Year in Review Tuberculosis, Lung Infections, Interstitial Lung Disease, Social Issues and Journalology in AJRCCM 2003 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
TUBERCULOSIS
Tuberculosis (28) Studies of Molecular Mechanisms in Tuberculosis (6) Epidemiology of Tuberculosis (3) Latent Tuberculosis Infection (2) Diagnosis of Tuberculosis (2) Treatment of Tuberculosis (12) Nontuberculous Mycobacteria (3) Nontuberculous Lung Infection (26) Human Immunodeficiency Virus Infection (1) Lung Infections (21) Host Defenses (11) Pneumonia (6) Antimicrobial Therapy (4) Bronchiectasis (4) Interstitial Lung Disease (47) Idiopathic Pulmonary Fibrosis (26) Genetics (1) Histopathological Subtypes (2) Clinical Assessment (7) Cellular and Molecular Mechanisms, in vivo (11) Cellular and Molecular Mechanisms, ex vivo (3) Treatment (2) Progressive Systemic Sclerosis (1) Sarcoidosis (6) Genetics (4) Molecular Mechanisms (1) Clinical Manifestations (1) Lymphangioleiomyomatosis (3) Pulmonary Drug Toxicity (1) Hypersensitivity Pneumonitis (3) Rodent Model of Bleomycin Fibrosis (7) Occupational Lung Disease (5) Social Issues, Professional Training, and Journalology (10) Social Issues and Professional Training (5) Journalology (5)
Studies of Molecular Mechanisms in Tuberculosis
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 169. pp 288–300, 2004 DOI: 10.1164/rccm.2312006 Internet address: www.atsjournals.org
To determine whether genetically determined decreased production of interferon-␥, interleukin-10, or both, alters susceptibility to pulmonary tuberculosis, Lopez-Manderuelo and coworkers (1) studied 113 patients with culture-proven pulmonary tuberculosis, 207 healthy close contacts (125 of whom were tuberculin reactive), and 100 healthy tuberculin-negative control subjects. Individuals who were homozygous for the interferon-␥ (⫹874) A allele had a 3.75-fold increased risk of developing tuberculosis. Stimulated production of interferon-␥ by peripheral mononuclear cells from patients with genotype AA was depressed as compared with that of non-AA homozygotes at the time of diagnosis and after completing therapy. On multivariate analysis, AA genotype and the absolute number of lymphocytes were the only independent predictors of interferon-␥ production. Susceptibility to tuberculosis was not associated with polymorphism of the interleukin-10 gene. The authors conclude that a genetic defect in the production of interferon-␥ among individuals homozygous for the (⫹874) A allele contributes to increased risk of pulmonary tuberculosis. An editorial commentary by Bellamy (2) accompanies this article. Interleukin-2 has a central role in regulating T cell responses to Mycobacterium tuberculosis. Johnson and coworkers (3) did a randomized double-blind trial in 110 human immunodeficiency virus (HIV)-seronegative patients with smear-positive, drug-susceptible, newly diagnosed pulmonary tuberculosis. Patients were randomized to placebo or interleukin-2 (twice daily injections of 225,000 IU) for the first 30 days plus standard chemotherapy, and were followed for 1 year. At 1 month, sputum culture converted to negative in 17% of the interleukin-2 group and 30% of the placebo group. At 2 months, sputum culture was negative in 77% of the interleukin-2 group and 85% of the placebo group. Improvements in fever, cough, chest pain, or weight gain did not differ between the groups. The authors conclude that treatment with interleukin-2 did not enhance sputum bacillary clearance or improve clinical symptoms in HIV-seronegative adults with drug-susceptible pulmonary tuberculosis. An editorial commentary by Barnes (4) accompanies this article. Osteopontin is a noncollagenous matrix protein produced by macrophages and T lymphocytes, and is expressed in granulomatous lesions caused by Mycobacterium tuberculosis infection. Koguchi and coworkers (5) compared plasma osteopontin levels in 48 patients with tuberculosis, 20 patients with sarcoidosis, and 34 control subjects. Patients with tuberculosis had higher levels than the other two groups. Levels of osteopontin correlated with the size of tuberculosis lesions on chest X-rays, and levels fell with chemotherapy. In patients with tuberculosis, plasma osteopontin was correlated with interleukin-12. In vitro experiments revealed that production of peripheral blood mononuclear cells
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infected with Mycobacterium bovis bacillus Calmette-Guerin preceded the synthesis of interleukin-12 and interferon-␥; the neutralizing anti-osteopontin monoclonal antibody decreased the production of interleukin-12 and interferon-␥. The authors conclude that osteopontin modulates the pathology of active pulmonary tuberculosis by inducing interleukin-12–mediated type 1 T helper cell responses. Both CD4⫹ and CD8⫹ T cells are important for successful immunity to tuberculosis and have redundant effector functions, including the release of potent cytokines. Lewinsohn and coworkers (6) determined whether CD8⫹ T cells also play an important role in defense against Mycobacterium tuberculosis infection. In a study using human Mycobacterium tuberculosis– specific CD4⫹ and CD8⫹ T cell clones, after recognition of antigen-presenting cells displaying peptide antigen, CD4⫹ T cells preferentially released interferon-␥, whereas CD8⫹ T cells preferentially lysed antigen-presenting cells. In a study using dendritic cells infected with Mycobacterium tuberculosis, CD8⫹ T cells preferentially recognized heavily infected cells (which constitute the minority of infected cells). The authors conclude that CD8⫹ T cells, through preferential use of the granule exocytosis pathway and preferential recognition of heavily infected cells, plays an essential role in the control of infection with Mycobacterium tuberculosis. Epidemiology of Tuberculosis
In 17 acute care hospitals in Canada, Menzies and coworkers (7) determined the risk of tuberculosis infection among microbiology and pathology technicians without direct patient contact. The average annual risk of tuberculin conversion was 1.0% among laboratory workers. Conversion was associated with being a pathology technician (adjusted odds ratio, 5.4), missed diagnosis in the first 24 hours (odds ratio per 20% increase, 2.0), treatment delayed 1 week or more (odds ratio per 20% increase, 2.0), and higher mortality (odds ratio per 20% increase, 2.5). Only 51% of work areas had an adequate direction of airflow and air changes per hour. Tuberculin conversion was associated with lower air exchange rate per hour than in workers without conversion (16.7 versus 32.5). The authors conclude that the risk of tuberculin conversion is increased in laboratory technicians who work in hospitals that have a high proportion of patients with delayed or missed diagnoses, or high mortality from tuberculosis, and that the risk is modified by workplace ventilation. To evaluate risk factors for tuberculosis infection in highly endemic countries, Lienhardt and coworkers (8) did a household study in the Gambia. The risk of a positive tuberculin skin test (10 mm or more) was greater in household contacts of 315 patients with smear-positive pulmonary tuberculosis than in 305 control subjects in the community (odds ratio, 3.46). The risk of a positive skin test increased with age, male sex, and duration of stay in the household, but not with a BCG scar. Within the households of patients with tuberculosis, the risk of positive skin test was higher with male sex, social proximity to the case, and extent of disease on chest X-ray. The authors conclude that the risk of tuberculosis infection is associated with age, sex, intensity of exposure, and severity of disease in the case. The Arctic Inuit communities experienced dramatic increases in tuberculosis in the 1960s and 1970s, with rates that are at least 10–20 times that of the Canadian average. Using both traditional and molecular epidemiologic techniques, Nguyen and coworkers (9) studied all cases of culture-positive Mycobacterium tuberculosis among Arctic Inuit communities of Quebec between 1990 and 2000. The 46 cases had a bimodal age distribution (48% were younger than 25 years). Genotyping analysis revealed that 35 (76%) of the tuberculosis cases were clustered and that 29
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(63%) of the cases represented ongoing transmission. The authors conclude that the results of the genotyping clustering of tuberculosis in the Inuit community of Quebec are concordant with recognized epidemiologic links but mostly identify previously unrecognized transmission between villages. Latent Tuberculosis Infection
Two months of rifampin and pyrazinamide has been recommended in the treatment of latent tuberculosis infection. Stout and coworkers (10) evaluated the safety and tolerance of this regimen in 114 patients in North Carolina, 60.4% of whom were homeless and 17% of whom were alcoholic. The full 2-month course was completed by 67.5% of the patients. The total (confirmed and suspected) hepatitis rate was 5.3%. None of the patients developing hepatitis had a previous history of liver disease. No patient was hospitalized or died from side effects. The authors conclude that two months of rifampin and pyrazinamide results in a high completion rate in patients with latent tuberculosis, although the rate of hepatitis is higher than that described for isoniazid. An editorial commentary by Jasmer and Daley (11) accompanies this article. Diagnosis of Tuberculosis
