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| CONTENTS |
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| TOP CONTENTS TUBERCULOSIS NONTUBERCULOUS LUNG INFECTION INTERSTITIAL LUNG DISEASE OCCUPATIONAL LUNG DISEASE SOCIAL ISSUES, HEALTH POLICY,... REFERENCES |
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Studies of Molecular Mechanisms in Tuberculosis (7)
Epidemiology of Tuberculosis (7)
Diagnosis of Tuberculosis (1)
Treatment of Tuberculosis (5)
Nontuberculous Lung Infection (12)
Human Immunodeficiency Virus Infection (2)
Highly Active Antiretroviral Therapy (2)
Lung Infections (10)
Host Defenses (5)
Pneumonia (3)
Antimicrobial Therapy (2)
Interstitial Lung Disease (39)
Idiopathic Pulmonary Fibrosis (14)
Genetics (2)
Histopathological Subtypes (1)
Serum Markers (1)
Clinical Assessment (2)
Cellular and Molecular Mechanisms, in vivo (3)
Cellular and Molecular Mechanisms, ex vivo (1)
Animal Models (1)
Treatment (1)
Statements and Workshops (2)
Progressive Systemic Sclerosis (3)
Sarcoidosis (3)
Genetics (2)
Molecular Mechanisms (1)
Histiocytosis X (2)
Lymphangioleiomyomatosis (2)
Eosinophilic Pneumonia (3)
Acute Interstitial Pneumonitis (2)
Niemann-Pick Disease (1)
Lymphoproliferative Disorders (1)
Idiopathic Pulmonary Alveolar Proteinosis (1)
Pulmonary Drug Toxicity (2)
Calcium Deposition in the Lung (1)
Rodent Model of Bleomycin Fibrosis (4)
Occupational Lung Disease (12)
Social Issues, Health Policy, Economics, and Journalology (6)
Journalology (6)
| TUBERCULOSIS |
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| TOP CONTENTS TUBERCULOSIS NONTUBERCULOUS LUNG INFECTION INTERSTITIAL LUNG DISEASE OCCUPATIONAL LUNG DISEASE SOCIAL ISSUES, HEALTH POLICY,... REFERENCES |
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Although nitric oxide may contribute to host defense against tuberculosis, its expression in human tuberculous lungs has not been systematically characterized. In surgically resected lungs of eight patients with tuberculosis, Choi and coworkers (3) found increased levels of inducible nitric oxide synthase, endothelial nitric oxide synthase, and nitrotyrosine (a marker of nitric oxide expression) in the inflammatory zone of tuberculous granulomas and in the nongranulomatous pneumonitis zone; the level of neuronal nitric oxide synthase was not elevated. Tumor necrosis factor- was increased and principally localized to the necrotic areas of granulomas, and localized to a lesser degree in the inflammatory and fibrotic areas. The nitric oxide isoforms and tumor necrosis factor- were expressed by the epithelioid macrophages and giant cells within the granulomas and in alveolar macrophages and epithelial cells in areas of pneumonitis. The authors conclude that nitric oxide and isoenzymes of nitric oxide synthase are present in specialized areas of tuberculous granulomas. An editorial commentary by Nathan (4) accompanies this article.
Because CD8+ T cells play an important role in host defense against Mycobacterium tuberculosis, it is thought that a successful tuberculosis vaccine will need to elicit sustained responses of CD8+ T cells. To determine whether a potent CD4+ T cell antigen, Mtb39, is also a CD8+ T cell antigen, Lewinsohn and coworkers (5) used a replication-deficient adenovirus to introduce Mtb39 into the cytoplasm of dendritic cells derived from human monocytes. Mtb39-specific CD8+ T lymphocytes were detected in three healthy individuals with latent tuberculosis infection who also displayed strong responses against Mtb39-specific CD4+ T cells. A Mtb39-specific CD8+ T cell line was generated using Mtb39-expressing dendritic cells. All seven of the generated T cell clones were HLA-B44 restricted, recognized dendritic cells with Mtb, and were cytolytic. The authors conclude that infection of dendritic cells with adenoviral vectors expressing Mtb proteins allows for the measurement of antigen-specific CD8+ T cell responses from peripheral blood monocytes. An editorial commentary by Lalvani (6) accompanies this article.
In a pulmonary perspective, Lazarevic and Flynn (7) discuss CD8+ T cells in tuberculosis.
Epidemiology of Tuberculosis
Nitta and coworkers (8) studied the extent of transmission of multidrug-resistant tuberculosis in Los Angeles County. Of 102 multidrug-resistant cases, 71 had cavitary lesions on chest radiography, 94 had acid-fast bacilli in their sputa, and 15 were infected with HIV. Four molecular clusters of two cases each and one closely related pair were identified among the 102 cases; contact investigation identified all clusters but one. Among 946 contacts cross-matched with the Tuberculosis Registry of the County, one secondary case caused by drug-resistant Mycobacterium bovis was found. The authors conclude that a very high proportion of pulmonary multidrug-resistant cases of tuberculosis in Los Angeles County are infectious, and molecular strain-typing indicates limited spread of disease. An editorial commentary by Daley (9) accompanies this article.
To determine the occurrence and consequences of a delay in the diagnosis of active pulmonary tuberculosis among hospitalized patients, Greenaway and coworkers (10) studied 429 patients admitted to17 hospitals in Canada with a new diagnosis of active tuberculosis. Initiation of appropriate therapy was delayed one week or more in 127 patients (30%). After adjusting for atypical characteristics, a delay in starting therapy was associated with the following: admission to a hospital that has a low rate of admissions for tuberculosis (0.2 to 3.3 per 10,000 admissions), odds ratio, 7.4; admission to a hospital that has an intermediate rate of admissions for tuberculosis (3.4 to 9.9 per 10,000 admissions), odds ratio, 2.3; potentially preventable (late) admission to an intensive care unit, odds ratio, 16.8; and death, odds ratio, 3.3. After adjusting for characteristics of workers and ventilation in patient rooms, tuberculin conversions were higher in hospitals that had an overall tuberculosis mortality above 10% (odds ratio, 2.5). The authors conclude that a patient admitted to hospital because of active tuberculosis is more likely to have a poor outcome when the patient is admitted to a hospital that has a low rate of admissions for tuberculosis. An editorial commentary by Sepkowitz (11) accompanies this article.
Investigation of the contacts of active cases of tuberculosis is important in the control of tuberculosis. Based on a model of the variables that are most likely to predict a positive tuberculin skin test among contacts of tuberculosis cases, Gerald and coworkers (12) developed a decision tree for contact investigation. Several decision trees were developed based on data collected in 292 consecutive cases and their 2,941 contacts. The decision trees were then tested with prospective data collected in 366 new cases of tuberculosis and their 3,162 contacts. The decision trees had sensitivities of 87 to 94%, specificities of 22 to 28%, and false-negative rates of 7 to 10%. The use of a decision tree was estimated to decrease the number of contacts investigated by 17 to 25%. The authors conclude that the use of a decision tree in the investigation of contacts of cases of active tuberculosis would substantially reduce the number of contacts investigated and save resources. An editorial commentary by Weis (13) accompanies this article.
