Showing papers in "American Journal of Respiratory and Critical Care Medicine in 2006"

American Thoracic Society/European Respiratory Society Statement on Pulmonary Rehabilitation

Abstract: Linda Nici, Claudio Donner, Emiel Wouters, Richard Zuwallack, Nicolino Ambrosino, Jean Bourbeau, Mauro Carone, Bartolome Celli, Marielle Engelen, Bonnie Fahy, Chris Garvey, Roger Goldstein, Rik Gosselink, Suzanne Lareau, Neil MacIntyre, Francois Maltais, Mike Morgan, Denis O’Donnell, Christian Prefault, Jane Reardon, Carolyn Rochester, Annemie Schols, Sally Singh, and Thierry Troosters, on behalf of the ATS/ERS Pulmonary Rehabilitation Writing Committee

Pulmonary arterial hypertension in France: results from a national registry.

Abstract: Rationale: Pulmonary arterial hypertension (PAH) is an orphan disease for which the trend is for management in designated centers with multidisciplinary teams working in a shared-care approach.Objective: To describe clinical and hemodynamic parameters and to provide estimates for the prevalence of patients diagnosed for PAH according to a standardized definition.Methods: The registry was initiated in 17 university hospitals following at least five newly diagnosed patients per year. All consecutive adult (⩾ 18 yr) patients seen between October 2002 and October 2003 were to be included.Main Results: A total of 674 patients (mean ± SD age, 50 ± 15 yr; range, 18–85 yr) were entered in the registry. Idiopathic, familial, anorexigen, connective tissue diseases, congenital heart diseases, portal hypertension, and HIV-associated PAH accounted for 39.2, 3.9, 9.5, 15.3, 11.3, 10.4, and 6.2% of the population, respectively. At diagnosis, 75% of patients were in New York Heart Association functional class III or IV. ...

Reduction in fine particulate air pollution and mortality : Extended Follow-up of the Harvard Six Cities Study

Abstract: Rationale: A large body of epidemiologic literature has found an association of increased fine particulate air pollution (PM2.5) with acute and chronic mortality. The effect of improvements in particle exposure is less clear. Objectives: Earlier analysis of the Harvard Six Cities adult cohort study showed an association between long-term ambient PM2.5 and mortality between enrollment in the mid-1970s and follow-up until 1990. We extended mortality follow-up for 8 yr in a period of reduced air pollution concentrations. Methods: Annual city-specific PM2.5 concentrations were measured between 1979 and 1988, and estimated for later years from publicly available data. Exposure was defined as (1) city-specific mean PM2.5 during the two follow-up periods, (2) mean PM2.5 in the first period and change between these periods, (3) overall mean PM2.5 across the entire follow-up, and (4) year-specific mean PM2.5. Mortality rateratioswereestimatedwithCoxproportionalhazardsregression controlling for individual risk factors. Measurements and Main Results: We found an increase in overall mortality associated with each 10 g/m 3 increase in PM2.5 modeled either as the overall mean (rate ratio [RR], 1.16; 95% confidence interval [CI], 1.07–1.26) or as exposure in the year of death (RR, 1.14; 95% CI, 1.06–1.22). PM2.5 exposure was associated with lung cancer (RR, 1.27; 95% CI, 0.96–1.69) and cardiovascular deaths (RR, 1.28;95%CI, 1.13–1.44).Improved overallmortality wasassociated with decreased mean PM2.5 (10 g/m 3 ) between periods (RR, 0.73; 95% CI, 0.57–0.95). Conclusion: Total, cardiovascular, and lung cancer mortality were each positively associated with ambient PM2.5 concentrations. Reduced PM2.5 concentrations were associated with reduced mortality risk.

