A sensitive new bioassay for tumor necrosis factor.

Tumor necrosis factor is an important cytokine involved in inflammation and assay of this cytokine in biological fluids may be important in the understanding of several disease processes. This report describes an improved TNF bioassay employing a newly isolated subclone of the cell line NCTC-clone 929 as well as a novel fluorescence indicator system for detecting viability of the target cells. The limit of detection for the TNF hypersensitive cell line with this fluorescence viability assay was 68 +/- 2.5 fg/ml, which is approximately 3 x more sensitive than the parental clone and approximately 10 x more sensitive than that reported by Branch et al. (1991) using the neutral red indicator system. The hypersensitivity of the clone gradually declined over a 45-day period and at regular intervals new cells were cultivated from frozen stocks. Two different serum sources, bovine fetal serum and horse serum, and four different serum concentrations (5, 10, 15, 20%) were evaluated to optimize sensitivity. No difference was found between serum sources but sensitivity was significantly reduced if < 15% serum was used.

Human pulmonary responses to experimental inhalation of high concentration fine and ultrafine magnesium oxide particles.

Exposure to air polluted with particles less than 2.5 micron in size is associated epidemiologically with adverse cardiopulmonary health consequences in humans. The goal of this study was to characterize human pulmonary responses to controlled experimental high-dose exposure to fine and ultrafine magnesium oxide particles. We quantified bronchoalveolar lavage (BAL) cell and cytokine concentrations, pulmonary function, and peripheral blood neutrophil concentrations in six healthy volunteers 18 to 20 hr after inhalation of fine and ultrafine magnesium oxide particles produced from a furnace system model. We compared postexposure studies with control studies from the same six subjects. Mean +/- standard deviation (SD) cumulative magnesium dose was 4,138 +/- 2,163 min x mg/m3. By weight, 28% of fume particles were ultrafine (<0.1 micron in diameter) and over 98% of fume particles were fine (<2.5 micron in diameter). There were no significant differences in BAL inflammatory cell concentrations, BAL interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor, pulmonary function, or peripheral blood neutrophil concentrations postexposure compared with control. Our findings suggest that high-dose fine and ultrafine magnesium oxide particle exposure does not produce a measurable pulmonary inflammatory response. These findings are in marked contrast with the well-described pulmonary inflammatory response following zinc oxide particle inhalation. We conclude that fine and ultrafine particle inhalation does not result in toxicity in a generic manner independent of particle composition. Our findings support the concept that particle chemical composition, in addition to particle size, is an important determinant of respiratory effects.

Exaggerated responses to chlorine inhalation among persons with nonspecific airway hyperreactivity.

Although chlorine gas is a common irritant exposure, little is known about airway responses to chlorine inhalation among persons with baseline airway hyperreactivity. We wished to determine whether such persons manifest an exaggerated response to chlorine compared with normal subjects. We studied 10 subjects, five with and five without airway hyperresponsiveness (HR) after exposure to 1.0 ppm chlorine and five persons, all with HR, to 0.4 ppm chlorine. After 1.0 ppm inhalation, there was a significant (p < 0.05) fall (mean +/- SE) in FEV1 immediately following exposure among normal (-180 +/- 37 mL) and HR subjects (-520 +/- 171 mL). The fall was greater among the HR compared with the normal subjects (p = 0.04). Specific airway resistance (Sraw) increased to a greater degree among the HR group compared with normal subjects (p = 0.04). Among all subjects (n = 10), the proportional change in FEV1 after 1.0 ppm chlorine correlated with baseline reactivity (Spearman rank correlation r = 0.64, p < 0.05). At 24-h follow-up, there were no significant chlorine-related pulmonary function deficits. After 0.4 ppm chlorine inhalation, there was no significant pulmonary function effect. These data indicated that persons with hyperreactive airways manifest an exaggerated airway response to chlorine at 1.0 ppm. This suggests that when large numbers of persons are exposed to chlorine, a susceptible subpopulation may acutely respond with a greater decrement in pulmonary function.