In 113 patients with suspected pleural tuberculosis who were unable to produce sputum spontaneously, Conde and coworkers (12) determined the diagnostic reliability of induced sputum. A final diagnosis of pleural tuberculosis was made in 84 (71 HIVseronegative) patients. Histopathological examination of pleural biopsy tissue had a diagnostic yield of 78% (66 of 84). Bacteriologic yields were 62% for pleural biopsy, 12% for pleural fluid, and 52% for sputum cultures obtained by sputum induction. The yield for cultures of induced sputum was equivalent in patients without radiologic involvement (other than a pleural effusion) and in patients with parenchymal involvement suggestive of pulmonary tuberculosis: 55% versus 45%. The authors conclude that culture of induced sputum is positive in 52% of patients with suspected pleural tuberculosis who are unable to produce sputum spontaneously. An editorial commentary by Menzies (13) accompanies this article. Treatment of Tuberculosis
The fall in colony-forming units (per millimeter of sputum per day) over the first two days of antituberculosis therapy is termed early bactericidal activity and is widely used for assessing activity of a drug. To further delineate features of this activity, Jindani and coworkers (14) re-examined data from a 1980 study. Colonyforming units of Mycobacterium tuberculosis in sputum were counted at 2-day intervals in 100 patients treated with 22 antituberculosis drug regimens. The exponential fall in colony-forming units was measured by linear regression coefficients of the log counts during the initial 2 days of rapid, drug-determined killing and during the subsequent 12 days of much slower sterilizing activity. Regression coefficients during the first 2 days varied among drugs, and the greatest effects resulted with isoniazid and rifampin. The rapid kill obtained with isoniazid was unaffected by the addition of other drugs. Regression analysis of coefficients during the second to fourteenth day revealed significant effects for rifampin and streptomycin; isoniazid and pyrazinamide did not have significant effects. Analysis of combined drug regimens revealed that ethambutol reversed the sterilizing activity of other drugs. The authors conclude that early bactericidal activity during the first 2 days and the fall in counts after 2 days estimate different properties of antituberculosis drugs. An editorial commentary by Burman (15) accompanies this article. Among 430 patients being treated for active tuberculosis,
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between 1990 and 1999, Yee and coworkers (16) estimated the incidence and risk factors for side effects with antituberculosis drugs. The incidence of all major side effects was 1.48 (per 100 person-months of exposure) for pyrazinamide, 0.49 for isoniazid, 0.43 for rifampin, and 0.07 for ethambutol. Occurrence of any major side effect was associated with female sex (adjusted hazard ratio, 2.5), age over 60 years (adjusted hazard ratio, 2.9), birthplace in Asia (adjusted hazard ratio, 2.5), and HIV-positive status (adjusted hazard ratio, 3.8). Pyrazinamide-associated adverse effects were associated with age over 60 years (adjusted hazard ratio, 2.6) and birthplace in Asia (adjusted hazard ratio, 3.4). Rifampin-associated adverse effects were associated with age over 60 years (adjusted hazard ratio, 3.9) and HIV-positive status (adjusted hazard ratio, 8.0). The authors conclude that the incidence of pyrazinamide-induced hepatotoxicity and rash is substantially higher than with other first-line antituberculosis drugs and higher than previously recognized. An editorial commentary by Chaisson (17) accompanies this article. To determine adverse effects and treatment completion rates associated with use of isoniazid, LoBue and Moser (18) analyzed data collected at a county tuberculosis clinic. Outcomes were available for 3,788 patients started on isoniazid between 1999 and 2002. One or more adverse effect was experienced by 672 patients (18%), and 10 (0.3%) patients developed isoniazidassociated liver injury. No patient experiencing an adverse effect died or was admitted to the hospital. The incidence of adverse effects increased with age. Six or more months of isoniazid was completed by 64 patients. Higher completion rates were associated with younger age, Hispanic ethnicity, and being born outside of the United States. Lower completion rates were associated with homelessness, using excess alcohol, and occurrence of a side effect. The authors conclude that isoniazid is safe in the treatment of latent tuberculosis but its effectiveness is limited by a modest completion rate. An editorial by Nolan (19) accompanies this article. To better understand why once-weekly isoniazid/rifapentine therapy is less effective than twice weekly isoniazid/rifampin, Weiner and coworkers (20) studied 133 HIV-seronegative patients recruited from a comparative treatment trial (4 failed, 35 relapsed, and 94 were cured). Patients who failed or relapsed with once-weekly isoniazid/rifapentine had a lower plasma isoniazid than did control cases: area under the concentration–time curve for 12 hours after dosing of 36 versus 56 g · hour per ml; no difference was seen with twice-weekly isoniazid/rifampin. (Two patients who relapsed with Mycobacterium tuberculosis monoresistant to rifamycin had very low concentrations of isoniazid.) Isoniazid acetylator status (determined by N-acetyl-transferase type 2 genotype) was associated with outcome in the onceweekly isoniazid/rifapentine group but not in the twice-weekly isoniazid/rifampin group. No pharmacological parameter of rifamycin was consistently associated with outcome. The authors conclude that isoniazid pharmacokinetics explain at least in part the decrease in efficacy of once-weekly treatment with isoniazid/ rifapentine in patients with tuberculosis. An editorial commentary by Mitchison (21) accompanies this article. Quinolones are now used in patients with tuberculosis who are not able to tolerate first-line agents or who are infected with multiple drug–resistant strains. Gosling and coworkers (22) randomized 43 patients with smear-positive pulmonary tuberculosis to receive moxifloxacin (300 mg), isoniazid (300 mg), or rifampin (600 mg) for 5 days. Sputa were collected for 2 days before and for the 5 days of treatment with each agent. On the first measure of bactericidal activity, the time taken to kill 50% of viable bacilli (vt50), isoniazid (0.46 days) was more effective than moxifloxacin (0.88 days) or rifampin (0.71 days). On the second measure of bactericidal activity, the fall in sputum viable count during the
first two days (early bactericidal activity), isoniazid (0.77) was again more active that rifampin (0.28), but not more active than moxifloxacin (0.53). The authors conclude that moxifloxacin has an activity equivalent to that of rifampin in patients with pulmonary tuberculosis. An editorial commentary by O’Brien (23) accompanies this article. The American Thoracic Society, the Centers for Disease Control and Prevention, and Infectious Diseases Society of America (24) present a statement on the treatment of tuberculosis. In an occasional essay, Murray (25) recalls Bill Dock and location of tuberculosis in the lung. Nontuberculous Mycobacteria
To determine the prevalence of nontuberculous mycobacteria and clinical features in patients with cystic fibrosis, Olivier and coworkers (26) did a prospective cross-sectional study at 21 U.S. centers. The prevalence of nontuberculous mycobacteria in sputum was 13%. The most common species were Mycobacterium avium complex (72%) and Mycobacterium abscessus (16%). Compared with culture-negative patients, the culture-positive patients were older (26 versus 22 years), had a higher FEV1 (60 versus 54%), higher frequency of Staphylococcus aureus (43 versus 31%), and lower frequency of Pseudomonas aeruginosa (71 versus 82%). Molecular typing revealed unique strains in almost all patients. The authors conclude that nontuberculous mycobacteria are common in patients with cystic fibrosis, and that person-to-person spread or nosocomial acquisition does not explain the higher acquisition. An editorial commentary by Griffith (27) accompanies this article. To determine the short-term effect of nontuberculous mycobacteria on the clinical course of patients with cystic fibrosis, Olivier and coworkers (28) followed 60 incident-positive and 99 culture-negative patients for 15 months. The annual rate of decline in FEV1 was 5% in patients who met ATS criteria for nontuberculous mycobacteria disease, 3% in culture-positive patients not meeting the ATS criteria, and 3% in control subjects. Two or more characteristic findings on high-resolution computed tomography were seen in 60% patients with three or more positive cultures, in 32% of patients two or fewer positive cultures, and in 19% of patients with negative cultures. Progression of changes on computed tomography was seen in all of the patients with three or more positive cultures. The authors conclude that multiple positive cultures for nontuberculous mycobacteria in patients with cystic fibrosis predict progressive changes on computed tomography without affecting FEV1. An editorial commentary by Griffith (27) accompanies this article.
