatory protein-1, and granulocyte-macrophage colony-stimulating factor. Thirty healthy men exposed to air pollutant during the 1997 Southeast Asian forest fires had increased concentrations of interleukin-1, interleukin-6, and granulocyte-macrophage colony-stimulating factor in their serum. The authors conclude that stimulation of alveolar macrophages by atmospheric particles causes the production of proinflammatory cytokines, and that these cytokines are also found in the blood of subjects exposed to acute atmospheric pollution. Exposure to airborne particles exacerbates heart and lung disease, but it is not known whether underlying disease predisposes to this effect. To determine whether diabetes increases susceptibility, Zanobetti and Schwartz (86) analyzed Medicare data for the years 1988 to 1994 in the Chicago area. For particulate matter with an aerodynamic diameter of less than 10 m (PM10), a 10 g per cubic meter increase in concentration was associated with a 2% increase in admission to hospital for heart disease among patients with diabetes, but only a 0.9% increase in admissions among individuals without diabetes. Exposure did not influence admissions for lung disease. The authors conclude that increased exposure to airborne particles resulted in twice the risk of admission to hospital for heart disease among individuals with diabetes. To investigate the causal relationship between exposure to airborne particulate matter and the development of asthmalike manifestations, Walters and coworkers (87) exposed naïve mice to a single dose of ambient particulate matter, coal fly ash, or diesel particulate matter. Ambient particulate matter induced increases in bronchoalveolar cellularity and airway hyperreactivity. Exposure to diesel particulate matter induced increases in bronchoalveolar cellularity but did not increase airway hyperreactivity. Exposure to coal fly ash induced no changes. The airway hyperreactivity induced by airborne particulate matter was sustained over seven days. The increase in airway hyperreactivity was preceded by a marked increase in bronchoalveolar eosinophils, whereas the decline in hyperreactivity was associated with an increase in macrophages. A type 2 (Th2) cytokine pattern (interleukin-5, interleukin-13, eotaxin) was observed in the early phase. A type 1 (Th1) pattern (interferon-) response was initially depressed and increased after 2–3 days. The active component(s) of the ambient particulate matter was not soluble in water, and the airway hyperreactivity and inflammation caused by ambient particulate matter was dose dependent. The authors conclude that ambient particulate matter can induce sustained asthmalike manifestations in mice. Although epidemiologic studies show an association between exposure to particulate matter and human morbidity, the clinical
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presentation is not clear. Ghio and coworkers (88) described a 42-year-old man who was exposed to suspended particles of oily fly ash while cleaning a domestic oil-burning stove. The patient developed cough, dyspnea, and wheezing within 24 hours of exposure. He gradually progressed to hypoxemic respiratory failure and required mechanical ventilation. A lung biopsy revealed particle-laden macrophages and diffuse alveolar damage. The patient’s condition improved with systemic glucocorticoids. Ash collected from the patient’s furnace was instilled into the trachea of rats and produced similar proinflammatory and biological effects. The authors conclude that exposure to particulate matter from an emission source can cause acute respiratory failure. Ultrafine particles, having diameters of 0.1 m or less, represent a substantial fraction of particulate matter with a diameter below 10 m (PM10). Because the mechanism whereby particulate pollution causes cardiovascular mortality is poorly understood, Nemmar and coworkers (89) studied the extent to which ultrafine particles pass into the circulation. Hamsters received a single intratracheal instillation of particles of less than 80 nm in diameter, which were labeled with technetium99m. In the blood, 2.9% of the dose per gram of blood was detectable at 5 minutes and the percentage gradually decreased over the subsequent 45 minutes. Lower percentages were found in the liver, heart, spleen, kidneys, and brain. The authors conclude that a substantial proportion of ultrafine particles instilled into the trachea pass into the circulation of hamsters. To determine the association between particulate air pollutions and emergency admission to hospital for respiratory problems, Atkinson and coworkers (90) analyzed data from participants in the APHEA2 (Air Pollution and Health: a European Approach) project, which was conducted in eight European cities. After controlling for environmental factors and temporal patterns, an increase in PM10 (particles with an aerodynamic diameter of less than 10 m) of 10 g per cubic meter was associated with a 1.2% increase in the number of daily admissions to hospital for asthma in subjects aged 0 to 14 years old, a 1.1% increase in admissions to hospital for asthma in subjects aged 15 to 64 years old, and a 1.0% increase in admissions to hospital for all respiratory problems. The combined effect for black smoke was smaller. In subjects older than 65 years, ozone accounted for a large proportion of the effect of particles. The authors conclude that admission to hospital for respiratory problems increases by about 1% for an increase of 10 g per cubic meter in particles of less than 10 m in diameter. To determine whether changes in air pollution might affect lung function during adolescence, a time of rapid lung growth, Avol and coworkers (91) studied 110 children who had moved between communities. The children were aged 10 years at enrollment and 15 years at follow-up. Across the six western states in the study, the annual levels of PM10 (particulate matter with a mean diameter of 10 m) varied from 15 to 66 g per cubic meter. An increase of 10 g per cubic meter in the annual average of PM10 was associated with a decrease in annual growth of both maximal midexpiratory flow (16.6 ml per year) and peak expiratory flow (34.9 ml per year). Children moving to communities with lower PM10 experienced an increase in the growth of lung function, and children moving to communities with higher PM10 experienced a decrease in the growth of lung function. The trend was stronger in children who had moved their community for three years or longer before the follow-up visit, as compared with children who had moved within 1 to 2 years. The authors conclude that a change in the level of air pollution affects the growth of lung function during adolescence. To assess the association between short-term variations in air pollutant levels and lung function, Schindler and cowork-
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ers (92) studied a random, cross-sectional sample of 3,912 adults who had never smoked and who lived in eight areas of Switzerland. After controlling for sex, age, height, weight, and seasonal fluctuations in meteorological factors, 10-g per cubic meter increments in the daily level of nitrogen dioxide, total suspended particulates, and ozone were associated with respective decrements in FEV1 of 0.67%, 0.46%, and 0.51%. Increments in nitrogen dioxide and total suspended particulates of 10 g per cubic meter were associated with respective decrements in FVC of 0.73% and 0.36%. An increment in ozone of 10 g per cubic meter was associated with a decrement in FEF25–75 of 1.04%. The authors conclude that daily concentrations of nitrogen dioxide, total suspended particulates, and ozone have a significant effect on lung function. Exposure to ambient particulate matter is associated with increased morbidity and mortality. In rabbits exposed to particles smaller than 10 m (PM10) twice a week for three weeks, Mukae and coworkers (93) used the thymidine analog, 5 -bromo2’-deoxyuridine, to study the bone-marrow response. Exposure to particulate matter caused a persistent increase in circulating band cells, a 13% decrease in the transit time of neutrophils through the post-mitotic pool in the marrow, and an increase in the marrow pool of neutrophils (especially the mitotic pool). The particles were diffusely distributed in the lung and they caused a mild mononuclear inflammation. The percentage of macrophages containing particles less than 10 m correlated with the size of the total marrow neutrophil pool (r2 0.56), the mitotic pool (r2 0.61), and the transit time of neutrophils through the postmitotic pool (r2 0.42). The authors conclude that particulate air pollution stimulates the bone marrow to produce more neutrophils and to release immature neutrophils into the circulation, and that these occurrences are related to the degree to which particles are phagocytosed by alveolar macrophages. Ozone