Nonprescription bronchodilator medication use in asthma.

STUDY OBJECTIVE: Many persons with asthma self-medicate with widely available and potentially hazardous nonprescription medicines. This study assessed the demographic and clinical covariates of self-treatment with over-the-counter asthma medications (OTCs). DESIGN AND SETTING: We conducted an analytical investigation using questionnaires and measures of lung function, comparing OTC and prescription medication users. We recruited adults with asthma by public advertisement. SUBJECTS: We studied 22 exclusive prescription asthma medication users, 15 exclusive OTC users, and 13 other subjects who combined prescription medication use with self-treatment with asthma OTCs. All but one OTC user self-medicated with a nonselective, sympathomimetic metered-dose inhaler. RESULTS: Taking income, access to care, and self-assessed disease severity into account, male gender was strongly associated with exclusive OTC use alone (odds ratio [OR]=8.9, 95% confidence interval [CI]= 1.3 to 61) and mixed OTC-prescription medication use (OR=9.7, 95% CI=1.1 to 83). The covariates of income, access to care, and self-assessed disease severity provided significant additional explanatory power to the model of exclusive OTC use (model chi2 difference 11.3, 5 df, p<0.05). Pulmonary function was similar among OTC and prescription medication users. However, prescription medication users' self-assessed asthma severity (mild compared to more severe) was associated with postbronchodilator reversibility of FEV1 obstruction (6% vs 18% reversibility, p<0.05) while exclusive OTC users' self-assessed severity showed the reverse pattern (19% vs 8%, p=0.2). CONCLUSION: Asthma education programs attempting to discourage unregulated bronchodilator use should give consideration to this profile of the "asthmatic-at-risk."

Clinical and chest radiographic findings among persons with sputum culture positive for Mycobacterium gordonae: a review of 19 cases.

STUDY OBJECTIVES: To describe the clinical and radiographic findings associated with growth of Mycobacterium gordonae in cultured sputum and to determine the proportion of cases that fulfill criteria for nontuberculous mycobacterial pulmonary disease as established by the American Thoracic Society. DESIGN: A retrospective review of charts and radiographs of all patients from whom M gordonae was isolated from sputum cultures between November 1996 and June 1998. SETTING: University-affiliated Veterans Affairs hospital. PATIENTS: Nineteen patients were identified with sputum culture positive for M gordonae. All patients had a chest radiograph within 1 month of sputum culture. RESULTS: Sixteen patients (84%) had suppressed local and/or general immunity. Sixteen patients (84%) had respiratory symptoms, weight loss, fever, or night sweats as an indication for chest radiography. Seventeen patients (89%) had abnormal chest radiographs; however, no typical radiographic pattern was observed. No patient met diagnostic criteria for nontuberculous mycobacterial pulmonary disease as delineated by the American Thoracic Society. All patients with abnormal chest radiographs and/or respiratory symptoms ultimately had alternative explanations for their pulmonary disease. CONCLUSIONS: There is a broad spectrum of chest radiographic findings among persons with sputum culture positive for M gordonae, arguing against the presence of a characteristic chest radiograph in this patient population. M gordonae is usually a nonpathogenic colonizing organism, even among persons with local or general immune suppression and abnormal chest radiograph findings.

Pulmonary responses to purified zinc oxide fume.

