Year in Review Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2000 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 Genetics (2) Alpha1-Antrypsin Deficiency (2) Risk Factors (6) Cellular and Anatomical Abnormalities (2) Lung Inflammation (4) Exhaled Markers Nitric Oxide (3) Other Markers (2) Airway Narrowing (2) Pulmonary Vasculature (3) Control of Breathing and Exercise (2) Respiratory Muscles (6) Peripheral Muscles (5) Health Care Delivery (1) Drug Therapy Beta Agonists (1) Muscarinic Antagonists (2) Glucocorticoids (5) Smoking Cessation (1) Other Therapies Lung Volume Reduction Surgery (2) Alpha1-Antitrypsin Replacement Therapy (2) Rehabilitation (3) Air Pollution General (3) Ozone (5) Diesel Exhaust (4) Statement (1) Pulmonary Hypertension Primary Pulmonary Hypertension (6) Pathology of Pulmonary Hypertension (2) Thromboembolic Disorders Diagnostic Studies (5) Pathophysiology (1) Treatment (2) High Altitude (3) Lung Transplantation Lung Preservation (4)
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 164. pp 1789–1804, 2001 DOI: 10.1164/rccm2108126 Internet address: www.atsjournals.org
Obliterative Bronchiolitis Animal Models (3) Cellular and Molecular Mechanisms (3) Early Detection (4) Quality of Life (1) Lymphoproliferative Disease (1) In Children (1) In Cystic Fibrosis (1) Pleural Disorders Physiology/Pathophysiology (2) Diagnostic Techniques (1) Pleurodesis (6) Lung Cancer Risk Factors (4) Diagnosis (3) Studies of Molecular Mechanisms (2) References
CHRONIC OBSTRUCTIVE PULMONARY DISEASE Genetics
As part of a study of the genetics of chronic obstructive pulmonary disease (COPD), Silverman and coworkers (1) assembled a group of 84 probands (index cases) with severe, earlyonset COPD that was not secondary to 1-antitrypsin deficiency. Of the 348 first-degree relatives of these probands, women accounted for 71%. Among first-degree relatives who were smokers or exsmokers, women had a lower FEV1/FVC ratio (forced expired volume in 1 second/forced vital capacity) than men (81 versus 87%) and a larger response to bronchodilator (8 versus 4%). Multivariate analysis revealed that female firstdegree relatives who were smokers or exsmokers had a greater risk of having an FEV1 of less than 80% predicted (odds ratio [OR] 1.9), FEV1 of less than 40% predicted (OR 3.6), and a bronchodilator response exceeding 10% of baseline FEV1 (OR 4.7). The authors conclude that women are at greater risk of developing COPD than men. The gene for angiotensin converting enzyme contains a polymorphism based on the presence (insertion, I) or absence (deletion, D) within an intron of a 287-bp nonsense DNA domain, resulting in three genotypes: DD homozygotes, II homozygotes, and DI heterozygotes. (A polymorphism is an allele with a frequency in a population of at least 1%.) In 19 patients with COPD, Kanazawa and coworkers (2) found seven patients with the II genotype, six with the ID genotype, and six with the DD genotype. After an incremental exercise test, patients with the DD genotype had a higher mean pulmonary artery pressure than patients with the II genotype (56 and 43 mm Hg), and pulmonary vascular resistance was likewise increased. While breathing oxygen, mean pulmonary artery pressure in
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patients with the DD genotype was higher (52 mm Hg) than in patients with the ID genotype (41 mm Hg) or II genotype (38 mm Hg); pulmonary vascular resistance followed the same pattern. The authors conclude that deletion/insertion polymorphism in the angiotensin converting enzyme gene may be associated with pulmonary hypertension evoked by exercise challenge in patients with COPD. Alpha1-Antrypsin Deficiency
To determine the relationship between exposure to toxins at work and pulmonary function in patients with PiZ 1-antitrypsin deficiency, Mayer and coworkers (3) analyzed data from 128 patients. Subjects exposed to high levels of mineral dust were 4.7 times more likely to complain of chronic cough and 2.7 times more likely to have left a job because of dyspnea than individuals without such exposure. Subjects with high dust exposure had a lower FEV1 than unexposed subjects (31 and 40% predicted). The authors conclude that occupational exposures are independently associated with respiratory symptoms and airflow limitation in individuals with severe 1-antitrypsin deficiency. Because of controversy regarding the risk of COPD in people who are heterozygous for 1-antitrypsin deficiency, Seersholm and coworkers (4) did an 18-year followup study of 1,551 subjects with the PiMZ phenotype. Each PiMZ subject was matched with ten controls from the Danish Population Registry. A discharge diagnosis of COPD was listed in 47 PiMZ subjects, yielding a relative risk of 2.2 when compared with the controls. The increased risk was significant only in the age group of 40–79 years, and only in subjects who were first-degree relatives of PiZ index cases. The authors conclude that PiMZ heterozygotes for 1-antitrypsin deficiency are at increased risk of hospital admission for COPD only if they are first-degree relatives of a PiZ index case. Risk Factors
To define the frequency and etiology of viral infections of the respiratory tract, Greenberg and coworkers (5) did a longitudinal cohort study of older patients with COPD. Of observed acute respiratory illnesses over a 26-month period, viral infections caused 27% of illnesses in patients with COPD and 44% in a control group. About 90% of the patients had received influenza vaccine, and the most commonly identified viruses were picornaviruses, parainfluenza viruses, and corona viruses. Viruses were documented in 23% of hospitalizations (45% in winter months). The authors conclude that viral infections of the respiratory tract have a major influence on use of health care resources by patients with COPD. To define the time course and recovery of exacerbations of COPD, Seemungal and coworkers (6) did a 2.5-year follow up study of 101 patients with moderate-to-severe COPD (FEV1 42% predicted), over which time the patients experienced 504 exacerbations. Patients recorded on diary cards worsening dyspnea, sore throat, cough, and features of the common cold before the onset of an exacerbation, but no change in lung function. Median recovery times were six days for peak expiratory flow rate (PEFR) and seven days for symptoms. Recovery of PEFR was incomplete in 25% of exacerbations at 35 days and in 7% at 91 days; dyspnea and colds at the onset of an exacerbation predicted delayed recovery. The authors conclude that recovery is delayed and incomplete in many exacerbations of COPD, and although symptoms do not correspond to lung function they do predict an exacerbation and a delayed recovery. Persistent infection with Chlamydia pneumoniae is linked to chronic diseases, but its importance in COPD is less well
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defined. Wu and coworkers (7) obtained lung tissue at thoracotomy from 16 patients with COPD (FEV1 64% predicted) and 21 smokers with normal lung function. All samples contained C. pneumoniae, but patients with COPD had 56% more positive cells per field. Macrophages stained positive in 54% of the patients with COPD and 29% of the controls. The authors conclude that persistent infection with C. pneumoniae is common, and immunostaining is increased in patients with COPD. Infection with Chlamydia pneumoniae has been linked to ischemic heart disease, but its importance as a risk factor for COPD has not been examined prospectively. In 1,773 men (aged 45–59 years), Strachan and coworkers (8) found IgG antibodies to C. pneumoniae in 642 men (36%), and 362 of them also had IgA antibodies. No significant association was found between either IgG or IgA titer and outcome measures, including FEV1 or death from respiratory disease. The authors conclude that chronic infection with C. pneumoniae is not a risk factor for progressive airflow obstruction. Because antioxidants, such as vitamin E and carotenoids, may prevent loss of lung function, Grievink and coworkers (9) studied the association in 528 individuals aged 65 to 85 years. Subjects in the fifth quintile of serum -carotene had a 257 ml higher FEV1 than subjects in the first quintile. Positive trends were found between -carotene, -carotene, lycopene and FEV1. The authors conclude that carotenoids are positively associated with lung function in the elderly. To evaluate the ability of high-resolution computed tomography to detect structural changes to the lungs over time in smokers, Soejima and coworkers (10) performed scans every year for five years in 36 never smokers, 35 current smokers, and 12 exsmokers. The only change in the never smokers was an increase in the relative area of low attenuation (less than 912 Hounsfield units) in the middle and lower lung fields, indicating that aging increases airspace abnormalities. Current smokers showed increased attenuation in the upper zones. Exsmokers showed increases in attenuation in all lung fields. The annual increase in attenuation of the upper zone differed little between current and exsmokers, and the changes were greater than in never smokers. The authors conclude that the worsening airspace abnormality in the upper lung zones of smokers does not slow down with cessation of smoking. Cellular and Anatomical Abnormalities
Saetta and coworkers (11) quantified the number of goblet cells and inflammatory cells in the epithelium of peripheral airways in ten smokers with symptoms of chronic bronchitis and COPD, six smokers without symptoms, and nine nonsmoking controls. The patients with chronic bronchitis and COPD had increased number of goblet cells, total leukocytes, CD45+ cells, macrophages, and CD8+ cells in the epithelium of peripheral airways. The authors conclude that smokers with symptoms of both chronic bronchitis and chronic airflow limitation have an increased number of goblet cells and inflammatory cells in the epithelium of the peripheral airways. Tachykinins are part of a family of neuropeptides. Because the precise location of the neurokinin-1 and -2 receptors in human airways is not known, Mapp and coworkers (12) examined lobar bronchi from 26 patients undergoing lung resection. Both neurokinin-1 and -2 receptors were found in bronchial glands, bronchial vessels, and bronchial smooth muscle, but were not seen in epithelium. Neurokinin-1 receptors were occasionally seen in nerves, and neurokinin-2 receptors were seen in lymphocytes, macrophages, and mast cells. The distribution of the neurokinin receptors did not differ among patients with COPD, smokers, and healthy subjects. The authors
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conclude that neurokinin-1 and -2 receptors are found in the central airways, and their expression does not differ among healthy subjects, smokers, patients with chronic bronchitis, and patients with COPD. Lung Inflammation
An imbalance between proteases and antiproteases is thought to be important in causing emphysema. In bronchoalveolar fluid of 11 smokers and 11 nonsmokers, Lim and coworkers (13) found that airway macrophages of the smokers released greater amounts of matrix metalloprotease-9, a protease, and tissue inhibitor of metalloprotease-1, an antiprotease, at baseline and in response to interleukin-1 and lipopolysaccharide. Macrophages from smokers also produced more tumor necrosis factor- and interleukin-10; interleukin-10 increased release of tissue inhibitor of metalloprotease-1 without modifying release of metalloprotease-9, with the result that the elastase-to-inhibitor ratio fell. The authors conclude that the airway macrophages of smokers release greater amounts of proteases and antiproteases and that this release can be regulated by endogenous interleukin-10. Because activity of cytochrome oxidase, the terminal enzyme of the mitochondrial electron chain, is upregulated in skeletal muscle of patients with COPD, Sauleda and coworkers (14) determined whether the enzyme was elevated in other cell types and other inflammatory diseases. In the circulating lymphocytes of 17 patients with COPD, the activity of cytochrome oxidase was 50% higher than in normal controls, and activity was negatively correlated with airflow obstruction (r = 0.53). Activity was increased six fold in patients with asthma, and by 47% in patients with chronic arthritis. The authors conclude that cytochrome oxidase is involved in COPD and other inflammatory disorders. Because tumor necrosis factor-, a multifunctional cytokine, is increased in weight-losing patients with COPD and because hypoxia enhances production of this cytokine in vitro, Takabatake and coworkers (15) studied factors influencing the tumor necrosis factor- system in vivo in patients with COPD. Compared with healthy controls, the patients had increased levels of serum tumor necrosis factor- and of soluble tumor necrosis factor receptors 55 and 75. Arterial PO2 was inversely correlated with tumor necrosis factor- (r 0.43), soluble tumor necrosis factor receptor 55 (r 0.59), and soluble receptor 75 (r 0.57). Body fat was also correlated with the levels of soluble receptors. The authors conclude that hypoxemia in patients with COPD is associated with activating the tumor necrosis factor- system in vivo, which may contribute to weight loss. In patients chronically infected with Haemophilus influenzae, Bresser and coworkers (16) compared airway inflammation in 10 patients who also had COPD and 10 patients with chronic bronchitis without airway obstruction. The patients with COPD had higher levels of myeloperoxidase and tumor necrosis factor- in expectored sputum. The two groups had similar levels of plasma protein leakage (estimated as the sputum-to-serum ratio of protein), interleukin-8, secretory IgA, and lactoferrin. Tumor necrosis factor- was not increased in the sputum of nine noninfected patients with COPD. The authors conclude that the increase of tumor necrosis factor- in patients chronically infected with Haemophilus influenzae may contribute to the development of airway obstruction in COPD. Exhaled Markers