NONTUBERCULOUS LUNG INFECTION Human Immunodeficiency Virus Infection
Nunes and coworkers (29) reported a series of 82 patients with HIV-associated pulmonary arterial hypertension. Pulmonary hypertension was the direct cause of death in 72% of the patients. Survival rate in the overall population was 73% at 1 year, 60% at 2 years, and 47% at 3 years. Compared with New York Heart Association functional Class I-II, patients in functional Class III-IV at the time of diagnosis had lower survival rates at 1 year (60 versus 100%), 2 years (45 versus 90%), and 3 years (28 versus 84%). In patients with functional Class III-IV, univariate analysis revealed that prognosis was related to CD4 lymphocyte count of more than 212 cells mm⫺3, use of combination antiretroviral therapy, and use of epoprostenol. Multivariate analysis revealed CD4 lymphocyte count as the only independent predictor of survival, probably because combination antiretroviral therapy and epoprostenol therapy were linked in these patients. The authors conclude that pulmonary artery hypertension has
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an independent negative effect on prognosis in patients with HIV infection, and that epoprostenol should be considered in the treatment of patients with severe pulmonary hypertension Lung Infections
Host defenses. The virulence of Pseudomonas aeruginosa is partly controlled by a quorum-sensing (cell-to-cell signaling) system, which allows bacteria to sense their own cell density and to communicate with each other. Lesprit and coworkers (30) investigated the impact of this system by comparing the virulence of two bacterial strains in a rat model of acute pneumonia. After a bacterial challenge (instillation of 106 cfu), mortality with PAO1, a wild bacterial strain that possesses two functional quorum-sensing systems, was 72%; mortality with PAOR, an isogenic mutant strain (produced by gene replacement) with deletion of lasR (a transcriptional activator of target genes), was zero. A 10-fold higher bacterial challenge (107 cfu) increased mortality induced by PAOR to 25%, but it remained lower than the mortality of 75% with the wild-type PAO1 strain. Bacterial counts in lung inocula and bronchoalveolar lavages were lower in rats infected with PAOR than in rats infected with PAO1. Histology revealed drastic vascular congestion and neutrophil infiltration of lungs in rats infected with PAO1, but mild, predominantly macrophage, infiltration in rats infected with PAOR. The authors conclude that the quorum-sensing system plays an important role in the pathophysiology of pneumonia caused by Pseudomonas aeruginosa. An editorial commentary by Prince (31) accompanies this article. Knapp and coworkers (32) investigated the role of alveolar macrophages in the clearance of bacteria and resolution of the inflammatory response in a model of murine pneumonia. Macrophages were depleted by pulmonary administration of liposomal dichloromethylenebisphosphonate. Inoculation with Streptococcus pneumonia caused a higher mortality in mice with depleted macrophages than in control mice, although bacterial clearance did not differ. Poor outcome was accompanied by increased local production of proinflammatory cytokines and elevated and prolonged accumulation of pulmonary neutrophils. The neutrophils contained a high proportion of apoptotic and secondary necrotic cells, reflecting impaired clearance. Caspase-3 staining was only slightly increased, indicating that apoptosis per se was not accelerated. The authors conclude that alveolar macrophages play an indispensable role in the host response to pneumococcal pneumonia, possibly through elimination of apoptotic neutrophils. An editorial commentary by Rubins (33) accompanies this article. Tumor necrosis factor-␣ plays an important role in innate immunity and also appears to serve as a growth factor for certain bacteria. Lee and coworkers (34) investigated this phenomenon in mice. In in vitro studies, tumor necrosis factor-␣ increased the proliferation of Escherichia coli, but not Pseudomonas aeruginosa, in a concentration-dependent manner; antibodies directed against tumor necrosis factor-␣ attenuated the effect. In in vivo studies, however, mice deficient in the gene for tumor necrosis factor-␣ (TNF-␣⫺/⫺) experienced a higher mortality after inoculation with intranasal bacteria than did wild-type (TNF-␣⫹/⫹) mice. The TNF-␣⫺/⫺ mice exhibited an impairment in clearance of bacteria, which was associated with decreased systematic clearance of chemokine macrophage inflammatory protein-␣, reduced neutrophil recruitment, and depressed expression of neutrophil CD11b and CD16/CD32; these findings suggest that the effect of tumor necrosis factor-␣ on growth of E. coli was outweighed by the recruited neutrophils. Counts of E. coli in the lungs of neutropenic wild-type mice were about 100-fold higher than in TNF-␣⫺/⫺ mice, and yet survival rates were equivalent in the two groups. The authors conclude that tumor necrosis factor-␣ augments growth of E. coli, both in vitro and in vivo,
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although the in vivo effect is only apparent in neutropenic animals. An editorial commentary by Mizgerd (35) accompanies this article. Platelet endothelial cell adhesion molecule-1 is believed to mediate transendothelial migration of leukocytes after CD11/ CD18-mediated adhesion. Tasaka and coworkers (36) studied the role of this adhesion molecule in the migration of neutrophils across pulmonary capillaries and the bronchial microvasculature in mice and rats. Neutrophil emigration was induced by E. coli, a stimulus eliciting CD11/CD18-dependent emigration, or by Streptococcus pneumoniae, a stimulus inducing CD11/CD18independent emigration. Antibodies that block platelet endothelial cell adhesion molecule-1 partially inhibited glycogen-induced emigration of neutrophils into the peritoneum; the antibodies, however, did not prevent emigration of neutrophils across either the pulmonary capillaries or the bronchial microvasculature in response to either E. coli or S. pneumoniae. The antibody did not increase the number of neutrophils within the bronchial vessels. The authors conclude that CD11/CD18-dependent or CD11/ CD18-independent adhesion pathways may individually lead to migration of neutrophils through the pulmonary or bronchial endothelium independently of platelet adhesion cell adhesion molecule-1. Destruction of the extracellular matrix is common in patients with hospital-acquired pneumonia. Hartog and coworkers (37) did mini bronchoalveolar lavages in 30 patients with hospitalacquired pneumonia and 16 control subjects, and assessed activity of matrix metalloproteinases. Compared with the control subjects, the patients had 10-fold increases in metalloproteinase-8 and -9, whereas tissue inhibitor of metalloproteinase-1 was not increased. The active form of metalloproteinase-9 was found in 80% of the patients with pneumonia, but in none of the control subjects; neutrophils were the main source of the enzyme. Basal release of metalloproteinase was higher from pulmonary neutrophils than from blood neutrophils; pulmonary neutrophils were maximally activated. Concentrations of metalloproteinase were five times higher in patients with positive cultures than in patients with negative cultures. The levels of metalloproteinase were related to clinical severity. The authors conclude the neutrophil-derived metalloproteinases are increased in hospital-acquired pneumonia and are associated with positive cultures and clinical severity. Wood and coworkers (38) describe three patients who developed disseminated histoplasmosis while being treated with an antibody directed against tumor necrosis factor-␣. In samples of alveolar macrophages and peripheral monocytes from healthy volunteers, both an antibody against tumor necrosis factor-␣ (infliximab) and control antibody enhanced fungal growth, suggesting a nonspecific antibody response. Lymphocyte proliferation in response to infection of blood monocytes and alveolar macrophages with Histoplasma capsulatum was inhibited by the addition of physiologic doses of infliximab but not by control antibodies (intracellular fungal loads were equivalent for both). In 5-day cultures of lymphocytes, monocytes, or alveolar macrophages, infliximab decreased the production of interferon-␥. The authors conclude that therapy with an antibody directed against tumor necrosis factor-␣ predisposes to disseminated histoplasmosis, possibly by inducing a defect in the type 1 (Th1) helper T cell arm of cellular immunity. Many genes elicited by bacteria in the lungs are regulated by B sites in DNA, which bind nuclear factor-B proteins. Mizgerd and coworkers (39) determined whether the p50 subunit of nuclear factor-B limits the expression of B-associated genes and prevents excessive inflammation and injury. During pneumonia caused by E. coli, gene-targeted deficiency of p50 caused increased mortality, but it did not alter bacterial clearance from mouse
