Showing papers in "American Journal of Respiratory and Critical Care Medicine in 2013"

An Official American Thoracic Society/European Respiratory Society Statement: Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias

Abstract: Background: In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical “gold standard” of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs.Purpose: The objective of this statement is to update the 2002 ATS/ERS classification of IIPs.Methods: An international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011.Results: Substantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis–interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific inte...

An official American thoracic society/European respiratory society statement: Key concepts and advances in pulmonary rehabilitation

Abstract: Background: Pulmonary rehabilitation is recognized as a core component of the management of individuals with chronic respiratory disease. Since the 2006 American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement on Pulmonary Rehabilitation, there has been considerable growth in our knowledge of its efficacy and scope. Purpose: The purpose of this Statement is to update the 2006 document, including a new definition of pulmonary rehabilitation and highlighting key concepts and major advances in the field. Methods: A multidisciplinary committee of experts representing the ATS Pulmonary Rehabilitation Assembly and the ERS Scientific Group 01.02, “Rehabilitation and Chronic Care,” determined the overall scope of this update through group consensus. Focused literature reviews in key topic areas were conducted by committee members with relevant clinical and scientific expertise. The final content of this Statement was agreed on by all members. Results: An updated definition of pulmonary rehabilitation is proposed. New data are presented on the science and application of pulmonary rehabilitation, including its effectiveness in acutely ill individuals with chronic obstructive pulmonary disease, and in individuals with other chronic respiratory diseases. The important role of pulmonary rehabilitation in chronic disease management is highlighted. In addition, the role of health behavior change in optimizing and maintaining benefits is discussed. Conclusions: The considerable growth in the science and application of pulmonary rehabilitation since 2006 adds further support for its efficacy in a wide range of individuals with chronic respiratory disease Read More: http://www.atsjournals.org/doi/abs/10.1164/rccm.201309-1634ST

Defining Phenotypic Causes of Obstructive Sleep Apnea. Identification of Novel Therapeutic Targets

Abstract: Rationale: The pathophysiologic causes of obstructive sleep apnea (OSA) likely vary among patients but have not been well characterized.Objectives: To define carefully the proportion of key anatomic and nonanatomic contributions in a relatively large cohort of patients with OSA and control subjects to identify pathophysiologic targets for future novel therapies for OSA.Methods: Seventy-five men and women with and without OSA aged 20–65 years were studied on three separate nights. Initially, the apnea-hypopnea index was determined by polysomnography followed by determination of anatomic (passive critical closing pressure of the upper airway [Pcrit]) and nonanatomic (genioglossus muscle responsiveness, arousal threshold, and respiratory control stability; loop gain) contributions to OSA.Measurements and Main Results: Pathophysiologic traits varied substantially among participants. A total of 36% of patients with OSA had minimal genioglossus muscle responsiveness during sleep, 37% had a low arousal threshold...

Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study.

Abstract: Rationale: For many patients with asthma, allergic airway inflammation is primarily a Th2-weighted process; however, heterogeneity in patterns of inflammation suggests phenotypic distinctions exist that influence disease presentation and treatment effects.Objectives: To assess the potential of fractional exhaled nitric oxide (FeNO), peripheral blood eosinophil count, and serum periostin as biomarkers of Th2 inflammation and predictors of treatment effects of omalizumab.Methods: The EXTRA omalizumab study enrolled patients (aged 12–75 yr) with uncontrolled severe persistent allergic asthma. Analyses were performed evaluating treatment effects in relation to FeNO, blood eosinophils, and serum periostin at baseline. Patients were divided into low- and high-biomarker subgroups. Treatment effects were evaluated as number of protocol-defined asthma exacerbations during the 48-week treatment period (primary endpoint).Measurements and Main Results: A total of 850 patients were enrolled. Data were available from 3...

Clusters of Comorbidities Based on Validated Objective Measurements and Systemic Inflammation in Patients with Chronic Obstructive Pulmonary Disease

Abstract: Rationale: Comorbidities contribute to disease severity and mortality in patients with chronic obstructive pulmonary disease (COPD). Comorbidities have been studied individually and were mostly based on self-reports. The coexistence of objectively identified comorbidities and the role of low-grade systemic inflammation in the pathophysiology of COPD remain to be elucidated.Objectives: To cluster 13 clinically important objectively identified comorbidities, and to characterize the comorbidity clusters in terms of clinical outcomes and systemic inflammation.Methods: A total of 213 patients with COPD (FEV1, 51 ± 17% predicted; men, 59%; age, 64 ± 7 yr) were included prospectively. Comorbidities were based on well-known cut-offs identified in the peer-reviewed English literature. Systemic inflammatory biomarkers were determined in all patients. Self-organizing maps were used to generate comorbidity clusters.Measurements and Main Results: A total of 97.7% of all patients had one or more comorbidities and 53.5%...

