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Current Issue

Editorial

Chest. 2016;149(5):1117-1118. doi:10.1016/j.chest.2016.02.653
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The Society of Critical Care Medicine and the European Society of Intensive Care Medicine recently released a consensus statement redefining the clinical syndrome of sepsis. The new diagnostic criteria eliminate the concept of the Systemic Inflammatory Response Syndrome (SIRS) and rely on known or suspected infection with a change in Sequential Organ Failure Assessment (SOFA) score ≥ 2, or a modified “quick SOFA” for simpler use., Physicians of multiple specialties have expressed concern that widespread application of this new definition could cost patient lives, and we cannot support its adoption.

Chest. 2016;149(5):1119-1120. doi:10.1016/j.chest.2016.02.666
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Today, the treatment of critically ill and injured adults involves complex care paradigms that are delivered by interprofessional teams at the time of the day or night when evaluation or management is needed. The need for time-sensitive critical care interventions and the steadily rising numbers of adult critically ill and injured patients have sparked interest in new ways to provide timely and effective treatments. Optimal outcomes for patients with serious infections, coronary artery occlusion, stroke, bleeding victims of blunt or penetrating trauma, and patients with acute respiratory failure require distinct treatments that are time sensitive. The rising need for critical care was accurately predicted from models of the aging dynamics of our population and increasing utilization of critical care with decades of life after adolescence.

Chest. 2016;149(5):1121-1122. doi:10.1016/j.chest.2015.12.038
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Much of the recent research in asthma has focused on delineating the causative factors that contribute to the pathobiology of both airway eosinophilia and neutrophilia, and steroid-refractory disease. The distal airway, once thought to be a sterile environment, is now known to be a complex arena of microorganisms, termed the lung microbiome. Complementary and counterbalancing mechanisms are essential to maintaining homeostasis in this environment. An altered lung microbiome has been well described in asthma, with a higher burden of bacteria and differing species seen in asthmatic lungs compared with normal lungs, and these differences are more marked in severe asthma. There are likely several different mechanisms that account for these differences, including the usage of inhaled or oral corticosteroids and the higher prevalence of antimicrobial prescription in patients with more severe asthma.

Chest. 2016;149(5):1123-1125. doi:10.1016/j.chest.2015.12.007
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In 2007, the Current Procedural Terminology (CPT) Editorial Panel and Medicare established CPT code 94012 to report fractional exhaled nitric oxide (Feno) measurements. Feno reflects airway inflammation in asthma, as summarized in CHEST shortly thereafter. Both the CPT code approval and subsequent Medicare coverage were predicated on a reasonable evidence base at the time, demonstrating that for people with asthma, Feno test results could alter medical treatment and improve clinically meaningful outcomes. Major professional societies had already established technical standards for the reliable measurement of Feno; so why did it take almost a decade to reach reasonable numbers of annual claims reported to Medicare (Fig 1) and for many other payers to cover this diagnostic test?

Giants in Chest Medicine

Chest. 2016;149(5):1126-1127. doi:10.1016/j.chest.2016.02.645
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Editorials: Point and Counterpoint

Chest. 2016;149(5):1128-1130. doi:10.1016/j.chest.2016.01.029
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Evidence-based medicine (EBM) is central to efforts to improve the quality, safety, and affordability of health care. Randomized controlled trials (RCTs) are generally considered the highest level of evidence for assessing the effectiveness of interventions, and they serve as a foundation for EBM practice standards and performance measurements. However, critics cite the limited usefulness of applying EBM to individual patients, partly because RCTs often fail to enroll subjects who are representative of patients seen in the community. This failure yields inequity in the provision of high-quality care and creates potential for patient harm. Trialists have come a long way since the landmark 1985 Physicians’ Health Study of low-dose aspirin for the primary prevention of cardiovascular disease enrolled > 90% white male subjects; disparate enrollment still occurs, however, for important and prevalent patient subgroups.