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lungs. Deficiency of p50 caused increased expression of proinflammatory cytokines. The dysregulation produced aggravation of inflammation (increased neutrophil recruitment), pulmonary edema, worse gas exchange, and leak of protein and bacteria from the lungs with consequent bacteremia and multiple organ failure. The authors conclude that the endogenous p50 subunit of nuclear factor-B limits the inflammatory injury that occurs during pneumonia. To characterize the antioxidant properties of the airway secretions of healthy subjects, El-Chemaly and coworkers (40) did tracheal lavages in eight nonsmokers without lung disease. The 20-l samples scavenged 0.57 mmol of hydrogen peroxide within 10 minutes. The scavenging activity was inhibited 60% by azide (an inhibitor of heme-containing peroxidases and catalase) and 42% by dapsone (an inhibitor of lactoperoxidase). An inhibitor of glutathione peroxidase (mercaptosuccinic acid) did not inhibit the scavenging activity. A fourfold dilution of the secretions revealed only nonenzymatic scavenging activity; addition of thiocyanate (a substrate for lactoperoxidase) restored scavenging activity. The addition of glutathione enhanced only nonenzymatic scavenging activity. The authors conclude that multiple enzymatic and nonsystematic systems for scavenging hydrogen peroxide are present in normal airway secretions and the lactoperoxidase system is the major consumer of hydrogen peroxidase. Pneumonia. To define the microbiology of severe aspiration pneumonia in institutionalized elderly patients, El-Solh and coworkers (41) prospectively studied 95 patients with severe aspiration pneumonia older than 65 years admitted to their ICU from a long-term care facility. Quantitative bronchial samples were obtained in 95 patients, and 67 pathogens were identified. Organisms were gram-negative enteric bacilli (49%), anaerobic bacilli (16%), and Staphylococcus aureus (12%); Prevotella and Fusobacterium species were the most common anaerobes. Aerobic gram-negative bacilli were recovered in conjunction with 55% of anaerobic isolates. Dental plaque did not differ between the aerobic and anaerobic groups. Functional status was the only determinant of anaerobic bacteria. Seven patients with anaerobic isolates initially received inadequate antimicrobial therapy, yet 6 had an effective clinical response. Crude mortality was 33% for the aerobic group and 36% for the anaerobic group. Multivariate analysis revealed hypoalbuminemia and the burden of comorbid diseases as independent risk factors for poor outcome. The authors conclude that anaerobes represent a significant proportion of oral flora in institutionalized elderly patients, but their role in causing aspiration pneumonia has been overemphasized To assess the relative efficacy of high-dose pulse glucocorticoids versus nonpulse glucocorticoids in the management of patients with severe acute respiratory syndrome (SARS), Ho and coworkers (42) retrospectively analyzed data on 72 patients with probable SARS. Pulse therapy (methylprednisolone of at least 500 mg daily) was used in 17 patients, and nonpulse therapy (methylprednisolone less than 500 mg daily) was initially used in 55 patients. After 21 days, mortality was equivalent in the two groups, as was cumulative dose of glucocorticoids, rate of ICU admission and mechanical ventilation, and hematologic and biochemical variables. Patients receiving pulse glucocorticoids had better radiographic outcomes, lower oxygen requirements, and less likelihood of requiring rescue therapy with pulse glucocorticoids than did the patients treated with nonpulse glucocorticoids. The authors conclude that patients with SARS achieve greater benefit with the use of high-dose pulse glucocorticoid therapy as compared with patients treated with lower dosages of glucocorticoids. An editorial commentary by Bernard (43) accompanies this article. In a clinical commentary, Tsang and Lam (44) discuss the experience of managing patients with SARS at Hong Kong University.
In a pulmonary perspective, Shortridge (45) discusses the role of zoonotic incursions from southern China in the development of SARS and influenza. In an occasional essay, Zhong and Zeng (46) discuss strategies for fighting SARS. Antimicrobial therapy. Because measurement of the concentration of antimicrobial agents in bronchial epithelial lining fluid would enable more informed decisions about dosing, Yamazaki and coworkers (47) developed a bronchoscopic microsampling probe for this purpose. Ten healthy subjects took levofloxacin orally. The concentration of levofloxacin in epithelial lining fluid was 43% of the corresponding serum value at 1 hour, reached the same level as serum at 2 hours, and decreased in a manner similar to that in serum, becoming undetectable at 24 hours. After 6 hours, the concentration of levofloxacin exceeded minimal inhibitory concentrations for Staphylococcus aureus, Klebsiella species, and Haemophilus influenzae. The subjects tolerated the procedure well without complications. The authors conclude that bronchoscopic microsampling of bronchial epithelial lining fluid is a feasible and promising method for directly and repeatedly measuring the concentrations of antimicrobial agents in target sites of the respiratory tract. An editorial commentary by Fish (48) accompanies this article In a state of the art review article, Gibson and colleagues (49) discusses the pathophysiology and management of infections in cystic fibrosis. In a clinical commentary, Tan and colleagues (50) discuss the use of aminoglycosides in the management of patients with cystic fibrosis. Bronchiectasis
To determine whether recurrent airway infection with nontypeable Haemophilus influenza is associated with nonclearing adaptive immunity, King and coworkers (51) studied 15 patients with idiopathic bronchiectasis who had severe chronic infection with H. influenza and 24 healthy subjects. All patients and control subjects had detectable antibody to nontypeable H. influenza, indicating that most people had developed an adaptive immune response. The healthy subjects made a type 1 (Th1) helper T cell response to nontypeable H. influenza with distinct CD40 ligand production. Patients with bronchiectasis mainly produced type 2 (Th2) helper T cell cytokines, with decreased expression of CD40 ligand, and higher levels of IgG1 and IgG3 subclasses. The authors conclude that infection with nontypeable H. influenza is common and that most normal people have developed protective immunity against the organism characterized by type 1 (Th1) helper T cell predominance, whereas a type 2 (Th2) helper T cell response predominates in patients with bronchiectasis. An editorial commentary by Murphy (52) accompanies this article. It is not clear why neutrophil elastase activity is dominant in bronchial secretions of patients with bronchiectasis, given that the local environment is replete with antiproteases. In sputum samples from 10 patients with bronchiectasis, Chan and workers (53) assessed whether components in the bronchial secretions bind neutrophil elastase and compromise the inhibitory efficiency of antielastases. In sputum sols from the patients, elastase activity was found in a polydisperse, alcian blue–stained zone of high molecular mass, suggesting that elastase was complexed with polyanionic partners. Western blot analysis revealed a polyanionic partner (heparan sulfate/syndecan-1) and physiological antielastases (secretory leukoproteinase inhibitor and ␣1-antitrypsin) in the complex. After the elastase was dissociated from heparan sulfate/syndecan-1, it was fully inhibited by endogenous antielastases. (This effect contrasts with that of exogenous antielastases on elastase activity of sputum neutrophils.) Complexed elastase on blots of sputum sol was bound and inhibited by exogenous
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secretory leukoproteinase inhibitor but not by exogenous ␣1-antitrypsin. The authors conclude that neutrophil elastase is found in bronchial secretions of patients with bronchiectasis as an active member of a supramolecular complex, which includes heparan sulfate/syndecan-1 and antielastases (secretory leukoproteinase inhibitor and ␣1-antitrypsin), rather than as a free enzyme. An editorial commentary by Luisetti (54) accompanies this article.
INTERSTITIAL LUNG DISEASE Idiopathic Pulmonary Fibrosis
Genetics. Erythrocyte complement receptor 1 is a membrane protein that mediates the transport of immune complexes to phagocytes. Evidence exists for a relationship between the gene for complement receptor 1 and sarcoidosis. To investigate the relationship between this gene and idiopathic pulmonary fibrosis (IPF), Zorzetto and coworkers (55) studied 74 patients with IPF and 166 control subjects. Three polymorphic sites of the gene were in linkage disequilibrium: A3650G exon 22, HindIII RFLP intron 27, and C5507G exon 33. The GG phenotype C5507G exon 33 polymorphism was more common in patients with IPF than in control subjects (odds ratio, 6.23). The authors conclude that G allele and the GG genotype of the complement receptor 1 gene C5507G exon 33 polymorphism are more frequent in patients with IPF than in healthy subjects. Histopathological subtypes. Patients with usual interstitial pneumonia associated with collagen vascular disease appear to have a better prognosis than patients without collagen vascular disease. To determine whether fibroblastic foci might discriminate between the two groups, Flaherty and coworkers (56) reviewed surgical lung biopsies from 108 patients with usual interstitial pneumonia, 9 of whom had collagen vascular disease. Patients with usual interstitial pneumonia had a higher profusion of fibroblastic foci than did patients with usual interstitial pneumonia and an associated collagen vascular disease (1.75 versus 1.0; score range, 0 to 3). Patients with an associated collagen vascular disease were younger, had a shorter duration of symptoms, and higher total lung capacity. Profusion of fibroblastic foci was the best discriminator between usual interstitial pneumonia alone and usual interstitial pneumonia associated with collagen vascular disease (odds ratio 8.31 for a 1-unit increase in fibroblastic foci score). No patient with associated collagen vascular disease died, whereas 52 patients with usual interstitial pneumonia on its own died. The authors conclude that patients with usual interstitial pneumonia associated with a collagen vascular disease have fewer fibroblastic foci and improved survival. In a state of the art review article, Ryu and colleagues (57) discuss bronchiolar disorders. Clinical assessment. Quantification of disease severity in patients with IPF is often confounded by emphysema. Wells and coworkers (58) first constructed a composite physiologic index (by fitting pulmonary function against extent of disease on computed tomography) in 106 patients with a diagnosis of IPF (based on clinical or computed tomography criteria), and then tested its validity in a second group of 106 patients. The composite index incorporated values for forced vital capacity, FEV1, diffusing capacity, and extent of disease on computed tomography. In the validation group, extent of disease on computed tomography was more closely correlated with the index (r 2 ⫽ 0.51) than with diffusing capacity (r 2 ⫽ 0.38). Subgroup analysis revealed that the better fit of the index arose from correcting for the confounding effects of emphysema. Mortality was better predicted by the composite physiological index than by pulmonary function tests. The authors conclude that a composite physiologic index that closely reflects morphologic extent of pulmonary fibrosis more accurately predicts prognosis than do individual pulmonary function tests.
