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The purpose of this guideline is to optimize evaluation and management of patients with obesity hypoventilation syndrome (OHS). A multidisciplinary panel identified and prioritized five clinical questions. The panel performed systematic reviews of available studies (up to July 2018) and followed the Grading of Recommendations, Assessment, Development, and Evaluation evidence-to-decision framework to develop recommendations. All panel members discussed and approved the recommendations. After considering the overall very low quality of the evidence, the panel made five conditional recommendations. We suggest that: ) clinicians use a serum bicarbonate level <27 mmol/L to exclude the diagnosis of OHS in obese patients with sleep-disordered breathing when suspicion for OHS is not very high (<20%) but to measure arterial blood gases in patients strongly suspected of having OHS, ) stable ambulatory patients with OHS receive positive airway pressure (PAP), ) continuous positive airway pressure (CPAP) rather than noninvasive ventilation be offered as the first-line treatment to stable ambulatory patients with OHS and coexistent severe obstructive sleep apnea, ) patients hospitalized with respiratory failure and suspected of having OHS be discharged with noninvasive ventilation until they undergo outpatient diagnostic procedures and PAP titration in the sleep laboratory (ideally within 2-3 mo), and ) patients with OHS use weight-loss interventions that produce sustained weight loss of 25% to 30% of body weight to achieve resolution of OHS (which is more likely to be obtained with bariatric surgery). Clinicians may use these recommendations, on the basis of the best available evidence, to guide management and improve outcomes among patients with OHS.

Measurement of fractional nitric oxide (NO) concentration in exhaled breath (Fe(NO)) is a quantitative, noninvasive, simple, and safe method of measuring airway inflammation that provides a complementary tool to other ways of assessing airways disease, including asthma. While Fe(NO) measurement has been standardized, there is currently no reference guideline for practicing health care providers to guide them in the appropriate use and interpretation of Fe(NO) in clinical practice. To develop evidence-based guidelines for the interpretation of Fe(NO) measurements that incorporate evidence that has accumulated over the past decade. We created a multidisciplinary committee with expertise in the clinical care, clinical science, or basic science of airway disease and/or NO. The committee identified important clinical questions, synthesized the evidence, and formulated recommendations. Recommendations were developed using pragmatic systematic reviews of the literature and the GRADE approach. The evidence related to the use of Fe(NO) measurements is reviewed and clinical practice recommendations are provided. In the setting of chronic inflammatory airway disease including asthma, conventional tests such as FEV(1) reversibility or provocation tests are only indirectly associated with airway inflammation. Fe(NO) offers added advantages for patient care including, but not limited to (1) detecting of eosinophilic airway inflammation, (2) determining the likelihood of corticosteroid responsiveness, (3) monitoring of airway inflammation to determine the potential need for corticosteroid, and (4) unmasking of otherwise unsuspected nonadherence to corticosteroid therapy.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary arterial pressures that can lead to right heart failure and death. No cure exists for this disease, but therapeutic advancements have extended its median survival from 2 to 7 years. Mechanistic research in PAH has been limited by factors including that a) animal models do not fully recapitulate the disease or provide insights into its pathogenesis, and b) cellular material from PAH patients is primarily obtained from donor lungs during autopsy or transplantation, which reflect end-stage disease. Therefore, there is a need to identify tools that can elucidate the specific mechanisms of human disease in individual patients, a critical step to guide treatment decisions based on specific pathway abnormalities. Here we demonstrate a simple method to isolate and culture circulating endothelial cells (CECs) obtained at the time of right heart catheterization in PAH patients. We tested these CECs using transcriptomics and found that they have typical traits of PAH, including those involving key treatment pathways, i.e. nitric oxide, endothelin, prostacyclin and BMP/activin pathways. CECs show important gene expression changes in other central PAH disease pathways. In summary, we present a new cellular model for the ex-vivo mechanistic evaluation of critical PAH pathways that participate in the pathogenesis of the disease and may help personalized therapeutic decisions.