To determine the transmission dynamics of tuberculosis in Tarrant County, Texas, Weis and coworkers (14) did a prospective epidemiological study of 159 patients with culture-proven tuberculosis. Patients whose isolates had identical or closely linked patterns on restriction fragment length polymorphism (RFLP) analysis were considered a cluster. Of the 159 patients, 76 (48%) were in 19 clusters, suggesting that recent transmission accounted for 36% of tuberculosis morbidity. Independent predictors for clustering were birth in the United States, continuous residence in Tarrant County, a history of homelessness, and a history of visiting or working in bars. Four homeless shelters and five bars were associated with specific clusters. Patients in some clusters recognized more photographs of patients in their cluster than did patients outside their cluster. The authors conclude that homeless shelters and bars are important sites of tuberculosis transmission and that recognizing individuals by photograph combined with molecular fingerprinting help identify epidemiologic links among patients.
Diagnosis of Tuberculosis
The number of bacilli found by acid-fast staining in tissue sections can be much fewer than the number expected based on sputum smear data or the patient's clinical condition. Fukunaga and coworkers (15) determined whether use of fixative fluid, organic solvent, or both might contribute to the low numbers. When mycobacteria were smeared on glass slides and examined microscopically, formalin caused a decrease in the sensitivity of acid-fast staining to 0.5% and xylene caused a decrease in the sensitivity to 0.2%. In tissue sections from 30 patients with tuberculosis lesions, M. tuberculosis DNA was detected in 83% of the cases by the real-time polymerase chain reaction and in only 40% of the cases by acid-fast microscopy. The number of bacilli revealed by microscopy was much lower than the number revealed by the polymerase chain reaction technique. The authors conclude that acid-fast microscopy of formalin-fixed and paraffin-embedded tissue causes tuberculosis bacilli to be frequently missed or underestimated.
Treatment of Tuberculosis
In 346 patients from northern India being treated for tuberculosis, Sharma and coworkers (16) determined the role of risk factors, including the major histocompatibility complex (MHC) class II alleles, in the development of hepatotoxicity. Drug-induced hepatotoxicity occurred in 56 patients (16%). Patients with a high alcohol intake had threefold higher odds of developing hepatotoxicity. Multivariate logistic regression analysis revealed the following independent risk factors: older age (odds ratio, 1.2), moderate or far advanced disease (odds ratio, 2.0), serum albumin of less than 3.5 g per dl (odds ratio, 2.3), absence of HLA-DQA1*0102 (odds ratio, 4.0), and the presence of HLA-DQB1*0201 (odds ratio, 1.9). The authors conclude that advancing age, moderate or far advanced disease, hypoalbuminemia, and the presence or absence of specific HLA-DQ alleles are associated with the development of hepatotoxicity during treatment with antituberculosis drugs. An editorial commentary by Bothamley (17) accompanies this article.
Once-weekly administration of rifapentine (a derivative of rifamycin) 600 mg in combination with isoniazid results in a higher relapse rate than does administration of rifampin plus isoniazid twice a week. To determine the safety and tolerability of higher doses of rifapentine, Bock and coworkers (18) did a randomized double-blind trial of rifapentine at three doses (600, 900, and 1,200 mg) plus isoniazid (15 mg per kg) once weekly in 150 patients with culture-positive tuberculosis (HIV seronegative). Treatment was discontinued in 6% of the 600-mg group, 4% of the 900-mg group, and 6% of the 1,200-mg group. Only one discontinuation, in the 1,200-mg arm, was attributed to therapy. The authors conclude that rifapentine 900 mg given once a week is safe, well tolerated, and is being evaluated in Phase III trials, whereas rifapentine 1,200 mg requires further evaluation.
Studies of the early bactericidal activity of antituberculosis drugs have historically focused on the log fall in the viable count in sputum over the first 48 hours of therapy. Gillespie and coworkers (19) present a mathematical model that suggests that the viable count in sputum follows an exponential decay curve with the equation: V = S + Me-kt, where V is the viable count, M is the population of bacteria susceptible to the test drug, S is the population susceptible only to sterilizing agents, t is the day of sputum collection as related to the start of therapy, k is the rate constant for the bacteria killed each day, and e is the Napierian constant. Data from clinical trials were shown to fit the model. Based on the model, the authors propose that further studies of early bactericidal activity be performed by measuring daily quantitative counts for at least 5 days, and that the bactericidal activity of antituberculosis drugs should be based on the time to reduce the viable count to 50%. An editorial commentary by O'Brien (20) accompanies this article.
| NONTUBERCULOUS LUNG INFECTION |
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| TOP CONTENTS TUBERCULOSIS NONTUBERCULOUS LUNG INFECTION INTERSTITIAL LUNG DISEASE OCCUPATIONAL LUNG DISEASE SOCIAL ISSUES, HEALTH POLICY,... REFERENCES |
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Lung Infections
Host defenses.
Neutrophils play a critical role in the defense against infection with Aspergillus. A subset of the CXC chemokine family, ELR+ CXC chemokines, are potent chemoattractants for neutrophils. Mehrad and coworkers (23) determined whether mice that overexpressed the ELR+ CXC chemokine, KC, would have a better outcome when exposed to invasive aspergillosis than do wild-type mice. A transgenic line of mice were developed that overexpressed KC solely in the lungs, and it was possible to tightly regulate expression by exposure to analogs of tetracycline. Compared with wild-type mice, the transgenic mice had greater induction of KC in the lung, an earlier and higher peak of neutrophil influx to the lungs, a 74% decrease in fungal burden, and a threefold greater survival. Compared with wild-type mice, the transgenic mice also had 1.8 times more monocytes-macrophages in the lungs, and greater expression of interferon- and interleukin-12 in response to infection. The authors conclude that overexpression of the ELR+ CXC chemokine, KC (a potent neutrophil chemoattractant), in the lungs causes improved host defense and survival in mice with invasive aspergillosis. An editorial commentary by Huffnagle (24) accompanies this article.
