Tuberculosis, Lung Infections, Interstitial Lung Disease, and Socioeconomic Issues in AJRCCM 2001 

MARTIN J. TOBIN

Division of Pulmonary and Critical Care Medicine, Loyola University of Chicago Stritch School of Medicine and Hines Veterans Affairs Hospital, Hines, Illinois

	CONTENTS

TOP CONTENTS TUBERCULOSIS NONTUBERCULOUS LUNG INFECTION INTERSTITIAL LUNG DISEASE OCCUPATIONAL LUNG DISEASE SOCIAL ISSUES, HEALTH POLICY,... REFERENCES

Tuberculosis (23)

    Studies of Molecular Mechanisms in Tuberculosis (2)

    Epidemiology of Tuberculosis (5)

    Risk Factors (3)

    Interaction with Human Immunodeficiency Virus (1)

    Latent Tuberculosis Infection (7)

          Screening (5)

          Risk, Reactivation and Treatment (2)

    Diagnosis of Tuberculosis (3)

    Treatment of Tuberculosis (2)

Nontuberculous Lung Infection (9)

            Human Immunodeficiency Virus Infection (5)

  Studies of Molecular Mechanisms (1)

          Infections (2)

          Asthma (1)

        Highly Active Antiretroviral Therapy (1)

    Lung Infections (3)

        Host Defenses (1)

        Pneumonia (2)

    Bronchiectasis (1)

Interstitial Lung Disease (39)

    Idiopathic Pulmonary Fibrosis (13)

        Genetics (1)

        Histopathological Subtypes (3)

        Clinical Assessment (6)

        Cellular and Molecular Mechanisms, in vivo (1)

        Cellular and Molecular Mechanisms, ex vivo (2)

    Sarcoidosis (11)

        Genetics (5)

        Molecular Mechanisms (2)

        Clinical Manifestations (4)

    Lymphangioleiomyomatosis (5)

    Idiopathic Pulmonary Alveolar Proteinosis (1)

    Pulmonary Drug Toxicity (1)

    Hypersensitivity Pneumonitis (4)

    Rodent Model of Bleomycin Fibrosis (4)

Occupational Lung Disease (10)

Social Issues, Health Policy, and Economics (5)

	TUBERCULOSIS

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Studies of Molecular Mechanisms in Tuberculosis

Superoxide dismutase catalyzes the conversion of superoxide anion to hydrogen peroxide and contributes to the virulence of intracellular pathogens. Pathogenic mycobacteria produce 93 times more superoxide dismutase as compared with nonpathogenic mycobacteria. To determine the role of superoxide dismutase in the pathogenesis of tuberculosis, Edwards and coworkers (1) used antisense RNA expression to construct mutants of M. tuberculosis H3FRv (a well-characterized virulent strain) that produces a reduced amount of superoxide dismutase. The isolates with diminished production of superoxide dismutase were more susceptible to killing by hydrogen peroxide. Four weeks after inoculating C57BL/6 mice, the control strains were associated with 100,000 times more bacilli in the lung and spleen, as compared with the strain with reduced production of superoxide dimutase. Within 24 hours, the attenuated strains induced a robust mononuclear cell infiltration of the interstitium and many cells were apoptotic. In contrast, the virulent strain induced minimal early inflammation, and apoptosis of mononuclear cells in the interstitium was rare. During prolonged infection, the mice tolerated the attenuated strain better than they tolerated BCG, and they exhibited a 68% greater weight gain, quicker eradication of bacilli from the spleen, and less alveolar infiltrates. The authors conclude that superoxide dismutase contributes to the pathogenesis of tuberculosis by preventing the early elimination of M. tuberculosis by innate immune responses, which include the early mononuclear cell infiltration of infected tissues and apoptosis. An editorial commentary by Woolwine and Bishai (2) accompanies this article.

Epidemiology of Tuberculosis

In patients previously treated for tuberculosis, the relative frequency of exogenous reinfection versus endogenous reactivation of tuberculosis is unclear. To address this issue, Caminero and coworkers (3) studied 962 cases of tuberculosis in Gran Canaria Island. Of the cases, 23 patients (2.4%) had two positive cultures separated by at least one year. DNA fingerprinting was performed in 18 of these patients, and eight patients (44%) had different genotypes in the first and final isolates, indicating exogenous reinfection. Six patients were seronegative for human immunodeficiency virus (HIV) and two were seropositive for HIV. The authors conclude that exogenous reinfection is an important cause of recurrent tuberculosis, even in HIV-seronegative patients. An editorial commentary by Bates (4) accompanies this article.

Of 721 patients diagnosed with tuberculosis on Gran Canaria Island between 1993 and 1996, Caminero and coworkers (5) did restriction fragment length polymorphism analysis on 566 isolates (79%). Of the 566 isolates, 72% belonged to clusters. The largest cluster, containing 75 cases, was caused by a strain of the Beijing genotype introduced into the island by an African refugee in 1,993. This strain was responsible for 6% of the cases in 1993, 8% of the cases in 1994, 16% of the cases in 1995, and 27% of the cases in 1996. The authors conclude that molecular techniques documented the introduction of the Beijing genotype of Mycobacterium tuberculosis and its rapid dissemination in Gran Canaria Island. This article is accompanied by an editorial commentary by Bishai (6).

Riley (7) recalls an early study on transmission of tuberculosis by airbone droplet nuclei.