Nitric oxide. To determine whether production of nitric oxide is related to the development of cor pulmonale, Clini and co-
workers (17) measured exhaled nitric oxide in 34 patients with stable COPD. Nitric oxide was correlated with systolic pulmonary artery pressure (r 0.51) and right ventricular wall dimensions on echocardiography (r 0.41), but not with any measurement of lung function. Levels were lower in patients with systolic pulmonary artery pressures exceeding 35 mm Hg than in those with normal pressures. The authors conclude that exhaled nitric oxide is inversely proportional to the development of cor pulmonale in patients with COPD. Because oxidative stress may be involved in COPD, Ichinose and coworkers (18) quantified the production of reactive nitrogen species in 10 patients with COPD, 11 patients with asthma, and 10 healthy subjects. Inducible nitric oxide synthase was increased equally in airway inflammatory cells of patients with COPD and asthma. Only patients with asthma had an increase in exhaled nitric oxide. Obvious nitrotyrosine immunoreactivity was found in the inflammatory cells of patients with COPD and to a lesser extent in patients with asthma, but not in the controls; the level was negatively correlated with FEV1 in the patients with COPD. The authors conclude that nitric oxide is produced in the airway of patients with COPD, presumably by inducible nitric oxide synthase, but is consumed by its reaction with superoxide anion and/or peroxidase-dependent mechanisms. To determine the relationship between the response to a -agonist and markers of airway inflammation, Papi and coworkers (19) studied 20 nonatopic patients with COPD. Albuterol (200 g) produced an increase in FEV1 of more than 200 ml but of less than 12% in 10 patients and these were termed partial responders; the other 10 patients had no reversibility. Partial responders had a higher level of exhaled nitric oxide than the nonresponders (24 and 9 ppb), and a higher level of sputum eosinophils than healthy subjects. The authors conclude that patients with COPD displaying even a partial response to a -agonist have more airway inflammation than nonresponders. Other markers. Because ethane is a marker of lipid peroxidation and an index of oxidative stress, Paredi and coworkers (20) measured its concentration in the exhalates of 12 patients with COPD. Patients exhaled 3.1 times more ethane than the control subjects, and it was correlated with FEV1 (r 0.67). Patients also exhaled 2.1 times more carbon monoxide and 1.8 times more nitric oxide than the controls. Patients receiving glucocorticoids had lower levels of ethane, whereas carbon monoxide and nitric oxide were not different from controls. The authors conclude that exhaled ethane may complement nitric oxide and carbon monoxide in monitoring oxidative stress in patients with COPD. Because most studies of oxidative stress in COPD have involved in vitro invasive techniques or systemic measurements, Montuschi and coworkers (21) measured 8-isoprostone in exhaled breath condensate to quantify oxidative stress in the lung. 8-isoprostane is a prostaglandin-F2 isomer that is formed in vivo by free radical-catalyzed peroxidation of arachidonic acid. In 15 current smokers with COPD and 25 ex-smokers with COPD, the concentrations were similar (45 and 40 pg/ml), and were 1.8 times higher than in 12 healthy smokers and 4 times higher than in 10 healthy nonsmokers. Smoking caused a 50% acute increase in 8-isoprostane. The authors conclude that free radical production is increased in patients with COPD and that smoking causes an increase in oxidative stress. Airway Narrowing
To determine the relationship between pulmonary function in patients with COPD and the mechanical properties of their isolated peripheral airways, Opazo Saez and coworkers (22)
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studied 15 patients undergoing lung resection. Maximal isometric force of smooth muscle was correlated with FEV1 (r 0.58) and FEV1/FVC (r 0.72); isotonic shortening was not related to lung function. Maximal isometric force, stress, and normalized airway smooth muscle were greater in patients than in the controls, whereas isotonic shortening was equivalent. The authors conclude that airway smooth muscle of patients with COPD has increased ability to generate force. Low attenuation scores on computed tomography represent emphysema, but tomography has not been used to quantify airway abnormalities in patients with COPD. In 114 smokers (94 had COPD), Nakano and coworkers (23) used high-resolution computed tomography to quantify emphysema and thinsection helical (spiral) tomography to quantify airway dimensions. A decrease in FEV1 was associated with increased area of the airway wall and an increase in low attenuation areas; combining the tomographic findings improved the prediction of pulmonary function abnormalities. The authors conclude that measurements of airway dimensions and attenuation on computed tomography provide complementary information on the lung. Pulmonary Vasculature
In 34 patients with stable COPD and no history of heart disease, Boussuges and coworkers (24) used echocardiography and Doppler ultrasound to assess cardiac function. The contribution of atrial contraction to filling of the left ventricle was increased in the patients, whereas left atrial filling during ventricular systole was decreased. Systolic function of the left ventricle was normal, and left atrial pressure was below 15 cm H2O. The authors conclude that a decrease in left ventricular preload contributes to tachycardia in patients with COPD. To determine the distribution of pulmonary transit time throughout the lung, Capderou and coworkers (25) did angiocardioscintigraphy in 11 patients with COPD, 7 patients with restrictive lung disease with comparable blood gases, 11 patients with normal lungs having a cardiac index equivalent to the patients with COPD, and 11 healthy control subjects. Descriptors of the distribution, including kurtosis, dispersion and mean transit time, differed among the groups. After normalization of cardiac output, the distribution in the patients with COPD remained different from the restrictive and low cardiac output groups. The authors conclude that cardiac output or abnormal blood gases could not explain changes in the distribution of pulmonary blood flow in patients with COPD. Fishman (26) recalls a study of the effect of acute hypoxia on the pulmonary circulation in patients with COPD. Control of Breathing and Exercise
To determine the mechanism of oxygen-induced hypercapnia, Robinson and coworkers (27) employed the multiple inert gas elimination technique in 22 patients with COPD. After breathing 100% oxygen for 20 minutes, 12 patients developed an increase in PCO2 of at least 3 torr (mean 8.3 torr) and 10 patients a decrease of 1 torr. Minute ventilation fell by 1.8 liters per minute in the retainers, but did not change in the nonretainers. The retainers, but not the non-retainers, developed an increase in an index of dead space ventilation, possibly because of bronchodilation, which will increase ventilation to poorly perfused regions and aggravate hypercapnia. The authors conclude that oxygen-induced hypercapnia is mainly due to a fall in minute ventilation and less so to an increase in dead space. To gain insight into the cause of physical impairment in COPD, Neder and coworkers (28) characterized the determinants of the power–duration relationship during exercise at
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high intensity and a constant load. The power–duration relationship was hyperbolic in both patients and controls. Absolute values of both the critical power asymptote and the curvature constant were lower in the patients. All of the patients were able to sustain exercise at the critical power asymptote for 20 minutes. The authors conclude that the decrease of both parameters of the hyperbolic power-duration relationship was due to ventilatory constraints and their sensory consequences. Respiratory Muscles
To determine the relationship between dyspnea and body weight in patients with COPD, Sahebjami and Sathianpitayakul (29) studied 33 underweight and 57 normal weight patients (body mass index 18.7 and 24.5 kg per m2). Underweight patients had higher ratings of dyspnea (3.1 versus 2.5), and lower maximum inspiratory pressures (55 versus 66 mm Hg), and lower diffusing capacity (36 versus 57% predicted). The authors conclude that underweight patients with COPD are more dyspneic, possibly because of inspiratory muscle weakness and low diffusing capacity. Montes de Oca and Celli (30) compared respiratory muscle function and exercise performance in 19 eucapnic (PCO2 40 torr) and 13 hypercapnic (PCO2 52 torr) patients with COPD. The hypercapnic patients had lower ventilation; functional residual capacity and maximum inspiratory pressure were equivalent. The pattern of respiratory muscle recruitment, assessed as the ratio of swings in gastric and esophageal pressure, was equally abnormal in both groups. The authors conclude that hypercapnia in stable patients with COPD results from decreased ventilation despite similar respiratory effort as eucapnic patients. Scherer and coworkers (31) compared a new portable device for normocapnic hyperpneic training of the respiratory muscles versus incentive spirometry (control group) in 30 patients with COPD. Both groups trained twice daily for 15 minutes, five days a week for eight weeks. Hyperpnea training produced larger increases in respiratory muscle endurance (sustained ventilation; incremental threshold leading), maximal expiratory pressure, six-minute walking distance, peak oxygen consumption, and the physical component score on SF-12. The authors conclude that home use of the hyperpnea training device is feasible and beneficial in patients with COPD. The equation for tension–time index includes mean esophageal pressure, making it an invasive measurement. Hayot and coworkers (32) determined whether substituting P0.1 (the airway pressure during a 0.1 second occlusion) in place of mean esophageal pressure would predict changes in tension–time index. In seven healthy subjects performing an incremental exercise test, the non-invasive estimate of tension–time index showed good agreement with the invasive measurement. Agreement was poor in nine patients with COPD. The authors conclude that use of airway occlusion pressure allows tension– time index to be measured noninvasively in healthy subjects. To determine whether high-intensity exercise would cause diaphragmatic fatigue in patients with COPD, Mador and coworkers (33) studied 12 men with airway obstruction of moderate severity (FEV1, 50% of predicted). The patients cycled at 60–70% of maximal capacity to the limit of tolerance (workload of 60 watts performed over 10 minutes). Before exercise, phrenic nerve stimulation produced a twitch transdiaphragmatic pressure of 20 cm H2O. Exercise did not produce a decrease in overall twitch pressure, although two patients had persistent reductions of more than 10%. The authors conclude that high-intensity exercise does not cause diaphragmatic fatigue in most patients with COPD. The development of symptoms during exercise causes many patients with COPD to become sedentary and their limb muscles