The inflammatory response to ozone is associated with the induction of enzymes—nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase (NAD[P]:NQO1) and glutathioneS-transferases (GSTs)—that protect against oxidative stress. To determine whether polymorphism of these enzymes accounts for the interindividual variability to ozone, Bergamaschi and coworkers (94) studied 24 healthy subjects during two-hour bicycle rides at ambient ozone concentrations between 32 and 103 ppb. Rides at ozone concentrations exceeding 80 ppb caused decrements in lung function and increases in the serum levels of Clara cell protein CC 16 (an indicator of increased permeability of the lung epithelial barrier). These changes were largely confined to a subgroup of subjects bearing both the NQO1wt and GSTM1null genotypes. Other haplotypes developed a rise in Clara cell protein CC16 but no change in lung function. In the subjects carrying both the NQO1wt and GSTM1null genotypes, the increase in Clara cell protein CC16 was related to ambient ozone (r2 0.48), and the increase in this protein was related to fall in FEV1 (r2 0.67). The authors conclude that the adverse affects of ozone on lung function and on the lung epithelial barrier are most apparent in individuals with a combination of the NQO1wt and GSTM1null genotypes, who are susceptible to developing increased free radicals. To determine whether tumor necrosis factor contributes to the airway hyperresponsiveness induced by ozone, Shore and coworkers (95) studied wild-type mice and knockout mice deficient in the p55 receptor for tumor necrosis factor, deficient in the p75 receptor for tumor necrosis factor, or deficient in both receptors. Three hours after exposure to ozone, the airway
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response to methacholine underwent a 1.2 log shift to the left in the wild-type mice, indicating hyperresponsiveness. The shift was only 0.5 log in the mice genetically deficient in the two tumor necrosis factor receptors; the results were similar in the mice deficient in the p75 receptor. Ozone caused an equivalent increase in neutrophils in the bronchoalveolar fluid of both the wild-type mice and the mice deficient in the two receptors. The authors conclude that tumor necrosis factor contributes to the airway hyperresponsiveness but not to the neutrophil migration induced by ozone. Samet and coworkers (96) studied susceptibility to ozone in two groups of subjects: one group was relatively well supplemented in ascorbate, -tocopherol, and carotenoids, and the second group was depleted of these antioxidants. After two weeks of the specialized diets, the reduction in FEV1 after ozone exposure was 30% less in the subjects receiving the antioxidant supplements as compared with the depleted subjects. The number of neutrophils and the concentration of interleukin-6 in bronchoalveolar fluid after ozone exposure did not differ in the two groups. The authors conclude that dietary antioxidants protect against the decrease in pulmonary function on exposure to ozone, but do not protect against the accompanying inflammatory response. Exposure to ozone causes airway inflammation and impairment of small airway function. To determine the response to repetitive exposure, Frank and coworkers (97) exposed eight healthy subjects to filtered air and to ozone for two hours on four consecutive days. Repeated exposure produced adaptive changes in the spirometric variables, that is, a diminution in the daily effect of ozone. Persistent change was confined to measures of small airway function and to rapid shallow breathing. Neutrophilia in bronchoalveolar fluid was evident one day after the end of ozone exposure. The authors conclude that healthy subjects exposed repeatedly to ozone develop both adaptive and persistent changes in lung function. To determine the role that neural afferents in the large conducting airways play in mediating the response to ozone, Schelegle and colleagues (98) exposed ozone-sensitive subjects to 0.3 ppm of ozone for 65 minutes. After 50 minutes of exercise, ozone caused decreases in FEV1 (by 24%) and tidal volume (by 31%), and increases in respiratory frequency (by 40%) and subjective symptoms (by 19-fold). Tetracaine, a local anesthetic delivered predominantly to the large airways when inhaled, caused reductions in subjective symptoms (by 70 to 90%), but had minimal effect on FEV1 or respiratory frequency. The authors conclude that the decrease in maximal inspiratory effort with ozone is reflex in origin rather than secondary to a conscious breathing discomfort, and that the subjective discomfort is mediated by afferents in the large airways. Diesel Exhaust
To elucidate the role of T cells in the early inflammatory response to diesel exhaust exposure, Fujimaki and coworkers (99) studied different groups of mice. Compared with mice exposed to diesel exhaust or with mice immunized with ovalbumin, the combined effect of immunizing mice with ovalbumin and exposing them to diesel exhaust resulted in considerably higher numbers of macrophages, neutrophils, and eosinophils in their bronchoalveolar fluid, increased production of interleukin-1, and decreased production of interleukin-12. Exposure to diesel exhaust increased the production of macrophage inflammatory protein-1 and macrophage inflammatory protein-2, but it did not increase the production of monocyte chemoattractant protein-1 and RANTES (regulated upon activation, normal T cell expressed and secreted). Treatment with anti-CD4 and anti-CD8 monoclonal antibodies abrogated
the adverse effect of exposure to diesel exhaust. Mice exposed to both diesel exhaust and sensitization with ovalbumin had increased numbers of CD45R/B220-, CD3-, CD4-, and CD8positive cells. The authors conclude that exposure to diesel exhaust leads to increased release of interleukin-1 and increased production of macrophage inflammatory protein-1 and -2, and that the effects are abrogated by treatment with anti-CD4 or anti-CD8 antibodies. To clarify the effect of exposure to diesel exhaust on exacerbations of asthma, Hashimoto and coworkers (100) exposed guinea pigs to diesel exhaust or to air for 12 hours daily over eight weeks, with or without sensitization to ovalbumin. Compared with unexposed animals, animals exposed to diesel exhaust had increases in both the immediate and late airway responses to challenge with ovalbumin. During the immediate airway response, exposure to diesel exhaust increased the accumulation of mucus, increased the number of eosinophils, and increased the level of sialic acid in bronchial lavage fluid. During the late airway response, exposure to diesel exhaust produced eosinophilic infiltration of the bronchial epithelium and an increase in airway permeability. The authors conclude that exposure of guinea pigs to diesel exhaust exacerbates the airway responses to allergen. Environmental Tobacco Smoke
To assess the effect of passive smoking on airway inflammation, Yates and coworkers (101) placed 15 healthy subjects in a specially designed exposure chamber for one hour. Compared with a sham exposure, exhaled nitric oxide decreased by 24% after 15 minutes of exposure to environmental tobacco smoke and the level remained low over the subsequent 45 minutes. Seven subjects actively smoked seven cigarettes over one hour. Exhaled nitric oxide fell by 30% within 15 minutes and the level remained low for the next 45 minutes. The authors conclude that both passive and active smoking cause a rapid decrease in exhaled nitric oxide.