Risk Factors

To determine whether patients are more willing to report risk factors for tuberculosis and HIV infection when a computer-assisted questionnaire as compared with an interviewer-assisted questionnaire is used, Riley and coworkers (8) studied 282 participants in a needle exchange program. Compared with the interviewer-assisted questionnaire, the participants using the computer-assisted questionnaire were more likely to report smoking marijuana (odds ratio, 5.6), crack (odds ratio, 1.9), and heroin (odds ratio, 2.6), sharing of cocaine smoking equipment (odds ratio, 4.5), sharing of heroin smoking equipment (odds ratio, 2.9), shotgunning (an individual inhales smoke and exhales it into the mouth of a second person; odds ratio, 4.5), and visiting crack houses (odds ratio, 4.4). The reporting of sociodemographic data and access to health care services was equivalent for the two questionnaire techniques. The authors conclude that individuals report higher rates of behavior associated with an increased risk of tuberculosis and HIV infection when a computer-assisted as compared with an interviewer-assisted interviewing technique is used.

Because persons entering the United States on nonimmigrant visas are not screened for tuberculosis, Weis and coworkers (9) examined the immigrant status of all patients with culture-positive tuberculosis in Tarrant County, Texas between January 1998 and December 2000. Of 274 eligible participants, 42% were foreign born. Of the 114 foreign-born participants, 59% were permanent residents, 17% had nonimmigrant visas (tourists, temporary workers, students), and 25% had no entry documents. Compared with the permanent residents, nonimmigrant visitors had a higher rate of multidrug-resistant tuberculosis (16 versus 1%), HIV infection (32 versus 5%), hospitalization (47 versus 19%), and longer hospital stay (87 versus 10 days). The authors conclude that nonimmigrant visitors are more likely to have multidrug-resistant tuberculosis and are more likely to be HIV-infected as compared with permanent residents. An editorial commentary by Menzies (10) accompanies this article.

Interaction with Human Immunodeficiency Virus

Whether or not infection with the human immunodeficiency virus (HIV) increases the infectiousness of pulmonary tuberculosis is controversial. To address this issue, Carvalho and coworkers (11) followed 104 close contacts of patients with pulmonary tuberculosis who were also HIV-seropositive and 256 close contacts of patients with pulmonary tuberculosis who were HIV-seronegative. At enrollment, infection with tuberculosis was equivalent among contacts of patients who were HIV-seropositive and HIV-seronegative: 27 versus 35%. On follow up after at least one year, 8% of the contacts of the HIV-seropositive index cases had converted their tuberculin skin test as compared with 26% of the contacts of the HIV-seronegative index cases. The authors conclude that patients with pulmonary tuberculosis who are also HIV-seropositive are less likely to infect their close contacts with M. tuberculosis as compared with patients with tuberculosis who are HIV-seronegative.

Latent Tuberculosis Infection

Screening Because jails are an important reservoir of tuberculosis infection, Jones and Schaffner (12) used decision analysis to assess the cost-effectiveness of routine miniature chest radiography for screening on admission to jail. The cost for an X-ray was estimated as $6.60 per inmate. To identify a case of active tuberculosis, radiographic screening cost $9,600, tuberculin skin testing cost $32,100, and symptom screening cost $54,100. Radiography also identified substantially more cases as compared with the other methods of screening. The authors conclude that screening with miniature chest radiography is cost-effective under a wide range of conditions. An editorial commentary by Davidson (13) accompanies this article.

Risk, reactivation, and treatment The American Thoracic Society and the Centers for Disease Control (17) presented an update on the risk of fatal liver injuries associated with the use of rifampin and pyrazinamide in the treatment of latent tuberculosis.

Diagnosis of Tuberculosis

Lalvani and coworkers (19) described a new blood test for diagnosing Mycobacterium tuberculosis infection. M. tuberculosis (but not BCG) secretes an antigen, ESAT-6 (early secreted antigenic target 6-kD protein). In vitro stimulation of mononuclear cells from a blood sample with this antigen causes the cells to produce interferon-. An ELISPOT (enzyme-linked immunospot) assay was used to enumerate interferon--secreting T cells in peripheral blood samples from four groups. The test was positive in 96% of 47 patients with bacteriologically confirmed tuberculosis, in 85% of 26 healthy household contacts (all had a positive tuberculin skin test), in 9% of 47 patients with diseases that cause nonspecific activation of the cellular immune system (77% of these patients were BCG vaccinated), and in zero of 26 healthy unexposed subjects. The authors conclude that a blood test for detecting T cells that secrete interferon- in response to a specific M. tuberculosis antigen rapidly and reliably detects M. tuberculosis infection, and distinguishes infection from BCG vaccination. An editorial commentary by Barnes (20) accompanies this article.

In a clinical commentary, Schluger (21) discusses changing approaches to the diagnosis of tuberculosis.

Treatment of Tuberculosis

In a pulmonary perspective, O'Brien and Nunn (22) discuss the obstacles, opportunities, and future steps involved in the development of new drugs against tuberculosis.

In a clinical commentary, Burman and Jones (23) discuss the influence of antiretroviral drugs on the treatment of tuberculosis related to HIV infection.

	NONTUBERCULOUS LUNG INFECTION

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Human Immunodeficiency Virus Infection

Studies of molecular mechanisms In the early stages of human immunodeficiency virus (HIV) disease, patients can develop a T cell alveolitis sustained by cytotoxic T lymphocytes with anti-HIV activity. As the disease progresses, the cytotoxic activity diminishes. To study this phenomenon, Agostini and coworkers (24) recovered T cells by bronchoalveolar lavage from 18 HIV-infected patients with T cell alveolitis. The cells were preactivated CD45R0⁺/CD69⁺ T cells bearing CXCR3, interleukin 12 R2, and interferon-, a pattern characteristic of Tc1 cells. When cultured for 24 hours, the T cells showed excessive spontaneous apoptosis. Activation of the T cells with an antibody to CD3 produced a 48% increase in the number of T cells undergoing cell death. The predisposition to spontaneous apoptosis was correlated with the level of Fas expression by the T cells. The intensity of T cell infiltration was paralleled by the expression of interleukin-15 by alveolar macrophages. The predisposition to cell death was downregulated in a dose-dependent manner by interleukin-15. The authors conclude that T cells accumulating in the lungs of HIV-infected patients are preactivated Tc1 cells prone to spontaneous and activation- induced apoptosis, and that alveolar macrophages are the major regulators of the T cell homeostasis.