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may get deconditioned. To determine whether high-intensity exercise causes fatigue of the quadriceps, Mador and coworkers (34) studied 19 men with COPD (FEV1, 42% of predicted) who cycled at 60–70% of maximal capacity to exhaustion (workload of 54 watts for 10 minutes). When the femoral nerves were stimulated at 30 minutes after exercise, twitch force of the quadriceps had fallen by 24%. The authors conclude that heavy exercise causes patients with COPD to develop quadriceps fatigue. Peripheral Muscles
Exercise performance in patients with COPD is related to impaired muscle metabolism involving a shift from oxidative to glycolytic metabolism. Because patients with COPD also have less glutamate in their peripheral muscles, Engelen and coworkers (35) asked whether the decrease was caused by increased glycolytic metabolism. Biopsies from the vastus lateralis of 13 patients with COPD had 36% less glutamate, but increased levels of lactate and pyruvate. Patients also had smaller amounts of two antioxidants, glutathione (24% reduction) and glutamine (7% reduction), of which glutamate is a precursor. Levels of glutamate and glutathione in muscle were correlated (r2 0.61). The authors conclude that skeletal muscles of patients with COPD have decreased levels of glutamate and glutathione, possibly due to increased glycolytic activity. In 24 malnourished patients with COPD, Creutzberg and coworkers (36) investigated factors predicting a weight gain of less than 2% after eight weeks of nutritional supplementation (an extra 500–750 kcal/day). Compared with 10 patients achieving a weight gain of at least 5%, five nonresponders were older, had a lower baseline dietary intake-to-energy expenditure ratio, greater use of supplemental oxygen, and higher concentrations of fasting glucose, LPS-binding protein, and soluble tumor necrosis factor receptors 55 and 75. On multiple linear regression, four factors explained 78% of weight change with nutritional supplements: age, ratio of dietary intake-to-energy expenditure, soluble tumor necrosis factor receptor 55, and ratio of extracellular-to-intracellular water. The authors conclude that many patients with COPD fail to respond to nutritional supplementation, and that the failure to respond is related to multiple factors including systemic inflammatory responsiveness. Leptin, a hormone produced by adipose tissue, regulates energy balance in a feedback mechanism involving the hypothalamus. In 17 patients with COPD (FEV1 36% predicted), Creutzberg and coworkers (37) noted depression of the ratio of dietary intake-to-resting energy expenditure on admission, but it gradually rose over the next seven days (1.65 versus 1.28). Plasma leptin was higher in the patients than in the controls (1.82 versus 0.32 ng% per ml), and it decreased by 20% on the seventh day. Glucose and insulin concentrations were elevated on admission, while soluble tumor necrosis factor receptors 55 and 75 did not differ from controls. On the seventh day, soluble tumor necrosis factor receptor 55 was correlated with leptin (r 0.65) and glucose (r 0.81); the ratio of dietary intake-to-resting energy expenditure was related to leptin (r 0.74) and soluble tumor necrosis factor receptor 55 (r 0.93). The authors conclude that the temporary disturbances in energy balance during an acute exacerbation of COPD are related to increases in leptin and the systemic inflammatory response. Because many patients with COPD have wasting of fat-free mass and altered amino acid levels in blood and muscle, Engelen and coworkers (38) measured protein breakdown and synthesis in 14 stable patients with COPD (FEV1 37% predicted) and eight healthy controls. Infusions of phenylalanine and tyrosine tracers revealed that synthesis and breakdown of whole
body protein was higher in the patients. Net protein breakdown (breakdown minus synthesis) was increased in both groups, indicating a comparable degree of catabolism. Infusing a leucine tracer did not detect differences between the groups. The authors conclude that protein turnover is increased in patients with COPD, and that a leucine tracer does not reflect whole-body protein metabolism in these patients. Because early onset of lactic acidosis decreases exercise capacity, Engelen and coworkers (39) determined whether the response to exercise was related to muscle substrates. Levels of glutamate and glycogen were higher in the vastus lateralis of seven control subjects who were physically active than in seven subjects who were physically inactive; the lactate threshold was also higher, while muscle lactate, pyruvate, and glucose did not differ. In 27 patients with COPD, lactate threshold and the level of glutamate in muscle were lower than in the physically inactive control subjects, while the levels of lactate and pyruvate in muscle were higher. A subgroup of patients with emphysema had a lower lactate threshold and less glutamate. The authors conclude that early onset of lactic acidosis during exercise in patients with COPD is due to decreased glutamate in skeletal muscle as a result of physical inactivity. Health Care Delivery
Using data from a cohort of 21,284 patients aged 65 year and older, Sin and Tu (40) asked, “Do elderly patients with very short hospital stays for airway obstruction have increased rates of readmission and mortality?” Compared with elderly patients kept in hospital for 4–6 days, those discharged in less than 4 days were 39% more likely to be readmitted over the following 15 days and they were 45% more likely to die within 15 days of discharge. The authors conclude that some elderly patients with obstructive airway disease are being discharged prematurely. Drug Therapy
Beta agonists. To determine whether lung function measured during a forced inspiration versus a forced expiration would better detect a decrease in dyspnea with a bronchodilator, Taube and coworkers (41) studied 61 patients with COPD. Albuterol 400 g induced a 160-ml increase in FEV1, a 360-ml increase in forced inspiratory volume in 1 second (FIV1), and a 300-ml increase in inspiratory capacity. Factor analysis revealed that the decrease in dyspnea was primarily associated with improvement in forced inspiratory volume, rather than with FEV1 or inspiratory capacity. Muscarinic antagonists. In 169 patients with stable COPD (FEV1, 42% predicted), Littner and coworkers (42) did a randomized, double-blind study of tiotropium, a long-acting anticholingeric agent. Patients received 0, 4.5, 9, 18, or 36 g once daily for four weeks. Over a 29-day study period, all doses achieved greater improvements in spirometry than placebo. The safety profile for tiotropium was similar to placebo. To compare the sensitivity of three different exercise tests for detecting improvement with a bronchodilator, Oga and coworkers (43) did a double-blind, crossover study of inhaled oxitropium in 42 patients with COPD. One hour after inhaling 400 g of oxitropium, patients showed a 1% (but significant) increase in distance walked during six minutes, no change in maximal oxygen consumption, and a 19% increase in the time of enduring 80% of the workload on progressive cycle ergometry. The authors conclude that endurance time was the most sensitive test for detecting improvement with oxitropium. Glucocorticoids. In patients experiencing an exacerbation of COPD, Niewoehner and coworkers (44) asked the question, “Does measurement of FEV1 on admission and over the first
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few days of treatment predict outcome?” As part of a randomized trial of glucocorticoid therapy, they had at least one measurement of FEV1 over the first 14 study days. Of 261 patients, 64 experienced a treatment failure, defined as death, intubation, readmission, or intensification of drug therapy. Treatment failure was predicted by both FEV1 at entry (odds ratio for a 100-ml increase, 0.87) and change in FEV1 over the first 2 days (odds ratio for a 100-ml increase, 0.80). The authors conclude that measurement of FEV1 on admission and over the first few days in hospital predicts the outcome of an exacerbation of COPD. To determine whether chronic glucocorticoid treatment can be safely withdrawn in “steroid-dependent” patients with COPD, Rice and coworkers (45) did a double-blind study of 38 patients over 6 months. Withdrawing prednisone at a rate of 5 mg a week resulted in an average daily dose of 6.3 mg, versus 10.7 mg in the group receiving usual maintenance therapy. The number of exacerbations of COPD per patient was 2.5 in the withdrawal group and 2.7 in the maintenance group; spirometry, dyspnea, or quality of life did not differ. The authors conclude that withdrawal of glucocorticoids does not increase exacerbations in patients with COPD. The benefit of inhaled glucocorticoids in management of patients with COPD is debated by Calverley (46) and Barnes (47), with rebuttals from each (48, 49). Smoking cessation. To determine the long-term benefit of smoking cessation, Scanlon and coworkers (50) analyzed data from 3,926 smokers with mild-to-moderate COPD followed for five years in the Lung Health Study. People who stopped smoking had a 2% increase in FEV1 over the first year. The subsequent rate of decline in FEV1 in the sustained quitters was half that in continued smokers (31 and 62 ml per year), and comparable to the rate in never-smokers. Predictors of change in lung function included baseline FEV1, response to -agonist, response to methacholine, age, sex, race, and baseline cigarette consumption. Other Therapies
Lung volume reduction surgery. To characterize patients developing acute respiratory failure after lung volume reduction surgery for COPD, Chatila and coworkers (51) analyzed data on 72 patients. Postoperative respiratory failure occurred in 21 patients (29%) due to hypoxemia (5 patients), hypercapnia (9 patients), and hemodynamic instability (7 patients). In these 21 patients, hospital mortality was 33%, and no variable predicted respiratory failure. Patients developing respiratory failure were older, had longer anesthesia time, higher incidence of coronary artery disease, and were more likely to have had a second operation during the surgery. The authors conclude that respiratory failure after lung volume reduction surgery is increased in older patients and in those undergoing concomitant cardiac surgery. Marchand and coworkers (52) studied the effects of lung volume reduction surgery in a hamster model of emphysema. Four months after instilling elastase into the trachea, 11 hamsters underwent volume reduction surgery and 9 underwent a sham operation. At nine months, functional residual capacity was 25% lower in the volume reduction surgery group than in the sham operation group. The mass of the diaphragm was decreased by 18% in the volume reduction surgery group and by 14% in the sham operation group. Twitch tension was lower in the volume reduction surgery group, and both groups showed increased resistance to fatigue and a shift from type IIx/b towards type IIa fibers. The authors conclude that lung volume reduction surgery does not improve the morphology and contractility of the diaphragm of hamsters with emphysema.
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Alpha1-antitrypsin replacement therapy. Using data from the NHLBI Registry of Patients with Severe Deficiency of 1Antitrypsin, Schluchter and coworkers (53) assessed the feasibility of a randomized trial of intravenous augmentation therapy in patients with FEV1 of 35–49% predicted. To detect a difference in decline of FEV1 of 23 ml per year (28% reduction), 47 patients would need to be followed for each treatment for four years. To detect a 40% decrease in mortality over five years, 342 patients would be needed in each treatment arm. Desmosine is a specific marker for the degradation of elastin. In 12 patients with severe 1-antitrypsin deficiency (FEV1 41% predicted), Gottlieb and coworkers (54) found that urinary excretion of desmosine was 13.0 g per g creatinine, which is 73% higher than in normal healthy subjects. The level did not change during eight weeks of treatment with 1-antitrypsin supplementation. The authors conclude that supplementation therapy achieves insufficient levels of 1-antitrypsin in the lungs or that degradation of elastin in the lungs is not dependent on neutrophil elastase. Rehabilitation
In 45 patients with stable COPD (FEV1 0.96 liter), Garrod and coworkers (55) did a randomized controlled trial of exercise training alone versus exercise training plus noninvasive positive pressure ventilation. At eight weeks, patients receiving both training and ventilation reached 72 meters more on a mean shuttle walk test than patients receiving training alone, and they had greater improvement in PO2 (3.7 mm Hg) and in a chronic respiratory disease questionnaire (12.3). The authors conclude that noninvasive ventilation can be used successfully in the home setting. The efficacy of non-invasive ventilation in patients with stable COPD is debated by Rossi (56) and Hill (57), with rebuttals from each (58, 59).