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In patients with fibrotic idiopathic interstitial pneumonia, survival has been linked to the histological distinction between usual interstitial pneumonia and nonspecific interstitial pneumonia. To determine the prognostic value of longitudinal changes in pulmonary function, Latsi and coworkers (59) studied 63 patients with usual interstitial pneumonia and 41 patients with nonspecific interstitial pneumonia. Median survival was higher for nonspecific interstitial pneumonia than for usual interstitial pneumonia: 56 versus 33 months. Mortality during the first two years was solely linked to the severity of functional impairment at presentation. A composite physiologic index (that combines measurements of FVC, FEV1, and diffusing capacity) was the strongest determinant of outcome. At 6 months, serial measurements of diffusing capacity and histopathologic diagnosis were equivalent prognostically. At 12 months, serial measurements of pulmonary function were the only major prognostic determinant; the distinction between nonspecific and usual interstitial pneumonia was not significant. The authors conclude that trends in serial measurements of pulmonary function predict 12-month survival in patients with usual interstitial pneumonia and nonspecific interstitial pneumonia, and that histological distinction is not important prognostically when functional impairment is severe. An editorial commentary by Noble and Morris (60) accompanies this article. To determine whether changes in pulmonary function over time are better than baseline measurements in predicting prognosis, Collard and coworkers (61) studied 81 patients with biopsyproven IPF. Changes over 6 months in dyspnea score, total lung capacity, FVC, FEV1, diffusing capacity, Po2, oxygen saturation, and alveolar-to-arterial oxygen gradient were predictive of survival (even after adjusting for baseline values). Changes over 12 months in dyspnea score, total lung capacity, FVC, Po2, oxygen saturation, and alveolar-to-arterial oxygen gradient were predictive of survival (after adjusting for baseline values). The authors conclude that changes in clinical and physiological variables over 6 and 12 months are more accurate in predicting prognosis in IPF than are measurements at baseline alone. An editorial commentary by Noble and Morris (60) accompanies this article. To determine whether change in physiological and radiographic variables predict prognosis, Flaherty and coworkers (62) studied 80 patients with usual interstitial pneumonia and 29 patients with nonspecific interstitial pneumonia. Compared with patients who had nonspecific interstitial pneumonia, patients with usual interstitial pneumonia were more likely to show a decrease in lung volume and diffusing capacity and increase in ground glass infiltrates on high-resolution computed tomography at 6 months. Change in FVC was the best predictor of mortality in patients with usual interstitial pneumonia. In a model controlling for multiple factors including histological diagnosis, a decrease in FVC was an independent predictor of mortality (hazard ratio, 2.47). The authors conclude that the changes in FVC over 6 months predicts prognosis, over and above baseline variables, in patients with idiopathic interstitial pneumonia. An editorial commentary by Noble and Morris (60) accompanies this article. To determine whether oxygen desaturation during a six-minute walk test predicts mortality, Lama and coworkers (63) studied 83 patients with usual interstitial pneumonia and 22 patients with nonspecific interstitial pneumonia over a 6-year period. Desaturation (to 88% or less) occurred in 53% of patients with usual interstitial pneumonia and 36% of patients with nonspecific interstitial pneumonia. In both groups of patients, mortality was greater in the patients who desaturated than in the patients who did not desaturate. After adjusting for possible confounders, desaturation was associated with an increased hazard of death (hazard ratio, 4.2) among patients with usual interstitial pneumonia.
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The authors conclude that measurement of oxygen desaturation during a six-minute walk test adds prognostic information in patients with usual interstitial pneumonia and nonspecific interstitial pneumonia. To better understand the pathogenesis of cough in patients with IPF, Hope-Gill and coworkers (64) studied 13 patients with IPF and 10 healthy subjects. The patients displayed greater cough sensitivity to capsaicin than did the control subjects. Substance P induced cough in 7 of 10 patients and bradykinin induced cough in 2 of 10 patients. Neither substance P nor bradykinin induced cough in the control subjects. Six patients were treated with prednisolone and all showed a decrease in cough sensitivity to capsaicin and substance P. Patients had more neutrophils and higher levels of nerve growth factor and brain-derived neurotrophic factor in their sputum. The authors conclude that patients with IPF have functional upregulation of lung sensory neurons, perhaps as a result of disrupted respiratory epithelium, and that glucocorticoids have a beneficial effect on the cough reflex in these patients. Cellular and molecular mechanisms, in vivo. Intraalveolar activation of the coagulation system secondary to decreased fibrinolytic function plays a critical role in the pathogenesis of interstitial lung disease. Fujimoto and coworkers (65) studied two fibrinolysis inhibitors, thrombin-activatable fibrinolysis inhibitor and protein C inhibitor, in bronchoalveolar fluid from 82 patients with interstitial lung disease and 8 healthy subjects. The patients had higher levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor than did the healthy subjects. The levels of thrombin activatable fibrinolysis inhibitor were correlated with the levels of protein C inhibitor (r ⫽ 0.70), thrombin–antithrombin complex (r ⫽ 0.40), and monocyte chemoattractant protein-1 (r ⫽ 0.40). Alveolar macrophages from patients with interstitial lung disease and immortalized lung epithelial cell lines expressed antigen for thrombin-activatable fibrinolysis inhibitor. The authors conclude that two fibrinolysis inhibitors, thrombin activatable fibrinolysis inhibitor and protein C inhibitor, modulate the intraalveolar fibrinolysis associated with interstitial lung disease. An editorial commentary by Strieter (66) accompanies this article. The cytokine, transforming growth factor-1, plays a key role in the development of IPF. In 128 patients with IPF and 140 healthy subjects, Xaubet and coworkers (67) investigated the relationship between two genetic polymorphisms in the DNA sequence encoding the leader sequence of the protein for transforming growth factor-1 (located in codons 10 and 25) and susceptibility to the disease and its progression. Compared with the control group, the patients showed no significant deviations in genotype or allele frequencies. On follow-up of 110 patients over 30 months, the presence of a proline allele at codon 10 was associated with an increase in Po2 during follow up (coefficient, 0.59). The authors conclude that genetic polymorphisms located in codons 10 and 25 of the protein for transforming growth factor-1 do not predispose to the development of IPF, although they appear to affect disease progression. An editorial commentary by Whyte (68) accompanies this article. Connective tissue growth factor is a downstream effector molecule that mediates the action of transforming growth factor-1, a cytokine known to induce severe and progressive fibrosis. To better define the in vivo fibrogenic effect of isolated expression of connective tissue growth factor, Bonniaud and coworkers (69) used an adenoviral gene transfer to transiently overexpress this growth factor in rat lungs after intratracheal administration. Moderate but reversible fibrosis developed over 6 to 10 days. Fibronectin, procollagen 1a2, and endogenous expression of the gene for connective tissue growth factor were increased at 14 days. Tissue inhibitor of metalloproteinase-1 was weakly and
transiently upregulated. When transforming growth factor-1 was administered, also by an adenovirus vector, the same genes were robustly and persistently stimulated from the third to twenty-first day. The authors conclude that transient overexpression of connective tissue growth factor is capable of initiating fibrogenic activity, but that additional cofactors are necessary for the development of chronic and progressive fibrosis that is seen after exposure to transforming growth factor-1. An editorial commentary by Selman (70) accompanies this article. Richard and coworkers (71) investigated the reliability of positron emission tomographic imaging in detecting the expression of genes delivered to the lungs by viral vectors. The study was conducted in normal rats and an enhanced mutant herpes simplex virus-1 thymidine kinase was used as the reporter gene. Rats were studied three days after the intratracheal administration of a replication-incompetent adenovirus containing a fusion gene for the mutant kinase and green fluorescent protein. The rats were injected with an imaging substance for the viral kinase, 9-(4-[18F]-fluoro-3-hydroxymethylbutyl)guanine; images were obtained one hour later. Measurements derived from imaging were linearly correlated with measures of thymidine kinase activity and green fluorescent protein levels in tissue (r 2 ⫽ 0.96). Imaging detected expression of thymidine kinase in 15 of 16 rats, even at low viral doses. Imaging for the viral kinase was correlated with in vitro assays for both kinase