PULMONARY VASCULAR AND RELATED DISORDERS Pulmonary Hypertension
Secondary pulmonary hypertension. Nitric oxide is a potent vasodilator that has antiproliferative effects on smooth muscle, whereas endothelin-1 is a powerful vasoconstrictor that has mitogenic activity on vascular smooth muscle cells. Barbera and coworkers (102) studied lung tissue samples from 23 smokers free of COPD (FEV1 90% of predicted; PO2 88 mm Hg) and 9 nonsmokers. The smokers had 24% lower expression of endothelial nitric oxide synthase in their pulmonary artery endothelium as compared with the nonsmokers. The content of endothelial nitric oxide synthase protein was decreased by 27% in the smokers. Cell expression and protein content of endothelin-1 did not differ between the two groups. The authors conclude that heavy smokers have decreased expression of endothelial nitric oxide synthase in their pulmonary arteries. Infection with Histoplasma capsulatum can cause mediastinal fibrosis, which can entrap and occlude pulmonary arteries and veins and mainstream bronchi. Doyle and coworkers (103) inserted stents into the pulmonary arteries or veins of four such patients percutaneously. Four months to 4.5 years after placement, the patients experienced improvement in symptoms and exercise tolerance. In 23 patients with pulmonary hypertension associated with the Eisenmenger syndrome, Sandoval and coworkers (104) did a controlled trial of nocturnal oxygen therapy. The patients had congenital heart defects, with a mean pulmonary artery pressure of 88 mg Hg, PO2 of 44 mm Hg, and hematocrit
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of 62%. After two years, survival was 20.7 months in the oxygen-treated group and 20.8 months in the untreated group. Nocturnal oxygen therapy had no effect on exercise capacity, hematologic variables, or the quality of life. Survival in the patients with a PO2 of less than 40 mm Hg was 12 months, as compared with survival of at least 23 months in patients with a PO2 higher than 40 mm Hg. The authors conclude that nocturnal oxygen therapy does not influence the natural history of disease in patients with the Eisenmenger syndrome. Molecular and pathophysiologic mechanisms. Isoprostanes are lipid peroxidation products of arachidonic acid that reflect oxidative stress. In 25 patients with pulmonary hypertension, Cracowski and coworkers (105) found that the urinary level of isoprostaglandin F2 type III, an F2-isoprostane, was 2.3 times higher as compared with the level in 25 healthy subjects. In 14 patients, the urinary level of isoprostaglandin F2 type III was correlated with the change in mean pulmonary artery pressure (r 0.53) and with the change in pulmonary vascular resistance (r 0.53) in response to inhaled nitric oxide. The authors conclude that patients with pulmonary hypertension have evidence of increased oxidative stress, and that the level of isoprostaglandin F2 type III is inversely related to the degree of vascular reactivity. Flow-associated pulmonary hypertension leads to pulmonary plexiform arteriopathy, characterized by abnormal vasodilation and endothelial cell proliferation. To assess the expression of endothelial and inducible isoforms of nitric oxide synthase in patients with this lesion, Berger and coworkers (106) studied 34 patients with congenital heart disease and 4 healthy subjects. Of the patients, 18 had flow-associated pulmonary hypertension (that is, the ratio of pulmonary to systemic blood flow was greater than 1.2). Immunoreactivity for the two isoforms of nitric oxide synthase was present in both the normal and diseased pulmonary arteries. In the total patient group, inducible nitric oxide synthase was related to the ratio of pulmonary to systemic blood flow (r 0.39). No correlation was seen between either of the isoforms and the severity of the vascular lesions on histology. The authors conclude that patients at risk for advanced pulmonary plexogenic arteriopathy have enhanced expression of inducible nitric oxide synthase. The C-C chemokine, monocyte chemoattractant protein-1, is believed to contribute to the development of congestive heart failure. To determine whether increased pressure or shear stress in the pulmonary vasculature upregulates this chemokine, Kimura and coworkers (107) studied 14 patients with chronic thromboembolic pulmonary hypertension. The plasma level of monocyte chemoattractant protein-1 was correlated with pulmonary vascular resistance (r 0.69). The cytokines interleukin-1 and tumor necrosis factor- were not correlated with pulmonary hemodynamics. Six patients underwent thromboendarterectomy, and one patient experienced a 71% decrease in pulmonary vascular resistance and a 58% decrease in monocyte chemoattractant protein-1. The chemokine was detected in the endothelium, smooth muscle cells, and macrophages within the neointima of the pulmonary arteries. The authors conclude that patients with chronic thromboembolic pulmonary hypertension display upregulation of monocyte chemoattractant protein-1 in remodeled pulmonary arteries in proportion to the increase in pulmonary vascular resistance. Prostacyclin decreases pulmonary vascular resistance and the proliferation of vascular smooth muscle cells. To determine the role of prostacyclin in vascular remodeling, Hoshikawa and coworkers (108) studied knockout mice that do not have the prostacyclin receptor. Exposure to hypoxia (inspired PO2, 76 mm Hg) for three weeks caused a 29% increase in right-ven-
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tricular hypertrophy, a 38% increase in the thickening of the pulmonary arterial wall, and a 25% increase in the right-ventricular systolic pressure in the knockout mice as compared with the wild-type mice. The authors conclude that the absence of the prostacyclin receptor causes greater right-ventricular hypertrophy and more severe pulmonary hypertension and vascular remodeling after exposure to chronic hypoxia. To determine the molecular mechanisms whereby hypoxia stimulates the proliferation of pulmonary artery fibroblasts, Welsh and coworkers (109) studied pulmonary and aortic fibroblasts from normoxic and hypoxic rats. In rats exposed to chronic hypoxia, the mitogen-activated protein kinase, Erk, and the related stress-activated kinase, p38 mitogen-activated protein kinase, were constitutively activated in fibroblasts from the remodeled pulmonary artery but not in fibroblasts from the aorta. The enhanced proliferative capacities of these fibroblasts were sustained as compared with fibroblasts from the pulmonary artery of normoxic rats or with fibroblasts from the aorta of either normoxic or hypoxic rats. A specific inhibitor of p38 mitogen-activated protein kinase prevented the enhanced proliferative capacity of the pulmonary artery fibroblasts. An inhibitor of Erk mitogen-activated protein kinase did not prevent the enhancement. The authors conclude that enhanced activity of p38 mitogen-activated protein kinase provides a molecular mechanism to explain the proliferation of pulmonary artery fibroblasts required for remodeling of the pulmonary vasculature. Inhaled nitric oxide is commonly combined with high concentrations of oxygen and the combination can result in the generation of oxygen free radicals, such as superoxide. By scavenging superoxide, superoxide dismutase may increase the bioavailability of inhaled nitric oxide and simultaneously reduce peroxynitrite formation. Steinhorn and coworkers (110) induced persistent pulmonary hypertension in newborn lambs by prenatal ligation of the ductus arteriosus, and then studied the effects of superoxide dismutase alone or in combination with inhaled nitric oxide. In in vitro studies on pulmonary arteries taken from the lambs with pulmonary hypertension, pretreatment with superoxide dismutase enhanced the vascular relaxation induced by the nitric oxide donor, S-nitrosylacetylpenicillamine (SNAP). In in vivo studies, a single dose of recombinant human superoxide dismutase produced selective dilation of the pulmonary circulation. The pulmonary vascular effects of superoxide dismutase were enhanced by brief periods of inhaling nitric oxide (both at 50 and 80 ppm). The authors conclude that superoxide dismutase reduces pulmonary vascular resistance and enhances the vasodilator action of inhaled nitric oxide in a lamb model of persistent pulmonary hypertension. Ligating the common bile duct of rats produces cirrhosis and the manifestations of the hepatopulmonary syndrome seen in humans. Nunes and coworkers (111) studied the role of overproduction of nitric oxide in this rat model. Cirrhotic rats had an increased alveolar-arterial oxygen difference, increased cerebral uptake of intravenous 99mTc-labeled albumin (indicating intrapulmonary vascular dilatations), decreased pulmonary vascular resistance, and a lesser response of pulmonary vascular resistance to hypoxia and angiotensin II. The cirrhotic rats had increases in exhaled nitric oxide, total and calcium-independent activities of nitric oxide synthase in lung homogenates, and pulmonary expression of inducible and, to a lesser extent, endothelial nitric oxide synthase. The inducible nitric oxide synthase expression resulted from accumulation of intravascular macrophages. A six-week course of the nonspecific nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), normalized the alveolar-arterial oxygen