Gram-positive inflammation is presumed to result from components of the bacterial cell wall, such as lipoteichoic acid and peptidoglycan. To study the effect of these components of the wall of Staphylococcus aureus and the modulating influence of interleukin-6, Leemans and coworkers (25) administered the cell-wall components to two groups of mice. In wild-type mice, lipoteichoic acid and peptidoglycan induced acute pulmonary inflammation in a dose-dependent manner, characterized by neutrophilic influx and production of interleukin-6 in bronchoalveolar fluid. Compared with wild-type mice, instillation of 10 µg of lipoteichoic acid caused increases in neutrophil influx, tumor necrosis factor-, macrophage inflammatory protein-1, and cytokine-induced neutrophil chemoattractant in mice deficient in the gene for interleukin-6. Instillation of 100 µg of lipoteichnoic acid, however, tended to attenuate cytokine and chemokine release in the interleukin-6–deficient mice. Compared with wild-type mice, instillation of peptidoglycan induced less neutrophil influx into the lungs of the interleukin-6–deficient mice. The authors conclude that interleukin-6 plays an anti-inflammatory role in the acute inflammation caused by lipoteichoic acid and a proinflammatory role in the inflammation caused by peptidoglycan.
The migration of neutrophils into airspaces in response to Streptococcus pneumoniae is primarily independent of CD18, whereas only 20 to 30% of neutrophil migration in response to Escherichia coli is independent of CD18. Tasaka and coworkers (26) studied the role of very late antigen-4 on neutrophil migration during acute bacterial pneumonia in mice. In wild-type mice, expression of very late antigen-4 on the neutrophils that emigrated into airspaces was less than on circulating neutrophils. Messenger RNA for vascular cell adhesion molecule-1, the major endothelial ligand for very late antigen-4, was increased more during E. coli pneumonia than during S. pneumoniae pneumonia. The adhesion molecule was not detected in the capillaries, the major site of neutrophil emigration. Mice given antibodies to both CD18 and to very late antigen-4 displayed a similar level of neutrophil emigration, as did mice receiving an antibody to CD18 alone. In hematopoietically reconstituted mice that had both wild-type and CD18-deficient neutrophils in their blood, the migration of CD18-deficient neutrophils in response to S. pneumoniae was less in animals pretreated with an antibody to very late antigen-4 than in animals receiving a control antibody. The authors conclude that most but not all of the CD18-independent emigration of neutrophils induced by bacteria in the lungs is mediated through mechanisms that do not involve very late antigen-4.
Application of exogenous CC chemokine ligand 2 (JE, monocyte chemotactic protein-1) induces monocyte accumulation in airspaces, and the combination of CC chemokine ligand 2 and endotoxin (E. coli) provokes enhanced monocyte accumulation, extensive neutrophil influx, and loss of the pulmonary endothelial–epithelial barrier. Maus and coworkers (27) studied the role of the CC chemokine receptor 2 (the receptor for CC chemokine ligand 2) in alveolar leukocyte traffic. The accumulation of monocytes in response to alveolar CC chemokine ligand 2 (alone or in combination with endotoxin) was almost completely inhibited in knockout mice with disruption of the gene for CC chemokine receptor 2 and in wild-type mice treated with MC21 (a monoclonal antibody that blocks CC chemokine receptor 2). Both approaches of interfering with CC chemokine receptor 2 also markedly decreased the accumulation of alveolar neutrophils when the mice were challenged with the combination of CC chemokine ligand 2 and endotoxin. In wild-type mice, administration of an anti–Gr-1 monoclonal antibody (which selectively depletes neutrophils) or antileukinate (an inhibitor of the CXC receptor) markedly decreased the accumulation of alveolar monocyte when the mice were challenged with the combination of CC chemokine ligand 2 and endotoxin. Treating wild-type mice with MC21 (an inhibitor of CC chemokine receptor 2) or with anti–Gr-1 (a selective depletor of neutrophils) prevented the vascular leakage that normally occurs with the combination of CC chemokine receptor 2 and endotoxin. The authors conclude that CC chemokine receptor 2 plays a central role in the recruitment of alveolar monocytes in response to CC chemokine ligand 2, alone or in combination with endotoxin, and that the interdependence of monocytes and neutrophils contribute to vascular permeability.
Pneumonia.
In 52 patients (aged 70 years and older) admitted from a nursing home to the ICU with presumed pneumonia, El-Solh and coworkers (28) determined the causes of failure to respond to antibiotic therapy. All patients had failed to respond to 72 hours of antibiotic therapy before admission and required mechanical ventilation. Microbial investigations (including blood culture, serology, pleural fluid, and bronchoalveolar specimens) revealed a diagnosis in 24 (46%) patients. The most common isolates were methicillin-resistant Staphylococcus aureus (33%), enteric gram-negative bacilli (24%), and Pseudomonas aeruginosa (14%). In 20 cases of definite pneumonia, invasive bronchial sampling directed a change in antibiotics in 8 patients (40%) and discontinuation of antibiotics in 2 patients (10%). The overall hospital mortality was 42%. Mortality did not differ between patients with verified and nonverified pneumonia, or between patients who did or did not have their antibiotics changed on the basis of bronchial sampling. The authors conclude that patients admitted to an ICU from a nursing home because of suspected pneumonia and who have failed prior antibiotics should receive antimicrobial therapy directed at nosocomial pathogens.
Kaplan and coworkers (29) did an observational cohort study to better define the incidence, patterns of care, and outcome among elderly patients admitted to hospital with community-acquired pneumonia. The study sample consisted of all Medicare recipients 65 years or older admitted to hospital with a diagnostic code for community-acquired pneumonia. Among 623,718 hospital admissions (18.3 per 1,000 of that population), 10.6% died. Between 65–69 years to older than 90 years, the incidence of community-acquired pneumonia rose fivefold, and the mortality doubled. Mortality was higher in men (odds ratio, 1.21). Mean length of stay in hospital was 7.6 days, and costs per admission were $6,949. Among the 22.4% of patients admitted to an ICU, length of stay was 11.3 days and costs were $14,294. Among the 7.2% of patients requiring mechanical ventilation, length of stay was 15.7 days and costs were $23,961. Overall hospital costs were $4.4 billion, and $2.1 billion was incurred by cases managed in intensive care units. The authors conclude that community-acquired pneumonia is common and frequently fatal in elderly subjects, and that it frequently necessitates admission to the ICU and results in considerable expenditure.
To compare features of community-acquired pneumonia in patients admitted to an ICU or managed outside of the ICU, Angus and coworkers (30) studied a prospective cohort of patients. Compared with 1,169 patients who were not admitted to the ICU, 170 patients requiring ICU admission were more likely to be admitted from home and to have comorbid conditions. Reasons for admission to the ICU were: respiratory failure (57%) hemodynamic monitoring (32%), and shock (16%). Compared with patients who were not admitted to the ICU, the patients requiring ICU admission had longer hospital stays (23 versus 9 days), higher hospital costs ($21,144 versus $5,785), more nonpulmonary organ dysfunction, and higher hospital mortality (18 versus 5%). Among four sets of criteria for severe pneumonia, the revised criteria of the American Thoracic Society were the best discriminator for ICU admission (areas under a receiver operating characteristic curve, 0.68), although discrimination was still relatively weak. The authors conclude that many patients with community-acquired pneumonia are admitted to the ICU and that available criteria are not robust in guiding clinical care.