Comparison of the Respiratory Microbiome in Healthy Nonsmokers and Smokers

Abstract: Rationale: Results from 16S rDNA-encoding gene sequence–based, culture-independent techniques have led to conflicting conclusions about the composition of the lower respiratory tract microbiome. Objectives: To compare the microbiome of the upper and lower respiratory tract in healthy HIV-uninfected nonsmokers and smokers in a multicenter cohort. Methods: Participants were nonsmokers and smokers without significantcomorbidities.Oralwashesandbronchoscopicalveolarlavages were collected in a standardized manner. Sequence analysis of bacterial 16S rRNA-encoding genes was performed, and the neutral modelincommunityecologywasusedtoidentifybacteriathatwere the most plausible members of a lung microbiome. Measurements and Main Results: Sixty-four participants were enrolled. Mostbacteriaidentifiedinthelungwerealsointhemouth,butspecific bacteria such as Enterobacteriaceae, Haemophilus, Methylobacterium, and Ralstonia species were disproportionally represented in the lungs compared with values predicted by the neutral model. Tropheryma was

Evolution of Mortality over Time in Patients Receiving Mechanical Ventilation

Abstract: Rationale: Baseline characteristics and management have changed over time in patients requiring mechanical ventilation; however, the impact of these changes on patient outcomes is unclear.Objectives: To estimate whether mortality in mechanically ventilated patients has changed over time.Methods: Prospective cohort studies conducted in 1998, 2004, and 2010, including patients receiving mechanical ventilation for more than 12 hours in a 1-month period, from 927 units in 40 countries. To examine effects over time on mortality in intensive care units, we performed generalized estimating equation models.Measurements and Main Results: We included 18,302 patients. The reasons for initiating mechanical ventilation varied significantly among cohorts. Ventilatory management changed over time (P < 0.001), with increased use of noninvasive positive-pressure ventilation (5% in 1998 to 14% in 2010), a decrease in tidal volume (mean 8.8 ml/kg actual body weight [SD = 2.1] in 1998 to 6.9 ml/kg [SD = 1.9] in 2010), and an...

Randomized, Double-Blind, Placebo-controlled Study of Brodalumab, a Human Anti–IL-17 Receptor Monoclonal Antibody, in Moderate to Severe Asthma

Abstract: Rationale: IL-17 signaling has been implicated in development and persistence of asthma. Cytokine-targeted strategies blocking IL-17 receptor signaling may be beneficial in asthma treatment.Objectives: To determine efficacy and safety of brodalumab, a human anti–IL-17 receptor A monoclonal antibody, in subjects with inadequately controlled moderate to severe asthma taking regular inhaled corticosteroids.Methods: Three hundred two subjects were randomized to brodalumab (140, 210, or 280 mg) or placebo. Primary endpoint was change in Asthma Control Questionnaire (ACQ) score from baseline to Week 12. Secondary endpoints included FEV1, symptom scores, and symptom-free days. Prespecified subgroup analyses were conducted to identify potential responsive subpopulations. Analyses included randomized subjects receiving one or more doses of investigational product using last-observation-carried-forward imputation.Measurements and Main Results: Demographics and baseline characteristics were generally balanced among ...

Clinical risk factors for primary graft dysfunction after lung transplantation

Abstract: Rationale: Primary graft dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplantation. Previous studies have yielded conflicting results for PGD risk factors.Objectives: We sought to identify donor, recipient, and perioperative risk factors for PGD.Methods: We performed a 10-center prospective cohort study enrolled between March 2002 and December 2010 (the Lung Transplant Outcomes Group). The primary outcome was International Society for Heart and Lung Transplantation grade 3 PGD at 48 or 72 hours post-transplant. The association of potential risk factors with PGD was analyzed using multivariable conditional logistic regression.Measurements and Main Results: A total of 1,255 patients from 10 centers were enrolled; 211 subjects (16.8%) developed grade 3 PGD. In multivariable models, independent risk factors for PGD were any history of donor smoking (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2–2.6; P = 0.002); FiO2 during allograft reperfusion (OR, 1.1 per 10% ...