Year in Review
difference, brain radioactivity, pulmonary vascular resistance, reactivity to hypoxia and angiotensin II, exhaled nitric oxide, and activities of nitric oxide synthase. The authors conclude that manifestations of the hepatopulmonary syndrome in cirrhotic rats are related to increased production of nitric oxide secondary to increases in the expression and activities of inducible nitric oxide synthase within pulmonary intravascular macrophages. Sildenafil (Viagra), an inhibitor of phosphodiesterase V, causes vascular relaxation. Using the multiple inert gas elimination technique, Kleinsasser and coworkers (112) studied the effect of sildenafil on pulmonary hemodynamics and gas exchange in anesthetized pigs. Both 50 mg (usual human dose) and 100 mg of sildenafil caused PO2 to fall by about 14 mm Hg, although the dose of 25 mg did not cause hypoxemia. All of the doses produced an increase in intrapulmonary shunt (from 4 to 12%). Cardiac index increased by about 39% with 50 or 100 mg of sildenafil, and mean pulmonary artery pressure fell by 1 mm Hg. The authors conclude that usual dose of sildenafil causes significant increases in cardiac output and intrapulmonary shunt. An editorial commentary by Lodato (113) accompanies this article. Free hemoglobin increases hypoxic pulmonary vasoconstriction, possibly by scavenging nitric oxide. In isolated and perfused rabbit lungs, Deem and coworkers (114) studied the effects of various modifications of hemoglobin on nitric oxide flux and vascular tone. Perfusate containing either oxyhemoglobin or hemoglobin that was S-nitrosated caused an increase in pulmonary artery pressure during normoxia and hypoxia, accompanied by an 80% fall in exhaled nitric oxide. Hemoglobin that was chemically modified to prevent heme binding or oxidation, cyanomethemoglobin, had no effect on pulmonary artery pressure or on exhaled nitric oxide. When excess glutathione was added to a perfusate containing S-nitrosated hemoglobin, the level of S-nitrosated hemoglobin fell by 20–40% with a concomitant increase in methemoglobin; pulmonary vascular pressure or exhaled nitric oxide did not change. The authors conclude that free hemoglobin increases pulmonary vascular tone and augments hypoxic pulmonary vasoconstriction by reducing available nitric oxide, and that this effect is not prevented by S-nitrosation of hemoglobin. To determine the role of tissue angiotensin-converting enzyme in mediating changes in the pulmonary vasculature induced by hypoxia, van Suylen and coworkers (115) studied mice that are deficient in the gene for angiotensin-converting enzyme. Plasma from mice homozygous for this mutant allele has one-third the level of angiotensin-converting activity as compared with plasma from wild-type mice. On exposure to hypoxia for four weeks, the deficient mice developed the same increase in right-ventricular pressures and hypertrophy as compared with the wild-type mice. Pulmonary vascular remodeling was attenuated in the enzyme-deficient mice: the percentage of completely muscularized arterioles was less compared with the wild-type mice (29 versus 41%), and the percentage of partially muscularized arterioles was increased (48 versus 39%). The authors conclude that the absence of tissue angiotensin-converting enzyme does not prevent rightventricular hypertrophy that occurs with chronic hypoxia, but that it attenuates the associated pulmonary vascular remodeling. Strenuous exercise causes the flow of lung lymph to rapidly increase (7- to10-fold) and the protein content of lung lymph to rapidly decrease. For similar intravascular pressures, passive pulmonary hypertension produces slower changes in the flow and protein content of lymph. Koizumi and colleagues (116) studied sheep to determine whether hyperpnea might
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explain the different patterns. At rest, an increase in minute ventilation to that seen during exercise did not alter lymph flow or hemodynamics. Combining hyperpnea with left atrial hypertension (achieved by occluding the mitral valve with a balloon catheter) produced changes in the flow and protein content of lymph to the values that are usual during exercise. The authors conclude that hyperpnea causes clearance of interstitial fluid during exercise and that hyperpnea may be responsible for preventing pulmonary edema at the high microvascular pressures seen with exercise. Treatment. Nitric oxide, a potent vasodilator, is synthesized from the amino acid, L-arginine, by nitric oxide synthase. In 19 patients with precapillary hypertension (mean pulmonary artery pressure of at least 25 mm Hg), Nagaya and coworkers (117) randomized 10 patients to oral L-arginine and nine to placebo. Patients receiving L-arginine developed an increase in plasma L-citrulline, indicating increased production of nitric oxide. One week of treatment with L-arginine produced a 9% decrease in mean pulmonary artery pressure, a 16% decrease in pulmonary vascular resistance, and a 5% fall in mean systemic arterial pressure. On exercise testing, L-arginine produced an 8% increase in peak oxygen consumption and a 14% decrease in the slope of the ventilatory response to carbon dioxide. Placebo had no effect on hemodynamics or exercise capacity. The authors conclude that short-term oral administration of L-arginine decreased pulmonary vascular resistance and improved exercise capacity in patients with precapillary pulmonary hypertension. Iloprost, a prostacyclin analog, has been recommended in the treatment of pulmonary hypertension, but it requires multiple daily inhalations because of its short duration of action. In rabbits with pulmonary hypertension induced by U46619, a thromboxane mimetic, Schermuly and coworkers (118) assessed whether the combination of iloprost with a phosphodiesterase inhibitor that stabilizes the second messenger, cyclic AMP, would achieve greater pulmonary vasodilation. Subthreshold doses of nonspecific phosphodiesterase inhibitors, pentoxifylline and dipyridamole, and of a selective inhibitor of phosphodiesterase 3 and 4, tolafentrine, administered either by inhalation or intravenously, caused prolongation, but not augmentation, of the vasodilatory effect of iloprost. Administering higher doses of the phosphodiesterase inhibitors with iloprost as aerosols caused a twofold to fourfold increase in pulmonary vasodilation and a markedly prolonged duration of action. Gas exchange was maintained and systemic hypotension did not occur. The authors conclude that the combination of phosphodiesterase inhibitors with iloprost in aerosolized form increases the pulmonary vasodilator response without inducing systemic adverse effects. Rapamycin is a macrolide immunosuppressant that prevents the proliferation of endothelial cells mediated by vascular endothelial growth factor. Nishimura and coworkers (119) studied the effect of three regimens of an oral derivative of rapamycin in a rat model of pulmonary hypertension (injecting monocrotaline one week after pneumonectomy causes pulmonary hypertension within the subsequent month). The derivative of rapamycin attenuated the development of pulmonary hypertension, right ventricular hypertrophy, and neointimal formation in the pulmonary vasculature. When delayed for one week after injecting monocrotaline, the derivative of rapamycin was not effective in attenuating the neointimal formation or the pulmonary hypertension, although it did attenuate the right-ventricular hypertrophy. The authors conclude that an oral derivative of rapamycin attenuates the pulmonary hypertension that occurs in pneumonectomized rats after injection of monocrotaline.
