Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts.

OBJECTIVE: To assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II. METHODS: SLS I randomised 158 patients with SSc-ILD to 1 year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling. RESULTS: After a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data. CONCLUSION: In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

Electronic cigarette use in youths: a position statement of the Forum of International Respiratory Societies.

Children and adolescents are highly susceptible to nicotine addiction, which affects their brain development, even in those who smoke infrequently. Young people who become addicted to nicotine are at greater risk of becoming lifelong tobacco consumers. The use of nicotine-delivering electronic cigarettes has risen dramatically among youths worldwide. In addition to physical dependence, adolescents are susceptible to social and environmental influences to use electronic cigarettes. The product design, flavours, marketing, and perception of safety and acceptability have increased the appeal of electronic cigarettes to young people, thus leading to new generations addicted to nicotine. Moreover, there is growing evidence that electronic cigarettes in children and adolescents serve as a gateway to cigarette smoking. There can be no argument for harm reduction in children. To protect this vulnerable population from electronic cigarettes and other nicotine delivery devices, we recommend that electronic cigarettes be regulated as tobacco products and included in smoke-free policies. Sale of electronic cigarettes should be barred to youths worldwide. Flavouring should be prohibited in electronic cigarettes, and advertising accessible by youths and young adults be banned. Finally, we recommend greater research on the health effects of electronic cigarettes and surveillance of use across different countries.

Endothelial p110γPI3K Mediates Endothelial Regeneration and Vascular Repair After Inflammatory Vascular Injury.

BACKGROUND: The integrity of endothelial monolayer is a sine qua non for vascular homeostasis and maintenance of tissue-fluid balance. However, little is known about the signaling pathways regulating regeneration of the endothelial barrier after inflammatory vascular injury. METHODS AND RESULTS: Using genetic and pharmacological approaches, we demonstrated that endothelial regeneration selectively requires activation of p110γPI3K signaling, which thereby mediates the expression of the endothelial reparative transcription factor Forkhead box M1 (FoxM1). We observed that FoxM1 induction in the pulmonary vasculature was inhibited in mice treated with a p110γ-selective inhibitor and in Pik3cg(-/-) mice after lipopolysaccharide challenge. Pik3cg(-/-) mice exhibited persistent lung inflammation induced by sepsis and sustained increase in vascular permeability. Restoration of expression of either p110γ or FoxM1 in pulmonary endothelial cells of Pik3cg(-/-) mice restored endothelial regeneration and normalized the defective vascular repair program. We also observed diminished expression of p110γ in pulmonary vascular endothelial cells of patients with acute respiratory distress syndrome, suggesting that impaired p110γ-FoxM1 vascular repair signaling pathway is a critical factor in persistent leaky lung microvessels and edema formation in the disease. CONCLUSIONS: We identify p110γ as the critical mediator of endothelial regeneration and vascular repair after sepsis-induced inflammatory injury. Thus, activation of p110γ-FoxM1 endothelial regeneration may represent a novel strategy for the treatment of inflammatory vascular diseases.

Oxidized LDL signals through Rho-GTPase to induce endothelial cell stiffening and promote capillary formation.

Endothelial biomechanics is emerging as a key factor in endothelial function. Here, we address the mechanisms of endothelial stiffening induced by oxidized LDL (oxLDL) and investigate the role of oxLDL in lumen formation. We show that oxLDL-induced endothelial stiffening is mediated by CD36-dependent activation of RhoA and its downstream target, Rho kinase (ROCK), via inhibition of myosin light-chain phosphatase (MLCP) and myosin light-chain (MLC)2 phosphorylation. The LC-MS/MS analysis identifies 7-ketocholesterol (7KC) as the major oxysterol in oxLDL. Similarly to oxLDL, 7KC induces RhoA activation, MLCP inhibition, and MLC2 phosphorylation resulting in endothelial stiffening. OxLDL also facilitates formation of endothelial branching networks in 3D collagen gels in vitro and induces increased formation of functional blood vessels in a Matrigel plug assay in vivo. Both effects are RhoA and ROCK dependent. An increase in lumen formation was also observed in response to pre-exposing the cells to 7KC, an oxysterol that induces endothelial stiffening, but not to 5α,6α epoxide that does not affect endothelial stiffness. Importantly, loading cells with cholesterol prevented oxLDL-induced RhoA activation and the downstream signaling cascade, and reversed oxLDL-induced lumen formation. In summary, we show that oxLDL-induced endothelial stiffening is mediated by the CD36/RhoA/ROCK/MLCP/MLC2 pathway and is associated with increased endothelial angiogenic activity.