Infections To determine whether the baseline level of antipneumolysin antibody influences the risk of invasive pneumococcal disease in intravenous drug users who are HIV-seropositive, Sullivan and coworkers (25) did a case-control study of 28 HIV-positive drug users with a confirmed pneumococcal infection and of 56 HIV-positive and 28 HIV-negative drug users who were free of pneumococca1 disease. The titer of antipneumolysin antibody before disease did not differ between the HIV-positive drug users developing pneumococcal disease (60 units) and either the HIV-positive (70 units) or the HIV-negative (80 units) control subjects. The HIV-positive drug users had a 1.2-fold increase in antipneumolysin antibody titer after developing pneumococcal disease. The authors conclude that the baseline antipneumolysin antibody titer does not differ between HIV-positive intravenous drug users who develop pneumococcal bacteremia and either HIV-positive or HIV-negative drug users who remain free of severe pneumococcal disease.

Asthma Because T cell-mediated immune responses are depressed in patients with HIV infection and increased in patients with asthma, Poirier and coworkers (27) compared the prevalence of asthma and related conditions between 248 HIV-seropositive and 236 HIV-seronegative men. The seropositive men had more frequent episodes of wheezing (54 versus 21%), bronchial hyperresponsiveness to methacholine (26 versus 14%), and elevated serum IgE (38 versus 26%) as compared with the seronegative men. The increase in bronchial hyperreactivity in seropositive men was greater in smokers as compared with nonsmokers (30 versus 20%). The principal determinants of bronchial hyperreactivity among the seropositive men were a lower FEV₁/FVC ratio and elevated IgE. The authors conclude that the frequency of asthma in HIV-infected individuals is higher than previously suspected, and that the risk is especially high in infected men who smoke.

Highly active antiretroviral therapy The introduction of highly active antiretroviral therapy (HAART) has resulted in a marked decrease in opportunistic infections in patients with AIDS. Wislez and coworkers (28) describe three patients with Pneumocytis carinii pneumonia who developed acute respiratory failure within 7 to 17 days after starting HAART. The patients developed high fever and patchy infiltrates on the chest radiograph. Lung biopsy revealed severe nonspecific foci of inflammation surrounding a few persistent P. carinii cysts. The patients recovered after interrupting HAART and reinstituting glucocorticoid therapy. The authors conclude that the initiation of antiretroviral therapy for a first episode of P. carinii pneumonia in patients with AIDS may cause acute respiratory failure.

Lung Infections

Host defenses To determine whether a decrease in physical clearance of particles from the mouth predisposes to oropharyngeal colonization, Palmer and coworkers (29) studied 75 patients (mean age, 79 years) institutionalized in a nursing home or a geriatrics ward. Oral clearance was measured with ^99mTc-human serum albumin, and between 0 and 98% of the particles were cleared over two hours. Oropharyngeal clearance was decreased by at least 20% in patients whose oropharynx was colonized with gram-negative bacilli, Staphylococcus aureus, or yeast. Clearance was also decreased in patients taking antidepressants. Colonized patients displayed increased levels of lymphocytes and buccal cells in their saliva. Patients colonized with gram-negative bacilli had a 4.8-fold increase in elastase activity in their saliva. The authors conclude that colonization of the oropharynx of elderly patients with pathogenic organisms is associated with impaired oropharyngeal clearance of particles, and they speculate that abnormal clearance may be the first step in colonization.

Pneumonia To determine the organisms responsible for pneumonia in the elderly, El-Solh and coworkers (30) studied 104 ventilated patients who were 75 years of age and older and who had a diagnosis of pneumonia. In patients with community-acquired pneumonia, the predominant organisms were Streptococcus pneumoniae (14%), gram-negative enteric bacilli (14%), Legionella (9%), Hemophilus influenzae (7%), and Staphylococcus aureus (7%). In patients with nursing-home acquired pneumonia, the predominant organisms were S. aureus (29%), gram-negative enteric baccilli (15%), S. pneumoniae (9%), and Pseudomonas aeruginosa (4%). The case fatality rate was 53% for community-acquired pneumonia and 57% for nursing home-acquired pneumonia. Hospital mortality was associated with the 24-hour urinary output (odds ratio, 5.6), septic shock (odds ratio, 4.3), multilobar involvement on X-ray (odds ratio, 3.7), and inadequate antimicrobial therapy (odds ratio, 2.6). The authors conclude that the pathogens responsible for pneumonia in elderly patients depend on whether the patient comes from the community or from a nursing home.

Bronchiectasis

To assess the bronchial and systemic inflammatory response and its relationship to bacterial colonization in patients with bronchiectasis, Angrill and coworkers (32) did bronchoalveolar lavage in 49 patients with stable bronchiectasis and in nine healthy subjects. Compared with the control subjects, the patients with bronchiectasis had higher levels of neutrophils, elastase, myeloperoxidase, tumor-necrosis factor-, interleukin-8, and interleukin-6. Compared with the control subjects, the patients with bronchiectasis but without bacterial colonization had higher levels of interleukin-8 and interleukin-6. The level of the inflammatory reaction was related to the bronchial bacterial load. The levels of inflammatory mediators in blood were poorly correlated with the levels in bronchial samples, suggesting that the inflammatory process was compartmentalized. The authors conclude that patients with bronchiectasis have active inflammation in the airways that is proportional to the bacterial load.