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The avesicular zone is a thin part of the endothelial cell that separates the vascular and alveolar compartments. A glycoprotein, gp85, is an antigen that localizes to the avesicular zone and thus might be useful for delivering drugs to the luminal surface of the endothelium. To test this possibility, Murciano and coworkers (120) studied the uptake of a monoclonal antibody against gp85 in perfused rat lungs and in intact animals. Compared with a control of IgG, the antibody to gp85 accumulated 45 times more in the isolated lungs and 12 times more in the lungs after intravenous injection. Conjugation of the antibody with plasminogen activator, 125I-tPA, resulted in a 21-fold higher lung-to-blood ratio for the conjugate as compared with the conjugation of IgG with 125I-tPA. The authors conclude that an antibody directed to gp85, an antigen localized to the avesicular zone, permits the immunotargeting of drugs to the surface of pulmonary endothelium. Thromboembolic Disorders
Diagnostic studies. To determine the reliability of symptoms and perfusion scans in diagnosing pulmonary embolism in patients who already have a proximal deep vein thrombosis (proven by phlebography), Girard and coworkers (121) analyzed data on 400 patients included in the prospective PREPIC trial. All patients underwent lung scanning, pulmonary angiography, or both; angiography was recommended when the scan was nondiagnostic. The presence or absence of pulmonary embolism could be confirmed or refuted in 350 (88%) of the patients, and 197 (56%) had an embolus. Symptoms of pulmonary embolism had a sensitivity of 74% and a specificity of 67%. Among 37 patients with symptoms and a nondiagnostic scan, only 8 (22%) had an embolus on angiography. During anticoagulant therapy for the proximal deep venous thrombosis, 29 episodes of suspected embolism occurred in 27 patients. Comparison of a new scan with a baseline scan excluded pulmonary embolism in 21 of the episodes (72%). The authors conclude that about a quarter of patients who have a proven proximal deep vein thrombosis that develop symptoms of pulmonary embolism, either at baseline and during anticoagulant therapy, do not have a pulmonary embolus. Molecular and pathophysiologic mechanism. In a canine model of acute pulmonary thromboembolism induced by autologous blood clots, Lee and coworkers (122) investigated the role of endothelin-1 in the pathogenesis of the hemodynamic derangements. Embolization produced a twofold increase in the arterial and mixed venous plasma levels of endothelin-1. Messenger RNA expression of prepro-endothelin-1 was increased in the embolized lungs, and endothelin-1 preptide expression was especially increased in the muscular pulmonary arteries. Administration of ZD2574, an antagonist of the endothelinA receptor, produced decreases in pulmonary artery pressure and pulmonary vascular resistance, without causing systemic hypotension or deterioration in gas exchange. The authors conclude that local production of endothelin-1 contributes to the hemodynamic derangements of acute pulmonary embolism, and that an antagonist of the endothelinA receptor decreases the derangements. High Altitude
Busch and coworkers (123) asked “Is susceptibility to highaltitude pulmonary edema related to the release of nitric oxide in the respiratory tract?” On exposure to two hours of hypoxia, nine mountaineers who had previously documented high-altitude pulmonary edema developed a decrease in nitric oxide excretion from the lower respiratory tract (21 versus 28 nl per minute). Hypoxia did not alter exhaled nitric oxide in
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nine mountaineers known to be resistant to pulmonary edema. Hypoxia caused a greater increase in pulmonary artery systolic pressure, measured by echocardiography, in the susceptible mountaineers, and the change in pressure was related to the change in exhaled nitric oxide (r 0.49). Nasal excretion of nitric oxide did not differ between the groups, nor was it altered by hypoxia. The authors conclude that a decrease in the production of nitric oxide in the lower respiratory tract contributes to the increase in pulmonary vasoconstriction that is central to the development of high-altitude pulmonary edema. Sickle Cell Disease
Acute chest syndrome occurs in about 40% of patients with sickle cell disease and is associated with abnormalities in endothelial cell nitric oxide metabolism and oxidant status. In 19 patients with sickle cell disease, Klings and coworkers (124) found that the plasma level of F2 isoprostanes, which are formed from peroxidation of lipid-bound arachidonic acid and reflect oxidative stress, were nine times higher in patients with acute chest syndrome, as compared with 12 healthy subjects. The levels fell by 50 to 60% after an exchange transfusion, reaching a level similar to that at baseline. The levels during nonpulmonary vasocclusive crises did not differ from baseline. The authors conclude that patients with sickle cell disease have increased oxidative stress, as reflected by the level of F2 isoprostanes, during acute chest syndrome. Acute chest syndrome accounts for 25% of premature deaths in patients with sickle cell disease. Sullivan and coworkers (125) determined whether the level of exhaled nitric oxide is altered in patients with acute chest syndrome and whether the level is associated with a polymorphism of the gene for nitric oxide synthase I. The level of exhaled nitric oxide was lower in 13 patients with sickle cell disease who had experienced at least one episode of acute chest syndrome (10.4 ppb) as compared with seven patients with the disease but who had never had an episode of acute chest syndrome (23.4 ppb) or in six healthy subjects (30.4 ppb). Plasma levels of nitrite, nitrate, arginine, and citrulline did not differ among the groups. The number of AAT repeats in intron 20 of the gene for nitric oxide synthase I was inversely correlated with the level of exhaled nitric oxide (r 0.62). The authors conclude that exhaled nitric oxide is decreased in children with sickle cell disease who have experienced an episode of acute chest syndrome and that the decrease is associated with a genetic variant in the gene for nitric oxide synthase I. In a pulmonary perspective, Minter and Gladwin (126) discuss the need for increased recognition, treatment, and research on the pulmonary complications of sickle cell anemia.