AIR POLLUTION General
To examine the relationship between atmospheric pollution and the release of neutrophil precursors from the bone marrow, Tan and coworkers (60) studied 30 subjects during and after the haze resulting from forest fires in Southeast Asia in 1997. Indices of atmospheric pollution were correlated with the number of band neutrophils, expressed as a percentage of total neutrophils. The authors conclude that atmospheric pollution is associated with increased release of neutrophil precursors from the bone marrow. To determine whether exposure to concentrated ambient air particles causes airway inflammation, Ghio and coworkers (61) exposed 38 volunteers to particle concentrations of 23 to 311 g per m3 for two hours. The subjects did not develop symptoms or change in pulmonary function. Bronchoalveolar lavage, performed 18 hours later, revealed a mild increase in neutrophils, and blood fibrinogen was also increased. The authors conclude that exposure to ambient air particles produces mild inflammation in the lower respiratory tract, accompanied by an increase in blood fibrinogen. To better understand the importance of air pollution in the initiation of asthma, Hamada and coworkers (62) studied neonatal mice that were also exposed to residual oily fly ash, a surrogate for ambient air particles. Repeated exposure of the neonatal mice to allergen alone or pollutant alone had no effect on airway hyperresponsiveness and did not cause antibody production. Adult mice exposed to allergen or allergen plus pollutant did develop airway hyperreactivity, but the combination
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did not have an additive effect. Neonatal mice exposed to both allergen and pollutant developed greater airway hyperreactivity than on exposure to allergen alone, and reexposure to allergen produced IgE and IgG specific to ovalbumin. The authors conclude that exposure to pollutant aerosols can disrupt normal resistance to sensitization to inhaled allergens, and thereby promote the development of airway hyperreactivity. Ozone
Because pretreatment with inhaled glucocorticoids decreases the inflammatory response to inhaled ozone in dogs, Nightingale and coworkers (63) did a double-blind, crossover study of the protection afforded by two weeks of inhaled budesonide against ozone. Fifteen healthy subjects were exposed to ozone 400 ppb for two hours. Ozone produced decreases in spirometry, increases in methacholine reactivity, and increases in sputum neutrophils and myeloperoxidase; exhaled nitric oxide did not change. Effects with placebo and budesonide were not different. The authors conclude that inhaled glucocorticoids do not protect against the effects of ozone exposure. To determine the nature of airway inflammation after repeated exposure to ozone, Jorres and coworkers (64) studied 23 healthy subjects. Single exposure to ozone 220 ppb caused a decrease in FEV1, and increased neutrophils, lymphocytes, total protein, interleukin-6, interleukin-8, reduced glutathione, urate and ortho-tyrosine in bronchoalveolar fluid; biopsy showed no changes in cells. After repeated exposure to ozone on four consecutive days, the effects on lung function and cell counts in bronchoalveolar lavage were abolished, but increases were still seen in interleukin-6, interleukin-8, reduced glutathione, and ortho-tyrosine. Macroscopic scores for bronchitis, erythema, and increased vulnerability of the airway mucosa were increased, as were neutrophils in the bronchial mucosa. The authors conclude that repeated exposure to ozone causes persistent airway inflammation, despite attenuation of some inflammatory markers and adaptation of lung function. To develop an animal model for research on ozone-induced epithelial injury, Sterner-Kock and coworkers (65) compared findings in ferrets, rats, and monkeys exposed to ozone 1 ppm for 8 hours. Ozone caused increases in neutrophils in bronchoalveolar fluid, but neutrophils per mm were 3–4-fold higher in the ferrets and monkeys than in the rats. Ozone produced severe, acute infiltration of neutrophils in regions with necrotic epithelial cells, especially in the centriacinar region, which was more severe in ferrets and monkeys than in rats. The authors conclude that the epithelial injury induced by ozone is similar in ferrets and monkeys and represents a better model for humans than does a model in rodents. Antioxidants in the epithelial lining fluid, such as glutathione peroxidase, are the first line of defense against inhaled oxidants. Exposing 21 healthy subjects to four hours of ozone (0.22 ppm), Avissar and coworkers (66) found a 40% decrease in basal glutathione peroxidase and in its extracellular protein concentration; the decreases were still evident on bronchoalveolar lavage at 18 hours. The extracellular glutathione peroxidase in epithelial lining fluid was inversely related to the change in neutrophils. A three-hour exposure to nitrogen dioxide (0.6 and 1.5 ppm) had no effect. The authors conclude that ozone decreases the activity of glutathione peroxidase and its extracellular protein concentration in epithelial lining fluid, whereas nitrogen dioxide does not. Inoue and coworkers (67) investigated the contribution of endogenous nitric oxide to airway inflammation and hyperresponsiveness, and the potential involvement of interleukin-8. In transformed cells of the bronchial epithelium of humans,
nitric oxide donors increased production of interleukin-8; production was also increased by tumor necrosis factor- plus interleukin-1 plus interferon-, and production was attenuated by a combination of nitric oxide synthase inhibitors (aminoguanidine and N4-nitro-L-arginine methyl ester [L-NAME]). Exposure of guinea pigs to ozone induced airway hyperresponsiveness and increased neutrophils in bronchoalveolar fluid; nitric oxide synthase inhibitors prevented these changes five hours after the exposure, and decreased interleukin-8 mRNA expression in epithelial cells. The authors conclude that endogenous nitric oxide may play a role in airway inflammation and hyperresponsiveness caused by ozone, presumably through upregulation of interleukin-8. Diesel Exhaust
Diesel exhaust particles stimulate airway epithelial cells to produce cytokines, but the involvement of intracellular signal transduction pathway and redox state has not been investigated. Hashimoto and coworkers (68) found that diesel exhaust particles increased the production of a CXC chemokine, interleukin-8, and a CC chemokine, RANTES (regulated on activation normal T-cell expressed and secreted), by epithelial cells of the human bronchus. The particles also activated p38 mitogen-activated protein kinase in the epithelium; a specific inhibitor of the enzyme prevented the production of interleukin-8 and RANTES. N-Acetylcysteine, a thiol-reducing agent, inhibited the activation of p38 mitogen-activated protein kinase, and the production of interleukin-8 and RANTES. The authors conclude that the cellular redox state and p38 mitogen-activated protein kinase are critical in the production of interleukin-8 and RANTES in response to diesel exhaust particles. Because short-term exposure to diesel exhaust induces marked leukocytic infiltration in human airways, Salvi and coworkers (69) determined whether the inflammation was caused by increased production of chemokines and cytokines by resident cells. Fifteen healthy subjects were exposed to diluted diesel exhaust for one hour, and bronchoscopic biopsies were obtained six hours later. Exposure enhanced gene transcription of interleukin-8 in bronchial tissue and the cells of a bronchial wash. Exposure also increased interleukin-8 and growth-regulated oncogene- protein expression in the bronchial epithelium, and tended to increase interleukin-5 mRNA in the bronchial tissue. The authors conclude that the findings suggest a mechanism for airway leukocyte infiltration induced by exposure to diesel exhaust. To determine whether exposure to diesel exhaust aggravates nasal allergy, Kobayashi (70) exposed guinea pigs to diesel exhaust for five weeks. During exposure, ovalbumin was administered once a week into the nasal cavity. Exposure to diesel exhaust increased the number of sneezes, rhinorrhea, and the number of eosinophils infiltrating the nasal epithelium and subepithelium. Levels of ovalbuminspecific IgE and IgG were increased. The authors conclude that diesel exhaust enhances nasal reactions to repeated allergen challenge. To investigate the effect of diesel particulates on airway inflammation, Nightingale and coworkers (71) did a double-blind crossover study of two-hour exposure in 10 healthy subjects. Exposure did not change lung function, but it produced a 50% increase in exhaled carbon monoxide (an index of oxidative stress), a 30% increase in sputum neutrophils, and a 30% increase in sputum myeloperoxidase, but no change in inflammatory markers in the blood. The authors conclude that exposure to diesel exhaust particulates leads to airway inflammation.
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Statement
What constitutes an adverse health effect of air pollution is discussed in an ATS statement (72).
PULMONARY HYPERTENSION Primary Pulmonary Hypertension
Previous studies in patients with primary pulmonary hypertension had mapped the disease locus, PPH1, to a 27-cM region on chromosome 2q31-q32, with a maximum logarithm of the odds favoring linkage (lod) score of 3.87 with markers D2S350 and D2S364. Deng and coworkers (73) extended these studies to narrow the minimal genetic region by genotyping 44 individuals with primary pulmonary hypertension and 133 unaffected individuals using 33 highly polymorphic microsatellite markers. Recombination events were found that substantially reduced the interval for PPH1 to a 3-cM region separating D2S311 and D2S1384; the entire region lay within chromosome 2q33. A maximum lod score of 7.23 was observed for marker D2S307, and an lod score of 7.41 was observed close to marker D2S1367. The authors conclude that the observed minimal genetic region contains multiple candidate genes for primary pulmonary hypertension. In 43 patients with primary pulmonary hypertension, Miyamoto and coworkers (74) determined the relationship between the six-minute walk test with more detailed cardiopulmonary assessment, and they also assessed the ability of the test to predict mortality. Patients walked 297 meters in six minutes (55% less than healthy subjects). The distance walked was related to baseline cardiac output (r 0.48) and pulmonary vascular resistance (r 0.49) on right heart catheterization, and to peak oxygen consumption (r 0.70) and oxygen pulse (r 0.57) on maximal exercise testing. Over 21 months of followup, 12 patients (27%) died. The only independent predictor of mortality was the distance walked in six minutes; mortality was higher in patients walking a distance of less than 332 meters. The authors conclude that the distance walked in six minutes has a strong, independent association with mortality in patients with primary pulmonary hypertension. Vascular endothelial growth factor is contained in platelets, and is released at sites of vascular injury to promote vascular repair in conjunction with non-specific mitogens, such as platelet-derived growth factor. Eddahibi and coworkers (75) found that the amount of vascular endothelial growth factor was increased three fold in the platelets of 21 patients with primary pulmonary hypertension, and increased four fold in the platelets of eight patients with secondary pulmonary hypertension. The level of platelet-derived growth factor was similar in the platelets of patients and controls. An infusion of prostacyclin produced an increase in vascular endothelial growth factor, with no change in platelet-derived growth factor. The authors conclude that the platelets of patients with pulmonary hypertension have an increase in vascular endothelial growth factor, but not of platelet-derived growth factor, and that administration of prostacyclin produces a further increase. When patients with primary pulmonary hypertension are treated with inhibitors of angiotensin-converting enzyme, the dose needs to be selected carefully to avoid systemic hypotension. To determine the dose that specifically blocks the enzyme in the pulmonary circulation, Qing and coworkers (76) used positron emission tomography to measure the combined forward rate constant for fluorine-18 labeled fluorocaptopril, because it is proportional to the mass of angiotensin-converting enzyme in the lung. In five healthy subjects, enalapril 5 mg daily for a week decreased the rate constant from 0.177 to
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0.028 per second. In five patients with primary pulmonary hypotension, one week’s treatment with enalapril decreased the rate constant from 0.052 to 0.020 per second. The authors conclude that the mass of pulmonary angiotensin-converting enzyme is markedly reduced in patients with primary pulmonary hypertension and only low doses of an inhibitor may be needed to prevent vascular remodeling. Administration of monocrotaline to pneumonectomized rats produces pathological changes resembling those of primary pulmonary hypertension in humans. Using this model, Faul and coworkers (77) studied the effect of triptolide, an inhibitor of gene transcription in many cells. Treatment every other day achieved a lower mean pulmonary artery pressure on day 35 than in untreated rats (21 and 42 mm Hg). Treated rats had less hypertrophy of the right ventricle and less neointimal formation in the pulmonary arteries. Initiating rescue treatment on day 21 produced a dose-dependent decrease in pulmonary artery pressure. The authors conclude that triptolide attenuates the development of pulmonary hypertension in this rat model and promotes regression of pulmonary arterial neointimal formation. An editorial commentary by Newman and Lane (78) accompanies this article. Pathology of Pulmonary Hypertension
Hojoong and coworkers (79) investigated the distribution of arterial abnormalities in 51 patients with chronic pulmonary hypertension using quantitative histopathology. Intimal thickening in primary pulmonary hypertension was most prominent in small pulmonary arteries and arterioles less than 200 m in diameter. Arteries larger than 400 m showed significant intimal thickening only in chronic thromboembolic disease. Plexiform lesions in primary pulmonary hypertension involved significantly smaller arteries than in Eisenmenger’s syndrome. A spectrum of intermediate lesions obstructing the intima, ranging between plexiform and thrombotic lesions, were seen in pulmonary hypertension secondary to some other known cause. Myofibroblasts within the various intimal lesions stained positively for vimentin and -smooth muscle actin, but negatively for desmin and endothelial markers. The authors conclude that the major types of pulmonary hypertension have characteristic distribution patterns of obstructive intimal lesions, showing mainly a myofibroblastic phenotype and variable vascular differentiation. Mandel and coworkers (80) provide a state-of-the-art review of pulmonary veno-occlusive disease.