Incidence and Prevalence of Idiopathic Pulmonary Fibrosis

Abstract: Rationale: Idiopathic pulmonary fibrosis is a chronic interstitial lung disease of unknown etiology; its epidemiology in the United States has not been well characterized.Objective: To estimate the annual incidence and prevalence of idiopathic pulmonary fibrosis in the United States.Methods: Retrospective cohort design utilizing a large health care claims database spanning the period January 1996 through December 2000.Measurements and Main Results: Persons with idiopathic pulmonary fibrosis were identified based on diagnosis and procedure codes. Using broad case-finding criteria, prevalence was estimated to range from 4.0 per 100,000 persons aged 18 to 34 yr to 227.2 per 100,000 among those 75 yr or older; annual incidence was estimated to range from 1.2 to 76.4 per 100,000. Using narrow case-finding criteria, prevalence ranged from 0.8 to 64.7 per 100,000 persons; comparable figures for incidence were 0.4 to 27.1 per 100,000 persons. Extrapolating these rates to the overall United States' population, pre...

Association of nocturnal arrhythmias with sleep-disordered breathing: The sleep heart health study

Abstract: Rationale: Sleep-disordered breathing recurrent intermittent hypoxia and sympathetic nervous system activity surges provide the milieu for cardiac arrhythmia development.Objective: We postulate that the prevalence of nocturnal cardiac arrhythmias is higher among subjects with than without sleep-disordered breathing.Methods: The prevalence of arrhythmias was compared in two samples of participants from the Sleep Heart Health Study frequency-matched on age, sex, race/ethnicity, and body mass index: (1) 228 subjects with sleep-disordered breathing (respiratory disturbance index ⩾ 30) and (2) 338 subjects without sleep-disordered breathing (respiratory disturbance index < 5).Results: Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy (nonsustained ventricular tachycardia or bigeminy or trigeminy or quadrigeminy) were more common in subjects with sleep-disordered breathing compared with those without sleep-disordered breathing: 4.8 versus 0.9% (p = 0.003) for atrial fibri...

Tricuspid annular displacement predicts survival in pulmonary hypertension.

Abstract: Rationale: Right ventricular (RV) function is an important determinant of prognosis in pulmonary hypertension. However, noninvasive assessment of the RV function is often limited by complex geometry and poor endocardial definition.Objectives: To test whether the degree of tricuspid annular displacement (tricuspid annular plane systolic excursion [TAPSE]) is a useful echo-derived measure of RV function with prognostic significance in pulmonary hypertension.Methods: We prospectively studied 63 consecutive patients with pulmonary hypertension who were referred for a clinically indicated right heart catheterization. Patients underwent right heart catheterization immediately followed by transthoracic echocardiogram and TAPSE measurement.Results: In the overall cohort, a TAPSE of less than 1.8 cm was associated with greater RV systolic dysfunction (cardiac index, 1.9 vs. 2.7 L/min/m2; RV % area change, 24 vs. 33%), right heart remodeling (right atrial area index, 17.0 vs. 12.1 cm2/m), and RV–left ventricular (L...

Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations.

Abstract: Rationale: Severe exacerbations of chronic obstructive pulmonary disease (COPD) are major causes of health care costs mostly related to hospitalization. The role of infections in COPD exacerbations is controversial.Objectives: We investigated whether COPD exacerbations requiring hospitalization are associated with viral and/or bacterial infection and evaluated relationships among infection, exacerbation severity, assessed by reduction of FEV1, and specific patterns of airway inflammation.Methods: We examined 64 patients with COPD when hospitalized for exacerbations, and when in stable convalescence. We measured lung function, blood gases, and exhaled nitric oxide, and examined sputum for inflammation and for viral and bacterial infection.Results: Exacerbations were associated with impaired lung function (p < 0.01) and increased sputum neutrophilia (p < 0.001). Viral and/or bacterial infection was detected in 78% of exacerbations: viruses in 48.4% (6.2% when stable, p < 0.001) and bacteria in 54.7% (37.5% ...

An official ATS statement: hepatotoxicity of antituberculosis therapy.

Abstract: Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.

Procalcitonin guidance of antibiotic therapy in community-acquired pneumonia: a randomized trial.