An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction.

Abstract: Background: Exercise-induced bronchoconstriction (EIB) describes acute airway narrowing that occurs as a result of exercise. EIB occurs in a substantial proportion of patients with asthma, but may also occur in individuals without known asthma.Methods: To provide clinicians with practical guidance, a multidisciplinary panel of stakeholders was convened to review the pathogenesis of EIB and to develop evidence-based guidelines for the diagnosis and treatment of EIB. The evidence was appraised and recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach.Results: Recommendations for the treatment of EIB were developed. The quality of evidence supporting the recommendations was variable, ranging from low to high. A strong recommendation was made for using a short-acting β2-agonist before exercise in all patients with EIB. For patients who continue to have symptoms of EIB despite the administration of a short-acting β2-agonist before exercise, stron...

Circulating histones are mediators of trauma-associated lung injury.

Abstract: Rationale: Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology.Objectives: To investigate the pathological roles of circulating histones in trauma-induced lung injury.Methods: Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause–effect relationship was studied using cells and mouse models.Measurements and Main Results: In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of...

Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea: a randomized controlled trial.

Abstract: Rationale: Continuous positive airway pressure (CPAP) and mandibular advancement device (MAD) therapy are commonly used to treat obstructive sleep apnea (OSA). Differences in efficacy and compliance of these treatments are likely to influence improvements in health outcomes.Objectives: To compare health effects after 1 month of optimal CPAP and MAD therapy in OSA.Methods: In this randomized crossover trial, we compared the effects of 1 month each of CPAP and MAD treatment on cardiovascular and neurobehavioral outcomes.Measurements and Main Results: Cardiovascular (24-h blood pressure, arterial stiffness), neurobehavioral (subjective sleepiness, driving simulator performance), and quality of life (Functional Outcomes of Sleep Questionnaire, Short Form-36) were compared between treatments. Our primary outcome was 24-hour mean arterial pressure. A total of 126 patients with moderate-severe OSA (apnea hypopnea index [AHI], 25.6 [SD 12.3]) were randomly assigned to a treatment order and 108 completed the trial...

Extracorporeal membrane oxygenation for pandemic influenza A(H1N1)-induced acute respiratory distress syndrome: a cohort study and propensity-matched analysis.

Abstract: Rationale: Many patients with severe acute respiratory distress syndrome (ARDS) caused by influenza A(H1N1) infection receive extracorporeal membrane oxygenation (ECMO) as a rescue therapy.Objectives: To analyze factors associated with death in ECMO-treated patients and the influence of ECMO on intensive care unit (ICU) mortality.Methods: Data from patients admitted for H1N1-associated ARDS to French ICUs were prospectively collected from 2009 to 2011 through the national REVA registry. We analyzed factors associated with in-ICU death in ECMO recipients, and the potential benefit of ECMO using a propensity score–matched (1:1) cohort analysis.Measurements and Main Results: A total of 123 patients received ECMO. By multivariate analysis, increasing values of age, lactate, and plateau pressure under ECMO were associated with death. Of 103 patients receiving ECMO during the first week of mechanical ventilation, 52 could be matched to non-ECMO patients of comparable severity, using a one-to-one matching and us...

Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation

Abstract: Rationale: Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation.Objectives: This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6–11 years with a G551D-CFTR mutation on at least one allele.Methods: Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies.Measurements and Main Results: Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were e...

Primary Ciliary Dyskinesia. Recent Advances in Diagnostics, Genetics, and Characterization of Clinical Disease

Abstract: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia that leads to oto-sino-pulmonary diseases and organ laterality defects in approximately 50% of cases. The estimated incidence of PCD is approximately 1 per 15,000 births, but the prevalence of PCD is difficult to determine, primarily because of limitations in diagnostic methods that focus on testing ciliary ultrastructure and function. Diagnostic capabilities have recently benefitted from (1) documentation of low nasal nitric oxide production in PCD and (2) discovery of biallelic mutations in multiple PCD-causing genes. The use of these complementary diagnostic approaches shows that at least 30% of patients with PCD have normal ciliary ultrastructure. More accurate identification of patients with PCD has also allowed definition of a strong clinical phenotype, which includes neonatal respiratory distress in >80% of cases, daily nasal congestion and wet cough starting soon after birth, and early development of...