THROMBOEMBOLIC DISORDERS Diagnostic Studies
In 247 consecutive patients with clinically suspected pulmonary embolism, Lorut and coworkers (81) assessed the reliability of a noninvasive diagnostic strategy. Of the 228 patients who could be evaluated, 42% had a pulmonary embolus. The diagnosis was confirmed by spiral computed tomography in 73% of patients, by high-probability ventilation–perfusion scan in 4%, and by venous ultrasound (when computed tomography was normal and D-dimers were elevated) in 23%. Pulmonary embolism was ruled out by a normal ventilation–perfusion scan in 14% of patients, by normal D-dimers in 31%, by an obvious alternative diagnosis on computed tomography in 18%, by similar previous lung scan in 11%, and by a combination of normal venous ultrasound, computed tomography, lung scan, and D-dimers in 26%. Pulmonary angiography was performed in only two patients: both had a high-probability scan and normal computed tomography, and angiography was normal in both. Patients in whom pulmonary embolism was ex-
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cluded were not treated with anticoagulants. At three-month follow-up, 1.7% had thromboembolism and no deaths had occurred. The authors conclude that this noninvasive diagnostic strategy yielded a definite diagnosis in 99% of patients with suspected pulmonary embolism. A high-probability ventilation–perfusion lung scan generally indicates proximal occlusion of the pulmonary artery by thromboemboli. Bailey and coworkers (82) describe three patients with high probability scans and negative pulmonary angiography. All three patients were independently shown to have pulmonary venoocclusive disease. A variety of prediction rules based on arterial blood gas data have been developed to predict the likelihood, or not, of pulmonary embolism. In 293 consecutive referrals for imaging because of a suspected pulmonary embolism, Rodger and coworkers (83) obtained arterial blood gases and other clinical data from consenting patients. None of the published prediction rules had sufficient negative prediction value, specificity, or likelihood ratio to be useful in the management of patients with suspected pulmonary embolism. Since the clinical signs and symptoms of an acute exacerbation of COPD can mimic those of pulmonary embolism, Hartmann and coworkers (84) studied the accuracy of tests used to diagnose acute pulmonary embolism. In 627 consecutive patients with suspected pulmonary embolism, 91 patients (15%) had COPD. The prevalence of pulmonary embolism in patients with COPD was similar to the other patients (29 versus 31%). The diagnostic value of spiral computed tomography, D-dimers, and pulmonary angiography was comparable in patients with and without COPD. A nondiagnostic ventilation– perfusion scan was found in 46% of the patients with COPD and in 21% of the other patients. The ventilation–perfusion scan was conclusive in 39% of patients with COPD. The authors conclude that the presence of COPD does not influence the accuracy of clinical probability estimates, D-dimers, spiral computed tomography or angiography, and, despite the increased likelihood of non-conclusive ventilation–perfusion scans in patients with COPD, the test remains informative. The sensitivity of contrast-enhanced spiral computed tomography for diagnosing central, lobar, or segmental pulmonary emboli is about 90%, but its ability to detect subsegmental emboli has not been tested. Baile and coworkers (85) produced subsegmental pulmonary emboli in 16 pigs by injecting beads. Spiral computed tomography and pulmonary angiography were performed, and a methacrylate cast of the pulmonary vessels was made after killing the pigs. With the cast serving as gold standard, sensitivities were: angiography 87%, 3 mm collimation computed tomography 82%, and 1 mm collimation computed tomography 87%. Positive predictive values were: angiography 88%, 3 mm collimation computed tomography 94%, and 1 mm collimation computed tomography 81%. The authors conclude that spiral computed tomography is comparable to angiography for detecting subsegmental-sized pulmonary emboli. Pathophysiology
Chronic obstruction of the pulmonary arteries may decrease the supply of substrates for the endothelial nitric oxide synthase system unless compensatory expansion of the systemic circulation maintains an adequate supply. To address these possibilities, Fadel and coworkers (86) ligated the left pulmonary artery of piglets and made measurements at two days and five weeks. Markers of ischemia (decrease in ATP and increase in lactate) had attenuated by five weeks. Long-term occlusion produced decreases in calcium-dependent nitric oxide synthase activity and endothelial nitric oxide synthase protein,
but calcium independent activity was unchanged. Relaxation of the pulmonary artery in response to acetylcholine and calcium ionophore was impaired, while the response to sodium nitroprusside was unchanged. The authors conclude that despite relative conservation of substrate delivery, prolonged occlusion of the pulmonary artery produces a decrease in endothelial nitric oxide synthase function and protein in the postobstructive arteries. Treatment
Because consensus concerning the efficacy of prophylactic measures against thromboembolism in critically ill patients is lacking, Fraisse and coworkers (87) judged it ethical to do a randomized comparison of nadroparin, a low molecular weight heparin, and placebo in 223 patients receiving mechanical ventilation for an acute exacerbation of COPD. Over 11 days, the incidence of deep venous thrombosis was 15% in patients receiving subcutaneous nadroparin and 28% in the placebo group. Adverse effects or mortality did not differ. The authors conclude that nadroparin achieved a 45% decrease in the incidence of deep venous thrombosis in mechanically ventilated patients without a high rate of adverse effects. Because the reperfusion lung injury that occurs after thromboendarterectomy is mediated by neutrophils, Kerr and coworkers (88) did a double-blind, randomized trial of an inhibitor of selectin (a molecule that mediates adhesion of neutrophils to the endothelium). Lung injury occurred in 31% of 26 patients receiving the selectin inhibitor versus 60% of 25 patients receiving placebo. Days of mechanical ventilation, days in the intensive care unit, and mortality did not differ. Patients with reperfusion injury had increased neutrophils, protein, and P-selectin in bronchoalveolar fluid. The authors conclude that reperfusion injury after pulmonary thromboendarterectomy is a high-permeability injury and that an adhesion molecule inhibitor decreases its occurrence.
HIGH ALTITUDE To study the effects of altitude-induced hypoxia on cardiac function, Boussuges and coworkers (89) simulated a climb to Mount Everest using a hypobaric chamber. During the simulated ascent in eight volunteers, echocardiography revealed decreases in the diameters of the aorta, left atrium, left ventricle, and right ventricle. Stroke volume fell but the resulting tachycardia kept cardiac output constant. The left ventricle showed a decrease in early filling, with increased contribution from atrial contraction and no increase in end-diastolic pressure. Systolic pulmonary artery pressure increased progressively. The authors conclude that hypoxia at high altitude produces an increase in pulmonary artery pressure, while preserving left-ventricular contractility. Pulmonary edema occurs in some individuals at altitudes above 2,500 meters. To investigate the role of airway inflammation in causing this disorder, Duplain and coworkers (90) serially measured exhaled nitric oxide in 28 mountaineers with a previous history of this disorder and 24 mountaineers without such a history. On exposure to 4,559 meters of altitude, 13 subjects developed pulmonary edema and their exhaled nitric oxide did not change. Exhaled nitric oxide was 30% lower in subjects with a previous history of the disorder than in the controls, and its level was inversely correlated with pulmonary artery pressure (r 0.52). The authors conclude that development of high-altitude pulmonary edema is not preceded by airway inflammation, and that decreased synthesis of nitric oxide in vulnerable subjects may aggravate hypoxic pulmonary vasoconstriction, causing pulmonary edema.
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Severinghaus (91) recalls a study of alterations in cerebrospinal fluid chemistry at high altitude.
LUNG TRANSPLANTATION Lung Preservation
Using a single-lung transplant model in rats, Fischer and coworkers (92) assessed the mode of cell death in transplanted lung experiencing an ischemia–reperfusion injury. When rat lungs were preserved at 4 for intervals between 20 minutes and 12 hours, less than 2% of the cells were dead; when preservation time was increased to 24 hours, 27% of cells were dead and most were necrotic. When the lungs were transplanted and reperfused for 2 hours, about 30% of cells in the 6- and 12-hour groups were apoptotic and less than 2% were necrotic; 29% of cells in the 24-hour group were necrotic and less than 1% were apoptotic. Lung function decreased with increasing preservation time. The percentage of necrotic cells was correlated inversely with posttransplant graft function. The authors conclude that the duration of cold preservation and extent and mode of cell death influences lung function after transplantation. An increase in the level of cyclic adenosine monophosphate protects lungs against ischemia–reperfusion injury. With a goal of developing better lung preservation solutions, Featherstone and coworkers (93) compared the effect of adding phosphodiesterase inhibitors to a cardioplegic solution. Rat lungs were stored for eight hours in a 4 C solution containing theophylline (a nonselective phosphodiesterase inhibitor), Milrinone (a subtype III inhibitor), rolipram (a subtype IV inhibitor), or zaprinast (a subtype V inhibitor). After 40 minutes of reperfusion, compliance was 0.07 ml per cm H2O in lungs stored in the solution alone; when theophylline or rolipram had been added, compliance was 0.17 ml per cm H2O. Theophylline also improved perfusate PO2 on transit through the lung. The authors conclude that theophylline provided the best protection of function after prolonged hypothermic storage and reperfusion of rat lungs. To determine whether differences in ischemia–reperfusion injury after lung preservation result from variations in the stability of intraalveolar surfactant, Fehrenbach and coworkers (94) used an isolated perfused rat lung model. After ischemia– reperfusion, the total amount of intraalveolar surfactant was increased. A significant amount of tubular myelin was displaced into the alveolar lumen and the lattices of tubular myelin were wider than in the controls. In lungs preserved with modified EuroCollins solution, epithelial tubular myelin was significantly reduced, resulting in an increase in the ratio of surface-inactive unilamellar vesicles to surface-active tubular myelin. In lungs preserved with Celsior solution, about half the tubular myelin pool was epithelial, and this was associated with improved function. The authors conclude that the beneficial effects of lung preservation on tubular myelin integrity were associated with improved lung function during reperfusion. Kawashima and coworkers (95) studied strategies for avoiding the ischemia–reperfusion injury that hinders lung transplantation. In harvested lung and heart blocks from rats that were immersed in perfusate at 4 C for 15 hours and then reperfused for one hour, nitroglycerin, a nitric oxide donor that suppresses oxidative stress, decreased reperfusion-induced pulmonary edema. Immunohistochemical studies revealed less oxidative DNA damage with use of nitroglycerin. The authors conclude that adding nitroglycerin to a lung preservation solution attenuates the oxidative stress of ischemia–reperfusion injury.