activity (r 2 ⫽ 0.48) and fluorescent protein (r 2 ⫽ 0.46). The authors conclude that positron emission tomographic imaging is a sensitive and quantitative method for noninvasive detection of pulmonary reporter gene expression. Hepatocyte growth factor protects alveolar epithelial cells from pulmonary fibrosis in animal models. Marchand-Adam and coworkers (72) compared in vitro production of hepatocyte growth factor by human lung fibroblasts in 8 patients with IPF and 6 control subjects. Basal secretion of hepatocyte growth factor by fibroblasts was 50% less in the patients than in the control subjects. The patients with IPF had less messenger RNA for hepatocyte growth factor in their fibroblasts, and their fibroblasts also secreted less prostaglandin E2. The addition of prostaglandin E2 or dibutyryl cyclic AMP to patient fibroblasts caused them to secrete normal amounts of hepatocyte growth factor. In control fibroblasts, indomethacin (an inhibitor of prostaglandin E2 synthesis) decreased the secretion of hepatocyte growth factor; it had no effect on patient fibroblasts. Transforming growth factor-1 slightly inhibited the secretion of hepatocyte growth factor by control fibroblasts, and antibody against transforming growth factor-1 stimulated its secretion; neither agent had an effect on patient fibroblasts. The authors conclude that fibroblasts of patients with IPF have decreased production of hepatocyte growth factor and that the deficit is secondary to a defect in the secretion of prostaglandin E2. An editorial commentary by Peters-Golden (73) accompanies this article. In a pulmonary perspective, Turino and Cantor (74) discuss the role of hyaluronan in respiratory injury and repair. In a state of the art review article, Kinnula and Crapo (75) discuss superoxide dismutase in lung disease. Cellular and molecular mechanisms, ex vivo. Dendritic cells are the most potent antigen-presenting cells. Kantengwa and coworkers (76) investigated the effects of superoxide, a frequent product of inflammation, on the phenotype and functional maturation of human dendritic cells. Unlike hydrogen peroxide, reactive oxygen species, generated by the reaction of oxidase on xanthine, induced early phenotypic maturation of dendritic cells. The maturation resulted from upregulation of specific markers, CD80, CD83, and CD86, and from downregulation of endocytosis mediated by the mannose receptor. Maturation induced by xanthine oxidase was prevented by allopurinol and by N-acetyl-
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cysteine. The proteasome inhibitor, MG-132, which blocks the activation of nuclear factor-B, also inhibited CD86 upregulation; it did not, however, inhibit endocytosis downregulation by reactive oxygen species. Antigen presentation by dendritic cells was enhanced, or blocked, by xanthine-xanthine oxidase depending on whether the cells had, or had not, been prepulsed by the antigen. The authors conclude that oxidative stress induces phenotypic and functional maturation of dendritic cells, partly mediated by nuclear factor-B. To determine whether fibrotic lung fibroblasts migrate and invade across basement membranes by integrin-mediated mechanisms, White and coworkers (77) studied lung fibroblasts from patients with IPF. In the fibroblasts, fibronectin signaling was both necessary and sufficient for migration and invasion across basement membranes. The effect was mediated through ␣51 integrin because the response was attenuated by fibronectin–␣5 integrin ligation. Conversely, ligation of ␣41 integrin inhibited invasion of the basement membrane by normal lung fibroblasts but not by fibrotic lung fibroblasts. The phenotypic difference was not related to surface expression of ␣41 integrin. In normal lung fibroblasts, but not in fibrotic lung fibroblasts, ligation of ␣41 integrin induced a significant increase in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) activity. Compared with normal lung fibroblasts, fibrotic lung fibroblasts express constitutively less PTEN messenger RNA as well as protein and phosphatase activity. The authors conclude that a loss of ␣41 signaling via PTEN confers a migratory and invasive phenotype to fibrotic lung fibroblasts, and the data implicate a loss of PTEN function in the pathophysiology of IPF. Sirianni and coworkers (78) determined whether there are fibroblasts in the alveolar walls of the human lung that link type 2 pneumocytes to capillary endothelium through aperatures in their respective basal laminae. In the rabbit lung, these fibroblasts have been shown to provide a bridge between capillaries and the airway lumen along which leukocytes may migrate without disrupting the extracellular matrix. Transmission electron microscopy of human lungs revealed contacts between fibroblasts and type 2 pneumocytes and between fibroblasts and type 1 pneumocytes that occurred at holes in the epithelial basal lamina. In a sample of 41 type 2 pneumocytes, at least one gap was found in the basal lamina of 54% of the cells. These gaps occupied about 5.6% of the area beneath the type 2 pneumocytes. The authors conclude that a population of single fibroblasts form a link between type 2 pneumocytes and adjacent capillary endothelial cells in the alveolar walls of the human lung. Treatment. Interferon-␥ has been proposed as treatment for IPF. Honore and coworkers (79) described four patients who developed new pulmonary opacities after being treated with interferon-␥. The patients had advanced IPF; no other cause of deterioration was found. Refractory hypoxemia led to death in three patients and the fourth patient underwent lung transplantation. Pathology revealed diffuse alveolar damage with preexisting usual interstitial pneumonia. The authors conclude that interferon-␥ can induce acute respiratory failure in patients with end-stage IPF. An editorial commentary by Selman (80) accompanies this article. Progressive Systemic Sclerosis
To evaluate angiogenesis and vascular distribution in the pulmonary interstitium in patients with interstitial lung disease, Renzoni and coworkers (81) obtained open lung biopsies from 8 patients with IPF, 9 patients with IPF associated with systemic sclerosis, and 12 patients with normal lung tissue (the patients had lung cancer). Vascular density was less in the patients with IPF associated with systemic sclerosis (3.9%) and in patients with IPF (4.5%) than in the control samples (20.4%). The percentage of tissue occupied by vessels decreased with increasing
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distance from the alveoli in the control samples, but not in the samples from the two patient groups. Indices of endothelial cell proliferation were increased in the patients with IPF associated with systemic sclerosis but not in the patients with IPF. The authors conclude that net vascular ablation and redistribution of blood vessels is found in areas of interstitial thickening in patients with IPF alone and in patients with IPF associated with systemic sclerosis, and the change may contribute to the impairment of gas exchange. Sarcoidosis
Genetics. To determine whether sarcoidosis is associated with single-nucleotide polymorphisms of the C-C chemokine receptor 2 (CCR2) gene, Spagnolo and coworkers (82) studied 8 singlenucleotide polymorphisms in 304 Dutch individuals (90 with non-Lofgren sarcoidosis, 47 with Lofgren’s syndrome, and 167 control subjects). Nine haplotypes were deduced from the investigated polymorphisms. Compared with control subjects, the patients with Lofgren’s syndrome exhibited an increased frequency of CCR2-haplotypes 2 (74% versus 38%). (This haplotype has four unique alleles: A at nucleotide position -6752, A at 3,000, T at 3,547, and T at 4,385.) No difference was noted between patients with non-Lofgren sarcoidosis and control subjects. The association between carriage frequency for CCR2-haplotype 2 and Lofgren’s syndrome (odds ratio, 4.4) remained significant after adjustment for two known risk factors for Lofgren’s syndrome: human leukocyte antigen haplotype DRB1*0301-DQB*0201 (odds ratio, 11.5) and female sex (odds ratio, 3.2). The authors conclude that haplotype 2 of the C-C chemokine receptor 2 gene is strongly associated with Lofgren’s syndrome subset of sarcoidosis. An editorial commentary by O’Regan and Berman (83) accompanies this article. In a study of 225 nuclear families ascertained through African American probands with a history of sarcoidosis, Rybicki and coworkers (84) asked, “Are genes of the major histocompatibility complex a risk factor for sarcoidosis in African Americans”? They genotyped six microsatellite markers, spanning 11.6 megabases, which overlapped the MHC region on chromosome 6p21–22. Sarcoidosis was strongly associated with the DQCAR marker less than two kilobases telomeric from the HLA-DQB1 gene. DQCAR-G51152 haplotypes were associated with sarcoidosis on a global level. The DQCAR 182 allele was transmitted to offspring more often than expected (observed, 66; expected, 53). The DQCAR 178 allele was transmitted to offspring less often than expected (observed, 10; expected, 21), as was the G51152 217 allele (observed, 14; expected, 26). The authors conclude that HLA-DQB1, but not HLA-DRB1, plays an important role in the susceptibility of African Americans to sarcoidosis. Iannuzzi and coworkers (85) conducted a family-based genetic association analysis of sarcoidosis and five HLA-DQB1 alleles in 225 African-American families that had at least one offspring with sarcoidosis. The DQB1*06 allele was about 20% more common among siblings with a history of sarcoidosis than among unaffected siblings (32.8 versus 29.6%), whereas the DQB1*02 allele was about half as common among affected siblings as expected (13.4 versus 19.1%). The risk of sarcoidosis associated with the *0201 allele often depended on environmental exposure, whereas the *0602 allele varied little with respect to exposure. The *0602 allele in affected probands was associated with radiographic progression of disease, whereas the *0201 allele was not associated with phenotype. The authors conclude that HLA-DQB1 alleles are associated with susceptibility to sarcoidosis in African Americans. Molecular mechanisms. Because sarcoidosis is a T cell–mediated disease, Gibejova and coworkers (86) studied three lymphocyte chemoattractants, leukotactin-1, macrophage inflammatory