Chest. 2016;149(5):1130-1132. doi:10.1016/j.chest.2016.01.028
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Deliberate experiments designed to assess the value and merits of therapeutic processes in patients are a critical part of modern medicine. These experiments are rarely easy, and they can be costly and time-consuming. If badly designed, they can even be a threat to patients. The efficiency of such experiments is very important. Over time, randomized controlled trials (RCTs) have been developed and have evolved to ensure clinical relevance, but it is impossible to ensure that everyone who has a disease is included in a study for reasons of scientific interpretation. I will use historical context and how research has evolved to explore this topic.

Chest. 2016;149(5):1132-1133. doi:10.1016/j.chest.2016.01.031
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“Variability is the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease.” Sir William Osler taught that a great physician practiced the art, not just the science, of medicine. Dr Tillotson analogously reasons that statistical and scientific principles oblige the exclusion of patient variability from randomized controlled trials (RCTs), and thus the application of their results to individual patients must rely on the art of medicine. Although this scenario is true to some extent, it should not absolve the biomedical researcher from seeking to continually improve the conduct of clinical research.

Chest. 2016;149(5):1133-1135. doi:10.1016/j.chest.2016.01.027
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Dr Courtright raises some excellent and valid points regarding the debate, and clearly this is an important aspect of improving medical practice. In essence, there are two “camps” of clinical research, those of academia and industry, each with their own perspective and aims. The topic of underrepresented or minority populations in studies has been examined with respect to oncology, multiple sclerosis (MS), stroke, and other conditions. However, before we believe that we have totally failed these populations, it is important to consider the actual incidence of various minorities in the United States in 2014. Almost 80% of US citizens were white; 12.8%, “black”; 4.4%, Asian; and < 1% were American Indian/Alaskan. It is important to remember these data when discussing this sensitive topic. Three specific conditions have been reviewed with respect to minority balance: MS, stroke, and cancer.

Commentary: Ahead of the Curve

Chest. 2016;149(5):1136-1142. doi:10.1016/j.chest.2016.03.001
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Recent advances in the three-dimensional (3D) printing industry have enabled clinicians to explore the use of 3D printing in preprocedural planning, biomedical tissue modeling, and direct implantable device manufacturing. Despite the increased adoption of rapid prototyping and additive manufacturing techniques in the health-care field, many physicians lack the technical skill set to use this exciting and useful technology. Additionally, the growth in the 3D printing sector brings an ever-increasing number of 3D printers and printable materials. Therefore, it is important for clinicians to keep abreast of this rapidly developing field in order to benefit. In this Ahead of the Curve, we review the history of 3D printing from its inception to the most recent biomedical applications. Additionally, we will address some of the major barriers to wider adoption of the technology in the medical field. Finally, we will provide an initial guide to 3D modeling and printing by demonstrating how to design a personalized airway prosthesis via 3D Slicer. We hope this information will reduce the barriers to use and increase clinician participation in the 3D printing health-care sector.

Commentary

Chest. 2016;149(5):1143-1145. doi:10.1016/j.chest.2016.03.015
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Despite their widespread use, the indications for the selective use of temporary inferior vena cava (IVC) filters remains uncertain with few trials supporting their use. Additionally, the risks of long-term temporary IVC filter insertion are being increasingly discussed amongst the mainstream media and through multiple class action lawsuits. Retrievable IVC filters were specifically designed to have a less secure implantation in order to facilitate retrieval. However, multiple reports have demonstrated significant filter-related complications, most commonly related to duration of implantation. Furthermore, the risk is not isolated to one manufacturer alone. The incidence of filter-related complications is linearly related to its duration of time on the market. Currently, the FDA recommends that IVC filters be removed within 25-54 days of their implantation. Unfortunately, little evidence exists to show that this recommendation is followed routinely. Recently, the PRESERVE Trial (NCT02381509) was initiated as a multicenter non-randomized open label study to determine the safety and effectiveness of commercially available IVC filters (both temporary and permanent) in individuals who require mechanical prophylaxis against pulmonary embolism. Until such evidence is developed, temporary IVC filters should be implanted based on best available evidence and routinely removed within the guidelines of the FDA of 25-54 days. A fair question at this point is whether the design features themselves that are required to manufacture a low profile removable IVC filter can achieve effective prophylaxis against pulmonary embolism at a low rate of short and long-term complications.