Mechanisms of Cardiac and Renal Dysfunction in Patients Dying of Sepsis

Abstract: Rationale: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined.Objectives: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death.Methods: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study.Measurements and Main Results: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (<1–2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P < 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens...

Spontaneous effort causes occult pendelluft during mechanical ventilation.

Abstract: Rationale: In normal lungs, local changes in pleural pressure (Ppl) are generalized over the whole pleural surface. However, in a patient with injured lungs, we observed (using electrical impedance tomography) a pendelluft phenomenon (movement of air within the lung from nondependent to dependent regions without change in tidal volume) that was caused by spontaneous breathing during mechanical ventilation.Objectives: To test the hypotheses that in injured lungs negative Ppl generated by diaphragm contraction has localized effects (in dependent regions) that are not uniformly transmitted, and that such localized changes in Ppl cause pendelluft.Methods: We used electrical impedance tomography and dynamic computed tomography (CT) to analyze regional inflation in anesthetized pigs with lung injury. Changes in local Ppl were measured in nondependent versus dependent regions using intrabronchial balloon catheters. The airway pressure needed to achieve comparable dependent lung inflation during paralysis versus ...

Spatial Analysis of Air Pollution and Mortality in California

Abstract: Rationale: Although substantial scientific evidence suggests that chronic exposure to ambient air pollution contributes to premature mortality, uncertainties exist in the size and consistency of this association.Uncertaintymayarisefrominaccurateexposureassessment. Objectives: To assess the associations of three types of air pollutants (fine particulate matter, ozone [O3], and nitrogen dioxide [NO2]) with the risk of mortality in a large cohort of California adults using individualized exposure assessments. Methods: For fine particulate matter and NO2, we used land use regression models to derive predicted individualized exposure at the home address. For O3, we estimated exposure with an inverse distance weighting interpolation. Standard and multilevel Cox survival models were used to assess the association between air pollution and mortality.

Prone Position in Acute Respiratory Distress Syndrome. Rationale, Indications, and Limits

Abstract: In the prone position, computed tomography scan densities redistribute from dorsal to ventral as the dorsal region tends to reexpand while the ventral zone tends to collapse. Although gravitational influence is similar in both positions, dorsal recruitment usually prevails over ventral derecruitment, because of the need for the lung and its confining chest wall to conform to the same volume. The final result of proning is that the overall lung inflation is more homogeneous from dorsal to ventral than in the supine position, with more homogeneously distributed stress and strain. As the distribution of perfusion remains nearly constant in both postures, proning usually improves oxygenation. Animal experiments clearly show that prone positioning delays or prevents ventilation-induced lung injury, likely due in large part to more homogeneously distributed stress and strain. Over the last 15 years, five major trials have been conducted to compare the prone and supine positions in acute respiratory distress syndrome, regarding survival advantage. The sequence of trials enrolled patients who were progressively more hypoxemic; exposure to the prone position was extended from 8 to 17 hours/day, and lung-protective ventilation was more rigorously applied. Single-patient and meta-analyses drawing from the four major trials showed significant survival benefit in patients with PaO2/FiO2 lower than 100. The latest PROSEVA (Proning Severe ARDS Patients) trial confirmed these benefits in a formal randomized study. The bulk of data indicates that in severe acute respiratory distress syndrome, carefully performed prone positioning offers an absolute survival advantage of 10-17%, making this intervention highly recommended in this specific population subset.

Comparison of the Berlin Definition for Acute Respiratory Distress Syndrome with Autopsy

Abstract: Rationale: A revised definition of clinical criteria for acute respiratory distress syndrome (ARDS), the Berlin definition, was recently established to classify patients according to their severity.Objective: To evaluate the accuracy of these clinical criteria using diffuse alveolar damage (DAD) at autopsy as the reference standard.Methods: All patients who died and had a clinical autopsy in our intensive care unit over a 20-year period (1991–2010) were included. Patients with clinical criteria for ARDS were identified from the medical charts and were classified as mild, moderate, or severe according to the Berlin definition using PaO2/FiO2 oxygenation criteria. Microscopic analysis from each pulmonary lobe was performed by two pathologists.Measurements and Main Results: Among 712 autopsies analyzed, 356 patients had clinical criteria for ARDS at time of death, classified as mild (n = 49, 14%), moderate (n = 141, 40%), and severe (n = 166, 46%). Sensitivity was 89% and specificity 63% to identify ARDS usi...