	INTERSTITIAL LUNG DISEASE

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Idiopathic Pulmonary Fibrosis

Genetics The nature of the genetic component of idiopathic pulmonary fibrosis (IPF) is unknown, but good candidates include polymorphisms in genes for proinflammatory cytokines and their receptors. In 74 patients with IPF and 100 control subjects, Pantelidis and coworkers (33) assessed single nucleotide polymorphisms (SNPs) in four candidate genes: tumor necrosis factor-, lymphotoxin , tumor necrosis factor-receptor , and interleukin-6. Compared with the control group, the patients showed no significant deviations in genotype, allele, or haplotype frequencies. The patients, but not the control group, showed an association between carriage of the interleukin-6 (intron 4G) allele and the tumor necrosis factor-receptor II (1690C) allele, despite the location of these two genes on different chromosomes. The interleukin-6 (intron 4GG) genotype was the only genotype independently associated with the rapidity of disease progression, as reflected by an adjusted value for diffusing capacity for carbon monoxide. The authors conclude that susceptibility to IPF is linked to carriage of a combination of alleles on different genes and that genetic variations within proinflammatory mediators may affect disease progression.

Histopathologic subtypes To determine the histologic features that predict prognosis in IPF, King and coworkers (34) prospectively studied 87 untreated patients with usual interstitial pneumonia that was confirmed by surgical lung biopsy. Over 17 years, 72% of the patients died. An increase of one unit in the degree of granulation and young connective tissue (so-called fibroblastic foci) was associated with a 2-fold increase in the risk of death. The degree of cellularity within the alveolar space or in the alveolar walls, and the degree of fibrosis of the interstitium and alveolar walls, did not influence survival. The risk of death was 22% greater in current smokers and 88% greater in former smokers as compared with never-smokers. An increase of two levels on the dyspnea scale resulted in a 49% increased risk of death. The degree of lung stiffness at presentation was also associated with an unfavorable outcome. The authors conclude that the degree of granulation and young connective tissue is the only histopathologic feature that predicts survival in patients with IPF. An editorial commentary by Nicholson and Wells (35) accompanies this article.

Clinical assessment In 91 patients suspected of having IPF, Hunninghake and coworkers (37) assessed the accuracy of clinical findings and radiologic techniques, including high-resolution computed tomography, in making the diagnosis. The reference standard was agreement by two of three pathologists for a diagnosis of usual interstitial pneumonitis on a surgical lung biopsy specimen; this diagnosis was made in 54 (59%) patients. The overall accuracy of a diagnosis of IPF was 68% for referring pulmonologists, 77% for a clinical core of three pulmonologists, and 75% for a core of four radiologists (who did not have clinical information). When only the confident diagnoses of IPF were considered, accurate diagnosis increased to 78% for the referring pulmonologists, to 86% for the clinical core, and to 90% for the radiology core. A confident clinical diagnosis identified only about half of the patients subsequently found to have IPF. The probability that two of the three pathologists would agree about the presence or absence of IPF was 0.85. The probability of agreement for some specific diagnosis other than IPF was only 0.48. The authors conclude that a surgical biopsy is not necessary when an experienced pulmonologist or radiologist is confident that a patient has IPF, but that a biopsy is indicated when the diagnosis is not certain or when a disorder other than IPF is considered likely. An editorial commentary by Katzenstein and Myers (38) accompanies this article.

Cellular and molecular mechanisms, in vivo. Insulin-like growth factor-1 induces fibroblast proliferation and increases fibroblast transcription of collagen genes. In seven patients with IPF, seven patients with sarcoidosis (four with normal lung function), and eight healthy subjects, Bloor and coworkers (43) studied the expression of four transcripts of insulin-like growth factor-1 in bronchoalveolar cells. Total expression of the growth factor was downregulated in the bronchoalveolar cells of both groups of patients. In contrast, fibroblast strains from fibrotic lungs expressed constitutively more of the growth factor as compared with normal cells and also showed enhanced responsiveness to treatment with transforming growth factor-. These changes were associated with differential expression of splice variants of the growth factor. Patients with sarcoidosis but free of fibrosis and the healthy subjects showed similar expression of Class 1 (exon 1)/Class 2 (exon 2) transcripts and of IGF-1Ea/IGF-1Eb transcripts. Bronchoalveolar cells of patients with IPF expressed more Class 1 over Class 2 transcripts and less IGF-1Ea over IGF-1Eb as compared with cells of subjects without fibrosis. Patients with sarcoidosis did not express IGF-1Eb in either the Class 1 or Class 2 form. Class 1 IGF-1Ea was the dominant form expressed by all fibroblasts, and the other variants were expressed by fibroblasts only after stimulation with transforming growth factor-. The authors conclude that expression of insulin-like growth factor 1 in fibrotic lung is altered in response to changes in local cell phenotypes and mediators, and that this effect is exerted through the pattern of alternative mRNA splicing.

Cellular and molecular mechanisms, ex vivo In patients with IPF, neovascularization leads to extensive vascular remodeling. To determine the role of epithelial neutrophil-activating peptide 78, an angiogenic CXC chemokine, in this process, Keane and coworkers (44) obtained open lung biopsies from 91 patients with IPF and 78 subjects without interstitial lung disease. The levels of epithelial neutrophil-activating peptide 78 were several times higher in the lung tissue from the patients as compared with tissue from the control subjects. Lung tissue from the patients produced greater angiogenic activity in a model of neovascularization in the cornea of rats. This angiogenic activity was markedly attenuated by the addition of neutralizing antibodies to the angiogenic factor. Immunolocalization studies showed that hyperplastic type II pneumocytes and macrophages were the predominant source of epithelial neutrophil-activating peptide 78. The authors conclude that epithelial neutrophil-activating peptide 78 is increased in the lung tissue of patients with IPF and that it is associated with increased angiogenic activity.