LUNG TRANSPLANTATION Lung Preservation
The predominant mechanism underlying early graft failure is ischemia-reperfusion injury, and the quality of lung preservation is the key determinant of initial graft function. Thabut and coworkers (127) assessed the early postoperative outcome in 170 patients undergoing lung transplantation. Preservation of the donor lung involved a single flush of the pulmonary artery with a solution of either intracellular or extracellular composition (85 cases of each). Reimplantation edema occurred in 48% of the patients and survival at one month was 84%. Graft ischemia time was associated with an increased risk of edema (odds ratio, 1.3) and an increased one-month mortality (odds ratio, 1.3). After adjusting for graft ischemia time, multivariate analysis revealed a lower risk of edema with the Cambridge extracellular preservation solution (odds ratio,
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0.44) without an effect on survival. The authors conclude that use of a preservation solution that has an extracellular composition is associated with better lung preservation. If lungs from donors with nonbeating hearts could be used for lung transplantation, the procedure would become available to more patients. Hoffmann and coworkers (128) retrieved lungs from rats with nonbeating hearts at varying intervals after death, and determined whether increasing the level of adenosine 3 ,5 -cyclic monophosphate (cAMP) decreased ischemia-reperfusion injury. The lungs were reperfused with Earle’s solution, with or without a combination of isoproterenol (which activates adenylate cyclase to increase intracellular cAMP) and rolipram (a type IV phoshophodiesterase inhibitor that prevents the breakdown of cAMP). Two hours after ischemia, the drug combination markedly decreased capillary permeability, as reflected by the capillary filtration coefficient. The filtration coefficient was correlated with the levels of total adenine nucleotide in the lungs perfused with isoproterenol and rolipram (r 0.97) and also in the absence of the additives (r 0.89). The filtration coefficient was also correlated with the level of cAMP in the lungs perfused with the two additives (r 0.93). The authors conclude that agents that increase cAMP minimize the increase in capillary permeability that occurs in lungs obtained from donors with nonbeating hearts. Patient Selection
Because patients with idiopathic pulmonary fibrosis have the highest mortality among patients awaiting lung transplantation, Mogulkoc and coworkers (129) assessed the ability of baseline clinical assessment to predict mortality. Of 115 patients with usual interstitial pneumonitis who were followed for 26 months, 40% died. The areas under received operating characteristic (ROC) curves were 0.69 for FVC, 0.80 for diffusing capacity, 0.86 for a fibrosis score on high-resolution CT, and 0.91 for a model combining diffusing capacity and CT. The best discrimination was achieved by the combination of diffusing capacity (at a threshold of 39% of predicted) and a fibrosis score on CT (threshold of 2.25 on a scale of 0 to 5). The authors conclude that a model combining diffusing capacity and a score for fibrosis on CT may provide guidance for deciding the best time to refer patients with idiopathic pulmonary fibrosis for lung transplantation. Obliterative Bronchiolitis
Animal models. When the trachea of a rat is transplanted into the greater omentum of another rat, the transplanted trachea develops obstructive changes resembling obliterative bronchiolitis in humans. Tikkanen and coworkers (130) investigated the role of rat cytomegalovirus (CMV) in causing the obstructive lesions. Infection with CMV at the time of transplantation was used to mimic acute CMV infection, and infection with CMV two months before transplantations was used to mimic chronic CMV infection. Compared with uninfected animals receiving immunosuppression, both acute and chronic CMV infection increased the occlusion in transplanted tracheas. These alterations were linked to an increase in the immunoreactivity of interleukin-2 and tumor necrosis factor-, and a decrease in the expression of interleukin-10. Prophylaxis with either ganciclovir or hyperimmune serum completely prevented the adverse effects of acute CMV infection. Treatment with these drugs, singly or in combination, was of only slight benefit. Prophylaxis with ganciclovir also prevented the obliterative changes with chronic CMV infection. The decrease in tracheal occlusion achieved by the prophylactic agents was accompanied by a decrease in the number of ED1 macro-
phages and in cells staining for type 1 (Th1) helper T cell cytokines and tumor necrosis factor-. Immunosuppression with cyclosporine A caused upregulation of interleukin-10 production and a decrease in the tracheal occlusion resulting from acute CMV infection. The prophylactic agents had no effect on the amount of infectious CMV recovered. The authors conclude that CMV enhances chronic rejection of transplanted tracheas in mice through immune activation as compared with a direct effect of the virus on smooth muscle cells. Patients with obliterative bronchiolitis have increased deposition of type III collagen. To investigate genetic mechanisms involved, Alho and coworkers (131) studied a model of obliterative bronchiolitis caused by heterotopic bronchial transplantation in pigs. Obliterative lesions developed within 21 days. The fibroblast-like cells expressed messenger RNA predominantly for type III procollagen and for lesser amounts of type I procollagen. When sufficient immunosuppression was given to prevent the airway obliterative lesions, the allografts showed only a minor degree of procollagen gene activation. The authors conclude that fibrosis is accompanied by an increase in fibroblast-like cells expressing messenger RNA for type III procollagen in a porcine model of obliterative bronchiolitis. Cellular and molecular mechanisms. To determine factors that predispose to obliterative bronchiolitis, and especially the role of HLA mismatching, Schulman and coworkers (132) studied 152 consecutive patients followed for a mean of 33 months after lung transplantation. Obliterative bronchiolitis occurred in 56% of the patients by 3 years, with a median time to onset of 2.7 years. Risk factors for obliterative bronchiolitis were mild or moderate acute rejection (risk ratio, 2.2), mismatch at the HLA-A locus (risk ratio, 2.1), and cytomegalovirus pneumonitis (risk ratio, 1.9). Mismatches at the HLA-DR and HLA-B loci were not predictive. The risk of obliterative bronchiolitis at three years was 92% in patients with a HLA-A mismatch who experienced cytomegalovirus pneumonitis and acute rejection; the risk was 25% in patients free of those three problems. The authors conclude that mismatching between donors and recipients at the HLA-A locus increases the risk of obliterative bronchiolitis. Early detection. About 40% of patients with a lung transplant display bronchial hyperreactivity on exposure to methacholine, and this hyperreactivity has a 72% positive predictive value for detecting bronchiolitis obliterans. To determine the relative contribution of the proximal conducting airway and the distal small airways to the bronchial hyperreactivity, Van Muylem and coworkers (133) studied 15 heart-lung transplant recipients (7 of whom had bronchial hyperreactivity) and 17 nontransplanted subjects who had a history of atopy and bronchial hyperreactivity. Methacholine produced equivalent decreases in FEV1 in the 7 transplanted subjects with hyperreactivity and the 17 nontransplanted subjects: 29 versus 31%. On single-breath washouts, methacholine induced equivalent increases in the slope of the alveolar plateau for SF6 (178%) and helium (285%) in the nontransplanted subjects, whereas the increase in slope for helium (549%) was greater than that for SF6 (178%) in the transplanted subjects. (The slope for helium is more sensitive to the development of inhomogeneities in the terminal bronchioles.) The authors conclude that bronchial hyperreactivity arises from involvement of the small airways in transplanted subjects but not in nontransplanted subjects, and that the measurement may prove useful in monitoring patients at risk of bronchiolitis obliterans. Rejection