Chronic Bronchitis and Chronic Obstructive Pulmonary Disease

Abstract: Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). It has numerous clinical consequences, including an accelerated decline in lung function, greater risk of the development of airflow obstruction in smokers, a predisposition to lower respiratory tract infection, higher exacerbation frequency, and worse overall mortality. CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse. Despite its clinical sequelae, little is known about the pathophysiology of CB and goblet cell hyperplasia in COPD, and treatment options are limited. In addition, it is becoming increasingly apparent that in the classic COPD spectrum, with emphysema on one end and CB on the other, most patients lie somewhere in the middle. It is known now that many patients with severe emphysema can ...

The Decision to Extubate in the Intensive Care Unit

Abstract: The day of extubation is a critical time during an intensive care unit (ICU) stay. Extubation is usually decided after a weaning readiness test involving spontaneous breathing on a T-piece or low levels of ventilatory assist. Extubation failure occurs in 10 to 20% of patients and is associated with extremely poor outcomes, including high mortality rates of 25 to 50%. There is some evidence that extubation failure can directly worsen patient outcomes independently of underlying illness severity. Understanding the pathophysiology of weaning tests is essential given their central role in extubation decisions, yet few studies have investigated this point. Because extubation failure is relatively uncommon, randomized controlled trials on weaning are underpowered to address this issue. Moreover, most studies evaluated patients at low risk for extubation failure, whose reintubation rates were about 10 to 15%, whereas several studies identified high-risk patients with extubation failure rates exceeding 25 or 30%. Strategies for identifying patients at high risk for extubation failure are essential to improve the management of weaning and extubation. Two preventive measures may prove beneficial, although their exact role needs confirmation: one is noninvasive ventilation after extubation in high-risk or hypercapnic patients, and the other is steroid administration several hours before extubation. These measures might help to prevent postextubation respiratory distress in selected patient subgroups.

An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy

Abstract: Background: There is growing recognition and understanding of the entities that cause interstitial lung disease (ILD) in infants. These entities are distinct from those that cause ILD in older children and adults.Methods: A multidisciplinary panel was convened to develop evidence-based guidelines on the classification, diagnosis, and management of ILD in children, focusing on neonates and infants under 2 years of age. Recommendations were formulated using a systematic approach. Outcomes considered important included the accuracy of the diagnostic evaluation, complications of delayed or incorrect diagnosis, psychosocial complications affecting the patient’s or family’s quality of life, and death.Results: No controlled clinical trials were identified. Therefore, observational evidence and clinical experience informed judgments. These guidelines: (1) describe the clinical characteristics of neonates and infants (<2 yr of age) with diffuse lung disease (DLD); (2) list the common causes of DLD that should be e...

Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis.

Abstract: Rationale: The origin of cells that make pathologic fibrillar collagen matrix in lung disease has been controversial. Recent studies suggest mesenchymal cells may contribute directly to fibrosis.Objectives: To characterize discrete populations of mesenchymal cells in the normal mouse lung and to map their fate after bleomycin-induced lung injury.Methods: We mapped the fate of Foxd1-expressing embryonic progenitors and their progeny during lung development, adult homeostasis, and after fibrosing injury in Foxd1-Cre; Rs26-tdTomato-R mice. We studied collagen-I(α)1–producing cells in normal and diseased lungs using Coll-GFPTg mice.Measurements and Main Results: Foxd1-expressing embryonic progenitors enter lung buds before 13.5 days post-conception, expand, and form an extensive lineage of mesenchymal cells that have characteristics of pericytes. A collagen-I(α)1–expressing mesenchymal population of distinct lineage is also found in adult lung, with features of a resident fibroblast. In contrast to resident f...

Association between Obstructive Sleep Apnea and Cancer Incidence in a Large Multicenter Spanish Cohort

Abstract: Rationale: Obstructive sleep apnea (OSA) has been associated with increased cancer mortality, but whether it is also associated with cancer incidence is unknown.Objectives: To investigate whether OSA is associated with increased cancer incidence in a large clinical cohort.Methods: A multicenter, clinical cohort study including consecutive patients investigated for suspected OSA between 2003 and 2007 in seven Spanish teaching hospitals. Apnea-hypopnea index (AHI) and percent nighttime with oxygen saturation less than 90% (TSat90) were used as surrogates of OSA severity, both as continuous variables and categorized by tertiles. Cox proportional hazards regression analyses were used to calculate hazard ratio (HR) and 95% confidence interval (CI) for cancer incidence after adjusting for confounding variables.Measurements and Main Results: A total of 4,910 patients were analyzed (median follow-up, 4.5 yr; interquartile range, 3.4–5.2). Compared with the lower TSat90 category (<1.2%), the adjusted hazards (95% ...