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Obliterative Bronchiolitis
Animal models. To investigate the role of complement activation in obliterative bronchiolitis, Kallio and coworkers (96) used a tracheal allograft model in rats (graft from a genetically dissimilar individual of same species). Compared with syngeneic grafts (graft from a genetically identical rat), the allografts developed airway occlusion and progressive loss of respiratory epithelium associated with increased deposition of complement components C3 and C5b-9. Treatment with complement receptor type 1, an inhibitor of the classic and alternative complement pathways, decreased the obliterative changes by 40%, and decreased the deposits of C5b-9 and IgG, neutrophil chemoattractant interleukin-8, and expression of ICAM-1. Treatment also produced increased staining for Th 2 cytokines. The authors conclude that blocking the activation of complement attenuates the development of obliterative bronchiolitis. Because of growing evidence that the angiotensin system plays a prominent role in the pathogenesis of fibrosis, Maclean and coworkers (97) examined the role of angiotensin converting enzyme in a rat heterotopic tracheal transplant model (organ transplanted into a different location than the native organ) of bronchiolitis obliterans. In allograft rats, the obliterated portion of the trachea showed heavy staining for angiotensin-converting enzyme on day 21 after transplantation. Rats started on captopril, an inhibitor of angiotensin-converting enzyme, showed 45% less airway obstruction. The authors conclude that angiotensin-converting enzyme is found in the fibroproliferative lesion in a model of bronchiolitis obliterans, and inhibiting the enzyme limits the development of airway obstruction. In a rat heterotopic tracheal transplant model, Suga and coworkers (98) investigated the role of RANTES (regulated upon activation, normal T cell expressed and secreted), a member of the C-C chemokine family and a chemoattractant for memory T cells, monocytes, and eosinophils. In both allogenic grafts (graft from a genetically dissimilar individual of same species) and isogenic grafts (graft from a genetically identical rat), RANTES was highly expressed in infiltrating mononuclear cells. A neutralizing anti-RANTES antibody decreased the number of CD4+ infiltrating cells in the allotrachea and prevented fibrous airway obliteration. An infusion of RANTES in isografts did not induce fibrous airway obstruction, despite causing an increase in CD4+ cell migration. The authors conclude that RANTES is relevant to the recruitment of CD4+ cells and the development of fibrous airway obstruction of allorejection, and speculate that an anti-RANTES antibody might be a useful therapy for bronchiolitis obliterans after transplantation. Cellular and molecular mechanisms. Antigen presentation by dendritic cells, the most potent antigen presenting cells, are thought to be important in obliterative bronchiolitis. In biopsies from 22 lung transplant patients, Leonard and coworkers (99) found increased numbers of dendritic cells, when defined by morphology and expression of major histocompatibility complex Class II (rather than by expression of CD1a). Eight patients with obliterative bronchiolitis had higher numbers of dendritic cells than 14 stable patients. The number of dendritic cells did not correlate with rejection or cytomegalovirus pneumonitis. The authors conclude that dendritic cells are increased in patients with obliterative bronchiolitis, but when identified by the monoclonal marker, CD1a, their number may be underestimated. To determine whether insulin-like growth factor-1, a stimulator of collagen synthesis by fibroblasts, is involved in the development of obliterative bronchiolitis, Charpin and coworkers (100) studied nine patients who had undergone lung
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transplantation. Three patients developed bronchiolitis obliterans syndrome at 8, 14, and 17 months after the surgery. Compared with the six patients who did not develop the syndrome, the affected patients developed 3 to 13-fold increases in insulin-like growth factor in their bronchoalveolar fluid at 7, 13, and 17 months before the diagnosis was made. The binding protein for insulin-like growth factor was also highly expressed. The authors conclude that insulin-like growth factor-1 contributes to the fibrotic process in obliterative bronchiolitis and may serve as an early marker. De Andrade and coworkers (101) assessed whether reactive nitrogen species are increased in patients who had undergone lung transplantation. In bronchoalveolar fluid, the percent nitration of tyrosines was 10 times higher in the patients than in healthy controls, and chlorotyrosine was found only in the patients. In the patients, total nitrite was 2.5 times higher, serum nitrite was 2 times higher, and the level of nitrotyrosine was one-third of that in the controls, Airway inflammation on bronchoscopy was correlated with nitrotyrosine in bronchoalveolar fluid. The authors conclude that concentrations of reactive nitrogen species are increased in the airways of lung transplant patients. Early detection. The International Society for Heart and Lung Transplantation recommends that the diagnosis of obliterative bronchiolitis be based on histopathologic features or a persistent decrease in FEV1 of at least 20% below baseline. To determine whether tests of small airway function or bronchoalveolar lavage would result in earlier detection, ReynaudGaubert and coworkers (102) studied 45 patients who had survived at least one year after transplantation. Obliterative bronchiolitis occurred in 46% of the patients, and the diagnosis was made 57 (range, 122 to 2,619) days after transplantation. Decline in FEV1, tests of small airways disease, and alveolar neutrophilia (greater than 20% of the total bronchoalveolar count) showed good agreement regarding the diagnosis of obliterative bronchiolitis. These tests reached the diagnostic threshold value sooner than did FEV1: decline in forced expiratory flow at 25 to 75% of FVC (FEF25–27), 110 days; increase in the slope of a nitrogen washout curve, 150 days; and alveolar neutrophilia, 131 days. The diagnosis of obliterative bronchiolitis in lung transplant patients is based on pathology or an irreversible fall in FEV1 to less than 80% of the best preoperative value. To determine whether indices of ventilation distribution would provide earlier detection of obliterative bronchiolitis, Estenne and coworkers (103) followed 57 lung transplant patients for 1,215 days. A greater than 20% fall in FEV1 occurred in 18 (33%) patients. This alteration was preceded by a rise in the slope of the alveolar plateau for helium on a single-breath washout in 17 patients, indicating more heterogeneous ventilation; this change predated the change in FEV1 by one year. Of the 39 patients not showing a fall in FEV1, seven developed changes in ventilation distribution. The authors conclude that tests of ventilation distribution detect obliterative bronchiolitis earlier than FEV1, and speculate that earlier increases in immunosuppression may prevent irreversible airway damage. To determine whether abnormalities in bronchoalveolar fluid predict the risk of obliterative bronchiolitis, Scholma and coworkers (104) performed lavage about 40 days after lung transplantation. Compared with 41 patients with a good clinical outcome, 19 patients with obliterative bronchiolitis had a 50% increase in total cell count, 4.5-fold more lymphocytes, higher eosinophilic granulocyte counts, 5 times higher neutrophilic granulocytes, 4 times higher interleukin-6, and 4.7 times higher interleukin-8. On logistic regression, the risk of obliterative bronchiolitis was increased with higher total cell, neutro-
philic granulocyte and lymphocyte counts, presence of eosinophilic granulocytes, and higher concentrations of interleukin-6 and -8. The authors conclude that monitoring inflammatory markers in bronchoalveolar fluid provides better identification of patients at risk for developing obliterative bronchiolitis. In a study of 40 lung transplant recipients, Gabbay and coworkers (105) asked, “In patients with bronchiolitis obliterans, does an increase in exhaled nitric oxide reflect airway inflammation?” Exhaled nitric oxide was elevated in eight patients with bronchiolitis obliterans syndrome (20 ppb) and in six patients with airway infection (24.7 ppb), but was normal in six patients with acute rejection (13.4 ppb) and in 20 recipients of a lung transplant who were stable (12.5 ppb). Inducible nitric oxide synthase was expressed in the bronchial epithelium of patients with bronchiolitis obliterans and bacterial infection, and it was correlated with exhaled nitric oxide (r2 0.79). Expression of constitutive nitric oxide synthase was decreased in patients with bronchiolitis obliterans syndrome, but not in the other groups. The authors conclude that exhaled nitric oxide arises primarily from inducible nitric oxide synthase in the epithelium, and, because the level reflects the degree of airway inflammation, serial measurements might identify bronchiolitis obliterans at a stage while it is still reversible. Quality of life. To assess the effect of bronchiolitis obliterans syndrome on morbidity, van den Berg and coworkers (106) used self-administered questionnaires to measure health related quality of life cross-sectionally and longitudinally. Questionnaires were completed by 72 patients at 4 months and by 27 patients at 49 months after transplantation. Patients with bronchiolitis obliterans syndrome reported more restrictions on energy and physical mobility, and more depressive symptoms and anxiety. The authors conclude that bronchiolitis obliterans syndrome is associated with reduced health-related quality of life. Lymphoproliferative Disease
To determine the factors associated with the development of lymphoproliferative disease after lung transplantation, Cohen and coworkers (107) analyzed data on 128 patients having their first transplant (61 of the patients had cystic fibrosis). Of 16 patients with the disease, 13 had cystic fibrosis; of 61 patients with cystic fibrosis undergoing transplantation, 23% developed lymphoproliferative disease. In a case-control analysis of the patients with cystic fibrosis, the only factor associated with the disease was at least two episodes of acute rejection within the first three months of transplantation. The authors conclude that the greatest risk factor for the development of lymphoproliferative disease after lung transplantation is cystic fibrosis, and that the risk is greatest in patients experiencing at least two episodes of rejection. In Children
Because little information exists concerning airway complications following lung transplantation in children, Kaditis and coworkers (108) reviewed their experience in 53 patients (mean age, 14 years). Major anastomotic airway complications requiring intervention occurred in 4% of heart-lung transplants and 25% of the lung transplant patients. Granulation tissue occluding the airway occurred in four patients; it was treated with forceps resection, laser ablation, or balloon dilatation. Fibrotic strictures occurred in three patients, and were treated with silicone stents, laser ablation, or balloon dilatation. Bronchomalacia or diffuse stricture below the anastomosis occurred in two patients, and required a metal stent. The authors conclude that major anastomotic airway complica-
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tions are more common in pediatric lung transplant patients than in adults. In Cystic Fibrosis
In patients waiting for lung transplantation, donor lungs are allocated according to seniority (accrued time on the waiting list). To determine the outcome in patients with cystic fibrosis awaiting transplantation, Vizza and coworkers (109) analyzed data of a consecutive cohort. Of 146 patients, 52% underwent transplantation, 23% were alive and waiting, and 25% died while waiting. Actuarial survival for the entire cohort was 81% at one year, 67% at two years, and 59% at three years. Risk factors for dying on the waiting list were shorter six-minute walking distance, elevated systolic pulmonary artery pressure, and diabetes mellitus. These factors, however, were also common in survivors. The authors conclude that the lack of reliable predictors for survival hinders the ability to allocate donor lungs according to medical urgency.
PLEURAL DISORDERS Physiology/Pathophysiology
The volume and cellular content of pleural fluid in normal humans has not been previously measured. In 34 subjects undergoing thoracoscopy as part of management of essential hyperhidrosis, Noppen and coworkers (110) used lavage and a urea marker. The volume of fluid in the right pleural cavity was 8.4 ml or 0.26 ml per kg. The total white blood cell count was 1,716 103 per ml. The differential cell count was macrophages 75%, lymphocytes 23%, and mesothelial cells 2%. Injection of carrageenan into the pleural space causes pleurisy and lung injury. To determine the role of inducible nitric oxide synthase in these injuries, Cuzzocrea and coworkers (111) examined the responses in knockout mice lacking inducible nitric-oxide synthase. Contrasted with wildtype mice, injection of carrageenan in the knockout mice produced less pleural exudate and neutrophil migration, less lung myeloperoxidase and lipid peroxidation, and less staining for nitrotyrosine and poly adenosine diphosphate (ADP)-ribose synthetase (PARS) in the alveolar macrophages and airway epithelium. The knockout mice had less DNA strand breakage, and less nicotinamide adenine dinucleotide (NAD+) in the macrophages. The authors conclude that inducible nitric oxide plays an important role in the pleurisy and lung injury caused by carrageenan. Diagnostic Techniques
In patients with a pleural effusion, aspirating a large volume of fluid predisposes to reexpansion pulmonary edema, probably caused by markedly negative pleural pressures. Villena and coworkers (112) monitored pleural pressure during thoracentesis using a system for monitoring central venous pressure. In four patients with a visceral peel and suspected trapped lung, the mean of inspiratory and expiratory pleural pressure was lower than 4 cm H2O; their pleural elastance, measured as change in pleural pressure over volume of fluid removed, was higher than 33 cm H2O per liter. Pleural elastance ranged from 10 to 14 cm H2O per liter in 57 patients with pleural effusions. Elastance during aspiration of the first 500 ml of fluid was correlated with the total fluid aspirated (r 0.52). None of the variables predicted the appropriateness of aspirating more than 1.5 liter. The authors conclude that measurement of pleural pressure aids in the diagnosis of trapped lung, and it allows large volumes of fluid to be aspirated with few complications.