Early rejection after lung transplantation is recognized histologically as lymphocytic bronchiolitis. To determine whether
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exhaled nitric oxide would serve as a marker of lymphocytic bronchiolitis and to determine whether an inhaled glucocorticoid would control the bronchiolitis, De Soyza and coworkers (134) studied 120 recipients of a lung transplant. In 14 patients who developed isolated lymphocytic bronchiolitis, FEV1 fell from 2.28 liters at baseline to 1.91 liters and the concentration of exhaled nitric oxide rose from 4.3 ppb at baseline to 10.9 ppb. Inhaled budesonide (800 g twice daily) caused FEV1 to rise to 2.32 liters and exhaled nitric oxide to fall to 4.9 ppb. Seven patients developed acute vascular rejection (with and without lymphocytic bronchiolitis) and they were treated with oral glucocorticoids. These patients showed no change in exhaled nitric oxide at diagnosis or after treatment. The authors conclude that serial measurements of exhaled nitric oxide provide a useful noninvasive method of identifying airway inflammation in recipients of a lung transplant and that inhaled glucocorticoids help in controlling the inflammation. Because of controversy concerning the value of repeat transbronchial lung biopsy, Aboyoun and coworkers (135) analyzed data in 99 patients who showed mild rejection (grade A2) on an initial biopsy. Over a period of 5 years, 173 repeat biopsies were performed within 45 days of an initial biopsy. Rejection was associated with cytomegalovirus (CMV) in 16 patients (9%) and a mild lymphocytic bronchitis or bronchiolitis in the remaining patients (grade B2 or higher). Persistent rejection (of at least grade A2) was found in 26% of the follow-up biopsies. A new lymphocytic bronchitis or bronchiolitis (grade B2 or higher) developed in 6% of the follow-up biopsies. Rejection of grade B2 or higher was associated with rejection of grade A2 or higher in 3% of the biopsies and with CMV pneumonitis in half of these cases. A new diagnosis of CMV pneumonitis was made in 19% of the biopsies. Bronchiolitis obliterans syndrome occurred at a median of 1.3 years in 47% of 32 patients with persistent rejection (grade A2 or higher) and at a median of 2 years in 53% of 38 patients without rejection or CMV pneumonitis. The authors conclude that follow-up transbronchial biopsies after a proven episode of rejection provide useful information for managing lung transplant patients. Because early rejection has features resembling the acute respiratory distress syndrome, Fisher and coworkers (136) determined whether interleukin-8, a neutrophil chemokine linked with the acute respiratory distress syndrome (ARDS), might predispose to early rejection. Among 26 patients undergoing lung transplantation, nine developed acute rejection and six died after a median of 24 days. The level of interleukin-8 in the lungs being donated was related to the percentage of neutrophils in donor lavage fluid (r 0.42) and to impaired oxygenation in recipients of the donated lungs (r 0.51). The level of interleukin-8 was about five times higher in lungs donated to patients who developed early dysfunction as compared with the lungs donated to patients who tolerated transplantation. The authors conclude that donor lungs containing a high level of interleukin-8 are associated with a poor prognosis after they are transplanted. Immunology and Biochemistry
Because unopposed activity of neutrophil elastase may injure the lung, Meyer and coworkers (137) analyzed 2,137 bronchoalveolar lavage specimens from 329 lung transplant recipients. Unopposed activity of neutrophil elastase was present in 8% of all lavage specimens, and 22% of the recipients had unopposed activity in at least one specimen. The highest incidence of unopposed elastase activity (59%) was in 17 recipients who had 1-antitrypsin deficiency. Most episodes of unopposed activity of neutrophil elastase occurred in the setting of bacterial
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infection. Levels of 1-antiprotease were elevated in the early post-transplant period, and the levels increased considerably in patients with 1-antitrypsin deficiency when they developed an infection or rejection. The authors conclude that unopposed activity of neutrophil elastase occurs in recipients of lung transplantation, usually in association with a bacterial infection and irrespective of the presence or absence of 1-antitrypsin deficiency. In Cystic Fibrosis
Patients with cystic fibrosis who are infected with Burkholderia cepacia complex have a high mortality, and are excluded from lung transplantation at some centers. To determine the influence of genomovar type on outcome, Aris and coworkers (138) studied 121 patients with cystic fibrosis undergoing lung transplantation. Three patients were infected with B. cepacia complex after surgery and all were treated successfully. Six-month mortality was 33% among 21 patients infected pre-operatively, as compared with a mortality of 12% in patients without infection. The increase in mortality was completely attributable to genomovar III of the B. cepacia complex, and 5 of the 12 patients with this genomovar died. The authors conclude that more than 40% of patients with cystic fibrosis who are infected with genomovar III of the Burkholderia cepacia complex before transplantation die in the early post-operative period. Because many centers have refused to offer lung transplantation to patients infected with Burkholderia cepacia, Chaparro and coworkers (139) analyzed their experience. Of 56 transplant procedures in 53 recipients, 28 (50%) had B. cepacia isolated before the surgery and 25 remained positive after surgery. One-year survival was 67% for patients with B. cepacia and 92% for those without it. The authors conclude that B. cepacia infection in patients with cystic fibrosis produces an increase in early mortality.
PLEURAL DISORDERS Diagnostic Techniques
Mucins are proteins found on the surface of epithelial cells, and the aberrant expression of mucin genes is associated with advanced cancer. To determine the accuracy of three gene loci of mucins in the detection of exfoliated cancer cells, Yu and coworkers (140) studied pleural fluid from 54 patients who had malignant pleural effusions associated with positive cytology, 35 patients who had a benign pleural exudate, and 23 patients who had cancer and a pleural effusion with negative cytology. For MUC1 (which is widely expressed in epithelial cells), a threshold value of 0.126 had a sensitivity of 65% and a specificity of 96%. For MUC5AC (which is expressed mainly in airway and gastric epithelial cells), a threshold value of 0.028 had a sensitivity of 72% and a specificity of 96%. For combined evaluation with both MUC1 and MUC5AC, sensitivity was 86% and specificity was 92%. The MUC2 gene (which is mainly expressed in intestinal epithelial cells) did not discriminate between malignant and benign effusions. The authors conclude that measurements of the MUC1 and MUC5AC genes in pleural fluid are helpful in diagnosing malignant effusions. Pleurodesis
Transforming growth factor-2, a profibrotic cytokine, produces effective pleurodesis in rabbits. To determine the temporal evolution of the pleurodesis, Lee and coworkers (141) compared the effects of injecting transforming growth factor-2 or talc slurry into the pleural space of rabbits. After seven days, the growth factor produced more effective pleurodesis
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as compared with talc: 4.2 times more collagen, 1.7 times more pleural fibrosis, and 3.4 times more pleural thickness. The degree of pleural inflammation did not differ. The authors conclude that intrapleural administration of transforming growth factor-2 produces more rapid pleurodesis, with greater deposition of collagen, as compared with talc.