Diaphragm dysfunction on admission to the intensive care unit. Prevalence, risk factors, and prognostic impact-a prospective study.

Abstract: Rationale: Diaphragmatic insults occurring during intensive care unit (ICU) stays have become the focus of intense research. However, diaphragmatic abnormalities at the initial phase of critical illness remain poorly documented in humans.Objectives: To determine the incidence, risk factors, and prognostic impact of diaphragmatic impairment on ICU admission.Methods: Prospective, 6-month, observational cohort study in two ICUs. Mechanically ventilated patients were studied within 24 hours after intubation (Day 1) and 48 hours later (Day 3). Seventeen anesthetized intubated control anesthesia patients were also studied. The diaphragm was assessed by twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (Ptr,stim).Measurements and Main Results: Eighty-five consecutive patients aged 62 (54–75) (median [interquartile range]) were evaluated (medical admission, 79%; Simplified Acute Physiology Score II, 54 [44–68]). On Day 1, Ptr,stim was 8.2 (5.9–12.3) cm H2O and 64% of pa...

Outgrowth of the Bacterial Airway Microbiome after Rhinovirus Exacerbation of Chronic Obstructive Pulmonary Disease

Abstract: Rationale: Rhinovirus infection is followed by significantly increased frequencies of positive, potentially pathogenic sputum cultures in chronic obstructive pulmonary disease (COPD). However, it remains unclear whether these represent de novo infections or an increased load of organisms from the complex microbial communities (microbiome) in the lower airways.Objectives: To investigate the effect of rhinovirus infection on the airway bacterial microbiome.Methods: Subjects with COPD (n = 14) and healthy control subjects with normal lung function (n = 17) were infected with rhinovirus. Induced sputum was collected at baseline before rhinovirus inoculation and again on Days 5, 15, and 42 after rhinovirus infection and DNA was extracted. The V3–V5 region of the bacterial 16S ribosomal RNA gene was amplified and pyrosequenced, resulting in 370,849 high-quality reads from 112 of the possible 124 time points.Measurements and Main Results: At 15 days after rhinovirus infection, there was a sixfold increase in 16S...

Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria.

Abstract: Rationale: Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells’ immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury.Objectives: Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance.Methods: We developed an Escherichia coli pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury.Measurements and Main Results: Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyt...

The Effects of Airway Microbiome on Corticosteroid Responsiveness in Asthma

Abstract: Rationale: The role of airway microbiome in corticosteroid response in asthma is unknown.Objectives: To examine airway microbiome composition in patients with corticosteroid-resistant (CR) asthma and compare it with patients with corticosteroid-sensitive (CS) asthma and normal control subjects and explore whether bacteria in the airways of subjects with asthma may direct alterations in cellular responses to corticosteroids.Methods: 16S rRNA gene sequencing was performed on bronchoalveolar lavage (BAL) samples of 39 subjects with asthma and 12 healthy control subjects. In subjects with asthma, corticosteroid responsiveness was characterized, BAL macrophages were stimulated with pathogenic versus commensal microorganisms, and analyzed by real-time polymerase chain reaction for the expression of corticosteroid-regulated genes and cellular p38 mitogen-activated protein kinase (MAPK) activation.Measurements and Main Results: Of the 39 subjects with asthma, 29 were CR and 10 were CS. BAL microbiome from subject...

Non–Cystic Fibrosis Bronchiectasis

Abstract: There is renewed interest in non–cystic fibrosis bronchiectasis, which is a cause of significant morbidity in adults and can be diagnosed by high-resolution chest computed tomography scan. No longer mainly a complication after pulmonary infection with Mycobacterium tuberculosis, diverse disease processes and mechanisms have been demonstrated to result in the chronic cough, purulent sputum production, and airway dilation that characterize this disease. Improved understanding of the role of mucus stasis in causing bacterial colonization has led to increased emphasis on the use of therapies that enhance airway clearance. Inhalational antibiotics reduce the bacterial burden associated with a worse outcome. Low-dose, chronic macrolide therapy has been shown to decrease exacerbation frequency and airway inflammation. For the first time, a number of therapies for non–cystic fibrosis bronchiectasis are undergoing testing in clinical research trials designed specifically for this population. This concise clinical ...