Antimicrobial therapy.
To make better informed decisions about the dosage of antibiotic therapy, Herkner and coworkers (31) developed an approach to measure drug levels in human lung tissue. Flexible microdialysis catheters were inserted to sample lung interstitial fluid in five patients undergoing lung surgery for tumors. A single dose of cefpirome was given intravenously. Over the first 4 hours, the concentration of cefpirome in lung interstitial fluid was 66% of the corresponding plasma value, and it exceeded the minimal inhibitory concentrations of most relevant bacteria. Patients tolerated the catheters and adverse events were not seen. The authors conclude that closed chest microdialysis is a feasible and safe technique for measuring antibiotic concentration in human lung tissue.
Macrolide antibiotics inhibit the production of intercellular adhesion molecule-1, which plays a vital role in the accumulation of immune effector cells at sites of local inflammation, and is also known as a receptor for a major subgroup of rhinoviruses, RV14. To study the effects of erythromycin on rhinovirus infection, Suzuki and coworkers (32) infected cultures of human tracheal epithelial cells with the major rhinovirus subgroup, RV14, and the minor subgroup, RV2. Infection with RV14 caused upregulation of the expression of messenger RNA and protein of intercellular adhesion molecule-1, and increased production of cytokines. Erythromycin caused decreases in the titers of RV14 in the supernatant, messenger RNA for RV14, susceptibility to infection with RV14, and production of intercellular adhesion molecule-1 and cytokines. Erythromycin decreased the activation of nuclear factor-B by RV14, and the number of acidic endosomes in the epithelial cells. Erythromycin also reduced the titers of RV2 in supernatant, messenger RNA for RV2, susceptibility to infection with RV2 and cytokine production, although the effects on the receptor were small. The authors conclude that erythromycin inhibits infection caused by the major rhinovirus subgroup through reducing intercellular adhesion molecule-1 and blocking the entry of rhinovirus RNA into endosomes.
| INTERSTITIAL LUNG DISEASE |
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| TOP CONTENTS TUBERCULOSIS NONTUBERCULOUS LUNG INFECTION INTERSTITIAL LUNG DISEASE OCCUPATIONAL LUNG DISEASE SOCIAL ISSUES, HEALTH POLICY,... REFERENCES |
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Histopathological subtypes.
Nicholson and coworkers (35) studied 53 patients with idiopathic pulmonary fibrosis to determine whether four individual histological features can predict prognosis. The four histological features were: fibroblastic foci, interstitial mononuclear cell infiltrate, established fibrosis, and intra-alveolar macrophages. Interobserver agreement between pathologists was moderate to good (, 0.56 to 0.76). Mortality was independently associated with a high score for fibroblastic foci and a low diffusing capacity (as percent predicted). On univariate analysis, increasing interstitial mononuclear cell infiltrate or fibroblastic foci had the strongest correlations with the declines in FVC or diffusing capacity at 6 months. On multivariate analysis, increase in fibroblastic foci was associated with greater decline in FVC and diffusing capacity at both 6 and 12 months, and increase in a score for mononuclear cell infiltrate was linked to functional decline at 6 months. The authors conclude that the described method of histological analysis is reproducible and provides a means of predicting progression of disease in patients with idiopathic pulmonary fibrosis.
Serum markers.
To determine the relative accuracy of serum markers for interstitial lung disease, Ohnishi and coworkers (36) studied 21 patients with idiopathic pulmonary fibrosis, 12 patients with collagen vascular disease, and 82 control subjects. Receiver operating characteristic curves revealed that KL-6 provided the best discrimination. A KL-6 value of 465 U per ml had a sensitivity of 94% and a specificity of 96%. A surfactant protein-A level of 48.2 ng per ml had a sensitivity of 82% and a specificity of 87%. A surfactant protein-D level of 116 ng per ml had a sensitivity of 70% and a specificity of 95%. A monocyte chemoattractant protein-1 level of 1,080 pg per ml had a sensitivity of 52% and a specificity of 93%. The authors conclude that the glycoprotein KL-6 is the most discriminating serum marker for diagnosing interstitial lung disease.
Clinical assessment.
To define the clinical course and outcome of patients with idiopathic pulmonary fibrosis admitted to the intensive care unit, Saydain and coworkers (37) analyzed data on 38 patients. Predicted mortality by APACHE (Acute Physiology and Chronic Health Evaluation) score was 12%, but actual mortality in the intensive care unit was 45%. Predicted hospital mortality was 26% and actual mortality was 61%. Pulmonary function and echocardiography did not differ between survivors and nonsurvivors. Mechanical ventilation was used in 50% of patients, and sepsis developed in 24% of patients. Multiple organ failure developed in 14% of survivors and 43% of the nonsurvivors. Of patients surviving admission to hospital, 92% died at a median of 2 months after discharge. The authors conclude that patients with idiopathic pulmonary fibrosis requiring admission to an intensive care unit have poor short-term and long-term prognosis.
To determine whether the variability of breathing pattern is altered in patients with restrictive lung disease and to determine whether any such alteration is related to dyspnea, Brack and coworkers (38) measured ventilation nonobtrusively in 10 patients with restrictive lung disease and in 7 healthy subjects. Compared with the healthy subjects, the random fraction of breath variability was reduced in the patients: 27 times for expiratory time, 12 times for tidal volume, and 6 times for inspiratory time. Conversely, the nonrandom, correlated fraction for tidal volume was increased almost threefold in the patients. On a separate occasion, dyspnea was measured while the patients and control subjects voluntarily copied different tidal volumes and frequencies. Small variations from the average resting tidal volume caused marked increases in dyspnea in the patients, and the relationship was parabolic (r2 = 0.97). The authors conclude that patients with restrictive lung disease adopt a tightly constrained breathing pattern, probably as a strategy for avoiding dyspnea.
Cellular and molecular mechanisms, in vivo.
Vascular endothelial growth factor is involved in the development and maintenance of vascular function, and inhibition of its receptor causes endothelial cell apoptosis and emphysema. Koyama and coworkers (39) determined whether its level is altered in patients with lung disease. The level of vascular endothelial growth factor in bronchoalveolar fluid was 256 pg per ml in 16 healthy nonsmokers, 27 pg per ml in 11 healthy smokers, 62 pg per ml in 14 patients with idiopathic pulmonary fibrosis, 78 pg per ml in 21 patients with pulmonary fibrosis associated with connective tissue disease, and 133 pg per ml in 14 patients with sarcoidosis. The isoform in the healthy nonsmokers was VEGF165. The authors conclude that vascular endothelial growth factor is decreased in the bronchoalveolar fluid of healthy nonsmokers, and in patients with idiopathic pulmonary fibrosis, pulmonary fibrosis associated with connective tissue disease, and sarcoidosis.