BACKGROUND: Metal fume fever is a flu-like illness caused by zinc oxide fume inhalation and mediated by unknown mechanisms. It is one of a group of work-related febrile inhalational syndromes. We studied bronchoalveolar lavage (BAL) obtained from cigarette smoking and nonsmoking human volunteers after controlled exposure to purified zinc oxide fume to explore the possible roles of proinflammatory cytokines in this condition. METHODS: We studied 14 volunteers after inhalation exposure to purified zinc oxide fume and after sham exposure to air. The mean cumulative exposure was 537 +/- 232 mg min per cubic meter elemental zinc. Twenty hours after exposure we performed BAL. We analyzed BAL cells and studied BAL supernatant for cytokines including tumor necrosis factor-alpha (TNF alpha), interleukin(IL)-8, and IL-1 by enzyme-linked immunosorbant assay (ELISA). RESULTS: Polymorphonuclear leukocytes (PMNs) were significantly increased in the BAL fluid obtained post-exposure compared to sham (mean difference = 41.3 +/- 16.8 x 10(3) per mL; p < 0.05). Cumulative zinc exposure positively correlated with exposure-sham differences in BAL supernatant concentrations of both TNF (r2 = 0.58; p = .002) and IL-8 (r2 = 0.44, p = 0.01). Exposure-sham concentration differences in BAL supernatant IL-8 and BAL PMNs were also positively correlated (r2 = 0.60; p < 0.001). Cigarette smoking was not associated with exposure-sham differences in BAL TNF or IL-8, but did demonstrate a packs-per-day dependent increase in BAL supernatant IL-1 (t = 2.3, p = 0.04) post-exposure compared to sham, after taking into account the zinc exposure response. CONCLUSIONS: Purified zinc oxide fume inhalation causes an exposure-dependent increase in proinflammatory cytokines and PMNs in the lung. This supports a role for cytokine networking in mediating metal fume fever.

Tumor necrosis factor-alpha and interleukin-8 release from U937 human mononuclear cells exposed to zinc oxide in vitro. Mechanistic implications for metal fume fever.

Respiratory exposure to zinc oxide results in metal fume fever, a flu-like illness characterized by dose-dependent increases in pulmonary tumor necrosis factor-alpha (TNF) and interleukin-8 (IL-8). To examine whether mononuclear cells are a source of these proinflammatory cytokines, we exposed U937 cells to zinc oxide in vitro. Cell culture supernatant TNF and IL-8 was measured after 3, 8, and 24 hours of exposure to zinc oxide in varying concentrations. Zinc oxide exposure in vitro led to TNF release in a dose-dependent manner at 3, 8, and 24 hours (analysis of variance [ANOVA] P = 0.0001). IL-8 demonstrated a statistically significant zinc exposure response at 8 hours (ANOVA P = 0.005) and 24 hours (ANOVA P = 0.02). IL-8 at 8 hours correlated with 3-hour TNF levels (r = 0.52, P = 0.04). These data demonstrate that in vitro zinc oxide exposure stimulates U937 mononuclear cells to release TNF and IL-8 consistent with in vivo observations in metal fume fever.

Pulmonary responses after wood chip mulch exposure.

Organic Dust Toxic Syndrome (ODTS) is a flu-like syndrome that can occur after inhalation of cotton, grain, wood chip dusts, or other organic dusts or aerosols. We investigated whether inflammatory pulmonary responses occur, even after relatively brief, low-level wood chip mulch exposure. Six volunteers were exposed to wood chip mulch dust. Total dust and/or endotoxin levels were measured in five subjects. Pulmonary function and peripheral blood counts were measured before and after exposure in each subject. Bronchoalveolar lavage (BAL) was performed in each subject after exposure, and cell, cytokine, and protein concentrations were measured. Control BAL without previous exposure was also performed on three of the subjects. Three of six subjects had symptoms consistent with ODTS. No clinically relevant or statistically significant changes in pulmonary function tests after exposure were found. Three subjects manifested a marked elevation in neutrophil percentage in their BAL (range, 10 to 57%). When these three subjects underwent control BAL, the postexposure comparison demonstrated an increase in neutrophil levels of 154 +/- 89 x 10(3)/mL (mean +/- standard error; P = 0.22). The mean increase in BAL interleukin-8 levels after exposure, compared with paired control values, was 11.2 +/- SE 2.5 pg/mL (P = 0.047). There was also an increase in BAL interleukin-6 levels that reached borderline significance (6.4 +/- SE 2.0 pg/mL; P = 0.08). Tumor necrosis factor levels were increased in all three subjects' BAL as well (0.4 +/- SE 0.2 pg/mL), but this change was not statistically significant (P = 0.2). Our findings of increased BAL proinflammatory cytokine and neutrophil levels are consistent with the theory that cytokine networking in the lung may mediate ODTS.