Electronic cigarettes. A position statement of the forum of international respiratory societies.

BACKGROUND: Awareness and usage of electronic cigarettes has exponentially increased during the last few years, especially among young people and women in some countries. The rapid acceptance of electronic cigarettes may be attributed in part to the perception created by marketing and the popular press that they are safer than combustible cigarettes. GOALS: To alert and advise policy makers about electronic cigarettes and their potential hazards. METHODS: Using The Union's position paper on electronic cigarettes as the starting template, the document was written using an iterative process. Portions of the manuscript have been taken directly from the position papers of participating societies. RESULTS: Because electronic cigarettes generate less tar and carcinogens than combustible cigarettes, use of electronic cigarettes may reduce disease caused by those components. However, the health risks of electronic cigarettes have not been adequately studied. Studies looking at whether electronic cigarettes can aid smoking cessation have had inconsistent results. Moreover, the availability of electronic cigarettes may have an overall adverse health impact by increasing initiation and reducing cessation of combustible nicotine delivery products. CONCLUSIONS: The health and safety claims regarding electronic nicotine delivery devices should be subject to evidentiary review. The potential benefits of electronic cigarettes to an individual smoker should be weighed against potential harm to the population of increased social acceptability of smoking and use of nicotine, the latter of which has addictive power and untoward effects. As a precaution, electronic nicotine delivery devices should be restricted or banned until more information about their safety is available. If they are allowed, they should be closely regulated as medicines or tobacco products.

Computed Tomography of the Esophagus in Scleroderma and Lung Disease.

Systemic sclerosis, or scleroderma, is a collagen vascular disease characterized by hardening of the skin and involvement of internal organs, most commonly the esophagus. The most frequent cause of death in these patients is lung disease. Esophageal dysfunction has been implicated in the pathogenesis of interstitial lung disease. We previously developed a standard for the esophageal diameter on chest computed tomography (CT) and hypothesized that patients with esophageal dilation would be more likely to have interstitial lung disease than those without. In this study, we test this in 121 systemic sclerosis patients with interstitial lung disease and 48 of those without interstitial lung disease. For controls, we evaluated 121 patients followed at a general pulmonary clinic and the previously studied normal healthy standards. This study demonstrated that esophageal dilation is common in systemic sclerosis patients (66.3% for the maximal esophageal diameter more than or equal to 15 mm), that systemic sclerosis patients with interstitial lung disease have more dilated esophagi than those without interstitial lung disease (median 19.4 mm vs. 14.1 mm), and that esophageal parameters are negatively correlated with pulmonary function. We also found that patients from general pulmonary clinic were more likely to have dilated esophagi than normal controls (median 12.1 mm vs. 9.7 mm). The CT measurement of esophageal diameter may be a useful marker of patients at risk for developing lung disease.

An official American Thoracic Society/European Respiratory Society policy statement: disparities in respiratory health.

BACKGROUND: Health disparities, defined as a significant difference in health between populations, are more common for diseases of the respiratory system than for those of other organ systems, because of the environmental influence on breathing and the variation of the environment among different segments of the population. The lowest social groups are up to 14 times more likely to have respiratory diseases than are the highest. Tobacco smoke, air pollution, environmental exposures, and occupational hazards affect the lungs more than other organs, and occur disproportionately in ethnic minorities and those with lower socioeconomic status. Lack of access to quality health care contributes to disparities. METHODS: The executive committees of the American Thoracic Society (ATS) and European Respiratory Society (ERS) established a writing committee to develop a policy on health disparities. The document was reviewed, edited, and approved by the full executive committees and boards of directors of the societies. RESULTS: This document expresses a policy to address health disparities by promoting scientific inquiry and training, disseminating medical information and best practices, and monitoring and advocating for public respiratory health. ERS and ATS have strong international commitments, and work with leaders from governments, academia, and organizations to address and reduce avoidable health inequalities. Their training initiatives improve the function of health care systems and health equality. Both the ATS and ERS support all aspects of this document, confer regularly, and act together when possible, but the activities to bring about change may vary because of the differences in the continents where the two organizations carry out most of their activities. CONCLUSIONS: The ATS and ERS pledge to frame their actions to reduce respiratory health disparities. The vision of the ATS and ERS is that all persons attain better and sustained respiratory health. They call on all their members and other societies to join in this commitment.