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Pleurodesis
The mechanism of symptomatic improvement with talc pleurodesis in patients with mesothelioma is not known. To address this issue, Nasreen and coworkers (113) assessed the direct effect of therapeutic concentrations of talc on malignant mesothelioma cells. Exposure to talc induced apoptosis in malignant mesothelioma cells, but not in normal pleural cells. Because all agents being used for pleurodesis have problems, Light and coworkers (114) investigated whether injecting a solitary cytokine into the pleural space would produce effective pleurodesis in rabbits. The intrapleural injection of transforming growth factor-2 produced effective pleurodesis in a dose-dependent fashion. Use of larger doses resulted in large pleural effusions. The authors conclude that a single intrapleural injection of transforming growth factor-2 may produce pleurodesis both safely and painlessly. In 36 patients with malignant pleural effusion, Diacon and coworkers (115) did a prospective comparison of two pleurodesis procedures. Bleomycin (60 IU) was instilled through a small-bore thoracostomy tube, which remained in place for at least 48 hours. Talc poudrage (5 g) was done by thorascopy under local anesthesia. In 32 treatments available for analysis, recurrence rates for effusion with bleomycin were 41% at one month, 59% at three months, and 65% at six months. Recurrence with talc was 13% at one and six months. Both procedures were equally tolerated and talc poudrage was more cost effective. The authors conclude that talc poudrage is more effective than bleomycin in the management of malignant pleural effusion. The use of talc for pleurodesis is debated by Sahn (116) and Light (117), with rebuttals from each (118, 119). The management of malignant pleural effusion is discussed in an ATS official statement (120).
LUNG CANCER Risk Factors
In 563 patients with nonasbestos pneumoconiosis, Katabami and coworkers (121) determined the incidence of diffuse interstitial fibrosis by computed tomography. Of 563 patients, 55 (10%) had diffuse interstitial fibrosis. Lung cancer occurred in 53% of patients with interstitial fibrosis and in 15% of patients without fibrosis. Squamous cell carcinomas were peripheral in type in all patients with interstitial fibrosis and in 72% of patients without fibrosis; histology revealed dysplasia in peripheral bronchioli in 69% of patients with fibrosis and in 30% of patients without fibrosis. The authors conclude that patients with pneumoconiosis and diffuse interstitial fibrosis have an increased incidence of lung cancer, especially of peripheraltype squamous cell carcinoma. Doubt about the relationship between cryptogenic fibrosing alveolitis, also known as idiopathic pulmonary fibrosis, and lung cancer has arisen because cigarette smoking may also be a risk factor for cryptogenic fibrosis alveolitis. To address this issue, Hubbard and coworkers (122) analyzed data from 890 patients with cryptogenic fibrosing alveolitis and 5,884 control subjects. The incidence of lung cancer was 7.3 times higher in patients with cryptogenic fibrosing alveolitis, and the relationship did not decrease after adjusting for smoking history. The authors conclude that the risk of lung cancer is increased in patients with cryptogenic fibrosing alveolitis, independently of cigarette smoking. This article was accompanied by an editorial commentary by Samet (123). About 10–13% of patients with idiopathic pulmonary fibrosis die from bronchogenic carcinoma. Carcinogenesis may
Year in Review
result from the inactivation of tumor-suppressor genes, and loss of heterogeneity and microsatellite instability is frequently detected in cancers. To investigate genetic alterations at the microsatellite level in sputum cells, Vassilakis and coworkers (124) used 10 polymorphic microsatellite markers in 26 patients with idiopathic pulmonary fibrosis and 26 healthy controls. Half of the patients had genetic alterations. Microsatellite instability was seen in five patients, and 10 showed loss of heterogeneity in at least one microsatellite marker. Genetic alterations were not correlated with severity of disease, and they were not seen in the controls. The authors conclude the genetic alterations are frequent in patients with idiopathic pulmonary fibrosis, and may be related to tumorigenesis. Doll (125) recalls the discovery of the link between cigarette smoking and lung cancer. Diagnosis
The expression of the glycoprotein, MUC1, is increased in a variety of adenocarcinomas. Hirasawa and coworkers (126) examined whether a natural autoantibody to MUC1 is present in the serum of patients with lung cancer. In 30 patients with non-small cell lung cancer, levels of the antibody were lower than in healthy controls. One-year survival was 21% in patients with a low level of the antibody versus 91% in patients with high levels. The authors conclude that the extent of decrease in the level of an autoantibody to MUC1 portends an ominous outcome. Harrow and coworkers (127) prospectively assessed the value of transbronchial needle aspiration for staging bronchogenic carcinoma. Positive aspirates were found in 62% of 81 patients with small cell carcinoma and in 48% of patients with non-small cell carcinoma. Of the 360 patients, transbronchial needle aspiration precluded thoracic surgery in 29% of patients, and it was the sole source of diagnosis in 18% of cases. Positive results were more likely with histologic than with cytologic aspirates (57 and 41%), and with tumors on the right side. The authors conclude that transbronchial needle aspiration is likely to provide positive results when nodes are large and on the right side, when a histology needle is used, and in patients with small cell carcinoma. The evaluation and management of the solitary pulmonary nodule is discussed by Ostand and Fein (128). Studies of Molecular Mechanisms
Angiogenesis is required for the growth and progression of solid tumors. Interleukin-8, originally classified as a neutrophil chemoattractant, has recently been shown to be an important angiogenic growth factor. In 29 patients with squamous cell carcinoma and 29 patients with adenocarcinoma, Yuan and coworkers (129) found that expression of interleukin-8 mRNA was greater in tumor tissue, and increased expression was correlated with tumor microvessel count (r 0.56), an advanced stage of malignancy, and distant lymph node malignancy. Multivariate analysis showed that interleukin-8 mRNA expression and intratumor microvessel count were the most important predictors of patient survival and relapse. The authors conclude that interleukin-8 is a useful prognostic indicator in patients with non-small-cell lung cancer. Molecular and genetic aspects of lung cancer are discussed by Rom and coworkers (130) in a state-of-the-art review. References 1. Silverman EK, Weiss ST, Drazen JM, Chapman HA, Carey V, Campbell EJ, Denish P, Silverman RA, Celedon JC, Reilly JJ, Ginns LC, Speizer FE. Gender-related differences in severe, early-onset chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:2152–2158.
1801 2. Kanazawa H, Okamoto T, Hirata K, Yoshikawa J. Deletion polymorphisms in the angiotensin converting enzyme gene are associated with pulmonary hypertension evoked by exercise challenge in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1235–1238. 3. Mayer AS, Stoller JK, Bucher BB, James RA, Sandhaus RA, Newman LS. Occupational exposure risks in individuals with PI*Z 1- antitrypsin deficiency. Am J Respir Crit Care Med 2000;162:553–558. 4. Seersholm N, Wilcke JT, Kok-Jensen A, Dirksen A. Risk of hospital admission for obstructive pulmonary disease in 1-antitrypsin heterozygotes of phenotype PiMZ. Am J Respir Crit Care Med 2000;161: 81–84. 5. Greenberg SB, Allen M, Wilson J, Atmar RL. Respiratory viral infections in adults with and without chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:167–173. 6. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608–1613. 7. Wu L, Skinner SJ, Lambie N, Vuletic JC, Blasi F, Black PN. Immunohistochemical staining for Chlamydia pneumoniae is increased in lung tissue from subjects with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1148–1151. 8. Strachan DP, Carrington D, Mendall M, Butland BK, Yarnell JW, Elwood P. Chlamydia pneumoniae serology, lung function decline, and treatment for respiratory disease. Am J Respir Crit Care Med 2000; 161:493–497. 9. Grievink L, de Waart FG, Schouten EG, Kok FJ. Serum carotenoids, -tocopherol, and lung function among Dutch elderly. Am J Respir Crit Care Med 2000;161:790–795. 10. Soejima K, Yamaguchi K, Kohda E, Takeshita K, Ito Y, Mastubara H, Oguma T, Inoue T, Okubo Y, Amakawa K, Tateno H, Shiomi T. Longitudinal follow-up study of smoking-induced lung density changes by high-resolution computed tomography. Am J Respir Crit Care Med 2000;161:1264–1273. 11. Saetta M, Turato G, Baraldo S, Zanin A, Braccioni F, Mapp CE, Maestrelli P, Cavallesco G, Papi A, Fabbri LM. Goblet cell hyperplasia and epithelial inflammation in peripheral airways of smokers with both symptoms of chronic bronchitis and chronic airflow limitation. Am J Respir Crit Care Med 2000;161:1016–1021. 12. Mapp CE, Miotto D, Braccioni F, Saetta M, Turato G, Maestrelli P, Krause JE, Karpitskiy V, Boyd N, Geppetti P, Fabbri LM. The distribution of neurokinin-1 and neurokinin-2 receptors in human central airways. Am J Respir Crit Care Med 2000;161:207–215. 13. Lim S, Roche N, Oliver BG, Mattos W, Barnes PJ, Fan CK. Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers. Regulation by interleukin-10. Am J Respir Crit Care Med 2000;162:1355–1360. 14. Sauleda J, Garcia-Palmer FJ, Gonzalez G, Palou A, Agusti AG. The activity of cytochrome oxidase is increased in circulating lymphocytes of patients with chronic obstructive pulmonary disease, asthma, and chronic arthritis. Am J Respir Crit Care Med 2000;161:32–35. 15. Takabatake N, Nakamura H, Abe S, Inoue S, Hino T, Saito H, Yuki H, Kato S, Tomoike H. The relationship between chronic hypoxemia and activation of the tumor necrosis factor- system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1179–1184. 16. Bresser P, Out TA, van Alphen L, Jansen HM, Lutter R. Airway inflammation in nonobstructive and obstructive chronic bronchitis with chronic Haemophilus influenzae airway infection. Comparison with noninfected patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:947–952. 17. Clini E, Cremona G, Campana M, Scotti C, Pagani M, Bianchi L, Giordano A, Ambrosino N. Production of endogenous nitric oxide in chronic obstructive pulmonary disease and patients with cor pulmonale. Correlates with echo-Doppler assessment. Am J Respir Crit Care Med 2000;162:446–450. 18. Ichinose M, Sugiura H, Yamagata S, Koarai A, Shirato K. Increase in reactive nitrogen species production in chronic obstructive pulmonary disease airways. Am J Respir Crit Care Med 2000;162:701–706. 19. Papi A, Romagnoli M, Baraldo S, Braccioni F, Guzzinati I, Saetta M, Ciaccia A, Fabbri LM. Partial reversibility of airflow limitation and increased exhaled NO and sputum eosinophilia in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1773– 1777. 20. Paredi P, Kharitonov SA, Leak D, Ward S, Cramer D, Barnes PJ. Exhaled ethane, a marker of lipid peroxidation, is elevated in chronic
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obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162: 369–373. Montuschi P, Collins JV, Ciabattoni G, Lazzeri N, Corradi M, Kharitonov SA, Barnes PJ. Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med 2000;162:1175–1177. Opazo Saez AM, Seow CY, Pare PD. Peripheral airway smooth muscle mechanics in obstructive airways disease. Am J Respir Crit Care Med 2000;161:910–917. Nakano Y, Muro S, Sakai H, Hirai T, Chin K, Tsukino M, Nishimura K, Itoh H, Pare PD, Hogg JC, Mishima M. Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function. Am J Respir Crit Care Med 2000;162: 1102–1108. Boussuges A, Pinet C, Molenat F, Burnet H, Ambrosi P, Badier M, Sainty JM, Orehek J. Left atrial and ventricular filling in chronic obstructive pulmonary disease. An echocardiographic and Doppler study. Am J Respir Crit Care Med 2000;162:670–675. Capderou A, Aurengo A, Derenne JP, Similowski T, Zelter M. Pulmonary blood flow distribution in stage 1 chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:2073–2078. Fishman AP. The Fick principle and the steady state. Am J Respir Crit Care Med 2000;161:692–693. Robinson TD, Freiberg DB, Regnis JA, Young IH. The role of hypoventilation and ventilation–perfusion redistribution in oxygen-induced hypercapnia during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1524–1529. Neder JA, Jones PW, Nery LE, Whipp BJ. Determinants of the exercise endurance capacity in patients with chronic obstructive pulmonary disease. The power–duration relationship. Am J Respir Crit Care Med 2000;162:497–504. Sahebjami H, Sathianpitayakul E. Influence of body weight on the severity of dyspnea in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:886–890. Montes de Oca M, Celli BR. Respiratory muscle recruitment and exercise performance in eucapnic and hypercapnic severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161: 880–885. Scherer TA, Spengler CM, Owassapian D, Imhof E, Boutellier U. Respiratory muscle endurance training in chronic obstructive pulmonary disease: impact on exercise capacity, dyspnea, and quality of life. Am J Respir Crit Care Med 2000;162:1709–1714. Hayot M, Ramonatxo M, Matecki S, Milic-Emili J, Prefaut C. Noninvasive assessment of inspiratory muscle function during exercise. Am J Respir Crit Care Med 2000;162:2201–2207. Mador MJ, Kufel TJ, Pineda LA, Sharma GK. Diaphragmatic fatigue and high-intensity exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:118–123. Mador MJ, Kufel TJ, Pineda L. Quadriceps fatigue after cycle exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:447–453. Engelen MP, Schols AM, Does JD, Deutz NE, Wouters EF. Altered glutamate metabolism is associated with reduced muscle glutathione levels in patients with emphysema. Am J Respir Crit Care Med 2000; 161:98–103. Creutzberg EC, Schols AM, Weling-Scheepers CA, Buurman WA, Wouters EF. Characterization of nonresponse to high caloric oral nutritional therapy in depleted patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:745–752. Creutzberg EC, Wouters EF, Vanderhoven-Augustin IM, Dentener MA, Schols AM. Disturbances in leptin metabolism are related to energy imbalance during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1239–1245. Engelen MP, Deutz NE, Wouters EF, Schols AM. Enhanced levels of whole-body protein turnover in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1488–1492. Engelen MP, Schols AM, Does JD, Gosker HR, Deutz NE, Wouters EF. Exercise-induced lactate increase in relation to muscle substrates in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1697–1704. Sin DD, Tu JV. Are elderly patients with obstructive airway disease being prematurely discharged? Am J Respir Crit Care Med 2000;161: 1513–1517. Taube C, Lehnigk B, Paasch K, Kirsten DK, Jorres RA, Magnussen H. Factor analysis of changes in dyspnea and lung function parameters after bronchodilation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:216–220.