The role of inflammatory mechanisms in of the pathogenesis of idiopathic pulmonary fibrosis is debated by Gauldie (40) and Strieter (41), with rebuttals from each (42, 43).
Cellular and molecular mechanisms, ex vivo.
Infection with the Epstein-Barr virus has been linked to idiopathic pulmonary fibrosis. Replication of the virus is associated with a rearrangement of genomes for Epstein-Barr virus, termed the WZhet recombinant fragment. To determine whether WZhet genomes are associated with idiopathic pulmonary fibrosis, Kelly and coworkers (44) studied 39 patients with idiopathic pulmonary fibrosis, 26 lung transplant recipients, and 24 healthy subjects. Of lung biopsies from patients with idiopathic pulmonary fibrosis that contained DNA of the Epstein-Barr virus, 11 of 18 (61%) were positive for WZhet. WZhet was positive in the buffy coat of peripheral blood in 59% of patients with idiopathic pulmonary fibrosis, as compared with 4% of the healthy subjects and none of the lung transplant recipients. The presence of WZhet in lung tissue was correlated with the level in peripheral blood. The presence of WZhet was not related to immunosuppressive therapy. The authors conclude that a rearranged form of Epstein-Barr virus DNA, the WZhet recombinant fragment, is common in patients with idiopathic pulmonary fibrosis, and that it provides a marker for tracking Epstein-Barr virus in this disease.
Animal models.
Using fluorescence-activated cell sorting technology, Maus and coworkers (45) characterized the molecular pathways involved in the phenotyping of leukocyte traffic into the alveolar space of intact mice. The instillation of monocyte chemoattractant JE/monocyte chemotactic protein-1 combined with E. coli lipopolysaccharide into the trachea induced self-limiting alveolar inflammation involving migration of both monocytes and neutrophils. Challenge with JE/monocyte chemotactic protein-1 alone provoked the migration of only monocytes and it did not cause inflammation; this recruitment of monocytes was strictly dependent on CD11b/CD18, CD54 and CD-49d, partly dependent on CD11a, and not dependent on CD106. The recruitment of monocytes in response to the combination of JE-monocyte chemotactic protein-1 and E. coli lipopolysaccharide was associated with additional engagement of CD11a and CD106. Neutrophils comigrating under these conditions involved CD11b, CD18 and CD54, but not CD49d, CD106, or CD11a. The authors conclude that the molecular pathways involved in the migration of monocytes into the alveolar space in response to monocyte chemoattractant JE/monocyte chemotactic protein-1 differ depending whether or not there was accompanying inflammation.
Treatment.
Because nuclear factor-B promotes the transcription of genes encoding chemokines and cytokines involved in chronic inflammation, preventing the activation of this transcription factor may lessen the lung injury of idiopathic pulmonary fibrosis. Conron and coworkers (46) infected alveolar macrophages from patients with inflammatory lung disease with adenovirus constructs that express a defective ß subunit of IB kinase and a defective nuclear factor-B–inducing kinase. Constitutive and cytokine induced activation of nuclear factor-B by alveolar macrophages was found to require the catalytically active subunit of IB kinase, but was not dependent on signaling by nuclear factor-B–inducing kinase. The authors conclude that the IB kinase subunit is a potential target for gene therapy in diseases that involve transcription of nuclear factor-B.
Statements and workshops.
The American Thoracic Society and the European Respiratory Society (47) present a multidisciplinary consensus classification of the idiopathic interstitial pneumonias.
In a summary report from a NHLBI workshop, Crystal and colleagues (48) review future directions for research on idiopathic pulmonary fibrosis.
Progressive Systemic Sclerosis
To determine whether the better prognosis of idiopathic pulmonary fibrosis associated with systemic sclerosis is related to histopathologic findings, Bouros and coworkers (49) studied 80 patients with this condition. Nonspecific interstitial pneumonia was observed in 77.5%, usual interstitial pneumonia in 7.5%, end-stage lung disease in 7.5%, and other patterns in the remaining 7.5%. Five-year mortality was 91% in patients with nonspecific interstitial pneumonia and 82% in patients with usual interstitial pneumonia or the end-stage pattern. Mortality was associated with a low initial diffusing capacity and a low FVC. The authors conclude that idiopathic pulmonary fibrosis associated with systemic sclerosis has the histopathologic pattern of nonspecific interstitial pneumonia, but that the histopathologic pattern does not predict prognosis. An editorial commentary by King (50) accompanies this article.
To determine whether the alveolar concentration of nitric oxide is elevated in patients with pulmonary involvement of scleroderma, Girgis and coworkers (51) studied 20 patients and 20 healthy control subjects. Exhaled nitric oxide was measured at multiple flow rates and the output of nitric oxide was plotted against expiratory flow rate: the slope of the relationship was taken as a measure of alveolar concentration and the intercept was taken as a measure of flux in the conducting airways. The alveolar concentration of nitric oxide was higher in the patients than in the control subjects: 4.7 versus 1.8 ppb. Flux in the conducting airways was lower in the patients than in the control subjects: 0.6 versus 1.2 nl per second. The alveolar concentration of nitric oxide was negatively correlated with diffusing capacity (r = -0.66). The authors conclude that patients who have scleroderma with lung involvement have an increased alveolar concentration of nitric oxide.
Sarcoidosis
Genetics.
To determine whether polymorphisms in the genes of the interleukin-1 family are involved in the pathogenesis of sarcoidosis and idiopathic pulmonary fibrosis, Hutrova and coworkers (52) studied 95 patients with sarcoidosis, 54 patients with idiopathic pulmonary fibrosis, and 199 healthy subjects. The interleukin-1 -889 1.1 genotype was overrepresented in the patients as compared with the healthy subjects: 60% versus 44%. The distribution of genotypes for interleukin-1ß -511, interleukin-1ß +3953, and interleukin-1 receptor antagonist VNTR did not differ between the patients with sarcoidosis and the healthy subjects. None of the polymorphisms was associated with interstitial pulmonary fibrosis. The authors conclude that interleukin-1 -889 1.1 polymorphism is associated with the development of sarcoidosis.
In two well-defined groups of patients with sarcoidosis (96 British patients and 354 control subjects, and 100 Dutch patients and 222 control subjects), Grutters and coworkers (53) studied five potential functional polymorphisms in the promoter region of the gene for tumor necrosis factor-. The two populations of patients with sarcoidosis displayed an increase in the rare -857T allele (which involves a change from C to T at position -857 in the promoter region). This allele was carried by 25.5% of the patients with sarcoidosis and by 14.1% of the control subjects; the allele frequency of this polymorphism was 13.5% in the sarcoidosis patients and 7.3% in the control subjects. The rare -307A allele was increased in the subgroup of patients with Lofgren's syndrome, although linkage disequilibrium was not excluded. The authors conclude that patients with sarcoidosis display an increase in the rare -857T allele in the promoter region of the gene for tumor necrosis factor-.