LUNG CANCER Diagnosis
Premalignant and malignant tissue that appears normal on conventional bronchoscopy displays less fluorescence as compared with normal tissue on fluorescence endoscopy. Using fluorescence endoscopy to study the natural history of precancerous bronchial lesions, Bota and coworkers (142) followed the histologic changes in 416 bronchial intraepithelial lesions in 104 high-risk subjects. Over a two-year period, 17% of 36 normal areas of epithelium became dysplastic, 31% of 152 areas of metaplasia evolved to a low-grade dysplasia, 4% of 169 low-grade epithelial lesions progressed to a persistent severe dysplasia, 37% of 27 severe dysplastic lesions persisted or progressed, and 88% of carcinomas in situ persisted or progressed. Progression of the low-grade epithelial lesions during the study occurred only in patients with at least a high-grade lesion in another site at baseline (6% of 147 lesions). The authors conclude that the vast majority of low-grade precancerous lesions remain stable, and that follow-up surveillance can be limited to every two years, whereas carcinoma in situ should be treated immediately. The role of low-dose spiral computed tomography in screening for lung cancer is debated by Jett (143) and Patz and Goodman (144), with rebuttals from each (145, 146). Molecular Mechanisms
In a report from an NHLBI/NCI Workshop, Idell and colleagues (147) discuss fibrin turnover in lung inflammation and neoplasia. References 1. McCloskey SC, Patel BD, Hinchliffe SJ, Reid ED, Wareham NJ, Lomas DA. Siblings of patients with severe chronic obstructive pulmonary disease have a significant risk of airflow obstruction. Am J Respir Crit Care Med 2001;164:1419–1424. 2. Sakao S, Tatsumi K, Igari H, Shino Y, Shirasawa H, Kuriyama T. Association of tumor necrosis factor gene promoter polymorphism with the presence of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:420–422. 3. Sandford AJ, Chagani T, Weir TD, Connett JE, Anthonisen NR, Pare PD. Susceptibility genes for rapid decline of lung function in the lung health study. Am J Respir Crit Care Med 2001;163:469–473. 4. Feenstra TL, van Genugten ML, Hoogenveen RT, Wouters EF, Rutten-van Molken MP. The impact of aging and smoking on the future burden of chronic obstructive pulmonary disease: a model analysis in the Netherlands. Am J Respir Crit Care Med 2001;164:590–596. 5. Garcia-Aymerich J, Monso E, Marrades RM, Escarrabill J, Felez MA, Sunyer J, Anto JM. Risk factors for hospitalization for a chronic obstructive pulmonary disease exacerbation: EFRAM study. Am J Respir Crit Care Med 2001;164:1002–1007. 6. Dahl M, Tybjaerg-Hansen A, Vestbo J, Lange P, Nordestgaard BG. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1008–1011. 7. Dowson LJ, Newall C, Guest PJ, Hill SL, Stockley RA. Exercise capacity predicts health status in 1-antitrypsin deficiency. Am J Respir Crit Care Med 2001;163:936–941. 8. Seemungal T, Harper-Owen R, Bhowmik A, Moric I, Sanderson G, Message S, Maccallum P, Meade TW, Jeffries DJ, Johnston SL, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1618–1623.
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52. Macgowan NA, Evans KG, Road JD, Reid WD. Diaphragm injury in individuals with airflow obstruction. Am J Respir Crit Care Med 2001;163:1654–1659. 53. Poole DC, Kindig CA, Behnke BJ. Effects of emphysema on diaphragm microvascular oxygen pressure. Am J Respir Crit Care Med 2001;163:1081–1086. 54. Engelen MP, Wouters EF, Deutz NE, Does JD, Schols AM. Effects of exercise on amino acid metabolism in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:859–864. 55. Mador MJ, Kufel TJ, Pineda LA, Steinwald A, Aggarwal A, Upadhyay AM, Khan MA. Effect of pulmonary rehabilitation on quadriceps fatiguability during exercise. Am J Respir Crit Care Med 2001;163: 930–935. 56. Debigare R, Cote CH, Maltais F. Peripheral muscle wasting in chronic obstructive pulmonary disease: clinical relevance and mechanisms. Am J Respir Crit Care Med 2001;164:1712–1717. 57. Takabatake N, Nakamura H, Minamihaba O, Inage M, Inoue S, Kagaya S, Yamaki M, Tomoike H. A novel pathophysiologic phenomenon in cachexic patients with chronic obstructive pulmonary disease: the relationship between the circadian rhythm of circulating leptin and the very low-frequency component of heart rate variability. Am J Respir Crit Care Med 2001;163:1314–1319. 58. Goldberger AL. Heartbeats, hormones, and health: is variability the spice of life? Am J Respir Crit Care Med 2001;163:1289–1290. 59. Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, Shale DJ. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1414–1418. 60. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO global Initiative for chronic obstructive lung disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163:1256–1276. 61. Gross NJ. The GOLD standard for chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:1047–1048. 62. Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne AM, Thomson MH, Till D, Della CG. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:778–784. 63. Rennard SI, Anderson W. ZuWallack R, Broughton J, Bailey W, Friedman M, Wisniewski M, Rickard K. Use of a long-acting inhaled 2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163: 1087–1092. 64. Cook D, Guyatt G, Wong E, Goldstein R, Bedard M, Austin P, Ramsdale H, Jaeschke R, Sears M. Regular versus as-needed short-acting inhaled -agonist therapy for chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:85–90. 65. Sin DD, Tu JV. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:580–584. 66. Vestbo J. Another piece of the inhaled corticosteroids-in-COPD puzzle. Am J Respir Crit Care Med 2001;164:514–515. 67. van den Boom G, Rutten-van Molken MP, Molema J, Tirimanna PR, van Weel C, van Schayck CP. The cost effectiveness of early treatment with fluticasone propionate 250 g twice a day in subjects with obstructive airway disease: results of the DIMCA program. Am J Respir Crit Care Med 2001;164:2057–2066. 68. O’Brien A, Russo-Magno P, Karki A, Hiranniramol S, Hardin M, Kaszuba M, Sherman C, Rounds S. Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction. Am J Respir Crit Care Med 2001;164:365–371. 69. Spencer S, Calverley PM, Sherwood BP, Jones PW. Health status deterioration in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:122–128. 70. Britton J, Jarvis M, McNeill A, Bates C, Cuthbertson L, Godfrey C. Treating nicotine addiction: not a medical problem? Am J Respir Crit Care Med 2001;164:13–15. 71. Nakano Y, Coxson HO, Bosan S, Rogers RM, Sciurba FC, Keenan RJ, Walley KR, Pare PD, Hogg JC. Core to rind distribution of severe emphysema predicts outcome of lung volume reduction surgery. Am J Respir Crit Care Med 2001;164:2195–2199. 72. Gevenois P, Estenne M. Can computed tomography predict functional benefit from lung volume reduction surgery for emphysema? Am J Respir Crit Care Med 2001;164:2137–2138. 73. Cassart M, Hamacher J, Verbandt Y, Wildermuth S, Ritscher D, Russi EW, de Francquen P, Cappello M, Weder W, Estenne M. Effects of
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