Abstract: Rationale: In patients with community-acquired pneumonia, guidelines recommend antibiotic treatment for 7 to 21 d. Procalcitonin is elevated in bacterial infections, and its dynamics have prognostic implications.Objective: To assess procalcitonin guidance for the initiation and duration of antibiotic therapy in community-acquired pneumonia.Methods: In a randomized intervention trial, 302 consecutive patients with suspected community-acquired pneumonia were included. Data were assessed at baseline, after 4, 6, and 8 d, and after 6 wk.The control group (n = 151) received antibiotics according to usual practice. In the procalcitonin group (n = 151), antibiotic treatment was based on serum procalcitonin concentrations as follows: strongly discouraged, less than 0.1 μg/L; discouraged, less than 0.25 μg/L; encouraged, greater than 0.25 μg/L; strongly encouraged, greater than 0.5 μg/L. The primary endpoint was antibiotic use; secondary endpoints were measures of clinical, laboratory, and radiographic outcome.Res...

Cystic fibrosis since 1938.

Abstract: Cystic fibrosis (CF) was distinguished from celiac disease in 1938. Then, it was a pathologic diagnosis, life expectancy was approximately 6 months, and the autosomal recessive disease was believed to arise from abnormal mucus plugging exocrine ducts. Death often occurred from lung infection. Discovery of the sweat electrolyte defect in 1953 and standardization of the sweat test in 1959 allowed identification of milder cases, and CF was no longer considered only a disorder of mucus. In 1955, establishment of centers with programs of aggressive, comprehensive care initiated striking improvement in longevity. The pillars of care established then (attention to nutrition, airway clearance, treatment of lung infection) remain today. In 1983, chloride transport was identified as the basic physiologic CF defect, accompanied by increased sodium reabsorption. In 1980, we learned that inflammation contributes independently to lung disease and constitutes an independent therapeutic target. In 1989, the discovery of the CF gene demonstrated the basic defect to be in a cAMP-regulated chloride channel. This afforded new diagnostic tests, opportunities for research, and prospects for using the gene as therapy. Since then, substantial advances in basic and clinical research catalyzed therapeutic improvements: median survival age now exceeds 30 years. The Cystic Fibrosis Foundation center network provides not only opportunity to conduct clinical trials but also means to disseminate new therapies. In the future, treatments directed at the basic defect can be expected, with concomitant improvements in morbidity and mortality.

Randomized Study of Adding Inhaled Iloprost to Existing Bosentan in Pulmonary Arterial Hypertension

Abstract: Rationale: Small, open-label studies suggest that combinations of existing therapies may be effective for pulmonary arterial hypertension (PAH).Objective: To evaluate the safety and efficacy of adding inhaled iloprost, a prostacyclin analog, to the endothelin receptor antagonist bosentan in patients with PAH.Methods: In a randomized, multicenter, double-blind trial, inhaled iloprost (5 μg) or placebo was added to stable monotherapy with bosentan for 12 wk. Efficacy endpoints included change from baseline in 6-min-walk distance (6-MWD), modified New York Heart Association (NYHA) functional class, hemodynamic parameters, and time to clinical worsening.Measurements and Main Results: A total of 67 patients with PAH (55% idiopathic PAH, 45% associated PAH, 94% NYHA class III, and mean baseline 6-MWD of 335 m) were randomized. At Week 12, patients receiving iloprost had a mean increase in 6-MWD of 30 m (p = 0.001); placebo patients had a mean 6-MWD increase of 4 m (p = 0.69), with a placebo-adjusted difference ...

Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.