An official American Thoracic Society/European Respiratory Society statement: the role of the pulmonologist in the diagnosis and management of lung cancer.

BACKGROUND: Lung cancer is a common problem seen by pulmonologists. The American Thoracic Society (ATS) and European Respiratory Society (ERS) are professional organizations whose memberships are composed of large numbers of pulmonologists. PURPOSE: This document describes the key role of pulmonologists in the prevention, early diagnosis, and management of lung cancer. METHODS: A committee of ATS and ERS leaders and their oncology groups discussed the activities of pulmonologists in relation to lung cancer in various settings and reviewed available literature on the topic. The content of this statement was approved by the board of directors of both the ATS and ERS. RESULTS: Optimal lung cancer care requires a multidisciplinary team of specialists who care for a significant number of patients on a regular basis. Pulmonologists are responsible for and involved with patients from their initial diagnosis and staging through treatment and restaging. They are often involved with complications, palliative care, and end-of-life care, and thus have an important role in team leadership. CONCLUSIONS: Lung cancer is a disease with high mortality, profound effects on the quality of the lives of patients and their families, and an enormous cost and impact on society. To treat lung cancer optimally, care must be prompt, multidisciplinary, and patient-centered. In the entire process, pulmonologists have a key role. Pulmonologists and their professional societies should also enhance lung cancer research and education to provide better treatment options and patient care.

An official American Thoracic Society and European Respiratory Society policy statement: disparities in respiratory health.

Health disparities, defined as a significant difference in health between populations, are more common for diseases of the respiratory system than for those of other organ systems, because of the environmental influence on breathing and the variation of the environment among different segments of the population. The lowest social groups are up to 14 times more likely to have respiratory diseases than are the highest. Tobacco smoke, air pollution, environmental exposures, and occupational hazards affect the lungs more than other organs and occur disproportionately in ethnic minorities and those with lower socioeconomic status. Lack of access to quality healthcare contributes to disparities. The executive committees of the American Thoracic Society (ATS) and European Respiratory Society (ERS) established a writing committee to develop a policy on health disparities. The document was reviewed, edited, and approved by their full executive committees and boards of directors of the societies. This document expresses a policy to address health disparities by promoting scientific inquiry and training, disseminating medical information and best practices, and monitoring and advocating for public respiratory health. The ERS and the ATS have strong international commitments and work with leaders from governments, academia, and other organisational bodies to address and reduce avoidable health inequalities. Their training initiatives improve the function of healthcare systems and health equality. Both the ATS and the ERS support all aspects of this document, confer regularly, and act together when possible, but the activities to bring about change may vary because of the differences in the continents where the two organisations carry out most of their activities. The ATS and ERS pledge to frame their actions to reduce respiratory health disparities. The vision of the ATS and ERS is that all persons attain better and sustained respiratory health. They call on all their members and other societies to join in this commitment.

Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity.

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV ≥ 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P = .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P = .029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect -9 m; 95% confidence interval [95% CI] -56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531.

The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe.