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42. Littner MR, Ilowite JS, Tashkin DP, Friedman M, Serby CW, Menjoge SS, Witek TJ Jr. Long-acting bronchodilation with once-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1136–1142. 43. Oga T, Nishimura K, Tsukino M, Hajiro T, Ikeda A, Izumi T. The effects of oxitropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. A comparison of three different exercise tests. Am J Respir Crit Care Med 2000;161: 1897–1901. 44. Niewoehner DE, Collins D, Erbland ML. Relation of FEV1 to clinical outcomes during exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. Am J Respir Crit Care Med 2000;161:1201–1205. 45. Rice KL, Rubins JB, Lebahn F, Parenti CM, Duane PG, Kuskowski M, Joseph AM, Niewoehner DE. Withdrawal of chronic systemic corticosteroids in patients with COPD: a randomized trial. Am J Respir Crit Care Med 2000;162:174–178. 46. Calverley PM. Inhaled corticosteroids are beneficial in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:341–342. 47. Barnes PJ. Inhaled corticosteroids are not beneficial in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:342–344. 48. Calverley PM. Rebuttal. Am J Respir Crit Care Med 2000;161:344. 49. Barnes PJ. Rebuttal. Am J Respir Crit Care Med 2000;161:344. 50. Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS. Smoking cessation and lung function in mild-to-moderate chronic obstructive pulmonary disease. The Lung Health Study. Am J Respir Crit Care Med 2000;161:381–390. 51. Chatila W, Furukawa S, Criner GJ. Acute respiratory failure after lung volume reduction surgery. Am J Respir Crit Care Med 2000;162: 1292–1296. 52. Marchand E, De Leyn P, Gayan-Ramirez G, Palecek F, de Bock V, Dom R, Decramer M. Lung volume reduction surgery does not improve diaphragmatic contractile properties or atrophy in hamsters with elastase-induced emphysema. Am J Respir Crit Care Med 2000;162: 1052–1057. 53. Schluchter MD, Stoller JK, Barker AF, Buist AS, Crystal RG, Donohue JF, Fallat RJ, Turino GM, Vreim CE, Wu MC. Feasibility of a clinical trial of augmentation therapy for 1-antitrypsin deficiency. The 1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med 2000;161:796–801. 54. Gottlieb DJ, Luisetti M, Stone PJ, Allegra L, Cantey-Kiser JM, Grassi C, Snider GL. Short-term supplementation therapy does not affect elastin degradation in severe 1-antitrypsin deficiency. The American-Italian AATD Study Group. Am J Respir Crit Care Med 2000;162:2069–2072. 55. Garrod R, Mikelsons C, Paul EA, Wedzicha JA. Randomized controlled trial of domiciliary noninvasive positive pressure ventilation and physical training in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1335–1341. 56. Rossi A. Noninvasive ventilation has not been shown to be ineffective in stable COPD. Am J Respir Crit Care Med 2000;161:688–689. 57. Hill NS. Noninvasive ventilation has been shown to be ineffective in stable COPD. Am J Respir Crit Care Med 2000;161:689–690. 58. Rossi A. Rebuttal. Am J Respir Crit Care Med 2000;161:691. 59. Hill NS. Rebuttal. Am J Respir Crit Care Med 2000;161:691. 60. Tan WC, Qiu D, Liam BL, Ng TP, Lee SH, van Eeden SF, D’Yachkova Y, Hogg JC. The human bone marrow response to acute air pollution caused by forest fires. Am J Respir Crit Care Med 2000;161: 1213–1217. 61. Ghio AJ, Kim C, Devlin RB. Concentrated ambient air particles induce mild pulmonary inflammation in healthy human volunteers. Am J Respir Crit Care Med 2000;162:981–988. 62. Hamada K, Goldsmith CA, Goldman A, Kobzik L. Resistance of very young mice to inhaled allergen sensitization is overcome by coexposure to an air-pollutant aerosol. Am J Respir Crit Care Med 2000;161: 1285–1293. 63. Nightingale JA, Rogers DF, Fan CK, Barnes PJ. No effect of inhaled budesonide on the response to inhaled ozone in normal subjects. Am J Respir Crit Care Med 2000;161:479–486. 64. Jorres RA, Holz O, Zachgo W, Timm P, Koschyk S, Muller B, Grimminger F, Seeger W, Kelly FJ, Dunster C, Frischer T, Lubec G, Waschewski M, Niendorf A, Magnussen H. The effect of repeated ozone exposures on inflammatory markers in bronchoalveolar lavage fluid and mucosal biopsies. Am J Respir Crit Care Med 2000;161: 1855–1861. 65. Sterner-Kock A, Kock M, Braun R, Hyde DM. Ozone-induced epithelial injury in the ferret is similar to nonhuman primates. Am J Respir Crit Care Med 2000;162:1152–1156.
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Year in Review 66. Avissar NE, Reed CK, Cox C, Frampton MW, Finkelstein JN. Ozone, but not nitrogen dioxide, exposure decreases glutathione peroxidases in epithelial lining fluid of human lung. Am J Respir Crit Care Med 2000;162:1342–1347. 67. Inoue H, Aizawa H, Nakano H, Matsumoto K, Kuwano K, Nadel JA, Hara N. Nitric oxide synthase inhibitors attenuate ozone-induced airway inflammation in guinea pigs. Possible role of interleukin-8. Am J Respir Crit Care Med 2000;161:249–256. 68. Hashimoto S, Gon Y, Takeshita I, Matsumoto K, Jibiki I, Takizawa H, Kudoh S, Horie T. Diesel exhaust particles activate p38 MAP kinase to produce interleukin 8 and RANTES by human bronchial epithelial cells and N-acetylcysteine attenuates p38 MAP kinase activation. Am J Respir Crit Care Med 2000;161:280–285. 69. Salvi SS, Nordenhall C, Blomberg A, Rudell B, Pourazar J, Kelly FJ, Wilson S, Sandstrom T, Holgate ST, Frew AJ. Acute exposure to diesel exhaust increases IL-8 and GRO- production in healthy human airways. Am J Respir Crit Care Med 2000;161:550–557. 70. Kobayashi T. Exposure to diesel exhaust aggravates nasal allergic reaction in guinea pigs. Am J Respir Crit Care Med 2000;162:352–356. 71. Nightingale JA, Maggs R, Cullinan P, Donnelly LE, Rogers DF, Kinnersley R, Fan CK, Barnes PJ, Ashmore M, Newman-Taylor A. Airway inflammation after controlled exposure to diesel exhaust particulates. Am J Respir Crit Care Med 2000;162:161–166. 72. American Thoracic Society. What constitutes an adverse health effect of air pollution? Official statement of the American Thoracic Society. Am J Respir Crit Care Med 2000;161:665–673. 73. Deng Z, Haghighi F, Helleby L, Vanterpool K, Horn EM, Barst RJ, Hodge SE, Morse JH, Knowles JA. Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33. Am J Respir Crit Care Med 2000;161:1055–1059. 74. Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000;161:487–492. 75. Eddahibi S, Humbert M, Sediame S, Chouaid C, Partovian C, Maitre B, Teiger E, Rideau D, Simonneau G, Sitbon O, Adnot S. Imbalance between platelet vascular endothelial growth factor and platelet-derived growth factor in pulmonary hypertension. Effect of prostacyclin therapy. Am J Respir Crit Care Med 2000;162:1493–1499. 76. Qing F, McCarthy TJ, Markham J, Schuster DP. Pulmonary angiotensin-converting enzyme (ACE) binding and inhibition in humans. A positron emission tomography study. Am J Respir Crit Care Med 2000;161:2019–2025. 77. Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG, Kao PN. Triptolide attenuates pulmonary arterial hypertension and neointimal formation in rats. Am J Respir Crit Care Med 2000;162:2252–2258. 78. Newman JH, Lane KB. Hypertensive pulmonary vascular disease: dawn of the age of prevention? Am J Respir Crit Care Med 2000;162: 2020–2021. 79. Hojoong K, Yi ES, Ahn H, Strother J, Morris T, Masliah E, Hansen LA, Park K, Friedman PJ. Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension. A morphometric and immunohistochemical study. Am J Respir Crit Care Med 2000;162:1577–1586. 80. Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med 2000;162:1964–1973. 81. Lorut C, Ghossains M, Horellou MH, Achkar A, Fretault J, Laaban JP. A noninvasive diagnostic strategy including spiral computed tomography in patients with suspected pulmonary embolism. Am J Respir Crit Care Med 2000;162:1413–1418. 82. Bailey CL, Channick RN, Auger WR, Fedullo PF, Kerr KM, Yung GL, Rubin LJ. “High probability” perfusion lung scans in pulmonary venoocclusive disease. Am J Respir Crit Care Med 2000;162:1974–1978. 83. Rodger MA, Carrier M, Jones GN, Rasuli P, Raymond F, Djunaedi H, Wells PS. Diagnostic value of arterial blood gas measurement in suspected pulmonary embolism. Am J Respir Crit Care Med 2000;162: 2105–2108. 84. Hartmann IJ, Hagen PJ, Melissant CF, Postmus PE, Prins MH. Diagnosing acute pulmonary embolism: effect of chronic obstructive pulmonary disease on the performance of D-dimer testing, ventilation/ perfusion scintigraphy, spiral computed tomographic angiography, and conventional angiography. ANTELOPE Study Group. Advances in New Technologies Evaluating the Localization of Pulmonary Embolism. Am J Respir Crit Care Med 2000;162:2232–2237. 85. Baile EM, King GG, Muller NL, D’Yachkova Y, Coche EE, Pare PD, Mayo JR. Spiral computed tomography is comparable to angiogra-
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