Molecular mechanisms.
In bronchoalveolar fluid from 30 patients with different stages of sarcoidosis and 18 healthy subjects, Capelli and coworkers (54) measured the levels of two macrophage-derived CC chemokines that induce lymphocyte migration. Macrophage inflammatory protein-1 was increased in patients with Stage II and Stage III disease, whereas macrophage inflammatory protein-1ß was increased in all stages. Expression of CCR5, the receptor for both chemokines, was increased in both lymphocytes and macrophages of all patients. The concentration of macrophage inflammatory protein-1ß was correlated with the number of CD4 lymphocytes (r = 0.64) and with the number of CD8 lymphocytes (r = 0.62). The concentration of macrophage inflammatory protein-1 was correlated only with the number of CD8 lymphocytes (r = 0.45). The percentage of neutrophils was negatively related to expression of CCR5 in both alveolar macrophages (r = -0.53) and lymphocytes (r = -0.43). The authors conclude that lymphocytes and alveolar macrophages of patients with sarcoidosis display increased levels of two CC chemokines, macrophage inflammatory protein-1 and macrophage inflammatory protein-1ß, associated with increased expression of CCR5, the specific receptor for these chemokines.
Histiocytosis X
Pulmonary Langerhans cell histiocytosis (also called histiocytosis x) is characterized by destructive granulomas containing large numbers of activated Langerhans cells. The extent to which the granulomas are bronchocentric is unknown, and the mode of cyst formation has not been defined. To investigate these issues, Kambouchner and coworkers (55) studied serial sections obtained from seven patients. The granulomatous process exclusively affected the small airways in an acinar distribution. The lesions extended, without interruption, along the bronchiolar axis, forming continuous sleeve-like structures around the distant airways. The granulomatous reaction progressed along the bronchiolar axis over time, extending the abnormalities in both proximal and distal directions. Cystic lesions resulted from destruction of the bronchiolar wall and progressive dilation of the lumen, subsequently circumscribed by fibrous tissue. The authors conclude that it may be more accurate to classify pulmonary Langerhans cell histiocytosis as a bronchiolitis rather than as an interstitial lung disease because the lesions affect and progressively destroy the distal airways. An editorial commentary by Myers and Aubry (56) accompanies this article.
Lymphangioleiomyomatosis
Telomerase synthesizes nucleotide hexameric repeats (telomeres) at the end of chromosomes, replacing base sequences that are lost during each mitotic cycle and protecting the ends against the action of exonucleases and ligases. To evaluate the role of telomerase activity in the proliferation of lymphangioleiomyomatosis (LAM) cells (abnormal smooth muscle cells), Kumaki and coworkers (57) studied 22 women with LAM (14 untreated and 8 treated with progesterone or tamoxifen). Signals for telomerase protein and messenger RNA were observed in 5 to 20% of LAM cells (mostly of the spindle-shaped type) in 21 of the 22 patients. Signals were less intense in the treated group. Telomerase colocalized in the same cells with -smooth muscle actin, but only rarely with HMB-45 antibody (a marker for epithelioid LAM cells). The authors conclude that telomerase is present in 5 to 20% of LAM cells, and mostly in those of the proliferative spindle-shaped type.
Mast cells produce basic fibroblast growth factor, which is a potent mitogenic factor for proliferation of smooth muscle cells, myofibroblasts, and fibroblasts. Inoue and coworkers (58) studied involvement of this growth factor in lung sections from 14 patients with idiopathic pulmonary fibrosis, 9 patients with LAM, and 10 control subjects without lung disease. The lungs from the two patient groups contained more smooth muscle cells and myofibroblast-like cells than did the control lungs. Mast cells containing basic fibroblast growth factor were abundant in both patient groups, and were associated with collagen, elastic fibers, smooth muscle cells, and myofibroblast-like cells. Fibroblast growth factor receptor 1 (Flg) was expressed on epithelial cells, endothelial cells, smooth muscle cells, myofibroblast-like cells, and macrophages in idiopathic pulmonary fibrosis. The fibroblast growth factor receptor was expressed on epithelial cells adjacent to aggregates of smooth muscle cells and myofibroblast-like cells in LAM. Fibroblast growth factor receptor 2 (Bek) was expressed on smooth muscle cells and myofibroblast-like cells in both idiopathic pulmonary fibrosis and LAM, and also on neutrophils in idiopathic pulmonary fibrosis. The authors conclude that basic fibroblast growth factor derived from mast cells appears to exert proliferative fibrogenic effects on smooth muscle cells and myofibroblast-like cells in patients with idiopathic pulmonary fibrosis and LAM.
Eosinophilic Pneumonia
Thymus- and activation-regulated chemokine (TARC/CCL17) is a high-affinity ligand for CC chemokine receptor-4 (CCR4), which recruits CCR4-expressing type 2 (Th2) helper T cells. Miyazaki and coworkers (59) found that 25 patients with eosinophilic pneumonia had a median level of TARC in bronchoalveolar fluid of 240 pg per ml, whereas most patients with other interstitial lung diseases (11 with hypersensitivity pneumonitis, 20 with sarcoidosis, 18 with idiopathic pulmonary fibrosis) had a level of less than 7 pg per ml. Patients with eosinophilic pneumonia also had increased levels of interleukin-4, interleukin-5, and interleukin-13 in bronchoalveolar fluid. The concentration of TARC was correlated with the levels of interleukin-5 (r = 0.89) and interleukin-13 (r = 0.84) in bronchoalveolar fluid. On serial measurements, a fall in the level TARC preceded decreases in the level of interleukin-5 and in the number of eosinophils. The authors conclude that the level of TARC (thymus- and activation-regulated chemokine) is elevated in parallel with type 2 (Th2) cytokines, interleukin-5, and interleukin-13 in the bronchoalveolar fluid of patients with eosinophilic pneumonia.
Idiopathic acute eosinophilic pneumonia is characterized by acute febrile respiratory failure associated with diffuse radiographic infiltrates and pulmonary eosinophilia. Philit and coworkers (60) describe a series of 22 patients with this rare clinical entity. Within the first month after the onset of symptoms, the patients presented with severe hypoxemia (PaO2/FIO2 ratio, 156 mm Hg). Fourteen patients (64%) required mechanical ventilation, 12 patients met the criteria for acute lung injury, and 8 patients met the criteria for the acute respiratory distress syndrome. Radiographic studies revealed diffuse bilateral infiltrates. Bronchoalveolar lavage revealed 54% eosinophils. All patients recovered: 6 recovered without glucocorticoids and 12 received glucocorticoids. No patient relapsed. The authors conclude that idiopathic acute eosinophilic pneumonia should be considered in the differential diagnosis of acute respiratory distress syndrome, finding more than 25% eosinophilia on lavage obviates the need for lung biopsy, and a response to glucocorticoids should not be used as a diagnostic criterion. An editorial commentary by du Bois (61) accompanies this article.