Foreign body aspiration diagnosed by microscopy.

We report a rare case of foreign body aspiration diagnosed by microscopic analysis of a sample of the foreign body. A 50-year-old man presented with a 5-month history of 40 pound weight loss and a nonresolving right lower lobe pneumonia. Medical history, radiographic studies, direct visualization of the foreign body by flexible fiberoptic bronchoscopy, and gross examination of a sample of the foreign body retrieved by a forceps biopsy catheter failed to yield the diagnosis. Moderate bleeding associated with the bronchoscopic "biopsy" procedure contributed to a preliminary misdiagnosis of endobronchial tumor. Microscopic analysis of the "biopsy" specimen demonstrated vegetable matter. The patient underwent rigid bronchoscopy and a peanut was retrieved from the bronchus intermedius. He was maintained on antibiotics for an additional 8 weeks and had complete clinical and radiographic recovery. The epidemiology, presentation, and management strategies of foreign body aspiration in the adult are briefly reviewed.

Occupational inhalant exposure and respiratory disorders among never-smokers referred to a hospital pulmonary function laboratory.

BACKGROUND: Multiple reports have described associations between occupational inhalant exposure and lung disease. Previous occupational lung disease investigations have studied populations consisting of both smokers and nonsmokers. Smoking complicates interpretation of toxicant exposure-response relationships. The objective of this study was to determine whether, among never-smokers, occupational exposure to gases, dusts, or fumes is associated with a history of respiratory disorders and pulmonary function test defined obstructive lung disease. METHODS: We performed a retrospective analysis of 517 never-smoker patients who underwent pulmonary function testing in our clinical laboratory between 1986 and 1999. We calculated the relative risks of developing adverse respiratory health outcomes given a history of exposure to occupational inhalants. RESULTS: Compared with persons with a negative occupational exposure history, exposed persons had an increased risk of reporting a history of bronchitis [relative risk (RR), 1.59; 95% confidence interval (CI), 1.20-2.12], recurrent lung infections (RR, 2.09; 95% CI, 1.14-3.82), and bronchodilator use (RR, 1.61; 95% CI, 1.26-2.06). There was also a statistically significant association between a history of inhalant exposure and the finding of an obstructive ventilatory defect on pulmonary function testing (RR, 1.79; 95% CI, 1.12-2.85). A history of inhalant exposure was not associated with self-reported asthma (RR, 1.08; 95% CI, 0.83-1.41). The population attributable risk estimates for respiratory disorders due to inhalant exposure were: bronchitis, 23.6%; recurrent lung infection, 36.3%; bronchodilator use, 24.3%; and obstructive lung disease, 29.6%. CONCLUSIONS: Occupational inhalant exposure is a strong risk factor for lung disease in this population of never smokers. A significant burden of respiratory disease in this population may be attributable to occupational inhalant exposure.

Improved quality of life among patients completing a pulmonary rehabilitation program: one center's early experience.

INTRODUCTION: The conclusion of previous investigations that pulmonary rehabilitation (PR) is an effective intervention for the management of chronic lung disease may not be generalizable to PR programs with limited experience delivering this complex, interdisciplinary service. OBJECTIVE: Determine whether PR is effective for the first group of patients treated in a newly formed interdisciplinary PR program. METHODS: We conducted a longitudinal analysis of changes in health-related quality of life and 6-minute walk test for the first group of patients completing our newly formed 8-week outpatient PR program. We studied 6 men, age 65-77 years, with stable severe chronic obstructive pulmonary disease. Patients completed the Chronic Respiratory Disease Questionnaire immediately before and 1 year after participation in our PR program. RESULTS: Four patients completed the PR 6-minute walk test both before and after the program. We found improvement in all Chronic Respiratory Disease Questionnaire domains at follow-up (mean +/- SD before and after): dyspnea 1.67 +/- 0.82 vs 4.92 +/- 0.49; emotional function 2.33 +/- 0.82 vs 5.50 +/- 0.55; fatigue 2.00 +/- 0.63 vs 5.00 +/- 0.63; feeling of mastery over disease 1.83 +/- 0.41 vs 5.83 +/- 1.17. The interval improvements in all health-related quality of life domains were statistically significant (p < 0.02 for all comparisons). There was a trend toward improvement in exercise tolerance: 231 +/- 213 ft before PR vs 353 +/- 66 ft at the 1-year follow-up (p = 0.2). CONCLUSIONS: PR can result in sustained improvement in the quality of life of patients with severe chronic obstructive pulmonary disease, even when this complex, interdisciplinary service is delivered by a newly formed and inexperienced PR program.