Sarcoidosis

Genetics The genome contains a vast number of highly polymorphic short tandem DNA motifs (so-called microsatellites) that are widely used to label chromosomes. To identify chromosomal regions that contribute to the risk of sarcoidosis, Schurmann and colleagues (46) used the strategy of microsatellite genotyping and multipoint linkage analysis in a panel of 63 families with affected siblings (138 patients). On the basis of 225 microsatellite markers and multipoint nonparametric linkage analysis, seven chromosomal regions of increased allele sharing were found in the 63 families. The greatest linkage score occurred in the major histocompatibility complex region (six adjacent markers, including D6S1666), which is consistent with numerous reports of associations between gene variants in this region and the risk of sarcoidosis. Six minor peaks were found on chromosomes 1 (D1S1665), 3 (D3S1766), 7 (D7S821 and D7S3070), 9 (D9S934), and the X chromosome (DXS6789). The authors conclude that the results point to locus heterogeneity of susceptibility to sarcoidosis, with a major effect on the major histocompatibility complex. An editorial commentary by du Bois (47) accompanies this article.

Molecular mechanisms Wahlstrom and coworkers (51) investigated whether cytokine profiles might explain the better prognosis in patients with sarcoidosis who are positive for human leukocyte antigen type DR17. Patients with sarcoidosis had higher frequencies of cells positive for interferon-, interleukin-4, and interleukin-2 in their blood as compared with healthy control subjects. Patients with sarcoidosis had greater frequencies of T cells positive for interferon- and tumor necrosis factor- in bronchoalveolar fluid as compared with peripheral blood. A type 1 (Th1) helper T cytokine profile of CD4⁺ and CD8⁺ T cells was evident in bronchoalveolar fluid of the sarcoidosis patients. Patients positive for HLA-DR17 had a tendency toward a less pronounced type 1 (Th1) helper T cell response. The authors conclude that the higher number of cytokine-producing cells in the peripheral blood of patients with sarcoidosis as compared with healthy subjects may mirror the systemic nature of the disease.

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Clinical manifestations To determine the influence of sex, race, and age on the clinical characteristics of sarcoidosis, Baughman and coworkers (53) enrolled 736 patients within six months of diagnosis at 10 centers. Organ involvement was recorded using the ACCESS (A Case Control Etiologic Study of Sarcoidosis) assessment system. The study population was heterogeneous: 64% were women, 44% were African-American, and 46% were less than 40 years old. Compared with men, women with sarcoidosis were more likely to have eye and neurologic involvement, to have erythema nodosum and be 40 years or older, but were less likely to have hypercalcemia. Compared with whites, African-American patients were more likely to have involvement of the skin, liver, bone marrow, and extrathoracic lymph nodes. The authors conclude that the initial presentation of sarcoidosis is related to sex, race, and age. An editorial commentary by Freemer and King (54) accompanies this article.

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) may occur in isolation or in combination with tuberous sclerosis. Because only 5% of women with tuberous sclerosis develop LAM, Strizheva and coworkers (57) determined whether the risk was related to mutations on two genes that cause tuberous sclerosis: TSC1 on chromosome 9q34, and TSC2 on chromosome 16p13. In 14 women with both tuberous sclerosis and LAM, all 41 exons of the TSC2 gene and 21 coding exons of the TSC1 gene were examined for mutations. Seven mutations were found in TSC2 and one in TSC1. Three patients had mutations in exons 40 or 41 of TSC2, which are the final exons of this large gene. The authors conclude that germline alterations in the extreme carboxy-terminus of tuberin can result in LAM in women with tuberous sclerosis.

Germline mutations in two tumor suppressor genes, TSC1 and TSC2, cause the tuberous sclerosis complex. Somatic TSC2 mutations in pulmonary smooth muscle cells and angiomyolipomas have been found in patients with LAM, with loss of heterozygosity inactivating the wild-type TSC2 allele. In a patient with tuberous sclerosis complex, Yu and coworkers (58) found loss of heterozygosity in the TSC2 region of chromosome 16p13 in microdissected pulmonary LAM cells. The finding indicates that the two-hit tumor suppressor gene model applies not only to sporadic LAM, but also to the tuberous sclerosis complex. In two patients with sporadic LAM, markers spanning chromosome 16 revealed concordance for either the loss or the retention of heterozygosity in pulmonary LAM and angliolipoma cells, but not in normal pulmonary or renal cells. The authors conclude that the results are consistent with a model in which LAM cells and angiomyolipoma cells have a common genetic origin.

LAM produces cystic lesions and multifocal micronodular pneumocyte hyperplasia produces nodular lesions in patients with tuberous sclerosis. Franz and coworkers (59) determined the prevalence of pulmonary abnormalities in 23 women with the tuberous sclerosis complex who were asymptomatic. Nine women (39%) had cystic lesions on computed tomography, which were consistent with LAM. Three of these women had previously experienced a pneumothorax. Residual volume was 130% of predicted, and spirometry was normal. Renal angiomyolipomas were found in all 9 of the women who had cysts and in 8 of the 14 (57%) women who did not have cysts. Ten women had pulmonary parenchymal nodules, which were more common in women who had cysts (78 versus 12%). Mutations in the tumor suppressor gene, TSC2 (encoding tuberin), were identified in all of the women who had cysts. Mutations in both TSC1 (encoding hamartin) and TSC2 were found in women who had nodular disease. The authors conclude that cystic lesions consistent with LAM and nodular lesions consistent with multifocal micronodular pneumocyte hyperplasia are common in asymptomatic women with tuberous sclerosis.

To determine the prevalence of LAM in individuals with tuberous sclerosis, Moss and coworkers (60) studied 48 individuals with tuberous sclerosis but without a previous diagnosis of LAM. Thirteen of the 38 women (34%) had LAM diagnosed by the presence of cysts on high-resolution computed tomography. No man had LAM. FEV₁ was 100% of predicted in these 13 women. FEV₁ was 69% of predicted in 21 women with a previous diagnosis of LAM. FEV₁ was correlated with severity of disease on computed tomography. The authors conclude that the prevalence of LAM in women with tuberous sclerosis is 34%, which is 10 times higher than previous estimates.

