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Editorial

Chest. 2017;151(1):1-5. doi:10.1016/j.chest.2016.11.011
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As we have done in past years,,, we begin the new year with a recap of CHEST's accomplishments during the year gone by and previews of what is to come in the new year. We remain gratified that manuscript submissions from leading clinicians and scientists allow CHEST to present our readers with the best in pulmonary, critical care, and sleep medicine that will continue to advance both research and clinical practice. As our field evolves with new procedures, drugs, and therapies and greater understanding of the fundamental mechanisms of disease, we strive to present the most up-to-date research on best practices to diagnose and treat our patients. We are grateful to our authors from around the globe who submit to CHEST but also to our reviewers who dedicate themselves to selecting and improving manuscripts submitted to CHEST.

Chest. 2017;151(1):6-8. doi:10.1016/j.chest.2016.07.014
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Traditionally, studies investigating the usefulness of a biomarker focus on diagnostic measures such as sensitivity and specificity. This approach, however, mandates the existence of a well-accepted reference standard. For biomarkers that are used to help treat patients with systemic infections and sepsis there is no such reference standard, with blood cultures having low sensitivity of only 10% to 30%. Thus, randomized controlled trials are needed to assess the benefits and limitations of infection biomarkers by comparing outcomes of marker-assessed patients with patients receiving routine care. In the case of procalcitonin (PCT) and its effect in the treatment of patients with sepsis, numerous studies have investigated how well this marker differentiates patients with true sepsis from patients presenting with a sepsis-like syndrome but no infectious etiology. Depending on the cutoff used, reported sensitivities and specificities range between 70% and 95%, with the lack of a reference standard making the interpretation of these results challenging. Importantly, several randomized trials have investigated the effects of PCT protocols and report important reductions in antibiotic use in the range of 30% to 70%, depending on the clinical setting and main infection diagnosis,, with a recent trial finding a significant survival benefit associated with the use of PCT in the critical care setting.

Chest. 2017;151(1):9-10. doi:10.1016/j.chest.2016.08.1455
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In this issue of CHEST, Rush and colleagues add to a body of work that demonstrates a continued gap in the utilization of palliative care (PC). The authors’ objective was to investigate the use of PC in patients with end-stage COPD on home oxygen hospitalized for an exacerbation. Advanced care planning (ACP) and referral to PC for individuals with advanced COPD, and other chronic potentially life-limiting conditions, is an established recommendation.,,

Giants in Chest Medicine

Chest. 2017;151(1):11-13. doi:10.1016/j.chest.2016.09.048
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Topics: pulmonology

Editorials: Point and Counterpoint

Chest. 2017;151(1):14-17. doi:10.1016/j.chest.2016.09.021
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Over the past 10 years, the aims of asthma management have focused on achieving overall asthma control, which consists of two domains: current (day-to-day) control of symptoms, minimizing the use of asthma relievers, maintaining activities of daily living, and reducing future risk of severe asthma exacerbations and asthma instability, preventing the decline in lung function that occurs in some patients with asthma and preventing side effects from the medications used to treat asthma.

Chest. 2017;151(1):17-20. doi:10.1016/j.chest.2016.09.023
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Recently there has been great interest in the development of precision medicines that target a specific underlying disease mechanism so that responders will have a better therapeutic response and less adverse effects compared with the nonspecific therapies that are currently used. This approach has been very promising in the treatment of cancer, in which specific anticancer therapies have been targeted to particular molecular abnormalities identified in the cancer. The same approach is now being applied to complex inflammatory diseases, such as asthma and COPD, but so far with less success.

Chest. 2017;151(1):20-21. doi:10.1016/j.chest.2016.09.024
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Dr Barnes makes a number of cogent arguments as to why new anti-eosinophilic drugs, which are biologic agents, will not be widely used in the management of uncontrolled asthma. These include the fact that most uncontrolled asthma is caused by lack of adherence to effective therapies (particularly inhaled corticosteroids) and that some patients with severe refractory asthma do not have persistent airway eosinophilia. He is also correct that the use of anti-eosinophilic biologic agents must be restricted to those patients with evidence of persistent eosinophilic asthma who are not responding to high doses of conventional antiasthma treatment, many of whom require oral corticosteroids to manage their disease. However, identifying these patient phenotypes that may potentially respond to a very specific biological treatment, even if they represent a small proportion of the entire patient population with the disease, is the whole purpose of precision medicine.

Chest. 2017;151(1):21-22. doi:10.1016/j.chest.2016.09.025
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We both agree that poor adherence is the major reason for poor control of asthma and that true severe refractory asthma is rare. Asthma may also be difficult to control because of poor inhaler technique, comorbidities, and exposure to exacerbating factors. Dr O’Byrne suggests that patients with truly refractory asthma compose 5% to 8% of all patients with asthma, but recent accurate estimates suggest a figure of less than 4%. Of these patients, only a proportion (about 30%) have increased eosinophils in induced sputum, whereas others have increased neutrophils, a mixed granulocytic pattern, or no increase in inflammatory cells and therefore are presumably much less likely to respond to a specific anti-eosinophilic therapy. However, to classify the inflammatory phenotype of asthma, it is necessary to study induced sputum. This is technically demanding (especially in patients with severe disease), time consuming, and expensive with respect to staff costs, and not all patients with asthma are able to produce a suitable sputum sample. Another problem is that these inflammatory phenotypes of asthma are not stable; in a recent study, the phenotype in about half of patients with asthma changed on repeated testing. This means that induced sputum analysis is not practical in clinical practice. Determination of fractional exhaled nitric oxide is less invasive, is easy to perform in the clinic, and reflects airway eosinophilic inflammation, but results are affected by several factors, particularly cigarette smoking and the use of inhaled corticosteroids. Indeed, fractional exhaled nitric oxide is often used currently as a measurement of adherence to corticosteroid therapy. However, nitric oxide analyzers are relatively expensive so may not be available in most clinical practices. The simplest approach would be to measure eosinophils in blood, which is a readily available test, but the relationship between eosinophils in blood (total or differential counts) to eosinophils in sputum and the airways is not yet clear. Furthermore, inhaled corticosteroid therapy reduces eosinophils in blood.