Benzocaine-associated methemoglobinemia following bronchoscopy in a healthy research participant.

Benzocaine (ethyl aminobenzoate) is a local anesthetic commonly used to achieve topical anesthesia of the skin and mucous membranes prior to endoscopic procedures. Methemoglobinemia, a condition in which hemoglobin cannot bind and deliver oxygen normally, has been associated with benzocaine use in various patient populations. This is the first report of benzocaine-associated methemoglobinemia occurring in a healthy research participant. The research participant developed a methemoglobin level of 27% and marked cyanosis. No adverse sequelae other than cyanosis were identified. This report extends the population in which benzocaine-associated methemoglobinemia has been described. Additionally, this report supports the observation that methemoglobin levels approaching 30% may be tolerated in otherwise healthy individuals, producing few clinically important effects. Finally, this case also indicates that, in obtaining informed consent for a procedure in which benzocaine will be administered, patients and research participants should be specifically informed of the risk of benzocaine-induced methemoglobinemia. This information is especially important in those settings in which the manufacturer-recommended dose of benzocaine may either intentionally or inadvertently be exceeded.

Massive esophageal variceal hemorrhage triggered by complicated endotracheal intubation.

Esophageal variceal hemorrhage is frequently a catastrophic event. The specific events that trigger variceal rupture are not well understood. Acute elevations in systemic blood pressure and increased splanchnic blood flow, however, may lead to increased intravariceal pressure followed by variceal rupture and hemorrhage. This report describes a strong temporal association between complicated endotracheal intubation and abrupt onset of life-threatening variceal hemorrhage. A 52-year-old man with a history of portal hypertension was intubated emergently for airway protection because of respiratory insufficiency due to sepsis. Intubation was complicated by initial inadvertent esophageal intubation and by a peak mean arterial blood pressure of 155 mmHg. At the conclusion of the procedure, the patient sustained large volume hematemesis due to esophageal variceal rupture. This case suggests a risk of triggering variceal hemorrhage as a result of intubation-induced increase in blood pressure. A number of agents, including fentanyl, have been shown to be effective in attenuating the cardiovascular response to intubation. This case report provides strong evidence in support of administering fentanyl, or a suitable alternative adjunctive medication, before intubation of patients with documented portal hypertension and a history of esophageal variceal hemorrhage.

Ten asthma pearls every primary care physician should know.

Asthma is often easily identified and effectively treated. However, presenting symptoms are variable, and many cases of asthma may not be obvious or typical. Since asthma affects about 5% of the US population, primary care physicians should be prepared to identify and manage both atypical and classic types. Atypical symptoms include disturbed sleep, chest tightness, and persistent cough without audible wheezing. Occupational factors should be suspected in all cases of adult-onset asthma. The patient's history and results of simple pulmonary function tests are useful in diagnosing, staging, and managing asthma. A beta 2 agonist delivered by metered-dose inhaler (e.g., albuterol) should provide prompt relief of most exacerbations. Inhaled corticosteroid therapy delivered via a spacer helps prevent exacerbations and has an important role in long-term control of moderate and severe asthma. If symptoms do not improve with the use of standard asthma medications, alternative diagnoses should be considered.

Aspiration syndromes: 10 clinical pearls every physician should know.