Acute Interstitial Pneumonitis
Acute interstitial pneumonitis causes acute alveolar damage, and its sudden onset resembles the acute respiratory distress syndrome. Ichikado and coworkers (62) studied whether the findings on high-resolution computed tomography could predict prognosis in 10 nonsurvivors and 21 survivors of acute interstitial pneumonia. Two independent observers unaware of patient outcome graded the findings: interobserver agreement was good ( 0.75). Compared with nonsurvivors, survivors displayed less ground-glass attenuation or consolidation associated with traction bronchiolectasis or bronchiectasis, less architectural distortion, and more ground glass attenuation or consolidation without traction bronchiolectasis. Overall scores were lower in survivors than in nonsurvivors: 223 versus 324. A score of less than 245 had a positive predictive value of 80% and a negative predictive value of 90% for survival. The authors conclude that findings on computed tomography help in predicting the prognosis in acute interstitial pneumonitis irrespective of the underlying physiologic abnormality. An editorial commentary by Hansell (63) accompanies this article.
Niemann-Pick Disease
Niemann-Pick disease is a lipid storage disorder caused by a lack or deficiency of acid sphingomyelinase. Patients with Type B disease often survive into adulthood and can develop progressive pulmonary infiltrates. Nicholson and coworkers (64) describe a patient who presented with extensive endogenous lipoid pneumonia and severe hypoxemia after cardiac surgery. Bilateral whole lung lavage produced a decrease in the pulmonary infiltrates and an increase in PO2 of 15 mm Hg while breathing room air. The authors conclude that whole-lung lavage may be useful in treating pulmonary involvement caused by Neimann-Pick Type B disease.
Lymphoproliferative Disorders
Kurosa and coworkers (65) determined whether pulmonary lymphoproliferative lesions display selective oligoclonal expansion of tumor-infiltrating T lymphocytes. Denaturing gradient gel electrophoresis revealed some oligoclonal bands for T cell antigen receptor-V gene in 6 of 15 patients with low-grade mucosa-associated lymphoid tissue (MALT), in all of 5 patients with HIV-related lymphocytic interstitial pneumonia, and in 1 of 3 patients with HIV-negative lymphocytic interstitial pneumonia. The authors conclude that oligoclonal expansions occur in some pulmonary lymphoproliferative disorders.
Idiopathic Pulmonary Alveolar Proteinosis
In a state of the art review article, Seymour and Presneill (66) discuss the first 44 years of progress on pulmonary alveolar proteinosis.
Pulmonary Drug Toxicity
Idiopathic pneumonia syndrome, a noninfectious diffuse lung injury, is reported to occur in 39 to 64% of patients who undergo high-dose chemotherapy and bone marrow transplantation. Bhalla and Folz (67) developed a murine model that mimics the human disease. Using an autologous bone transplant regimen, mice developed pulmonary injury as early as the following day. The injury was characterized by intense infiltrates of activated macrophages and a decrease in lung compliance. The cellular influx was preceded by acute elevation in monocyte chemotactic protein-1 and macrophage inflammatory protein-1. The conditioning regimen caused substantial oxidative stress, as manifested by increase in lung lipid peroxidation and oxidized glutathione. Administration of N-acetylcysteine, an antioxidant, markedly decreased the lung injury. The authors conclude that the early stages of idiopathic pneumonia syndrome in mice treated with high-dose chemotherapy and bone marrow transplantation consists of severe oxidative stress, associated with the recruitment of alveolar macrophages and a decrease in lung compliance. An editorial commentary by Haddad (68) accompanies this article.
Calcium Deposition in the Lung
In a state of the art review article, Chan and colleagues (69) discuss calcium deposition with or without bone formation in the lung.
Rodent Model of Bleomycin Fibrosis
To determine the role of leukotrienes in pulmonary fibrosis, Peters-Golden (70) studied lung fibrosis caused by bleomycin in mice. In wild-type mice, bleomycin caused a fivefold increase in the levels of cyteinyl-leukotrienes, and the levels remained high for 21 days. In mice deficient in leukotrienes (achieved by targeted deletion of the gene for 5-lipoxygenase), bleomycin caused less collagen formation and a 60% decrease in lung hydroxyproline. Unlike the wild-type mice, the knockout mice did not develop increases in lung inflammatory cells after bleomycin, and they displayed greater expression of the antifibrotic cytokine, interferon-, and higher levels of the antiinflammatory and antifibrotic molecule, prostaglandin E2. The authors conclude that leukotrienes participate both directly and indirectly in pulmonary fibrosis caused by bleomycin. An editorial commentary by Zeldin (71) accompanies this article.
Because N-acetylcysteine ameliorates pulmonary fibrosis caused by bleomycin, Wang and coworkers (72) studied the effect of bilirubin, another powerful antioxidant, in this setting. Intravenous infusions were used to maintain a serum bilirubin of 3 to 10 mg per dl in rats. Mortality from pulmonary fibrosis caused by bleomycin was lower in rats with hyperbilirubinemia than in control animals. Rats with hyperbilirubinemia had lower levels of hydroxyproline in the lung, lower concentrations of transforming growth factor-ß1 in bronchoalveolar fluid, and decreased numbers of polymorphonuclear leukocytes and lymphocytes in bronchoalveolar fluid. Rats with hyperbilirubinemia had higher levels of oxidative metabolites of bilirubin in the urine. The authors conclude that the antioxidant action of bilirubin attenuates the pulmonary fibrosis caused by bleomycin, partly by inhibiting lung inflammation and the production of transforming growth factor-ß1.
Instilling bleomycin into the lungs of mice causes DNA damage and apoptosis within hours, and inflammation and fibrosis several weeks later. Ghosh and coworkers (73) evaluated the role of p53 tumor suppression protein, which mediates cellular responses to DNA damage, including the induction of apoptosis. Transgenic mice with a dominant-negative mutant form of human p53 expressed from the promoter for surfactant protein C displayed more severe lung damage, increased collagen deposition, and more pronounced eosinophilia after exposure to bleomycin than did control mice. The authors conclude that compromised function of p53 tumor suppressor protein in alveolar epithelium impairs the recovery of the lung after exposure to bleomycin.
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The cytokine tumor necrosis factor- plays a central role in the pathophysiology of silicosis. Corbett and coworkers (75) investigated the role of single nucleotide polymorphisms (SNPs) in the promoter region of tumor necrosis factor- in determining susceptibility to silicosis in black South African gold miners. No differences were seen for any loci in the promoter region between 112 patients with nonsevere silicosis and 120 miners without silicosis. Nine miners with severe silicosis were more likely than control subjects to have -238A (33 versus 5%) and -376A (33 versus 5%); these alleles were in linkage disequilibrium, indicating that they were not independent. Miners with severe silicosis were also more likely to have the -308A allele, but the result was confounded by ethnicity. The authors conclude that polymorphisms of the promoter region of tumor necrosis factor- are associated with severe silicosis, and that the polymorphism influences the severity of the disease rather than its frequency.