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protein-3␣, and macrophage inflammatory protein-3, in bronchoalveolar cells from 78 patients with sarcoidosis and 11 control subjects. Only messenger RNA for macrophage inflammatory protein-3 was upregulated in the patients. Protein levels of macrophage inflammatory protein-3 in bronchoalveolar fluid were 89% higher in the patients than in the control subjects; the levels were fivefold higher in 25 patients with stage II disease on chest X-ray than in 48 patients with stage I disease. Protein of macrophage inflammatory protein-3 was mainly associated with alveolar macrophages and was correlated with lymphocytes and T cells subsets. Messenger RNA expression for CC chemokine receptor 7, the receptor for macrophage inflammatory protein-3, was correlated with the protein levels for this chemoattractant. Dexamethasone and cyclosporine caused in vitro suppression of messenger RNA and protein expression of macrophage inflammatory protein-3. The authors conclude that macrophage inflammatory protein-3 modulates the recruitment of T cell in sarcoidosis, and that this chemoattractant is related to disease progression and is downregulated by drugs used in treating sarcoidosis. Clinical manifestations. Cox and coworkers (87) developed a questionnaire to enable patients with sarcoidosis to describe the effect of the disease on their quality of life. In the development stage, the questionnaire had 151 items generated by interviews with 107 patients, searching the relevant literature, and discussions with sarcoidosis experts. Based on responses from a separate group of 149 patients and the use of clinical impact methodology, the total number of items was reduced to 29. The final sarcoidosis health questionnaire had three domains: daily functioning, physical functioning, and emotional functioning. A validation study was conducted in another group of 111 patients. The questionnaire had good internal consistency reliability, evidence of content, criterion, and construct validity based on widely used measures of health-related quality of life and clinical variables, including spirometry. Only the sarcoidosis health questionnaire was sensitive to differences in health-related quality of life based on the number of organ systems involved. The authors conclude that the sarcoidosis health questionnaire is a self-completed questionnaire that is suitable for measuring health-related quality of life. Lymphangioleiomyomatosis
Lymphangiomyomatosis (LAM) has been reported to recur after lung transplantation, but it is unclear whether the recurrence arises from the patient or from the donor. Karbowniczek and coworkers (88) studied a 44-year-old woman who died of Aspergillus pneumonia at 22 months after lung transplantation for LAM. Specimens obtained from the transplanted lung (allograft) at autopsy were analyzed by microsatellite marker fingerprinting, which revealed patient-derived LAM cells. Before transplantation, a somatic one base pair deletion in exon 18 of the TSC2 gene was identified in LAM cells (lung and lymph nodes). The same mutation was found in the recurrence of LAM, indicating that the recurrence originated in the patient. The authors conclude that histologically benign LAM cells can migrate or metastasize to lung allografts after transplantation. To determine the causes of exercise intolerance in patients with LAM, Taveira-DaSilva and coworkers (89) undertook cardiopulmonary exercise testing in 217 patients with LAM. Maximum oxygen uptake was decreased in 162 patients, of whom 28 did not reach anaerobic threshold, 29 patients had a low oxygen uptake at anaerobic threshold, and 54 developed hypoxemia. Maximum oxygen uptake decreased as the score for histologic severity increased. Significant predictors of maximum oxygen uptake were FEV1 and diffusing capacity for carbon monoxide; uptake was also correlated with computed tomography, use of oxy-
gen, and resting Po2. Some patients with near-normal FEV1 and diffusing capacity developed hypoxemia during exercise. The authors conclude that cardiopulmonary exercise testing should be performed in patients with LAM to determine the severity of abnormal gas exchange and the need for supplemental oxygen therapy. An editorial commentary by Sietsema and McCormack (90) accompanies this article. Pulmonary Drug Toxicity
Venlafaxine is a new antidepressant that inhibits reuptake of both serotonin and nonrepinephrine. Drent and colleagues (91) described two patients who developed both interstitial pneumonia and cardiac failure shortly after initiation of treatment with venlafaxine. The first patient recovered completely after withdrawal of venlafaxine and on being treated with glucocorticoids. The second patient died from multiorgan failure; the temporal relationship, pattern on computed tomography, and organizing pneumonia on autopsy were consistent with drug-induced infiltrative lung disease. The authors conclude that the new antidepressant, venlafaxine, can cause both pneumonitis and heart failure. Hypersensitivity Pneumonitis
Lacasse and coworkers (92) examined whether a clinical prediction rule might be reliable for making a diagnosis of hypersensitivity pneumonitis without the need for bronchoalveolar lavage or biopsy. A cohort of 400 patients (116 with hypersensitivity pneumonitis and 284 control subjects) was recruited. Hypersensitivity pneumonitis was diagnosed on the basis of high-resolution computed tomography, bronchoalveolar lavage, and, if necessary, surgical lung biopsy. Six significant predictors of hypersensitivity pneumonitis were identified: (i ) exposure to a known offending antigen, (ii) positive precipitating antibodies to the offending antigen, (iii) recurrent symptoms, (iv) inspiratory crackles, (v ) symptoms within 4 to 8 hours of exposure, and (vi) weight loss. The area under a receiver operating characteristic curve was 0.93 for the clinical prediction rule. The rule retained its accuracy when validated in a separate cohort of 261 patients. The authors conclude that a clinical decision rule, not requiring bronchoalveolar lavage or biopsy, is reliable in the diagnosis of hypersensitivity pneumonitis, especially in areas of high or low prevalence. An editorial commentary by Morris (93) accompanies this article. The most common form of hypersensitivity pneumonitis in Japan is summer-type hypersensitivity pneumonitis, which is caused by inhalation of Trichosporon asahii or Trichosporon mucoides. To determine what proteins are involved in the pathogenesis, Matsunaga and coworkers (94) constructed a cDNA expression library of T. asahii. They identified and cloned a novel gene encoding a 19-kD protein, named TA-19. IgG, IgA, and IgM antibodies to the recombinant TA-19 protein were higher in serum and bronchoalveolar lavage fluid in patients than in control subjects. The protein induced pneumonitis-specific proliferation of mononuclear cells from both the peripheral blood and bronchoalveolar fluid. The authors conclude that a novel gene, TA-19, derived from Trichosporon asahii modulates cellular and immune responses of patients with summer-type hypersensitivity pneumonitis. Rodent Model of Bleomycin Fibrosis
Thioredoxin is a multifunctional redox (reduction/oxidation)active protein that scavenges oxygen species by itself or in conjunction with thioredoxin-dependent peroxiredoxin. Hoshino and coworkers (95) studied the effects of thioredoxin in two mouse models of interstitial lung disease: the conventional model of bleomycin-induced injury, and a new model of lethal lung in-