Original Research: Critical Care

Chest. 2017;151(1):23-33. doi:10.1016/j.chest.2016.06.046

Background  There is a growing use of procalcitonin (PCT) to facilitate the diagnosis and management of severe sepsis. We investigated the impact of one to two PCT determinations on ICU day 1 on health-care utilization and cost in a large research database.

Methods  A retrospective, propensity score-matched multivariable analysis was performed on the Premier Healthcare Database for patients admitted to the ICU with one to two PCT evaluations on day 1 of ICU admission vs patients who did not have PCT testing.

Results  A total of 33,569 PCT-managed patients were compared with 98,543 propensity score-matched non-PCT patients. In multivariable regression analysis, PCT utilization was associated with significantly decreased total length of stay (11.6 days [95% CI, 11.4 to 11.7] vs 12.7 days [95% CI, 12.6 to 12.8]; 95% CI for difference, 1 to 1.3; P < .001) and ICU length of stay (5.1 days [95% CI, 5.1 to 5.2] vs 5.3 days [95% CI, 5.3 to 5.4]; 95% CI for difference, 0.1 to 0.3; P < .03), and lower hospital costs ($30,454 [95% CI, 29,968 to 31,033] vs $33,213 [95% CI, 32,964 to 33,556); 95% CI for difference, 2,159 to 3,321; P < .001). There was significantly less total antibiotic exposure (16.2 days [95% CI, 16.1 to 16.5] vs 16.9 days [95% CI, 16.8 to 17.1]; 95% CI for difference, –0.9 to 0.4; P = .006) in PCT-managed patients. Patients in the PCT group were more likely to be discharged to home (44.1% [95% CI, 43.7 to 44.6] vs 41.3% [95% CI, 41 to 41.6]; 95% CI for difference, 2.3 to 3.3; P = .006). Mortality was not different in an analysis including the 96% of patients who had an independent measure of mortality risk available (19.1% [95% CI, 18.7 to 19.4] vs 19.1% [95% CI, 18.9 to 19.3]; 95% CI for difference, –0.5 to 0.4; P = .93).

Conclusions  Use of PCT testing on the first day of ICU admission was associated with significantly lower hospital and ICU lengths of stay, as well as decreased total, ICU, and pharmacy cost of care. Further elucidation of clinical outcomes requires additional data.

Chest. 2017;151(1):34-40. doi:10.1016/j.chest.2016.08.1465

Background  Widespread use of critical care ultrasonography (CCUS) for the management of patients in the ICU requires an effective training program. The effectiveness of national and regional CCUS training courses is not known. This study describes a national-level, simulation-based, 3-day CCUS training program and evaluates its effectiveness.

Methods  Five consecutive CCUS courses, with a total of 363 people, were studied. The 3-day CCUS training program consisted of didactic lectures, ultrasonography interpretation sessions, and hands-on modules with live models. Thoracic, vascular, and abdominal ultrasonography were taught in addition to goal-directed echocardiography. Learners rotated between hands-on training and interpretation sessions. The teacher-to-learner ratio was 1:3 during hands-on training. Interpretation sessions were composed of interactive small groups that reviewed normal and abnormal ultrasonography images. Learners completed a video-based examination before and after completion of the courses. Hands-on image acquisition skills were tested at the completion of the course.

Results  Average scores on the pretest and posttest were 57% and 90%, respectively (P < .001). The average score on the hands-on test was 86%. Learners aged 20 to 39 years compared with learners ≥ 40 years old scored better on the pretest (64% vs 51%; P < 0.001), posttest (91% vs 88%; P < .010), and hands-on test (90% vs 82%; P < .001).

Conclusions  Learners demonstrated a significant improvement in written test scores that assessed cognitive and image interpretation abilities. In addition, they demonstrated acquisition of practical skills as evidenced by high scores during hands-on testing. Further studies are needed to determine if a simulation-based CCUS course will translate into effective clinical practice and to measure the durability of training. This 3-day course is an effective method to train large groups of critical care clinicians in the skills requisite for CCUS (image acquisition and image interpretation).

Original Research: COPD

Chest. 2017;151(1):41-46. doi:10.1016/j.chest.2016.06.023

Background  To investigate the use of palliative care (PC) in patients with end-stage COPD receiving home oxygen hospitalized for an exacerbation.

Methods  A retrospective nationwide cohort analysis was performed, using the Nationwide Inpatient Sample. All patients ≥ 18 years of age with a diagnosis of COPD, receiving home oxygen, and admitted for an exacerbation were included.

Results  A total of 55,208,382 hospitalizations from the 2006-2012 Nationwide Inpatient Sample were examined. There were 181,689 patients with COPD, receiving home oxygen, and admitted for an exacerbation; 3,145 patients (1.7%) also had a PC contact. There was a 4.5-fold relative increase in PC referral from 2006 (0.45%) to 2012 (2.56%) (P < .01). Patients receiving PC consultations compared with those who did not were older (75.0 years [SD 10.9] vs 70.6 years [SD 9.7]; P < .01), had longer hospitalizations (4.9 days [interquartile range, 2.6-8.2] vs 3.5 days [interquartile range, 2.1-5.6]), and more likely to die in hospital (32.1% vs 1.5%; P < .01). Race was significantly associated with referral to palliative care, with white patients referred more often than minorities (P < .01). Factors associated with PC referral included age (OR, 1.03; 95% CI, 1.02-1.04; P < .01), metastatic cancer (OR, 2.40; 95% CI, 2.02-2.87; P < .01), nonmetastatic cancer (OR, 2.75; 95% CI, 2.43-3.11; P < .01), invasive mechanical ventilation (OR, 4.89; 95% CI, 4.31-5.55; P < .01), noninvasive mechanical ventilation (OR, 2.84; 95% CI, 2.58-3.12; P < .01), and Do Not Resuscitate status (OR, 7.95; 95% CI, 7.29-8.67; P < .01).