Hydrogen sulfide (H 2 S) plays important roles in metabolism and health. Its enzymatic generation from sulfur-containing amino acids (SAAs) is well characterized. However, the existence of non-enzymatic H 2 S production from SAAs, the chemical mechanism, and its biological implications remain unclear. Here we present non-enzymatic H 2 S production in vitro and in blood via a reaction specific for the SAA cysteine serving as substrate and requires coordinated catalysis by Vitamin B 6 , pyridoxal(phosphate), and iron under physiological conditions. An initial cysteine-aldimine is formed by nucleophilic attack of the cysteine amino group to the pyridoxal(phosphate) aldehyde group. Free or heme-bound iron drives the formation of a cysteine-quinonoid, thiol group elimination, and hydrolysis of the desulfurated aldimine back to pyridoxal(phosphate). The reaction ultimately produces pyruvate, NH 3 , and H 2 S. This work highlights enzymatic production is inducible and robust in select tissues, whereas iron-catalyzed production contributes underappreciated basal H 2 S systemically with pathophysiological implications in hemolytic, iron overload, and hemorrhagic disorders. Jie Yang et al. show the non-enzymatic production of hydrogen sulfide from sulfur-containing amino acids (SAA) in vitro and in blood. They find that the reaction uses SAA cysteine as a substrate, and requires coordinated catalysis by Vitamin B6 and iron, all under physiological conditions.

High Density Lipoprotein Cholesterol (HDL-C) has various anti-inflammatory, anti-atherogenic, anti-oxidant and anti-coagulant properties that improve vascular function. The utility of HDL-C as a biomarker of severity and predictor of survival was described in patients with pulmonary arterial hypertension (PAH). No prior study has assessed the utility of HDL-C in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH). We aim to measure HDL-C levels in CTEPH patients and compare it to those in PAH patients and controls and determine HDL-C associations with markers of disease severity, hemodynamics and mortality in CTEPH. We retrospectively included patients with CTEPH, identified from the Cleveland Clinic Pulmonary Hypertension Registry. All patients had right heart catheterization (RHC) and imaging studies consistent with CTEPH. We collected demographics, co-morbidities, baseline laboratory data including plasma HDL-C, six-minute walk test (6MWT), echocardiography and RHC. HDL-C levels were compared to a cohort of patients with cardiovascular risk factors and a previously published PAH cohort. HDL-C levels were available for 90 patients with CTEPH (age: 57.4±13.9 years; female 40%), 69 patients with PAH (age: 46.7±12.8 years; female 90%) and 254 control subjects (age: 56.7±13 years; female 48%). HDL-C levels in CTEPH patients were lower compared to controls and higher compared to PAH patients (median, IQR: CTEPH: 44, 34-57 mg/dl; PAH: 35.3, 29-39 mg/dl; Control: 49, 40-60 mg/dl; p < 0.01 for both pairwise comparisons). In CTEPH, higher HDL-C was associated with decreased prevalence of right ventricular dilation on echocardiography (p = 0.02). 57 patients with CTEPH underwent pulmonary thromboendarterectomy, higher HDL-C was associated with a larger decrement in postoperative pulmonary vascular resistance (PVR) (r = 0.37, p = 0.049). HDL-C was not associated with mortality or other markers of disease severity. HDL-C levels in CTEPH patients were lower compared to control subjects, but higher compared to PAH patients. Higher HDL-C in CTEPH was associated with less right ventricular dilation and greater decrement in postoperative PVR. These data suggest that HDL-C may be a useful marker of small vessel disease in CTEPH.

The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH). We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH. All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included. PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives. Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients.

Severe asthma occurs more often in older adult patients. We hypothesized that the greater risk for severe asthma in older individuals is due to aging, and is independent of asthma duration. This is a cross-sectional study of prospectively collected data from adult participants (N=1130; 454 with severe asthma) enrolled from 2002 - 2011 in the Severe Asthma Research Program. The association between age and the probability of severe asthma, which was performed by applying a Locally Weighted Scatterplot Smoother, revealed an inflection point at age 45 for risk of severe asthma. The probability of severe asthma increased with each year of life until 45 years and thereafter increased at a much slower rate. Asthma duration also increased the probability of severe asthma but had less effect than aging. After adjustment for most comorbidities of aging and for asthma duration using logistic regression, asthmatics older than 45 maintained the greater probability of severe asthma [OR: 2.73 (95 CI: 1.96; 3.81)]. After 45, the age-related risk of severe asthma continued to increase in men, but not in women. Overall, the impact of age and asthma duration on risk for asthma severity in men and women is greatest over times of 18-45 years of age; age has a greater effect than asthma duration on risk of severe asthma.

The Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma. To identify novel asthma phenotypes using an unsupervised hierarchical cluster analysis. Reduction of the initial 628 variables to 34 core variables was achieved by elimination of redundant data and transformation of categorical variables into ranked ordinal composite variables. Cluster analysis was performed on 726 subjects. Five groups were identified. Subjects in Cluster 1 (n = 110) have early onset atopic asthma with normal lung function treated with two or fewer controller medications (82%) and minimal health care utilization. Cluster 2 (n = 321) consists of subjects with early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilization. Cluster 3 (n = 59) is a unique group of mostly older obese women with late-onset nonatopic asthma, moderate reductions in FEV(1), and frequent oral corticosteroid use to manage exacerbations. Subjects in Clusters 4 (n = 120) and 5 (n = 116) have severe airflow obstruction with bronchodilator responsiveness but differ in to their ability to attain normal lung function, age of asthma onset, atopic status, and use of oral corticosteroids. Five distinct clinical phenotypes of asthma have been identified using unsupervised hierarchical cluster analysis. All clusters contain subjects who meet the American Thoracic Society definition of severe asthma, which supports clinical heterogeneity in asthma and the need for new approaches for the classification of disease severity in asthma.

The prevalence and prognostic implications of hypoxemia either at rest or during six-minute walk test (6MWT) in patients with idiopathic or heritable pulmonary arterial hypertension (IPAH or HPAH) have not been systemically studied. We sought to determine the prevalence, phenotypic and prognostic implications of hypoxemia in patients with IPAH and HPAH. Patients with IPAH or HPAH were identified from the Cleveland Clinic Pulmonary Hypertension Registry. Pulse oximetry (SpO2) at rest and during 6MWT was used to define hypoxemia at rest or during activities when measurements were lower than 90%, respectively. A total of 292 patients (age 50.6 ± 18.0 years, 73% females) with IPAH (88%) and HPAH (12%) were included. Of them, 143 (49%) had SpO2 >90% at rest and during 6MWT, 89 (31%) subjects had hypoxemia during 6MWT and 60 (20%) had hypoxemia at rest. Patients with hypoxemia had older age, greater body mass index, higher prevalence of cardiovascular risk factors, worse functional capacity and pulmonary function tests but less severe pre-capillary pulmonary hypertension. Individuals with hypoxemia either at rest or during the initial 6MWT had worse long-term survival when compared to subjects without hypoxemia, even when adjusting for a great number of potential confounders. (HR: 2.5 (95% CI: 1.54-3.98)). Hypoxemia in patients with IPAH and HPAH is associated with more comorbidities, less severe pre-capillary pulmonary hypertension and worse survival.

Beryllium continues to have a wide range of industrial applications. Exposure to beryllium can lead to sensitization (BeS) and chronic beryllium disease (CBD). The purpose of this statement is to increase awareness and knowledge about beryllium exposure, BeS, and CBD. Evidence was identified by a search of MEDLINE. The committee then summarized the evidence, drew conclusions, and described their approach to diagnosis and management. The beryllium lymphocyte proliferation test is the cornerstone of both medical surveillance and the diagnosis of BeS and CBD. A confirmed abnormal beryllium lymphocyte proliferation test without evidence of lung disease is diagnostic of BeS. BeS with evidence of a granulomatous inflammatory response in the lung is diagnostic of CBD. The determinants of progression from BeS to CBD are uncertain, but higher exposures and the presence of a genetic variant in the HLA-DP β chain appear to increase the risk. Periodic evaluation of affected individuals can detect disease progression (from BeS to CBD, or from mild CBD to more severe CBD). Corticosteroid therapy is typically administered when a patient with CBD exhibits evidence of significant lung function abnormality or decline. Medical surveillance in workplaces that use beryllium-containing materials can identify individuals with BeS and at-risk groups of workers, which can help prioritize efforts to reduce inhalational and dermal exposures.