To identify predictors of outcome, Taveira-DaSilva (61) examined lung function in 143 patients with LAM, 74 of whom also had lung biopsies. Airway obstruction was present in 68% of the patients. A quarter of the patients demonstrated a positive response to inhaled albuterol. On follow-up over more than three years, the proportion of positive responses to bronchodilator was associated with an accelerated decline in FEV₁ (r = 0.65). The rate of decline in FEV₁ was greater in the patients who had a solid pattern of LAM lesions on biopsy as compared with patients with a nonsolid pattern: 104 versus 48 ml per year. Airway inflammation was present in 61% of the specimens, and it was not associated with the severity of airway obstruction or the response to bronchodilator. Diffusing capacity was correlated with the extent of cystic lesions and infiltration of LAM cells on histology. The authors conclude that patients with LAM who have a positive response to bronchodilators are more likely to have a solid pattern of LAM lesions and an accelerated decline in lung function.

Idiopathic Pulmonary Alveolar Proteinosis

Because alveolar proteinosis is characterized by excessive surfactant and because granulocyte-macrophage colony-stimulating factor is required for normal surfactant homeostasis, Seymour and coworkers (62) administered the cytokine (5 µg per kilogram per day) to 14 patients over 6 to 12 weeks. Five patients (36%) achieved a partial response, with a mean improvement in the alveolar-to-arterial PO₂ gradient of 23 mm Hg. The dose was increased to 20 µg per kg per day in four patients and one responded, bringing the total response to 43%. The treatment was well tolerated, and the responses lasted a median of 39 weeks. Before treatment, all patients had autoantibodies against the cytokine. The authors conclude that granulocyte-macrophage colony-stimulating factor has therapeutic activity in patients with idiopathic alveolar proteinosis.

Pulmonary Drug Toxicity

Pneumonitis caused by methotrexate is difficult to diagnose and is fatal in about 10% of affected patients. Fuhrman and coworkers (63) did bronchoalveolar lavages in 14 consecutive patients with methotrexate pneumonitis, in 5 patients exposed to methotrexate but without pneumonitis, and in 29 healthy subjects. Within 2 to 10 days of the last dose of methotrexate, patients presented with a subacute diffuse interstitial pneumonitis, high-grade fever, and mild to severe hypoxemia. All patients recovered after discontinuing the methotrexate or with the institution of glucocorticoid therapy. Lymphocyte counts, as a percentage of total cells on lavage, were 58% in the cases, and 10% in the exposed patients and healthy subjects. The percentage of neutrophils was 25% in the cases, 28% in exposed patients, and 4% in the healthy subjects. The lymphocytic alveolitis resulted from increases in both CD4 and CD8 T cells, but the ratio of CD4 to CD8 lymphocytes varied widely: 0.4 to 9.6. The CD4-to-CD8 ratio was correlated with the lymphocyte count on lavage (r = 0.68), the elapsed time between last dose of methotrexate and the lavage (r = 0.73), and the cumulative dose of glucocorticoids (r = 0.74). The authors conclude that patients who have methotrexate-induced pneumonitis display a severe lymphocytic alveolitis with a homogeneous clinical and radiologic presentation, and that the variation in the ratio of CD4 to CD8 lymphocytes is related to the time elapsed between the last dose of methotrexate and the use of glucocorticoid therapy.

Hypersensitivity Pneumonitis

To determine whether genetic factors predispose individuals to pigeon breeder's disease, Camarena and coworkers (64) studied 44 patients with the disease, 50 exposed but asymptomatic subjects, and 99 healthy unrelated control subjects. Compared with the control groups, the patients with pigeon breeder's disease had increases in the frequencies of the HLA-DRB1*1305 allele (odds ratio, 15), the HLA-DQB1*0501 allele (odds ratio, 2.9), and the DRB1*1305-DQB1*0301 haplotype (odds ratio, 8.5). The patients also had an increased frequency of a polymorphism in the 5' regulatory region of the gene for tumor necrosis factor- at position -308 (odds ratio, 10); patients displaying this polymorphism were younger and had more lymphocytes in their bronchoalveolar fluid. The authors conclude that genetic factors located within the major histocompatibility complex contribute to the development of pigeon breeder's disease. An editorial commentary by Schuyler (65) accompanies this article.

To determine the role of tumor necrosis factor- in the pathogenesis of farmer's lung disease, Schaaf and coworkers (66) did a two-part study. A hay dust challenge produced a 12-fold increase in bioactivity of tumor necrosis factor in eight patients with farmer's lung disease, but no change in 12 farmers without the disease. Genotyping for the -308 TNF- promoter polymorphism revealed that the TNFA2 allele, a genotype associated with high production of tumor necrosis factor-, was more frequent in 20 patients with farmer's lung disease (frequency, 0.43) as compared with 25 patients with pigeon breeder's lung disease (frequency 0.16) or 216 healthy subjects (frequency 0.19). Genotyping for the first intron of the TNF- gene revealed no differences in allele frequencies. The authors conclude that patients with farmer's lung disease have an increased production of tumor necrosis factor- after exposure to hay dust and they have a high frequency of the TNFA2 allele at position -308 2 of the TNF- promoter, which predisposes to the increased production of tumor necrosis factor.

To determine the microorganisms responsible for farmer's lung disease in the east of France, Reboux and coworkers (67) did a case-control study in 11 patients with the disease, 11 asymptomatic farmers, and 22 nonexposed urban dwellers. The concentration of the fungus Absidia corymbifera was 1.9 times higher in the air of the cowsheds of the patients as compared with the air of the cowsheds of the asymptomatic farmers. Serologic testing with an A. corymbifera antigen differentiated 9 of the 11 patients from the control subjects. Significant results were not found for seven other antigens. The authors conclude that Absidia corymbifera is the main cause of farmer's lung disease in eastern France, and that new etiologies of farmer's lung disease may emerge as agricultural techniques evolve.