Original Research: Critical Care

Chest. 2016;149(5):1146-1154. doi:10.1016/j.chest.2015.12.015

Background  Acute care nurse practitioners (ACNPs) are increasingly being employed in ICUs to offset physician shortages, but no data exist about outcomes of critically ill patients continuously cared for by ACNPs.

Methods  Prospective cohort study of all admissions to an adult medical ICU in an academic, tertiary-care center between January 1, 2011, and December 31, 2013. The primary end point of 90-day survival was compared between patients cared for by ACNP and resident teams using Cox proportional hazards regression. Secondary end points included ICU and hospital mortality and ICU and hospital length of stay.

Results  Among 9,066 admissions, there was no difference in 90-day survival for patients cared for by ACNP or resident teams (adjusted hazard ratio [HR], 0.94; 95% CI, 0.85-1.04; P = .21). Although patients cared for by ACNPs had lower ICU mortality (6.3%) than resident team patients (11.6%; adjusted OR, 0.77; 95% CI, 0.63-0.94; P = .01), hospital mortality was not different (10.0% vs 15.9%; adjusted OR, 0.87; 95% CI, 0.73-1.03; P = .11). ICU length of stay was similar between the ACNP and resident teams (3.4 ± 3.5 days vs 3.7 ± 3.9 days [adjusted OR, 1.01; 95% CI, 0.93-1.1; P = .81]), but hospital length of stay was shorter for patients cared for by ACNPs (7.9 ± 11.2 days) than for resident patients (9.1 ± 11.2 days) (adjusted OR, 0.87; 95% CI, 0.80-0.95; P = .001).

Conclusion  Outcomes are comparable for critically ill patients cared for by ACNP and resident teams.

Chest. 2016;149(5):1155-1164. doi:10.1016/j.chest.2016.02.635

Objective  Diffuse alveolar damage (DAD) is considered the histologic hallmark of ARDS although DAD is absent in approximately half of patients with ARDS. The clinical implications of having the syndrome of ARDS with DAD vs other histologic patterns is unknown. To address this question, we conducted a meta-analysis of lung biopsy series for patients with ARDS.

Methods  Studies were identified using MEDLINE, EMBASE, Cochrane Register of Controlled Trials, LILACS, and citation review from January 1, 1967, to September 1, 2015. Studies were included if they included all of the following: open lung biopsies (OLB) performed after ARDS diagnosis; a clear definition of ARDS and DAD; histologic results of the OLB indicated the presence or absence of DAD; and mortality reported for the DAD and non-DAD groups. We excluded studies conducted solely on a specific histology subgroup (eg, DAD) and studies with fewer than 5 patients. Two authors independently selected studies for inclusion, and there were no language restrictions.

Results  Of 8 included studies, 4 were high-quality (n = 228) and 4 were middle-quality trials (n = 122). The meta proportion of DAD between all the groups was 0.45 (95% CI, 0.35-0.56; Q test, 21.1; I2, 66.8%; P ≤ .01). The pooled OR for mortality in ARDS with DAD compared with ARDS without DAD was 1.81 (95% CI, 1.14-2.80; Q test, 8.8; I2, 20.2%; P = .269). Age, sex, and days elapsed between ARDS diagnosis and OLB as well as sequential organ failure assessment score and Pao2/Fio2 ratio on the day of OLB did not differ between DAD and non-DAD groups.

Conclusions  This meta-analysis demonstrated that ARDS with DAD is associated with higher mortality than ARDS without DAD.