Aspiration syndromes are clinically and pathologically classified into three sets of disorders: (i) large airway mechanical obstruction caused by foreign bodies; (ii) aspiration pneumonitis; and (iii) aspiration pneumonia. In this article, we discuss the common clinical presentations, risk factors, radiographic features and methods of management of these disorders. We highlight recent recommendations and controversies surrounding the prevention of aspiration pneumonia in the critically ill patient. Finally, we review ethical dilemmas surrounding feeding and aspiration risk concerns in debilitated and demented patients.

Accuracy of transbronchial needle aspiration for mediastinal staging of non-small cell lung cancer: a meta-analysis.

BACKGROUND: The reported accuracy of transbronchial needle aspiration (TBNA) for mediastinal staging in non-small cell lung cancer (NSCLC) varies widely. We performed a meta-analysis to estimate the accuracy of TBNA for mediastinal staging in NSCLC. METHODS: Medline, Embase, and the bibliographies of retrieved articles were searched for studies evaluating TBNA accuracy with no language restriction. Meta-analytical methods were used to construct summary receiver-operating characteristic curves and to pool sensitivity and specificity. RESULTS: Thirteen studies met inclusion criteria, including six studies that surgically confirmed all TBNA results and enrolled at least 10 patients with and without mediastinal metastasis (tier 1). Methodological quality varied but did not affect diagnostic accuracy. In tier 1 studies the median prevalence of mediastinal metastasis was 34%. Using a random effects model, the pooled sensitivity and specificity were 39% (95% CI 17 to 61) and 99% (95% CI 96 to 100), respectively. Compared with tier 1 studies, the median prevalence of mediastinal metastasis (81%; p = 0.002) and pooled sensitivity (78%; 95% CI 71 to 84; p = 0.009) were higher in non-tier 1 studies. Sensitivity analysis confirmed that the sensitivity of TBNA depends critically on the prevalence of mediastinal metastasis. The pooled major complication rate was 0.3% (95% CI 0.01 to 4). CONCLUSIONS: When properly performed, TBNA is highly specific for identifying mediastinal metastasis in patients with NSCLC, but sensitivity depends critically on the study methods and patient population. In populations with a lower prevalence of mediastinal metastasis, the sensitivity of TBNA is much lower than reported in recent lung cancer guidelines.

Health-related quality of life in patients with idiopathic pulmonary fibrosis: a systematic review.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) profoundly affects the quality of patients' lives. A systematic review was performed to evaluate critically the published literature and to examine what is known about health-related quality of life (HRQL) in patients with IPF. METHODS: The MEDLINE, EMBASE, Health and Psychosocial Instruments, and Cochrane Library databases were searched to 1 April 2004. Abstracts and bibliographies of published articles were scanned and contact was made with investigators. Included studies analysed HRQL (or quality of life) in at least 10 patients with IPF. Two reviewers independently selected studies, evaluated their quality according to predetermined criteria, and abstracted data on study design, patients' demographic and clinical characteristics, and quality of life outcome measures. RESULTS: Seven studies met the inclusion criteria. The studies enrolled 512 patients with IPF and used three different instruments to measure HRQL. All studies had important limitations in methodological quality; none measured longitudinal changes in HRQL over time. Patients reported substantially impaired HRQL, especially in domains that measured physical health and level of independence. Patients with IPF appear to have similar impairments in HRQL to those with chronic obstructive pulmonary disease. Measures of dyspnoea were moderately correlated with scores from domains that measured physical health (R2 = 0.03-0.66) and energy/fatigue/pep (R2 = 0.19-0.55), but measures of pulmonary function and gas exchange did not correlate as strongly with these and other domains. CONCLUSION: Studies of HRQL in patients with IPF suggest that, in addition to the obvious effect on physical health, general health, energy level, respiratory symptoms, and level of independence are also impaired. Variability in HRQL among patients is not fully explained by measures of dyspnoea or pulmonary function, suggesting that HRQL measures provide unique information. More research is needed to identify or design appropriate measurement instruments for patients with IPF and to examine changes in HRQL over time or in response to specific treatments.