Conclusions  The use of PC increased dramatically during the study period; however, PC contact occurs only in a minority of patients with end-stage COPD admitted with an exacerbation.

Chest. 2017;151(1):47-59. doi:10.1016/j.chest.2016.08.1440

Background  Extracellular matrix (ECM) remodeling of the lung tissue releases protein fragments into the blood, where they may be detected as serologic surrogate markers of disease activity in COPD. Our goal was to assess the association of ECM turnover with severity and outcome of COPD.

Methods  In a prospective, observational, multicenter study including 506 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease grades II to IV), serum samples were analyzed at stable state, exacerbation, and 4 weeks after exacerbation. The analysis comprised a panel of five novel neoepitopes, including fragments of collagen type III (C3M) and collagen type VI (C6M), pro-forms of collagen type III (Pro-C3) and type VI (Pro-C6), and neutrophil elastase-generated fragments of elastin (EL-NE) according to enzyme-linked immunosorbent assay. These neoepitopes were also measured at stable state in a derivation cohort that included 100 patients with COPD.

Results  Serum levels of C3M, C6M, Pro-C3, Pro-C6, and EL-NE were associated with lung function. Patients with the lowest levels of Pro-C3 and Pro-C6 had more severe airflow limitation, hyperinflation, air trapping, and emphysema. C3M and C6M were associated with dyspnea. All ECM biomarkers, except Pro-C6, were increased at exacerbation compared with stable state but, except EL-NE, did not differ between stable state and exacerbation follow-up in the crude and adjusted analyses. In Cox regression adjusted analyses, Pro-C3 was associated with a shorter time to exacerbation (hazard ratio, 0.72; CI, 0.59-0.89; P = .002) and Pro-C6 with survival (hazard ratio, 2.09; CI, 1.18-3.71; P = .011).

Conclusions  Serum biomarkers of ECM turnover were significantly associated with disease severity and clinically relevant outcomes in patients with COPD.

Trial Registry  No.: ISRCTN99586989; URL: www.controlled-trials.com.

Chest. 2017;151(1):60-67. doi:10.1016/j.chest.2016.08.001

Background  Long-acting bronchodilators, including long-acting beta2-agonists (LABA) and the anticholinergic tiotropium, are recommended as initial maintenance therapy in COPD. Studies to date have been limited in size and reported ambivalent results on the comparative risk of cardiovascular, cerebrovascular, and pulmonary adverse events between these two long-acting bronchodilators. Moreover, little information is available for the period when treatment is first initiated, a time when subjects may be especially at risk.

Methods  We identified a cohort of new users of long-acting bronchodilators between 2002 and 2012, age 55 or older, from the United Kingdom’s Clinical Practice Research Datalink. Patients initiating tiotropium were matched on high-dimensional propensity scores and prior inhaled corticosteroid use with patients initiating LABAs, and followed for 1 year for the occurrence of acute myocardial infarction, stroke, heart failure, arrhythmia, and pneumonia.

Results  A total of 26,442 tiotropium initiators were matched to 26,442 LABA initiators, mainly single inhalers combined with inhaled corticosteroids. The hazard ratio of acute myocardial infarction associated with tiotropium initiation, relative to LABA initiation, was 1.10 (95% CI, 0.88-1.38), whereas for stroke it was 1.02 (95% CI, 0.78-1.34), for arrhythmia 0.81 (95% CI, 0.60-1.09), and heart failure 0.90 (95% CI, 0.79-1.02). The incidence of pneumonia was significantly less with tiotropium (hazard ratio, 0.81; 95% CI, 0.72-0.92).

Conclusion  COPD treatment initiation with tiotropium compared with LABA does not increase cardiovascular risk in the first year of treatment. The risk of pneumonia is higher with LABA, a likely effect of the inhaled corticosteroids present in many LABA inhalers used in real world clinical practice.

Chest. 2017;151(1):68-77. doi:10.1016/j.chest.2016.08.1432

Background  Obesity is prevalent in the United States; however, the impact of obesity on COPD morbidity is unclear. We hypothesized that obesity is associated with worse outcomes in COPD.

Methods  We examined 3,631 participants from the multicenter prospective cohort study Genetic Epidemiology of COPD (COPDGene) who had spirometry-confirmed COPD, a postbronchodilator FEV1 < 80% predicted, and a BMI ≥ 18.5 kg/m2. We conducted logistic and linear regression analyses to determine the association between COPD outcomes and obesity class, adjusting for relevant confounders. The referent for obesity classes included normal/overweight individuals (BMI range, 18.5-29.9 kg/m2).

Results  Overall, 35% of participants were obese, with 21% class I (BMI range, 30-34.9 kg/m2), 9% class II (BMI range, 35-39.9 kg/m2), and 5% class III (BMI ≥ 40 kg/m2). The number of comorbidities increased with increasing obesity class (P < .001). Increasing obesity class was independently associated with worse respiratory-specific and general quality of life (QOL) (St. George’s Respiratory Questionnaire score and Short Form-36 score version 2, respectively), reduced 6-min walk distance (6MWD), increased dyspnea (Modified Medical Research Council score ≥ 2), and greater odds of severe acute exacerbation of COPD (AECOPD). The associations between obesity and worse outcomes were independent of the presence of comorbidities, except in the case of SF-36 and severe exacerbations.