Original Research: Asthma

Chest. 2016;149(5):1165-1172. doi:10.1016/j.chest.2015.11.012

Background  Surfactant protein D (SP-D) is an essential component of the innate immune defense against pathogens within the airways. SP-D also regulates allergic inflammation and promotes the removal of apoptotic cells. SP-D dysregulation is evident in several pulmonary diseases. Our aim was to investigate whether airway and serum levels of SP-D are altered in treatment-resistant severe asthma.

Methods  SP-D concentrations were measured in matched serum and BAL samples collected from 10 healthy control subjects (HC) and 50 patients with asthma (22 with mild asthma [MA] and 28 with severe asthma [SA]). These samples were also evaluated by using Western blot analysis to investigate variations in SP-D size.

Results  SP-D levels in BAL samples were significantly lower in SA compared with HC and MA (P < .001) and inversely correlated with BAL eosinophil cationic protein concentrations in SA (P < .01). Serum SP-D was significantly increased in SA compared with HC and MA (P < .001), and BAL/serum ratios were significantly lower in SA compared with HC and MA (P < .001). Reduced SP-D levels in BAL samples, with concomitant increases in serum in SA, were associated with degraded fragments of SP-D in the serum and increased BAL neutrophil counts and lipopolysaccharide levels.

Conclusions  These findings suggest defective innate immunity within the airways in SA, as reflected by low BAL SP-D concentrations and altered bacterial presence with airway neutrophilia. Furthermore, BAL SP-D leakage into the serum in patients with SA may provide a peripheral blood biomarker, reflecting increased epithelial damage and/or epithelial permeability within the peripheral airways.

Original Research: Sleep Disorders

Chest. 2016;149(5):1173-1180. doi:10.1016/j.chest.2015.11.022

Background  Prior studies suggested an association between bisphosphonates and atrial fibrillation/flutter (AF) in women. This relationship in men, including those with sleep-disordered breathing (SDB), remains unclear. This study evaluated the relationship between bisphosphonate use and prevalent (nocturnal) and incident (clinically relevant) AF in a population of community-dwelling older men.

Methods  A total of 2,911 male participants (mean age, 76 years) of the prospective observational Osteoporotic Fractures in Men Study sleep cohort with overnight in-home polysomnography (PSG) constituted the analytic cohort. Nocturnal AF from ECGs during PSG and incident AF events were centrally adjudicated. The association of bisphosphonate use and AF was examined using multivariable-adjusted logistic regression for prevalent AF and Cox proportional hazards regression for incident AF.

Results  A total of 123 (4.2%) men were current bisphosphonate users. Prevalent nocturnal AF was present in 138 participants (4.6%). After multivariable adjustment, there was a significant association between current bisphosphonate use and prevalent AF (OR, 2.33; 95% CI, 1.13-4.79). In the subset of men with moderate to severe SDB, this association was even more pronounced (OR, 3.22; 95% CI, 1.29-8.03). However, the multivariable-adjusted relationship between bisphosphonate use and incident AF did not reach statistical significance (adjusted hazard ratio, 1.53; 95% CI, 0.96-2.45).

Conclusions  These results support an association between bisphosphonate use and prevalent nocturnal AF in community-dwelling older men. The data further suggest that those with moderate to severe SDB may be a particularly vulnerable group susceptible to bisphosphonate-related AF. Similar associations were not seen for bisphosphonate use and clinically relevant incident AF.

Original Research: COPD

Chest. 2016;149(5):1181-1196. doi:10.1016/j.chest.2016.02.646

Background  The wide availability of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combinations (FDCs) in the absence of head-to-head comparative pragmatic trials makes it difficult to choose which combination should be used. Therefore, we carried out a systematic review with meta-analysis that incorporated the data from trials lasting at least 3 months to evaluate the effectiveness of LAMA/LABA FDCs for COPD treatment.