Abstract: RATIONALE: Evidence suggests that tumor necrosis factor (TNF)-alpha plays an important role in the pathophysiology of sarcoidosis. OBJECTIVES: To assess the efficacy of infliximab in sarcoidosis. METHODS: A phase 2, multicenter, randomized, double-blind, placebo-controlled study was conducted in 138 patients with chronic pulmonary sarcoidosis. Patients were randomized to receive intravenous infusions of infliximab (3 or 5 mg/kg) or placebo at Weeks 0, 2, 6, 12, 18, and 24 and were followed through Week 52. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the change from baseline to Week 24 in percent of predicted FVC. Major secondary efficacy parameters included Saint George's Respiratory Questionnaire, 6-min walk distance, Borg's CR10 dyspnea score, and the proportion of Lupus Pernio Physician's Global Assessment responders for patients with facial skin involvement. Patients in the combined infliximab groups (3 and 5 mg/kg) had a mean increase of 2.5% from baseline to Week 24 in the percent of predicted FVC, compared with no change in placebo-treated patients (p = 0.038). No significant differences between the treatment groups were observed for any of the major secondary endpoints at Week 24. Results of post hoc exploratory analyses suggested that patients with more severe disease tended to benefit more from infliximab treatment. CONCLUSIONS: Infliximab therapy resulted in a statistically significant improvement in % predicted FVC at Week 24. The clinical importance of this finding is not clear. The results of this Phase 2 clinical study support further evaluation of anti-TNF-alpha therapy in severe, chronic, symptomatic sarcoidosis.

Obesity and Asthma

Abstract: Asthma and obesity are prevalent disorders, each with a significant public health impact, and a large and growing body of literature suggests an association between the two. The systemic inflammatory milieu in obesity leads to metabolic and cardiovascular complications, but whether this environment alters asthma risk or phenotype is not yet known. Animal experiments have evaluated the effects of leptin and obesity on airway inflammation in response to both allergic and nonallergic exposures and suggest that airway inflammatory response is enhanced by both endogenous and exogenous leptin. Cross-sectional and prospective cohort studies of humans have shown a modest overall increase in asthma incidence and prevalence in the obese, although body mass index does not appear be a significant modifier of asthma severity. Studying the obesity–asthma relationship in large cohorts, in which self-reports are frequently used to ascertain the diagnosis of asthma, has been complicated by alterations in pulmonary physiol...

An Official ATS Statement: Grading the Quality of Evidence and Strength of Recommendations in ATS Guidelines and Recommendations

Abstract: Grading the strength of recommendations and the quality of underlying evidence enhances the usefulness of clinical practice guidelines. Professional societies and other organizations, including the American Thoracic Society (ATS), should reach consensus about whether they will use one common grading system and which of the numerous grading systems they would apply across all guidelines. The profusion of guideline grading systems confuses consumers of guidelines, and undermines the value of the grading exercise in conveying a transparent message. In response to this dilemma, the international GRADE working group has developed an approach that is useful for many guideline contexts, and that several national and international organizations have adopted. The GRADE system classifies recommendations as strong or weak, according to the balance of the benefits and downsides (harms, burden, and cost) after considering the quality of evidence. The quality of evidence reflects the confidence in estimates of the true effects of an intervention, and the system classifies quality of evidence as high, moderate, low, or very low according to factors that include the study methodology, the consistency and precision of the results, and the directness of the evidence. On recommendation of the ATS Documents Development and Implementation Committee, the ATS adopted the GRADE approach for its guidelines in line with many other organizations that have recently chosen the GRADE approach. This article informs ATS guideline developers, investigators, and those interpreting future ATS guidelines that follow the GRADE approach about the methodology and applicability of ATS guidelines and recommendations.

Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City Heart Study.

Abstract: Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight2).Objectives: We explored distribution of low FFMI and its association with prognosis in a population-based cohort of patients with COPD.Methods: We used data on 1,898 patients with COPD identified in a population-based epidemiologic study in Copenhagen. FFM was measured using bioelectrical impedance analysis. Patients were followed up for a mean of 7 yr and the association between BMI and FFMI and mortality was examined taking age, sex, smoking, and lung function into account.Main Results: The mean FFMI was 16.0 kg/m2 for women and 18.7 kg/m2 for men. Among subjects with normal BMI, 26.1% had an FFMI lower than the lowest 10th percentile of the general population. BMI and FFMI were significant predictors of mortality, independent of relevant cov...