Conclusions  Obesity is prevalent among individuals with COPD and associated with worse COPD-related outcomes, ranging from QOL and dyspnea to 6MWD and severe AECOPD. These associations were strengthened when obesity was analyzed as a dose-dependent response. Obesity in patients with COPD may contribute to a worse COPD-related course.

Original Research: Asthma

Chest. 2017;151(1):78-89. doi:10.1016/j.chest.2016.09.035

Background  Asthma and COPD are common airway diseases. Individuals with overlapping asthma and COPD experience increased health impairment and severe disease exacerbations. Efficacious treatment options are required for this population. Omalizumab (anti-IgE) therapy is effective in patients with severe persistent asthma, but limited data are available on efficacy in populations with overlapping asthma and COPD.

Methods  Data from the Australian Xolair Registry were used to compare treatment responses in individuals with asthma-COPD overlap with responses in patients with severe asthma alone. Participants were assessed at baseline and after 6 months of omalizumab treatment. We used several different definitions of asthma-COPD overlap. First, we compared participants with a previous physician diagnosis of COPD to participants with no COPD diagnosis. We then made comparisons based on baseline lung function, comparing participants with an FEV1 < 80% predicted to those with an FEV1 > 80% predicted after bronchodilator use. In the population with an FEV1< 80%, analysis was further stratified based on smoking history.

Results  Omalizumab treatment markedly improved asthma control and health-related quality of life in all populations assessed based on the Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. Omalizumab treatment did not improve lung function (FEV1, FVC, or FEV1/FVC ratio) in populations that were enriched for asthma-COPD overlap (diagnosis of COPD or FEV1 < 80%/ever smokers).

Conclusions  Our study suggests that omalizumab improves asthma control and health-related quality of life in individuals with severe allergic asthma and overlapping COPD. These findings provide real-world efficacy data for this patient population and suggest that omalizumab is useful in the management of severe asthma with COPD overlap.

Original Research: Pulmonary Vascular Disease

Chest. 2017;151(1):90-105. doi:10.1016/j.chest.2016.08.1461

Background  We conducted a systematic review and network meta-analysis to examine comparative efficacy and tolerability of pharmacologic interventions for pulmonary arterial hypertension (PAH).

Methods  MEDLINE, the Cochrane Register, EMBASE, CINAHL, and clinicaltrials.gov were searched (January 1, 1990 to March 3, 2016). Randomized controlled trials (RCTs) studying the approved pharmacologic agents endothelin receptor antagonists (ERA), phosphodiesterase inhibitors (PDE5i), the oral/inhaled (PO/INH) and IV/subcutaneous (SC) prostanoids, and riociguat and selexipag, alone or in combination, for pulmonary arterial hypertension (PAH) and reporting at least one efficacy outcome were selected.

Results  Thirty-one RCTs with 6,565 patients were selected. In network meta-analysis, when compared with a median placebo rate of 14.5%, clinical worsening was estimated at 2.8% with riociguat (risk ratio [RR], 0.19; 95% CI, 0.05-0.76); at 3.9% with ERA + PDE5i (RR, 0.27; 95% CI, 0.14-0.52), and at 5.7% with PDE5i (RR, 0.39; 95% CI, 0.24-0.62). For improvement in functional status, when compared with 16.2% in the placebo group, improvement in at least one New York Heart Association/World Health Organization (NYHA/WHO) functional class was estimated at 81.8% with IV/SC prostanoids (RR, 5.06; 95% CI, 2.3211.04), at 28.3% with ERA + PDE5i (RR, 1.75; 95% CI, 1.05-2.92), and at 25.2% with ERA (RR, 1.56; 95% CI, 1.22-2.00). Differences in mortality were not significant. Adverse events leading to discontinuation of therapy were highest with the PO/INH prostanoids (RR, 2.92; 95% CI, 1.68-5.06) and selexipag (RR, 2.06; 95% CI, 1.04-3.88) compared with placebo.

Conclusions  Currently approved pharmacologic agents have varying effects on morbidity and functional status in patients with PAH. Future comparative effectiveness trials are warranted with a focus on a patient-centered approach to therapy.

Registration  PROSPERO CRD42016036803

Chest. 2017;151(1):106-118. doi:10.1016/j.chest.2016.08.1473
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Background  Pulmonary arterial hypertension (PAH) leads to reduced health-related quality of life (HRQoL). The objectives of this analysis were to evaluate the effect of macitentan on HRQoL in patients with PAH in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) study. The association between baseline HRQoL and long-term outcomes was also investigated.

Methods  Patients were randomized to placebo, macitentan 3 mg, or macitentan 10 mg once daily. Patients aged 14 years or older completed the 36-Item Short Form Survey (SF-36) at baseline, at month 6 and month 12, and at the end of treatment (EOT). The absolute change from baseline to month 6 in SF-36 scores was calculated. The time to a clinically meaningful deterioration in the SF-36 physical component summary and mental component summary (PCS and MCS) scores and associations between baseline PCS/MCS scores and time to morbidity/mortality events were also assessed.

Results  At month 6, macitentan 10 mg significantly improved seven of eight SF-36 domains and the PCS and MCS scores vs placebo. Macitentan 10 mg significantly reduced the risk of a three-point or greater deterioration in PCS (hazard ratio [HR], 0.60; 95% CI, 0.47-0.76; P < .0001) and MCS scores (HR, 0.76; 95% CI, 0.61-0.95; P = .0173) until EOT vs placebo. Patients with a baseline PCS score greater than the median baseline value had a significantly reduced risk of morbidity/mortality compared with patients with a PCS score less than the median; a similar result was observed for the MCS score.