Methods  Randomized controlled trials were identified by searching different databases of published and unpublished trials. We aimed to assess the influence of LAMA/LABA combinations on trough FEV1, transitional dyspnea index, St. George's Respiratory Questionnaire, and cardiac safety vs monocomponents.

Results  Fourteen papers and one congress abstract with 23,168 patients with COPD (combinations, n = 10,328; monocomponents, n = 12,840) were included in this study. Our results showed that all LAMA/LABA combinations were always more effective than the LAMA or LABA alone in terms of the improvement in trough FEV1. Although there was not significant difference among LAMA/LABA combinations, we identified a gradient of effectiveness among the currently available LAMA/LABA FDCs. LAMA/LABA combinations also improved both transitional dyspnea index and St. George's Respiratory Questionnaire scores, but did not increase the cardiovascular risk when compared with monocomponents.

Conclusions  The gradient of effectiveness emerging from this meta-analysis is merely a weak indicator of possible differences between the various LAMA/LABA FDCs. Only direct comparisons will document if a specific LAMA/LABA FDC is better than the other. In the meanwhile, we believe it is only proper to consider that dual bronchodilation is better than a LAMA or a LABA alone, regardless of the drugs used.

Chest. 2016;149(5):1197-1204. doi:10.1378/chest.15-1504

Background  Relative pulmonary arterial enlargement, defined by a pulmonary artery to aorta (PA/A) ratio > 1 on CT scanning, predicts hospitalization for acute exacerbations of COPD (AECOPD). However, it is unclear how AECOPD affect the PA/A ratio. We hypothesized that the PA/A ratio would increase at the time of AECOPD and that a ratio > 1 would be associated with worse clinical outcomes.

Methods  Patients discharged with an International Classification of Diseases, Ninth Revision, diagnosis of AECOPD from a single center over a 5-year period were identified. Patients were included who had a CT scan performed during the stable period prior to the index AECOPD episode as well as a CT scan at the time of hospitalization. A subset of patients also underwent postexacerbation CT scans. The pulmonary arterial diameter, ascending aortic diameter, and the PA/A ratio were measured on CT scans. Demographic data, comorbidities, troponin level, and hospital outcome data were analyzed.

Results  A total of 134 patients were included in the study. They had a mean age of 65 ± 10 years, 47% were male, and 69% were white; overall, patients had a mean FEV1 of 47% ± 19%. The PA/A ratio increased from baseline at the time of exacerbation (0.97 ± 0.15 from 0.91 ± 0.17; P < .001). Younger age and known pulmonary hypertension were independently associated with an exacerbation PA/A ratio > 1. Patients with PA/A ratio > 1 had higher troponin values. Those with a PA/A ratio > 1 and troponin levels > 0.01 ng/mL had increased acute respiratory failure, ICU admission, or inpatient mortality compared with those without both factors (P = .0028). The PA/A ratio returned to baseline values following AECOPD.

Conclusions  The PA/A ratio increased at the time of severe AECOPD and a ratio > 1 predicted cardiac injury and a more severe hospital course.

Original Research: Diffuse Lung Disease

Chest. 2016;149(5):1205-1214. doi:10.1016/j.chest.2015.12.026

Background  Acute respiratory worsening (ARW) requiring hospitalization in patients with fibrotic interstitial lung disease (f-ILD) is common. Little is known about the frequency and implications of ARW in IPF and non-IPF ILD patients hospitalized for acute exacerbation (AE) vs known causes of ARW.

Methods  All consecutive patients with f-ILD hospitalized with ARW at our institution from 2000 to 2014 were reviewed. ARW was defined as any worsening of respiratory symptoms with new or worsened hypoxemia or hypercapnia within 30 days of admission. Suspected AE was defined using modified 2007 American Thoracic Society/European Respiratory Society criteria. Known causes of ARW were reviewed and collated along with in-hospital and all-cause mortality postdischarge.