A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome

Abstract: Rationale: Ventilation in the prone position for about 7 h/d in patients with acute respiratory distress syndrome (ARDS), acute lung injury, or acute respiratory failure does not decrease mortality. Whether it is beneficial to administer prone ventilation early, and for longer periods of time, is unknown.Methods: We enrolled 136 patients within 48 h of tracheal intubation for severe ARDS, 60 randomized to supine and 76 to prone ventilation. Guidelines were established for ventilator settings and weaning. The prone group was targeted to receive continuous prone ventilation treatment for 20 h/d.Results: The intensive care unit mortality was 58% (35/60) in the patients ventilated supine and 43% (33/76) in the patients ventilated prone (p = 0.12). The latter had a higher simplified acute physiology score II at inclusion. Multivariate analysis showed that simplified acute physiology score II at inclusion (odds ratio [OR], 1.07; p < 0.001), number of days elapsed between ARDS diagnosis and inclusion (OR, 2.83; ...

Early noninvasive ventilation averts extubation failure in patients at risk: a randomized trial.

Abstract: Rationale: Respiratory failure after extubation and reintubation is associated with increased morbidity and mortality.Objectives: To assess the efficacy of noninvasive ventilation in averting respiratory failure after extubation in patients at increased risk.Methods: A prospective randomized controlled trial was conducted in 162 mechanically ventilated patients who tolerated a spontaneous breathing trial after recovery from the acute episode but had increased risk for respiratory failure after extubation. Patients were randomly allocated after extubation to receive noninvasive ventilation for 24 h (n = 79), or conventional management with oxygen therapy (control group, n = 83).Measurements and Main Results: The primary end-point variable was the decrease in respiratory failure after extubation. In the noninvasive ventilation group, respiratory failure after extubation was less frequent (13, 16 vs. 27, 33%; p = 0.029) and the intensive care unit mortality was lower (2, 3 versus 12, 14%; p = 0.015). However...

Reversibility of lung collapse and hypoxemia in early acute respiratory distress syndrome.

Abstract: Rationale: The hypothesis that lung collapse is detrimental during the acute respiratory distress syndrome is still debatable. One of the difficulties is the lack of an efficient maneuver to minimize it.Objectives: To test if a bedside recruitment strategy, capable of reversing hypoxemia and collapse in > 95% of lung units, is clinically applicable in early acute respiratory distress syndrome.Methods: Prospective assessment of a stepwise maximum-recruitment strategy using multislice computed tomography and continuous blood-gas hemodynamic monitoring.Measurements and Main Results: Twenty-six patients received sequential increments in inspiratory airway pressures, in 5 cm H2O steps, until the detection of PaO2 + PaCO2 ⩾ 400 mm Hg. Whenever this primary target was not met, despite inspiratory pressures reaching 60 cm H2O, the maneuver was considered incomplete. If there was hemodynamic deterioration or barotrauma, the maneuver was to be interrupted. Late assessment of recruitment efficacy was performed by co...

Alveolar Cell Senescence in Patients with Pulmonary Emphysema

Abstract: Rationale and Objectives: The prevalence of chronic obstructive pulmonary disease (COPD) is age-dependent, suggesting an intimate relationship between the pathogenesis of COPD and aging In this study we investigated whether the senescence of alveolar epithelial and endothelial cells is accelerated in emphysematous lungsMethods: Samples of lung tissue were obtained from patients with emphysema, asymptomatic smokers, and asymptomatic nonsmokers Paraffin-embedded lung tissue sections were evaluated for cellular senescence by quantitative fluorescence in situ hybridization to assess telomere shortening, and by immunohistochemistry to assess the expression of senescence-associated cyclin-dependent kinase inhibitors Tissue sections were also immunostained for proliferating cell nuclear antigen (PCNA), surfactant protein A, and CD31Main Results: The patients with emphysema had significantly higher percentages of type II cells positive for p16INK4a and p21CIP1/WAF1/Sdi1 than the asymptomatic smokers and nons

Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis.

Abstract: Rationale: T-cell responses during tuberculosis (TB) help contain Mycobacterium tuberculosis in vivo but also cause collateral damage to host tissues. Immune regulatory mechanisms may limit this immunopathology, and suppressed cellular immune responses in patients with TB suggest the presence of regulatory activity. CD4+CD25high regulatory T cells mediate suppressed cellular immunity in several chronic infections but have not been described in TB.Objective: To determine whether regulatory T cells are increased in patients with TB and whether they suppress cellular immune responses.Methods: We compared the frequency of circulating regulatory T cells in 27 untreated patients with TB and 23 healthy control subjects using two specific markers: cell-surface CD25 expression and FoxP3 mRNA expression in peripheral blood mononuclear cells.Measurements and Main Results: We detected a threefold increase in the frequency of CD4+CD25high T cells (p < 0.001) and a 2.2-fold increase in FoxP3 expression (p = 0.006) in p...

Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.

Abstract: Impact: This study explores the use of measuring plasma biomarkers at exacerbation of chronic obstructive pulmonary disease (COPD), providing insight into the underlying pathogenesis of these important events.Rationale: The use of measuring C-reactive protein (CRP) to confirm exacerbation, or to assess exacerbation severity, in COPD is unclear. Furthermore, it is not known whether there may be more useful systemic biomarkers.Objective: To assess the use of plasma biomarkers in confirming exacerbation and predicting exacerbation severity.Methods: We assessed 36 biomarkers in 90 paired baseline and exacerbation plasma samples from 90 patients with COPD. The diagnosis of exacerbation fulfilled both health care use and symptom-based criteria. Biomarker concentrations were related to clinical indices of exacerbation severity. Interrelationships between biomarkers were examined to gain information on mechanisms of systemic inflammation at exacerbation of COPD.Measurements and Main Results: To confirm the diagno...

Gene Expression Profiles Distinguish Idiopathic Pulmonary Fibrosis from Hypersensitivity Pneumonitis

Abstract: Rationale: Many of the interstitial lung diseases represent a diagnostic and therapeutic challenge because their clinical and even histologic features are often nonspecific. Likewise, the transcriptional signatures of most of them are unknown. Objective: To compare the gene expression patterns from patients with idiopathic pulmonary fibrosis (IPF) hypersensitivity pneumonitis (HP), and nonspecific interstitial pneumonia (NSIP) using custom oligonucleotide microarrays. Methods: We profiled lung biopsies from 15 patients with IPF, 12 with HP, and eight with NSIP. Labeled complementary ribonucleic acid was hybridized to a custom Affymetrix oligonucleotide DNA microarray using standard Affymetrix protocols. The custom array, Hu03, contained 59,619 probe sets representing an estimated 46,000 gene clusters. Results: We identified statistically significant gene expression signatures that characterize HP and IPF. The HP gene expression signature was enriched for genes that are functionally associated with inflammation, T-cell activation, and immune responses, whereas the IPF signature was characterized by the expression of tissue remodeling, epithelial, and myofibroblast genes. We then compared these gene expression signatures to classify NSIP, a histologic pattern that is often difficult to differentiate consistently from HP and IPF. Two cases exhibited an IPF-like gene expression, another one could be more properly classified as HP, whereas others did not resemble HP or IPF, suggesting that they may represent idiopathic NSIP. Conclusions: Our results underscore the value of gene expression signatures to classify the interstitial lung diseases and to understand pathogenic mechanisms, and suggest new ways to improve the diagnosis and treatment of patients with these diseases.

Predictors of mortality in patients with emphysema and severe airflow obstruction.

Abstract: Purpose: Limited data exist describing risk factors for mortality in patients having predominantly emphysema. Subjects and Methods: A total of 609 patients with severe emphysema (ages 40–83 yr; 64.2% male) randomized to the medical therapy arm of the National Emphysema Treatment Trial formed the study group. Cox proportional hazards regression analysis was used to investigate risk factors for all-cause mortality. Risk factors examined included demographics, body mass index, physiologic data, quality of life, dyspnea, oxygen utilization, hemoglobin, smoking history, quantitative emphysema markers on computed tomography, and a modification of a recently described multifunctional index (modified BODE). Results: Overall, high mortality was seen in this cohort (12.7 deaths per 100 person-years; 292 total deaths). In multivariate analyses, increasing age (p = 0.001), oxygen utilization (p = 0.04), lower total lung capacity % predicted (p = 0.05), higher residual volume % predicted (p = 0.04), lower maximal cardiopulmonary exercise testing workload (p = 0.002), greater proportion of emphysema in the lower lung zone versus the upper lung zone (p = 0.005), and lower upper-to-lower-lung perfusion ratio (p = 0.007), and modified BODE (p = 0.02) were predictive of mortality. FEV1 was a significant predictor of mortality in univariate analysis (p = 0.005), but not in multivariate analysis (p = 0.21). Conclusion: Although patients with advanced emphysema experience significant mortality, subgroups based on age, oxygen utilization, physiologic measures, exercise capacity, and emphysema distribution identify those at increased risk of death.

Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome.

Abstract: Rationale: Little is known about the long-term outcomes and costs of survivors of acute respiratory distress syndrome (ARDS).Objectives: To describe functional and quality of life outcomes, health care use, and costs of survivors of ARDS 2 yr after intensive care unit (ICU) discharge.Methods: We recruited a cohort of ARDS survivors from four academic tertiary care ICUs in Toronto, Canada, and prospectively monitored them from ICU admission to 2 yr after ICU discharge.Measurements: Clinical and functional outcomes, health care use, and direct medical costs.Results: Eighty-five percent of patients with ARDS discharged from the ICU survived to 2 yr; overall 2-yr mortality was 49%. At 2 yr, survivors continued to have exercise limitation although 65% had returned to work. There was no statistically significant improvement in health-related quality of life as measured by Short-Form General Health Survey between 1 and 2 yr, although there was a trend toward better physical role at 2 yr (p = 0.0586). Apart from ...

Receptor for advanced glycation end-products is a marker of type I cell injury in acute lung injury.

Abstract: Rationale: Receptor for advanced glycation end-products (RAGE) is one of the alveolar type I cell–associated proteins in the lung.Objectives: To test the hypothesis that RAGE is a marker of alveolar epithelial type I cell injury.Methods: Rats were instilled intratracheally with 10 mg/kg lipopolysaccharide or hydrochloric acid. RAGE levels were measured in the bronchoalveolar lavage (BAL) and serum in the rats and in the pulmonary edema fluid and plasma from patients with acute lung injury (ALI; n = 22) and hydrostatic pulmonary edema (n = 11).Main Results: In the rat lung injury studies, RAGE was released into the BAL and serum as a single soluble isoform sized ∼ 48 kD. The elevated levels of RAGE in the BAL correlated well with the severity of experimentally induced lung injury. In the human studies, the RAGE level in the pulmonary edema fluid was significantly higher than the plasma level (p < 0.0001). The median edema fluid/plasma ratio of RAGE levels was 105 (interquartile range, 55–243). The RAGE lev...

The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial.

Abstract: Rationale Experimental data suggest that manipulation of alveolar fluid clearance with beta-agonists can accelerate the resolution of alveolar edema and improve survival. Objective To determine if a sustained infusion of intravenous salbutamol (albuterol) would accelerate the resolution of alveolar edema in adult patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Methods This was a single-center, double-blind, randomized controlled trial. Patients with ALI/ARDS were randomized to treatment with intravenous salbutamol (15 microg kg(-1) h(-1)) or placebo for 7 d. The primary endpoint was extravascular lung water measured by thermodilution (PiCCO) at Day 7. Measurements and main results Sixty-six patients were screened; of these, 40 met the inclusion criteria and were enrolled during 2001-2003. Patients in the salbutamol group had significantly lower lung water at Day 7 than the placebo group (9.2 +/- 6 vs. 13.2 +/- 3 ml kg(-1); 95% confidence interval difference, 0.2-8.3 ml kg(-1); p = 0.038). Plateau airway pressure was lower at Day 7 in the salbutamol group (23.9 +/- 3.8 cm H2O) versus placebo (29.5 +/- 7.2 cm H2O; p = 0.049). There was a trend toward lower Murray lung injury score at Day 7 in the salbutamol group (1.7 +/- 0.9) versus placebo (2.0 +/- 0.6; p = 0.2). Patients in the salbutamol group had a higher incidence of supraventricular arrhythmias (26 vs. 10%; p = 0.2). Conclusion Although further research is required to confirm the efficacy and safety of intravenous salbutamol in ALI/ARDS, this trial provides the first proof of principle that, in humans with ALI/ARDS, sustained treatment with intravenous beta-agonists reduces extravascular lung water.