Conclusions  Macitentan significantly improved HRQoL in patients with PAH compared with placebo and significantly reduced the risk of a clinically meaningful HRQoL deterioration. An association between better baseline HRQoL and improved long-term outcomes was shown.

Trial Registry  ClinicalTrials.gov; No.: NCT00660179; URL: clinicaltrials.gov.

Chest. 2017;151(1):119-126. doi:10.1016/j.chest.2016.08.1439

Background  Fluid challenge may help in the differential diagnosis between pre- and postcapillary pulmonary hypertension (PH). However, the test is still in need of standardization and better defined clinical relevance.

Methods  Two hundred twelve patients referred for PH underwent a right-sided heart catheterization with measurements before and after rapid infusion of 7 mL/kg of saline. PH was defined as mean pulmonary artery pressure ≥ 25 mm Hg, and postcapillary PH was defined as pulmonary artery wedge pressure (PAWP) > 15 mm Hg. An increase in PAWP ≥ 18 mm Hg was considered diagnostic for postcapillary PH. At baseline, 66 patients received a diagnosis of no PH; 22, of postcapillary PH; and 124, of precapillary PH (mostly pulmonary arterial hypertension).

Results  After fluid challenge, five of 66 patients with no PH (8%) and eight of 124 with precapillary PH (6%) had the diagnosis reclassified as postcapillary PH. Fluid challenge was associated with an increase in PAWP by 7 ± 2 mm Hg in postcapillary PH and 3 ± 1 mm Hg in both precapillary PH and no-PH groups. Between-group differences were significant, but there was overlap. There were no adverse events related to fluid challenge. Prediction bands calculated from quadratic fits of the PAWP responses in pooled control subjects with no PH and patients with precapillary PH helped confirm 18 mm Hg as the cutoff for diagnosing postcapillary PH.

Conclusions  Fluid challenge with 7 mL/kg saline increases PAWP, more in postcapillary than in precapillary PH or in control subjects with no PH. A cutoff value of 18 mm Hg allows reclassification of 6% to 8% of patients with precapillary PH or normal hemodynamic characteristics at baseline.

Original Research: Antithrombotic Therapy

Chest. 2017;151(1):127-138. doi:10.1016/j.chest.2016.08.1462

Background  Direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or noncancer-associated venous thromboembolic disease. Although routine monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this review was to summarize systematically evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban, and edoxaban.

Methods  PubMed, Embase, and Web of Science were searched for studies reporting relationships between drug levels and coagulation assay results.

Results  We identified 109 eligible studies: 35 for dabigatran, 50 for rivaroxaban, 11 for apixaban, and 13 for edoxaban. The performance of standard anticoagulation tests varied across DOACs and reagents; most assays, showed insufficient correlation to provide a reliable assessment of DOAC effects. Dilute thrombin time (TT) assays demonstrated linear correlation (r2 = 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated linear correlation (r2 = 0.78-1.00) across a wide range of concentrations for rivaroxaban, apixaban, and edoxaban.

Conclusions  An ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend a dilute TT or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for direct Xa inhibitors. In the absence of these tests, TT or APTT is recommended over PT/INR for assessment of dabigatran, and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of drug interactions, and renal and hepatic function should impact clinical estimates of anticoagulant effect in a patient for whom laboratory test results are not available.

Original Research: Diffuse Lung Disease

Chest. 2017;151(1):139-148. doi:10.1016/j.chest.2016.08.1457

Objective  To assess the clinical characteristics, diagnosis, and outcome of cardiac sarcoidosis in a single institution sarcoidosis clinic.

Methods  Patients with cardiac sarcoidosis were identified using refined World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) criteria of highly probable and probable. Patient demographics, local and systemic treatments, and clinical outcome were collected.

Results  Of the 1,815 patients evaluated over a 6-year period, 73 patients met the WASOG criteria for cardiac sarcoidosis. The median age at diagnosis was 46 years, with a median follow-up of 8.8 years. Reduced left ventricular ejection fraction (LVEF) was the most common manifestation (54.8%). Patients with arrhythmias experienced ventricular tachycardia or severe heart block, (35.6% and 19.2%, respectively) with or without reduced LVEF. A total of 45 (61.6%) patients underwent cardiac PET scan and/or MRI, with 41 (91.1%) having a positive study. During follow-up, 10 patients (13.7%) either underwent transplant (n = 3) or died (n = 7) from sarcoidosis. Kaplan-Meier survival curves revealed 5- and 10-year survival rates of 95.5% and 93.4%, respectively. Univariate factors of age at diagnosis < 46 years, implantation of pacemaker or defibrillator, mycophenolate treatment, or LVEF > 40% were associated with improved survival. Cox regression analysis demonstrated that age ≥ 46 years and lack of an implanted pacemaker or defibrillator were the only independent predictors of mortality.

Conclusions  The new WASOG criteria were able to characterize cardiac involvement in our sarcoidosis clinic. Age and lack of pacemaker or defibrillator were the significant predictors of mortality for cardiac sarcoidosis, and reduced LVEF < 40% was associated with worse prognosis.

Trial Registry  ClinicalTrials.gov; No.: NCT02356445; URL: www.clinicaltrials.gov.

Original Research: Cardiovascular Disease

Chest. 2017;151(1):149-159. doi:10.1016/j.chest.2016.08.1476

Background  Postoperative atrial fibrillation/flutter (POAF) is associated with significant morbidity and mortality after general thoracic surgery, but the need for and the best agent for prophylaxis remains obscure.