Rodent Model of Bleomycin Fibrosis

Transforming growth factor- is a key cytokine involved in increased collagen deposition. Decorin is an endogenous proteoglycan that inhibits the growth factor. Kolb and coworkers (68) constructed an adenoviral vector for carrying the gene for human decorin, and studied its action in a bleomycin model of lung fibrosis in mice. Supernatant from cells infected with the transgene substantially reduced the profibrotic effects of bleomycin, as shown by histology and collagen content of the lungs. The treatment decreased the bioactivity of transforming growth factor- in a dose-dependent manner by binding and sequestering the growth factor to the extracellular matrix. The authors conclude that a single delivery of an adenovirus vector expressing decorin effectively blocked the fibrogenic response to bleomycin by inhibiting transforming growth factor-.

To investigate mechanisms of pulmonary fibrosis, bleomycin is commonly administered to laboratory animals. Because most researchers follow the animals for only a brief period, Borzone and coworkers (69) studied rats at four months after receiving intratracheal bleomycin. In the early stages, the rats showed the commonly reported histologic lesions. At four months, however, the animals did not have a restrictive ventilatory pattern. Functional residual capacity was normal or increased, and lung compliance was normal. The main histologic findings were focal peribronchiolar inflammation, peribronchiolar fibrosis, and paracicatricial emphysema. The authors conclude that the chronic changes resulting from administration of bleomycin do not resemble IPF.

Activated protein C has anticoagulant activity, profibrinolytic activity, and it may have anti-inflammatory activity. To determine whether activated protein C contributes to lung fibrosis, Yasui and coworkers (70) administered bleomycin to mice for 21 days. Bleomycin-treated animals had lower levels of activated protein C in their bronchoalveolar fluid as compared with control animals. Intratracheal instillation of activated protein C resulted in less lung fibrosis, less lung hydroxyproline, and a higher ratio of plasminogen activator activity to thrombin in bronchoalveolar fluid as compared with mice receiving bleomycin alone. Expression of tumor necrosis factor- and interleukin-1 was decreased in the lungs of animals treated with activated protein C. The authors conclude that intratracheal administration of activated protein C inhibits the lung fibrosis induced by bleomycin.

The small GTPase, Rho, and its target protein, ROCK (Rho-associated coiled-coil forming protein kinase), are major regulators of cell locomotion mediated by reorganization of the actin cytoskeleton. Shimizu and coworkers (71) investigated the role of the Rho/ROCK signaling pathway in the infiltration of inflammatory cells and fibroblasts in a murine model of lung fibrosis caused by bleomycin. A selective inhibitor of ROCK, Y-27632, improved the histopathologic features, decreased inflammatory cell numbers, decreased hydroxyproline levels, and prevented the increase in phosphorylation of myosin light chains. Expression of ROCK-II messenger RNA increased 9-fold, but expression of ROCK protein increased only slightly. The authors conclude that the Rho-ROCK-mediated pathway plays an important role in the pulmonary fibrosis caused by bleomycin and that blocking the pathway prevents the development of fibrosis.

	OCCUPATIONAL LUNG DISEASE

TOP CONTENTS TUBERCULOSIS NONTUBERCULOUS LUNG INFECTION INTERSTITIAL LUNG DISEASE OCCUPATIONAL LUNG DISEASE SOCIAL ISSUES, HEALTH POLICY,... REFERENCES

About 20% of exposed workers become sensitized to beryllium, and chronic beryllium disease develops in these workers at a rate of 10% per year. In patients with chronic beryllium disease, the beryllium antigen stimulates production of tumor necrosis factor- by bronchoalveolar cells. In 20 patients with chronic beryllium disease, Maier and coworkers (72) examined whether the concentration of tumor necrosis factor- was related to polymorphisms in the tumor necrosis factor- promoter. The concentration of tumor necrosis factor- produced in response to the beryllium antigen was correlated with markers of disease severity, including chest X-ray, spirometry, and beryllium lymphocyte proliferation. High concentrations were associated with Hispanic ethnicity, the TNF2 allele (a G to A transition at the 308 nucleotide position), the presence of HLA-DPB1 containing a glutamic substitution at position 69, and the absence of HLA-DR4. No novel tumor necrosis factor- polymorphisms were found. The authors conclude that the TNF2 A allele at 308 in the promoter region of the gene for tumor necrosis factor- is a functional polymorphism associated with high levels of tumor necrosis factor- in response to stimulation with beryllium antigen and that the levels indicate the severity of chronic beryllium disease.

In a group of 73 individuals who worked for 23 to 73 years in an asbestos-cement factory, Van Cleemput and coworkers (73) asked "Is it possible to infer the severity of past exposure from the size of a pleural plaque?" Plaques were detected by high-resolution computed tomography in 70% of the exposed workers, but in none of 21 individuals without asbestos exposure. The average size of a plaque was 48 cm² (the total surface area of the normal pleura is 2,000 cm²). The surface area of a plaque was not related to the cumulative asbestos exposure or to lung function. The authors conclude that the size of a pleural plaque is not related to cumulative asbestos exposure or to lung function. An editorial commentary by Begin and Christman (74) accompanies this article.

Refractory ceramic fibers have been used to replace asbestos since the 1970s. Workers exposed to refractory ceramic fibers can develop ferruginous bodies that mimic asbestos bodies on light microscopy. Dumortier and coworkers (75) did analytical electron microscopy on 1,800 bronchoalveolar fluid specimens. When refractory ceramic fibers were detected on electron microscopy, structures with the appearance of typical asbestos bodies under light microscopy were marked and then analyzed. Pseudoasbestos bodies were detected in samples from 9 workers (0.5%). Aluminum-silicate fibers compatible with refractory ceramic fibers accounted for 42% of the fibers, other nonasbestos fibers for 28%, and asbestos fibers for 30%. It was not possible to distinguish pseudoasbestos bodies from true asbestos bodies on light microscopy. The authors conclude that counting asbestos bodies in bronchoalveolar fluid remains a valid marker of asbestos exposure, but the possibility of pseudoasbestos bodies in people exposed to refractory ceramic fibers must be kept in mind.