A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18.

Abstract: Rationale: Recently, models of macrophage activation have been revised. Macrophages stimulated with Th2 cytokines have been classified as alternatively activated.Objectives: This article examines the expression and regulation of CC chemokine ligand 18 (CCL18), a marker of alternative activation, by human alveolar macrophages (AMs).Methods: AM were obtained from bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis, sarcoidosis, or hypersensitivity pneumonitis (n = 69) and healthy volunteers (n = 22). Expression of CCL18 was determined by quantitative reverse transcriptase–polymerase chain reaction, in situ hybridization, flow cytometry, and immunohistochemistry, respectively.Measurements and Main Results: Spontaneous CCL18 production by BAL-derived cells was markedly increased in patients with pulmonary fibrosis and correlated negatively with pulmonary function test parameters. CCL18 gene expression and protein production were up-regulated in normal AMs after Th2 cytokine stimu...

Rituximab for Refractory Wegener's Granulomatosis: Report of a Prospective, Open-Label Pilot Trial

Abstract: Rationale: Standard therapy for Wegener's granulomatosis is fraught with substantial toxicity and not always effective. B lymphocytes have been implicated in the pathogenesis of Wegener's granulomatosis. Their depletion has been proposed as salvage therapy for refractory disease. Earlier encouraging reports are confounded by concomitant immunosuppressive medications and include only limited available biomarker data.Objectives: To evaluate the efficacy and safety of rituximab for remission induction in refractory Wegener's granulomatosis.Methods: A prospective open-label pilot trial was conducted with 10 patients monitored for 1 yr. Included were patients with active severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, ANCA positivity, and resistance to (or intolerance of) cyclophosphamide. The remission induction regimen consisted of oral prednisone (1 mg/kg/d) and four weekly infusions of rituximab (375 mg/m2). Prednisone was tapered and discontinued over 5 mo. Failure to achieve remi...

Air pollution and markers of inflammation and coagulation in patients with coronary heart disease.

Abstract: Rationale: Ambient air pollution has been shown to be associated with cardiovascular morbidity and mortality.Objectives: A prospective panel study was conducted to study the early physiologic reactions characterized by blood biomarkers of inflammation, endothelial dysfunction, and coagulation in response to daily changes in air pollution in Erfurt, Germany.Methods: Blood parameters were repeatedly measured in 57 male patients with coronary heart disease during the winter of 2000/2001. Fixed-effects linear and logistic regression models were applied, adjusting for trend, weekday, and meteorologic parameters.Measurements: Hourly data on ultrafine particles (UFPs; number concentration of particles from 0.01 to 0.1 μm), mass concentration of particles less than 10 (PM10) and 2.5 μm in diameter, elemental and organic carbon, gaseous pollutants, and meteorologic data were collected at central monitoring sites.Main Results: Increased levels of C-reactive protein above the 90th percentile were observed for an inc...

Electromagnetic navigation diagnostic bronchoscopy: a prospective study.

Abstract: Rationale: Electromagnetic navigation bronchoscopy using superDimension/Bronchus System is a novel method to increase diagnostic yield of peripheral and mediastinal lung lesions.Objectives: A prospective, open label, single-center, pilot study was conducted to determine the ability of electromagnetic navigation bronchoscopy to sample peripheral lung lesions and mediastinal lymph nodes with standard bronchoscopic instruments and demonstrate safety.Methods: Electromagnetic navigation bronchoscopy was performed using the superDimension/Bronchus system consisting of electromagnetic board, position sensor encapsulated in the tip of a steerable probe, extended working channel, and real-time reconstruction of previously acquired multiplanar computed tomography images. The final distance of the steerable probe to lesion, expected error based on the actual and virtual markers, and procedure yield was gathered.Measurements: 60 subjects were enrolled between December 2004 and September 2005. Mean navigation times we...