Methods  A systematic literature search was performed to identify randomized controlled trials that compared regimens for POAF prophylaxis after general thoracic surgery. Random-effects meta-analyses with trial sequential analyses were performed to compare the effects of medical prophylaxis vs placebo/usual care. The risk of POAF among patients receiving various prophylactic regimens was subjected to Bayesian network meta-analysis.

Results  Twenty-two trials (2,891 patients and 11 regimens) were included. Overall, medical prophylaxis reduced the incidence of POAF (OR, 0.33; 95% CI, 0.22-0.49) but not short-term mortality (OR, 0.85; 95% CI, 0.41-1.73). There was no significant difference in patient withdrawal due to adverse events (OR, 1.67; 95% CI, 0.67-4.16). Trial sequential analysis showed that as of 2012, sufficient evidence had accrued in support of the effectiveness of medical prophylaxis in reducing POAF after general thoracic surgery. In network meta-analysis, β-blockers, angiotensin-converting enzyme inhibitors, amiodarone, magnesium, and calcium channel blockers significantly reduced the risk of POAF compared with placebo/usual care. β-Blockers had the highest probability of being the most effective agents (OR, 0.12; 95% credible interval [CrI], 0.05-0.27; probability of being best, 77.7%; number needed to treat, 5.2).

Conclusions  The current literature supports the effectiveness and tolerability of medical prophylaxis and the superiority of β-blockers in preventing POAF after general thoracic surgery. β-Blockers are recommended, taking into consideration the status of the bronchopulmonary system.

Evidence-Based Medicine

Chest. 2017;151(1):160-165. doi:10.1016/j.chest.2016.10.037
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Background  This clinical practice guideline addresses six questions related to liberation from mechanical ventilation in critically ill adults. It is the result of a collaborative effort between the American Thoracic Society (ATS) and the American College of Chest Physicians (CHEST).

Methods  A multidisciplinary panel posed six clinical questions in a population, intervention, comparator, outcomes (PICO) format. A comprehensive literature search and evidence synthesis was performed for each question, which included appraising the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The Evidence-to-Decision framework was applied to each question, requiring the panel to evaluate and weigh the importance of the problem, confidence in the evidence, certainty about how much the public values the main outcomes, magnitude and balance of desirable and undesirable outcomes, resources and costs associated with the intervention, impact on health disparities, and acceptability and feasibility of the intervention.

Results  Evidence-based recommendations were formulated and graded initially by subcommittees and then modified following full panel discussions. The recommendations were confirmed by confidential electronic voting; approval required that at least 80% of the panel members agree with the recommendation.

Conclusions  The panel provides recommendations regarding liberation from mechanical ventilation. The details regarding the evidence and rationale for each recommendation are presented in the American Journal of Respiratory and Critical Care Medicine and CHEST.

Chest. 2017;151(1):166-180. doi:10.1016/j.chest.2016.10.036
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Background  An update of evidence-based guidelines concerning liberation from mechanical ventilation is needed as new evidence has become available. The American College of Chest Physicians (CHEST) and the American Thoracic Society (ATS) have collaborated to provide recommendations to clinicians concerning liberation from the ventilator.

Methods  Comprehensive evidence syntheses, including meta-analyses, were performed to summarize all available evidence relevant to the guideline panel’s questions. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, and the results were summarized in evidence profiles. The evidence syntheses were discussed and recommendations developed and approved by a multidisciplinary committee of experts in mechanical ventilation.

Results  Recommendations for three population, intervention, comparator, outcome (PICO) questions concerning ventilator liberation are presented in this document. The guideline panel considered the balance of desirable (benefits) and undesirable (burdens, adverse effects, costs) consequences, quality of evidence, feasibility, and acceptability of various interventions with respect to the selected questions. Conditional (weak) recommendations were made to use inspiratory pressure augmentation in the initial spontaneous breathing trial (SBT) and to use protocols to minimize sedation for patients ventilated for more than 24 h. A strong recommendation was made to use preventive noninvasive ventilation (NIV) for high-risk patients ventilated for more than 24 h immediately after extubation to improve selected outcomes. The recommendations were limited by the quality of the available evidence.

Conclusions  The guideline panel provided recommendations for inspiratory pressure augmentation during an initial SBT, protocols minimizing sedation, and preventative NIV, in relation to ventilator liberation.

Translating Basic Research Into Clinical Practice

Chest. 2017;151(1):181-192. doi:10.1016/j.chest.2016.09.001

Hypoxic pulmonary vasoconstriction (HPV) is a homeostatic mechanism that is intrinsic to the pulmonary vasculature. Intrapulmonary arteries constrict in response to alveolar hypoxia, diverting blood to better-oxygenated lung segments, thereby optimizing ventilation/perfusion matching and systemic oxygen delivery. In response to alveolar hypoxia, a mitochondrial sensor dynamically changes reactive oxygen species and redox couples in pulmonary artery smooth muscle cells (PASMC). This inhibits potassium channels, depolarizes PASMC, activates voltage-gated calcium channels, and increases cytosolic calcium, causing vasoconstriction. Sustained hypoxia activates rho kinase, reinforcing vasoconstriction, and hypoxia-inducible factor (HIF)-1α, leading to adverse pulmonary vascular remodeling and pulmonary hypertension (PH). In the nonventilated fetal lung, HPV diverts blood to the systemic vasculature. After birth, HPV commonly occurs as a localized homeostatic response to focal pneumonia or atelectasis, which optimizes systemic Po2 without altering pulmonary artery pressure (PAP). In single-lung anesthesia, HPV reduces blood flow to the nonventilated lung, thereby facilitating thoracic surgery. At altitude, global hypoxia causes diffuse HPV, increases PAP, and initiates PH. Exaggerated or heterogeneous HPV contributes to high-altitude pulmonary edema. Conversely, impaired HPV, whether due to disease (eg, COPD, sepsis) or vasodilator drugs, promotes systemic hypoxemia. Genetic and epigenetic abnormalities of this oxygen-sensing pathway can trigger normoxic activation of HIF-1α and can promote abnormal metabolism and cell proliferation. The resulting pseudohypoxic state underlies the Warburg metabolic shift and contributes to the neoplasia-like phenotype of PH. HPV and oxygen sensing are important in human health and disease.