To determine the consequences of accelerated loss in lung function among coal miners, Beeckman and coworkers (76) studied 273 miners with a high rate of decline in FEV₁ and 288 miners with stable lung function 19 to 28 years after they had first participated in the U.S. National Study of Coal Workers' Pneumoconiosis. Compared with the miners who had stable lung function, the miners with a rapid loss of FEV₁ had higher incidences of respiratory complaints: cough (1.7), phlegm (2.0), dyspnea (1.9), wheezing (1.6), bronchitis (1.6), and self-reported asthma (7.6) and emphysema (2.5). Early retirement because of chest illnesses occurred in 15% of the miners with a rapid decline in FEV₁ and in 4% of those with stable function. After controlling for age and smoking, miners with a rapid decline had a 2-fold increased risk of death from cardiovascular and nonmalignant respiratory disease and a 3.2-fold increased risk of dying from COPD. The authors conclude that a rapid decline in lung function in coal miners is associated with increases in respiratory symptoms and mortality from cardiovascular and nonmalignant respiratory diseases.

To determine the chronic effects of exposure to cotton dust, Christiani and coworkers (77) did a 15-year follow-up study in Shanghai, China of 447 cotton textile workers and a control group of 472 silk textile workers. The prevalence of byssinosis increased from 8% at baseline to 15% in the final survey in the cotton workers; no byssinosis was found in the silk workers. The annual decline in FEV₁ was greater in the cotton as compared with the silk workers (32 versus 29 ml per year). After controlling for confounders, the change in FEV₁ was related to years worked in cotton mills, high levels of exposure to endotoxin, and across-shift drops in FEV₁. Workers who consistently reported byssinosis or chest tightness at work had a greater loss in FEV₁ over the 15 years. The authors conclude that long-term exposure to cotton dust is associated with chronic loss of pulmonary function.

To determine the relationship between occupational exposure and respiratory morbidity, Zock and coworkers (78) studied 13,253 individuals (aged 20 to 44 years) from 14 countries participating in the European Community Respiratory Health Survey. Exposures to vapors, gas, dust or fumes were associated with chronic bronchitis only in the smokers (prevalence ratio, 1.2 to 1.7). An interaction between occupational exposure and smoking was not found. The risk for chronic bronchitis was increased in agricultural, textile, paper, wood, chemical, and food processing workers. Lung function and bronchial hyperreactivity to methacholine were not related to occupational exposures. The authors conclude that occupational exposures contribute to symptoms of chronic bronchitis in young workers, but do not impair lung function.

To determine whether snoring and excessive daytime sleepiness contribute to accidents at work, Lindberg and coworkers (79) did a prospective population-based study over 10 years. In 1984, 2,874 men, aged 30 to 64 years, completed a questionnaire on snoring and sleepiness. In 1994, 2,009 men (74% of the survivors) completed a follow-up questionnaire. Information on occupational accidents between 1984 and 1994 were obtained from the Swedish registry. A total of 345 occupational accidents were reported by 247 of the men (12% of those in the follow-up survey). After adjusting for age, body mass index, smoking, alcohol dependence, years of work, type of job, and other factors, men who reported both snoring and excessive daytime sleepiness at baseline had a 2.2-fold greater risk of occupational accidents over the subsequent 10 years. An increased risk was not seen for either snoring without daytime sleepiness or for daytime sleepiness without snoring. The authors conclude that men with both snoring and excessive daytime sleepiness have a more than 2-fold increase in the risk of occupational accidents.

Silica causes enhanced expression of tumor necrosis factor- and matrix deposition. To better understand the mechanisms involved, Ortiz and coworkers (80) studied three sets of mice: wild-type (silica-sensitive) C57/BL/6 mice, and mice deficient in either of two receptors for tumor necrosis factor (p55 ^/, p75 ^/). Animals were killed 28 days after exposure to silica. In all the mice, silica caused enhanced expression of tumor necrosis factor and (1)collagen messenger RNA, activation of nuclear-factor B, and expression of interstitial collagenase (matrix metalloproteinase-13). Compared with wild-type mice, mice deficient in either of the two tumor necrosis factor receptors had less hydroxyproline, decreased expression of the inhibitor of interstitial collagenase (TIMP-1), and decreased activation of transcription factor AP-1. The authors conclude that deletion of receptors for tumor necrosis factor in mice exposed to silica shifts the balance between interstitial collagenase and its inhibitor in favor of matrix degradation.

Becklake (81) recalls an early study of lung impairment in gold miners.

	SOCIAL ISSUES, HEALTH POLICY, AND ECONOMICS

TOP CONTENTS TUBERCULOSIS NONTUBERCULOUS LUNG INFECTION INTERSTITIAL LUNG DISEASE OCCUPATIONAL LUNG DISEASE SOCIAL ISSUES, HEALTH POLICY,... REFERENCES

Benatar (82) outlines the economic disparities around the world and discusses their effect on the delivery of respiratory health in poorer countries.

Albert (83) and Cooper (84) comment on the report of the Committee on Manpower for Pulmonary and Critical Care Societies (COMPACCS).

In an Occasional Essay, Pack (85) argues that academic programs in pulmonary medicine have undervalued research on sleep and neurobiology.

In a clinical commentary, the Clinical Practice Committee of the American Thoracic Society (86) discusses the expense costs in the practice of pulmonary and critical care medicine.

	Footnotes

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: mtobin2{at}lumc.edu

Acknowledgments: Supported by a Merit Review grant from the Veterans Affairs Research Service.

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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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