The intensity of hemolytic anemia has been proposed as an independent risk factor for the development of certain clinical complications of sickle cell disease, such as pulmonary hypertension, hypoxemia and cutaneous leg ulceration. A composite variable derived from several individual markers of hemolysis could facilitate studies of the underlying mechanisms of hemolysis. In this study, we assessed the association of hemolysis with outcomes in sickle cell anemia. A hemolytic component was calculated by principal component analysis from reticulocyte count, serum lactate dehydrogenase, aspartate aminotransferase and total bilirubin concentrations in 415 hemoglobin SS patients. Association of this component with direct markers of hemolysis and clinical outcomes was assessed. As primary validation, both plasma red blood cell microparticles and cell-free hemoglobin concentration were higher in the highest hemolytic component quartile compared to the lowest quartile (P≤0.0001 for both analyses). The hemolytic component was lower with hydroxyurea therapy, higher hemoglobin F, and alpha-thalassemia (P≤0.0005); it was higher with higher systemic pulse pressure, lower oxygen saturation, and greater values for tricuspid regurgitation velocity, left ventricular diastolic dimension and left ventricular mass (all P<0.0001). Two-year follow-up analysis showed that a high hemolytic component was associated with an increased risk of death (hazard ratio, HR 3.44; 95% confidence interval, CI: 1.2-9.5; P=0.02). The hemolytic component reflects direct markers of intravascular hemolysis in patients with sickle cell disease and allows for adjusted analysis of associations between hemolytic severity and clinical outcomes. These results confirm associations between hemolytic rate and pulse pressure, oxygen saturation, increases in Doppler-estimated pulmonary systolic pressures and mortality (Clinicaltrials.gov identifier: NCT00492531).

Native-valve endocarditis caused by Mycobacterium chelonae, misidentified as polymicrobial gram-positive bacillus infection.

Mycobacterium chelonae, a species of rapidly growing mycobacteria, may grow in routine blood culture media and stain as gram-positive bacilli, which may cause diagnostic confusion. A patient with native-valve endocarditis caused by M. chelonae, which was misidentified as various gram-positive bacilli, is presented.

Echocardiographic markers of elevated pulmonary pressure and left ventricular diastolic dysfunction are associated with exercise intolerance in adults and adolescents with homozygous sickle cell anemia in the United States and United Kingdom.

BACKGROUND: Noninvasively assessed pulmonary pressure elevations and left ventricular (LV) diastolic dysfunction are associated with increased mortality in adults with sickle cell disease, but their relationship to exercise intolerance has not been evaluated prospectively. METHODS AND RESULTS: Echocardiography, 6-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the U.S. and U.K. Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) study. Tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/s (mean±SD, 2.8±0.1) in 26% of the subjects and ≥3.0 m/s (mean±SD, 3.4±0.4) in 11%. The LV lateral E/e' ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in sickle cell disease, was significantly higher in the groups with tricuspid regurgitation velocity ≥2.7 m/s. Increased hemolysis (P<0.0001), LV lateral E/e' ratio (P=0.0001), blood urea nitrogen (P=0.0002), and erythropoietin (P=0.002) were independently associated with an increased tricuspid regurgitation velocity. Furthermore, female sex (P<0.0001), older age (P<0.0001), LV lateral E/e' ratio (P=0.014), and tricuspid regurgitation velocity (P=0.019) were independent predictors of a shorter 6-minute walk distance. CONCLUSIONS: Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e' ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LV diastolic dysfunction will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00492531.

The health effects of ultrafine particles.

Ultrafine particles (PM0.1), which are present in the air in large numbers, pose a health risk. They generally enter the body through the lungs but translocate to essentially all organs. Compared to fine particles (PM2.5), they cause more pulmonary inflammation and are retained longer in the lung. Their toxicity is increased with smaller size, larger surface area, adsorbed surface material, and the physical characteristics of the particles. Exposure to PM0.1 induces cough and worsens asthma. Metal fume fever is a systemic disease of lung inflammation most likely caused by PM0.1. The disease is manifested by systemic symptoms hours after exposure to metal fumes, usually through welding. PM0.1 cause systemic inflammation, endothelial dysfunction, and coagulation changes that predispose individuals to ischemic cardiovascular disease and hypertension. PM0.1 are also linked to diabetes and cancer. PM0.1 can travel up the olfactory nerves to the brain and cause cerebral and autonomic dysfunction. Moreover, in utero exposure increases the risk of low birthweight. Although exposure is commonly attributed to traffic exhaust, monitored students in Ghana showed the highest exposures in a home near a trash burning site, in a bedroom with burning coils employed to abate mosquitos, in a home of an adult smoker, and in home kitchens during domestic cooking. The high point-source production and rapid redistribution make incidental exposure common, confound general population studies and are compounded by the lack of global standards and national reporting. The potential for PM0.1 to cause harm to health is great, but their precise role in many illnesses is still unknown and calls for more research.