Special Features

Chest. 2017;151(1):193-203. doi:10.1016/j.chest.2016.10.010

Stage classification provides a nomenclature about the anatomic extent of a cancer; a consistent language provides the ability to communicate about a specific patient and about cohorts of patients in clinical studies. This paper summarizes the eighth edition of lung cancer stage classification, which is the worldwide standard as of January 1, 2017. This revision is based on a large global database, a sophisticated analysis, extensive internal validation as well as multiple assessments confirming generalizability. Practicing clinicians must be familiar with the stage classification system when managing contemporary patients with lung cancer.

Recent Advances in Chest Medicine

Chest. 2017;151(1):204-214. doi:10.1016/j.chest.2016.08.002

Pulmonary hypertension (PH) can be triggered by any number of disease processes that result in increased pulmonary vascular resistance. Although historically associated with idiopathic pulmonary arterial hypertension (PAH), most patients with PH do not have the idiopathic subtype, but rather PH associated with another underlying diagnosis, such as left heart or lung disease. The World Health Organization (WHO) classification of PH helps conceptualize the different categories based on presumed etiology. WHO group 3 is PH associated with lung disease. This review focuses on PH in diffuse parenchymal lung diseases (DPLDs), such as the idiopathic interstitial pneumonias and other more rare forms of DPLD. Although there are clear associations of PH with DPLD, the exact pathophysiologic mechanisms and full clinical significance remain uncertain. Treatment of PH related to DPLD remains investigational, but an area of great interest given the negative prognostic implications and the growing number of available pulmonary vasoactive agents.

Contemporary Reviews in Critical Care Medicine

Chest. 2017;151(1):215-224. doi:10.1016/j.chest.2016.06.032

Prone positioning was first proposed in the 1970s as a method to improve gas exchange in ARDS. Subsequent observations of dramatic improvement in oxygenation with simple patient rotation motivated the next several decades of research. This work elucidated the physiological mechanisms underlying changes in gas exchange and respiratory mechanics with prone ventilation. However, translating physiological improvements into a clinical benefit has proved challenging; several contemporary trials showed no major clinical benefits with prone positioning. By optimizing patient selection and treatment protocols, the recent Proning Severe ARDS Patients (PROSEVA) trial demonstrated a significant mortality benefit with prone ventilation. This trial, and subsequent meta-analyses, support the role of prone positioning as an effective therapy to reduce mortality in severe ARDS, particularly when applied early with other lung-protective strategies. This review discusses the physiological principles, clinical evidence, and practical application of prone ventilation in ARDS.

Contemporary Reviews in Sleep Medicine

Chest. 2017;151(1):225-241. doi:10.1016/j.chest.2016.09.014

A surge of data has reproducibly identified strong associations of OSA with cardiac arrhythmias. As an extension of epidemiologic and clinic-based findings, experimental investigations have made strides in advancing our understanding of the putative OSA and cardiac arrhythmogenesis mechanistic underpinnings. Although most studies have focused on the links between OSA and atrial fibrillation (AF), relationships with ventricular arrhythmias have also been characterized. Key findings implicate OSA-related autonomic nervous system fluctuations typified by enhanced parasympathetic activation during respiratory events and sympathetic surges subsequent to respiratory events, which contribute to augmented arrhythmic propensity. Other more immediate pathophysiologic influences of OSA-enhancing arrhythmogenesis include intermittent hypoxia, intrathoracic pressure swings leading to atrial stretch, and hypercapnia. Intermediate pathways by which OSA may trigger arrhythmia include increased systemic inflammation, oxidative stress, enhanced prothrombotic state, and vascular dysfunction. Long-term OSA-associated sequelae such as hypertension, atrial enlargement and fibrosis, ventricular hypertrophy, and coronary artery disease also predispose to cardiac arrhythmia. These factors can lead to a reduction in atrial effective refractory period, triggered and abnormal automaticity, and promote slowed and heterogeneous conduction; all of these mechanisms increase the persistence of reentrant arrhythmias and prolong the QT interval. Cardiac electrical and structural remodeling observed in OSA animal models can progress the arrhythmogenic substrate to further enhance arrhythmia generation. Future investigations clarifying the contribution of specific OSA-related mechanistic pathways to arrhythmia generation may allow targeted preventative therapies to mitigate OSA-induced arrhythmogenicity. Furthermore, interventional studies are needed to clarify the impact of OSA pathophysiology reversal on cardiac arrhythmogenesis and related adverse outcomes.

Pectoriloquy

Chest. 2017;151(1):242. doi:10.1016/j.chest.2016.07.025
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    In darkness we steal bodies in plain grave clothes.
    Freshly dead, eyes membranous, modest;
    it seems almost a crime to snatch a pauper's rest.

    By candlelight we explore their crevices–
    four-chambered heart, leguminous kidney, muddy entrails.

    We will learn all they've eaten, posthumously.

    We whisper, cajole; they stare back furiously,
    knowing they've been tricked. Are silage for our greening field.

    We thought only of the kiss of life

    One draws with the silken feather of a goose
    coils of dank viscera
    while another lifts a lung, imagines a sigh.