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jury induced by the daily administration of the proinflammatory cytokines, interleukin-18 and interleukin-2. In the bleomycin model, administration of thioredoxin decreased cellular infiltrates and fibrosis in both wild-type and thioredoxin-transgenic mice. In the model caused by administration of proinflammatory cytokines, administration of thioredoxin suppressed the interstitial cell infiltrates, suppressed tissue damage, and prevented death; suppression was evident also in thioredoxin-transgenic mice. The authors conclude that thioredoxin modulates pulmonary inflammation and prevents lung injury caused by administration of either bleomycin or proinflammatory cytokines. An editorial commentary by Crapo (96) accompanies this article. In rabbits subjected to bleomycin-induced lung injury, Gunther and coworkers (97) investigated the role of alveolar fibrin formation in the resulting lung fibrosis. Four weeks after administration of the aerosol of bleomycin, animals exhibited typical features of pulmonary fibrosis. Delivery of either heparin or urokinase-type plasminogen activator to the bronchoalveolar space normalized lung compliance, suppressed the accumulation of collagen and hydroxylproline, and virtually abrogated the features of fibrosis on computer tomography and histology. The most prominent effects were seen with early administration of heparin or late administration of urokinase-type plasminogen activator. Bleeding complications were not observed. The authors conclude that alveolar fibrin generation plays an important role in the development of lung fibrosis after administration of bleomycin to rabbits. An editorial commentary by Idell (98) accompanies this article. ␥-Glutamyl transpeptidase is a key enzyme in glutathione and cysteine metabolism. Because cysteine deficiency may impair extracellular matrix synthesis, Pardo and coworkers (99) asked, “Would mice deficient in ␥-glutamyl transpeptidase (GGT⫺/⫺) develop less fibrosis after exposure to bleomycin than would wild-type (GGT⫹/⫹) mice”? At 72 hours after exposure to bleomycin, the null mice displayed a near absence of neutrophils in lung tissue and a less pronounced rise in matrix metalloproteinase-9 than did the wild-type mice; inflammation in null mice consisted mainly of lymphocytes and macrophages. At 1 month, an index of lung fibrosis was 74% less in null mice than in wildtype mice. Lung collagen almost doubled after bleomycin in wild-type mice, but not in the null mice. Control lungs in null mice showed a 45% decrease in cysteine and a 31% decrease in glutathione. Levels of cysteine and glutathione decreased at 72 hours after bleomycin in both null and wild-type mice, but returned to control values after 1 month. Supplementation with N-acetylcysteine partly ameliorated the effects of ␥-glutamyl transpeptidase deficiency. The authors conclude that increased neutrophils and matrix metalloproteinase-9 during the early inflammatory response and adequate thiol reserves are key elements in the fibrotic response after bleomycin-induced pulmonary injury. Platelet-derived growth factor is involved in the pathogenesis of lung fibrosis. Shimizu and coworkers (100) investigated the effect of a natural anticoagulant, activated protein C, on plateletderived growth factor expression in human cell lines and in an in vivo model of lung fibrosis. Activated protein C inhibited the secretion and expression of platelet-derived growth factor in human lung cell lines, primary bronchial epithelial cells, and macrophages. In vivo studies revealed that the endothelial activated protein C receptor was expressed by lung epithelial cells and macrophages; the receptor and proteolytic activity of the activated protein were implicated in inhibiting the expression of platelet-derived growth factor. In an in vivo model of lung fibrosis (bleomycin injury in mice), intratracheal administration of activated protein C decreased the expression of plateletderived growth factor and suppressed the development of lung
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fibrosis. The inhibitory activity of activated protein C was inhibited by the concomitant administration of anti-endothelial activated protein C receptor or anti–platelet-derived growth factor. The authors conclude that activated protein C inhibits the expression of platelet-derived growth factor in the lung and suppresses lung fibrosis caused by bleomycin. The rate of transferring small molecular solutes across the alveolar–capillary membrane is altered by acute lung damage. Suga and coworkers (101) did magnetic resonance imaging during and after inhalation of an aerosol of gadolinium diethylenetriaminepentaacetic acid in dogs with bleomycin-induced injury. Deposition of the aerosol was decreased heterogeneously at 7 and 40 days after intratracheal instillation of bleomycin. Seven days after intratracheal instillation of bleomycin, the slope of the clearance curve for the aerosol was increased by 47% over baseline and clearance half-time was decreased by 29%. Both measures of clearance had returned to baseline at 40 days after the instillation of bleomycin. The authors conclude that dogs display accelerated clearance of an aerosol of gadolinium diethylenetriaminepentaacetic acid during the acute exudative phase of bleomycin-induced injury and recovery occurs during the chronic fibrotic phase.
OCCUPATIONAL LUNG DISEASE To determine the role of aerosols of endotoxin, generated by working with mice, in causing respiratory symptoms in laboratory scientists and technicians, Pacheco and coworkers (102) did a cross-sectional study in 269 workers at a research institution. Symptoms related to mice were recorded in 16% (34 of 212) of workers not sensitized to mice and in 46% (26 of 57) of workers sensitized to mice. Symptomatic workers were more likely to be atopic irrespective of whether they were sensitive or not to mice. Among workers not sensitized to mice, symptomatic workers spent more time performing animal experiments and had higher daily exposure to endotoxin than did asymptomatic workers. Among workers not sensitized to mice, daily exposure to endotoxin was the strongest predictor of symptoms (odds ratio, 30.8). The authors conclude that airborne endotoxin is associated with development of respiratory symptoms to mice in laboratory scientists and technicians who are not sensitized to mice. Firefighters and rescue workers experienced massive exposure to airborne particulates at the World Trade Center site. To determine the association between intensity of exposure and bronchial hyperreactivity, Banauch and coworkers (103) studied a representative sample of 179 rescue workers. Highly exposed workers arrived within two hours of the collapse, moderately exposed workers arrived later within the first two days, and control subjects were not exposed. Hyperreactivity at 1, 3, and 6 months after the collapse was associated with intensity of exposure and was independent of ex-smoking and airway obstruction. At 6 months after the collapse, highly exposed workers were 6.8 times more likely to be hyperreactive than were moderately exposed workers and control subjects; hyperreactivity persisted in 55% of workers who were hyperreactive at 1 or 3 months. In highly exposed subjects, hyperreactivity at 1 to 3 months after the collapse was the sole predictor for reactive airways dysfunction. The authors conclude that the intensity of exposure to airborne particulates at the World Trade Center site was a strong predictor for the development and persistence of bronchial hyperreactivity and reactive airway dysfunction. An editorial commentary by Nemery (104) accompanies this article. The American Thoracic Society (105) presents a statement from the first Jack Pepys occupational asthma symposium on occupational asthma. The American Thoracic Society (106) presents a statement on the occupational contribution to the burden of airways disease.
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 169 2004
SOCIAL ISSUES, PROFESSIONAL TRAINING, AND JOURNALOLOGY Social Issues and Professional Training
To determine the demographics, professional activities, and needs of the members of the American Thoracic Society, Schnapp and coworkers (107) mailed a questionnaire to 13,598 members. Of responding members, 80% resided in the United States or Canada, and the remainder resided in 90 different countries. Of North American respondents, 79% were white and non-Hispanic. Women constituted 17% of the respondents; more women than men identified themselves as researchers (33 versus 22%). Most respondents (69%) had a medical school affiliation. Major activity was listed as clinical practice by 65%, research by 20%, and teaching by 5% of the respondents. The authors conclude that the American Thoracic Society represents a global organization with diverse clinical and scientific interests. An editorial commentary by Macklem (108) accompanies this article. In an occasional essay, Brody (109) discusses finding from the survey of members of the American Thoracic Society. To determine the level of understanding of mechanical ventilation among internal medicine residents, Cox and coworkers (110) administered a 19-question examination to 259 residents at 31 residency programs. The average score on the test was 74% correct (range, 37 to 100%). Most residents correctly identified tension pneumothorax (86% correct) and clinical findings suggestive of severe hypotension secondary to auto-PEEP (93% correct). High rates of incorrect answers were found for the setting of tidal volume in patients with ARDS (48% incorrect), identifying whether a patient was ready for a weaning trial (38% incorrect), and recognizing an indication for noninvasive ventilation (27% incorrect). Higher scores were associated with closedunit versus open-unit organization (76 versus 71% correct), resident perception of greater versus lesser knowledge (79 versus 71% correct), and graduation from a U.S. versus a foreign medical school (75 versus 69% correct). Only 46% of residents were satisfied with their training in mechanical ventilation. The authors conclude that residents in internal medicine programs may not be gaining knowledge essential for providing care to patients requiring mechanical ventilation. An editorial commentary by Dunn (111) accompanies this article. Journalology
In an editorial, Tobin (112) discusses three lessons from three papers on DNA published in Nature in 1953. In an editorial, Tobin (113) discusses the policy of AJRCCM on conflicts of interest. In an editorial, Tobin (114) discusses the role of a journal in a scientific controversy. In an editorial, Tobin (115) discusses impact factor and the Journal. In an editorial, Tobin (116) discusses the approach to writing a review article for AJRCCM.
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Conflict of Interest Statement : M.J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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