Some 1 to 8% of beryllium workers have beryllium hypersensitivity on immunologic testing, and 42 to 83% of workers with hypersensitivity have manifestations of chronic beryllium disease. Rossman and coworkers (76) studied three different human leukocyte antigen (HLA) Class II isotypes in 25 patients with established chronic beryllium disease, 30 subjects with beryllium hypersensitivity but without clinical disease, and 82 beryllium workers who did not have beryllium hypersensitivity. HLA-DPB1-E69 was a marker for beryllium hypersensitivity, but it did not distinguish between subjects who did or did not develop symptoms of chronic beryllium disease. Chronic beryllium disease was significantly associated with HLA-DQB1-G86 and HLA-DRB1-S11. The authors conclude that HLA-DPB1-E69 is a marker for susceptibility to beryllium hypersensitivity but not a marker for progression to disease, and that HLA amino acid epitodes on HLA-DRB1 and HLA-DQB1 may be associated with progression of disease.
Vermiculite is a silicate material that is used extensively in the insulation and building industry. Wright and coworkers (77) describe the case of a 65-year-old accountant who developed extensive fibrocalcific pleural plaques, end-stage pulmonary fibrosis, and rapidly progressive respiratory failure. The patient's only exposure to asbestos was during a summer job 50 years earlier in a California vermiculite expansion plant. Electron microscopy revealed over 8 million asbestos fibers per gram of dry lung, and 68% were tremolite asbestos. Additional asbestiform fibers of a composition not matching any of the standard varieties were also present in high concentration. Analysis of a sample of vermiculite from Libby, Montana—a major source of U.S. vermiculite—showed a similar mix of asbestiform fibers. The authors conclude that brief but intense exposure to asbestos can cause severe fibrotic disease after a long latency period, and that the risk of vermiculite-induced injury needs to be considered among former workers of the more 200 expansion plants.
Rom and coworkers (78) describe a firefighter who was exposed to high concentrations of dust from the World Trade Center for over 2 weeks and who subsequently developed acute eosinophilic pneumonia. The patient presented with cough, blackish sputum, and dyspnea, and had a PO2 of 53 mm Hg. Computed tomography revealed patchy ground glass density, thickened bronchial walls, and bilateral pleural effusions. Bronchoalveolar lavage revealed 70% eosinophilia and increased levels of interleukin-5. Mineralogical analysis revealed 305 commercial asbestos fibers per 106 macrophages; fly ash and degraded glass were also found. The patient responded to oxygen and glucocorticoids. An editorial commentary by Beckett (79) accompanies this article.
To determine the prevalence of sensitization to allergens in the workplace and the prevalence of occupational asthma among growers of greenhouse flowers or ornamental plants, Monso and coworkers (80) studied 39 growers. Thirteen of 38 growers (34%) were sensitized to flowers or molds, but sensitization was not related to characteristics of the greenhouses. Poor ventilation was a marginal risk factor for wheezing. Occupational asthma was confirmed by bronchial provocation in three workers (7.7%), all of whom were sensitized to workhouse flowers or molds. None of the nonsensitized workers had occupational asthma. The authors conclude that occupational asthma occurs in 8% of growers of greenhouse flowers, ornamental plants, or both, and in a quarter of workers sensitized to flowers or molds.
Peripheral blood monocytes of patients with diisocyanate asthma produce monocyte chemoattractant protein-1 in response to diisocyanate human serum albumin. To determine the diagnostic usefulness of this response, Bernstein and coworkers (81) studied 54 workers exposed to diisocyanate. A diagnosis of diisocyanate asthma was confirmed by a specific inhalation challenge in 19 (35%) of the workers. The assay for production of monocyte chemoattractant protein-1 (in response to diisocyanate-human serum albumin) had a diagnostic sensitivity of 79% and a specificity of 91%. Diisocyanate-specific IgG had a sensitivity of 47% and a specificity of 74%. Diisocyanate-specific IgE had a sensitivity of 21% and a specificity of 89%. The authors conclude that an in vitro assay for production of chemoattractant protein-1 in response to diisocyanate-human serum albumin is superior to specific IgE and IgG antibodies in the diagnosis of diisocyanate asthma. An editorial commentary by Hendrick (82) accompanies this article.
To determine the influence of occupational exposure on the incidence of respiratory symptoms and asthma, Eagan and coworkers (83) undertook an 11-year community cohort study in 2,819 Norwegian subjects. At baseline, the prevalence of exposure to quartz was 3.7%, to asbestos 5.0%, and to dust or fumes 28.3%. After adjusting for sex, age, educational level, and smoking, the odds ratios for the development of respiratory symptoms or asthma in subjects exposed to dust or fumes varied between 1.4 and 2.1. After adjusting for the confounding variables, 14% of the incidence of asthma and 6 to 19% of the incidence of respiratory symptoms were attributable to exposure to dust or fumes. The authors conclude that airborne occupational exposure increases the incidence of asthma and respiratory symptoms.
To investigate the relationship between pesticides and wheeze in farmers, Hoppin and coworkers (84) analyzed data from 20,468 certified pesticide applicators in Iowa and North Carolina. The applicators, ranging in age from 16 to 88 years, completed self-administered questionnaires. In the previous year, 19% reported wheezing. After controlling for age, state, smoking, and history of asthma or atopy, the odds ratios for wheeze were elevated for paraquat, three organophosphates (parathion, malathion, and chlorpyrifos), and one thiocarbamate (S-ethyl-dipropylthiocarbamate, EPTC). The herbicides, atrazine and alachlor, but not 2, 4-D, were associated with wheeze. Inclusion of crops and animals into the model did not alter the odds ratios. The authors conclude that specific pesticides are independent contributors to wheeze in farmers. An editorial commentary by Ernst (85) accompanies this article.
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In an editorial, Tobin (87) discusses the rigor of peer review and the standing of a journal.
In an editorial, Tobin (88) discusses the policy of AJRCCM on duplicate publication.
In an editorial, Tobin (89) discusses the expansion of web-based publishing in the Journal.
In an editorial, Tobin (90) discusses the Journal's policy on abbreviations.
In an editorial, Tobin (91) discusses the Journal in 2002.
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| TOP CONTENTS TUBERCULOSIS NONTUBERCULOUS LUNG INFECTION INTERSTITIAL LUNG DISEASE OCCUPATIONAL LUNG DISEASE SOCIAL ISSUES, HEALTH POLICY,... REFERENCES |
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