Results  A total of 220 patients (100 with IPF and 120 non-IPF) composed 311 admissions for ARW. Suspected AE (SAE) comprised 52% of ARW admissions, followed by infection (20%), and subacute progression of disease (15%). In-hospital mortality was similar in patients with IPF vs patients without (55 vs 45%, P = .18), but worse in suspected AE admission types (OR, 3.1 [1.9-5.14]). One-year survival after last ARW admission for the whole cohort was 22%, despite only 27% of patients presenting with baseline oxygen requirement at admission and a mean admission Charlson Comorbidity Index score of 5.4 (expected 1-year survival, 89%). Survival after discharge was similar between SAE and secondary ARW admission types in both IPF and non-IPF patients.

Conclusions  Among patients with f-ILD, hospitalization for ARW appears associated with significant in-hospital and postdischarge mortality regardless of underlying fibrotic lung disease or non-AE cause of acute respiratory decline.

Chest. 2016;149(5):1215-1222. doi:10.1016/j.chest.2015.11.009

Background  To determine the effect of the MUC5B promoter polymorphism (rs35705950) on the CT imaging appearance of pulmonary fibrosis.

Methods  High-resolution CT scans of 1,764 subjects were scored as part of a, genomewide association study with institutional review board approval; 1,491 of these had pulmonary fibrosis on CT scans and were included in the study. Two thoracic radiologists independently scored CT scans systematically. Discrepancies were resolved by a third thoracic radiologist. All patients were genotyped specifically for the rs35705950 single-nucleotide polymorphism (SNP). Two-tailed Fisher exact or χ2 tests and Student t tests or Mann-Whitney U tests were used to compare proportions and means, respectively.

Results  The major and minor alleles at the rs35705950 SNP are guanine (G) and thymine (T), respectively: 514 were homozygous for the major allele (G group), and 977 were heterozygous or homozygous for the minor allele (T group). The G group had a higher proportion than the T group with ground-glass opacity (62.1% vs 54.2%; P = .04). There was no significant difference between the G and T groups regarding presence of honeycombing. The T group showed a significantly higher subpleural axial distribution of fibrosis than did the G group (62.3% vs 42.2%; P < .0001). The T group showed a lower proportion of diagnoses inconsistent with usual interstitial pneumonitis (UIP; 20.3% compared with 30.5% for the G group) and a greater proportion of confident (probable UIP and UIP) UIP diagnoses (43.8% compared with 32.6% for the G group).

Conclusions  The MUC5B promoter polymorphism identifies a pattern of fibrosis that is different from other causes of fibrosis and may respond differently to potential therapies.

Chest. 2016;149(5):1223-1233. doi:10.1378/chest.15-1539

Background  Amyloid-associated cystic lung disease is rare. It can be associated with collagen vascular disease (CVD). We aimed to describe the clinical, radiology, and pathology findings of this entity.

Methods  We reviewed the records of subjects having biopsy-proven pulmonary amyloidosis with cystic lung disease demonstrated at high-resolution computed tomography (HRCT). Demographic characteristics, association with CVD and lymphoproliferative disorders, pulmonary function, and pathology results were reviewed. HRCT appearance was analyzed for number, size, distribution, and morphology of cysts and nodules.

Results  Twenty-one subjects (13 female, eight male; median age, 61 years) with cystic pulmonary amyloidosis were identified. The most common pulmonary function patterns were normal (42%) and obstructive (32%). The most common associated CVD was Sjögren syndrome (10 of 12). Nine subjects had no CVD. Cysts tended to be multiple (≥ 10 in 14 of 21, 67%), round (21 of 21, 100%), or lobulated (20 of 21, 95%); thin-walled (< 2 mm in 17 of 21, 81%); and of small (< 1 cm in 21 of 21, 100%) to moderate (1-2 cm in 17 of 21, 81%) size. Peribronchovascular (19 of 21, 90%) and subpleural (19 of 21, 90%) cysts were typically present. Seventeen (81%) subjects had lung nodules, which tended to be numerous (≥ 10 in 10 of 17, 59%; 4-9 in six of 17, 35%). At least one calcified nodule was present in 14 of 17 subjects (82%). Pulmonary mucosa-associated lymphoid tissue lymphoma (MALToma) was diagnosed in seven subjects (33%).