    Purple-black blossoms on the anterior skin–
    this love of everlasting, this anoxia.
    All you beauties.

    Within, the roil of internecine gases and salt,
    a great ship splitting at the hull. A quick draft of stale beer
    before we leave them lonely in the dawn.

Chest. 2017;151(1):243. doi:10.1016/j.chest.2016.07.041
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    An old man’s hands are withering on the wheel,
    his legs are wooden boards that will not bend,

    and I, a car ahead, must stop for a left-turner.
    Softly at first, he glides into me, then a thump,

    my fragile taillight crumbles while his front light shatters.
    I step out in traffic, ready for an encounter,

    but he cannot remove himself from his old Chevy,
    he trembles, breathless, as he rolls his window down

    and whispers,“I was looking for a sign.”
    I sigh. A sign. I, too, am looking for a sign

    that my way into heaven may not be this,
    a shove, crawling in on an old man’s shadow.

Correspondence

Chest. 2017;151(1):244. doi:10.1016/j.chest.2016.10.059
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I read with interest the article written by Jones et al published in CHEST (July 2016). I really enjoyed the last part that considers limitations. However, I think that there are other points to be discussed.

  • 1.

    In my opinion, the inclusion criteria consisting of patients from birth to 21 years could determine a selection bias. Community-acquired pneumonia in children has a range of patterns more related to patient age than to causative agent. In infants, air trapping may be the only radiologic sign. Edema and mucus in these airways can determine a peripheral atelectasis. Small plugs in peripheral airways generate lesser or greater accumulated small blotches of atelectasis. Up to 8 years of age, round pneumonias, which are often central and not detectable by ultrasonography, are possible. Major consolidations (exudate or other product of disease that replaces alveolar air) become common when developed channels and pores allow the spread of the infection.

  • 2.

    Ultrasonography is superior in identifying small subpleural echogenic areas. These focal atelectases are relatively usual in healthy lungs on CT imaging. They are common in patients with asthma and bronchiolitis (see earlier discussion).

  • 3.

    B-lines are nonspecific regarding a causative production of signals due to the modification of the plane immediately below the pleura (volume and arrangement of the alveoli, fluid, and so on). They are common in normal infants (Fig 1).

  • 4.

    Finally, imaging is insensitive for the identification of the cause of pneumonia.

Selected Reports

Chest. 2017;151(1):e1-e3. doi:10.1016/j.chest.2016.07.001

We report the case of a patient with a history of chronic bronchiectasis that presented with new onset fatigue, shortness of breath, peripheral blood eosinophilia and infiltrates on chest radiograph. Eight days previously, she was prescribed inhaled colistimethate sodium 75 mg bid to prevent exacerbations of her respiratory condition. To our knowledge, our case is the first to show the clinical and radiologic features of inhaled-colistimethate-induced pulmonary eosinophilia. It also shows the rapid resolution of its features following treatment with oral corticosteroids. Eosinophilic lung reaction to inhaled colistin is rarely reported in the literature. Clinicians should be aware of this possible side effect.

Ultrasound Corner

Chest. 2017;151(1):e5-e8. doi:10.1016/j.chest.2016.05.040
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A woman in her 80s presented with acute onset of chest pain and shock and was transported from the community by emergency medical services for primary percutaneous coronary intervention. The patient had no prior history of heart disease and on arrival was deemed to be Killip class IV, requiring levophed to maintain systolic BP > 80 mm Hg with normal heart sounds; bibasilar crackles were noted while oxygen saturation was maintained at 95% on room air. Her ECG was significant for sinus tachycardia, a right bundle branch block, and anterolateral ST-segment elevation, consistent with a culprit proximal left anterior descending artery lesion.

Chest. 2017;151(1):e9-e11. doi:10.1016/j.chest.2016.05.041
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A man in his 70s presented to the ED with left-sided chest pain and shortness of breath. The chest pain was pleuritic, localized to the left upper anterior chest, and occurred at rest. He also reported hematuria that started the morning of admission. His medical history was significant for hypertension, and his only medication was hydrochlorothiazide.

Topics: chest pain , hematuria

Pulmonary, Critical Care, and Sleep Pearls

Chest. 2017;151(1):e13-e16. doi:10.1016/j.chest.2016.07.026
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A 54-year-old French man was admitted for evaluation of a chronic nodular lesion of the tongue and mandibular lymphadenopathy. He reported active tobacco and cannabis smoking as well as excessive alcohol use. He also reported frequent use of cocaine for several months and a past addiction to IV heroin. He had traveled abroad as a journalist and lived for several months in Columbia and Venezuela 12 years ago. His medical history included chronic hepatitis C infection successfully treated with interferon and ribavirin 6 years ago and high BP.

Topics: lung , granuloma , tongue , infection
Chest. 2017;151(1):e17-e20. doi:10.1016/j.chest.2016.08.1435
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The patient is a 1-week-old boy born at 37+2 weeks' gestational age through spontaneous vaginal delivery. The pregnancy was complicated by maternal gestational diabetes mellitus and pre-eclampsia. The Apgar score was 9 at both 1 minute and 5 minutes after birth. Because of hypoglycemia at delivery that required IV dextrose, he was admitted to the local neonatal intensive care unit. His blood glucose levels quickly stabilized, dextrose administration was discontinued, and the patient began breast-feeding. On day 2 of life, the patient began having intermittent oxygen desaturation, with oxygen saturation as measured by pulse oximetry down to 70% while sleeping; he was transferred to a tertiary-care NICU for further management. Aside from the hypoxia, he was otherwise asymptomatic. He was breast-feeding without difficulty and had no vomiting or gastroesophageal reflux; no cyanosis, stridor, or snoring; and no seizure-like activity or hypertonicity.

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  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543