Global Alliance against Chronic Respiratory Diseases symposium on air pollution: overview and highlights.

A 1-day symposium before the annual meeting of the Global Alliance against Chronic Respiratory Diseases, gathered authorities and researchers from around the world to discuss the impact of air pollution on human and planetary health. Air quality is a high priority for Global Alliance against Chronic Respiratory Diseases and China, the host country. This article presents a summary, commentary, and amplification of the 17 presentations. Air pollution is closely linked with global warming and harms most body systems even at levels below international standards. Information about the genetic, cellular, and metabolic effects of exposure to air pollution is important for better understanding of individual responses and even potential therapeutic mediation. Reducing air pollution at its source leads to prompt and important benefits and should be the first priority for political and public action.

Cyclophosphamide versus placebo in scleroderma lung disease.

BACKGROUND: We conducted a double-blind, randomized, placebo-controlled trial to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis and scleroderma-related interstitial lung disease. METHODS: At 13 clinical centers throughout the United States, we enrolled 158 patients with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease on examination of bronchoalveolar-lavage fluid, thoracic high-resolution computed tomography, or both. Patients received oral cyclophosphamide (< or =2 mg per kilogram of body weight per day) or matching placebo for one year and were followed for an additional year. Pulmonary function was assessed every three months during the first year, and the primary end point was the forced vital capacity (FVC, expressed as a percentage of the predicted value) at 12 months, after adjustment for the baseline FVC. RESULTS: Of 158 patients, 145 completed at least six months of treatment and were included in the analysis. The mean absolute difference in adjusted 12-month FVC percent predicted between the cyclophosphamide and placebo groups was 2.53 percent (95 percent confidence interval, 0.28 to 4.79 percent), favoring cyclophosphamide (P<0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the cyclophosphamide group, but the difference between the two groups in the number of serious adverse events was not significant. CONCLUSIONS: One year of oral cyclophosphamide in patients with symptomatic scleroderma-related interstitial lung disease had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and the health-related quality of life. The effects on lung function were maintained through the 24 months of the study.

Health Benefits of Air Pollution Reduction.

Air pollution is a grave risk to human health that affects nearly everyone in the world and nearly every organ in the body. Fortunately, it is largely a preventable risk. Reducing pollution at its source can have a rapid and substantial impact on health. Within a few weeks, respiratory and irritation symptoms, such as shortness of breath, cough, phlegm, and sore throat, disappear; school absenteeism, clinic visits, hospitalizations, premature births, cardiovascular illness and death, and all-cause mortality decrease significantly. The interventions are cost-effective. Reducing factors causing air pollution and climate change have strong cobenefits. Although regions with high air pollution have the greatest potential for health benefits, health improvements continue to be associated with pollution decreases even below international standards. The large response to and short time needed for benefits of these interventions emphasize the urgency of improving global air quality and the importance of increasing efforts to reduce pollution at local levels.

Air Pollution and Noncommunicable Diseases: A Review by the Forum of International Respiratory Societies' Environmental Committee, Part 1: The Damaging Effects of Air Pollution.

Air pollution poses a great environmental risk to health. Outdoor fine particulate matter (particulate matter with an aerodynamic diameter < 2.5 µm) exposure is the fifth leading risk factor for death in the world, accounting for 4.2 million deaths and > 103 million disability-adjusted life years lost according to the Global Burden of Disease Report. The World Health Organization attributes 3.8 million additional deaths to indoor air pollution. Air pollution can harm acutely, usually manifested by respiratory or cardiac symptoms, as well as chronically, potentially affecting every organ in the body. It can cause, complicate, or exacerbate many adverse health conditions. Tissue damage may result directly from pollutant toxicity because fine and ultrafine particles can gain access to organs, or indirectly through systemic inflammatory processes. Susceptibility is partly under genetic and epigenetic regulation. Although air pollution affects people of all regions, ages, and social groups, it is likely to cause greater illness in those with heavy exposure and greater susceptibility. Persons are more vulnerable to air pollution if they have other illnesses or less social support. Harmful effects occur on a continuum of dosage and even at levels below air quality standards previously considered to be safe.