Conclusions  Amyloid-associated cystic lung disease can occur with or without underlying CVD. Cystic lesions in the lung are commonly numerous, often are peribronchovascular or subpleural, and are frequently associated with nodular lesions that are often calcified. MALToma was a relatively frequent association.

Original Research: Pulmonary Vascular Disease

Chest. 2016;149(5):1234-1244. doi:10.1016/j.chest.2015.11.008

Background  In recent years, the population of patients with pulmonary arterial hypertension (PAH) has changed dramatically, including more advanced age at diagnosis. We hypothesized that older patients have a distinct clinical profile with different disease characteristics and response to intervention.

Methods  All previously published treatment studies for PAH conducted by United Therapeutics including seven randomized, placebo-controlled trials and one extension study were included and analyzed to assess the association of age with various demographic, functional, hemodynamic, and outcome variables.

Results  A total of 2,627 patients across three age groups were included: ≤ 50 (n = 1,438, 54.7%), 51 to 64 (n = 780, 29.7%), and ≥ 65 years (n = 409, 15.6%). In comparison with the youngest group, the oldest age group had higher proportions of connective tissue disease-associated etiology (range across the studies, 27%-49% vs 13%-21%), higher proportions of New York Heart Association Functional classes III and IV (74%-91% vs 57%-84%), shorter baseline 6-min walk distance (6MWD) (261-316 vs 335-371 m), better hemodynamic measurements including lower baseline mean pulmonary artery pressure (48-51 vs 58-63 mmHg), and smaller changes in 6MWD from baseline to endpoint (–5.6 to 24 vs 14-43 m). Age remained associated with change in 6MWD when adjusting for covariates in multivariate analyses.

Conclusions  For the first time, using data from large randomized controlled trials, this study characterizes the different phenotype and outcomes of older patients with PAH, which includes different disease etiology, diminished functional status, and decreased response to intervention. This may have significant implications for the management of this patient population and design of future therapy trials.

Chest. 2016;149(5):1245-1251. doi:10.1016/j.chest.2015.10.069

Background  After diagnosis of cancer-associated VTE, guidelines recommend considering the continuation of anticoagulant treatment until the patient is cured of cancer, although the safety of stopping anticoagulant treatment after the patient is cured has never been evaluated.

Methods  We conducted a cohort study in consecutive patients in whom cancer-associated VTE was diagnosed at the Leiden University Medical Center between January 2001 and January 2010 and monitored for the effect of cancer treatment, occurrence of recurrent VTE, major hemorrhage, and death.

Results  Of the 358 patients with cancer-associated VTE, anticoagulant treatment was continued until the death of 207 patients. In another 12 patients anticoagulant treatment was continued because of an alternative indication despite their being cured of cancer. Anticoagulant treatment was stopped in 50 patients for reasons other than major hemorrhage despite active cancer, in 21 patients after major hemorrhage, and in 68 patients after they had been cured of cancer. Among these 68 patients, 10 patients received a diagnosis of symptomatic recurrent VTE during a cumulative follow-up of 311 years, resulting in an incidence rate of 3.2 per 100 patient-years (95% CI, 1.5-5.9). Seven of these 10 patients with recurrent VTE experienced a cancer relapse during follow-up. For the 50 patients who stopped anticoagulant treatment despite active cancer the recurrent VTE incidence rate was 19 per 100 patient-years (11 events during 59 years of follow-up; 95% CI, 9.3-33).

Conclusions  Our data support the recommendation to stop anticoagulant treatment of cancer-associated VTE in patients cured of cancer. A cancer relapse seems to be a strong risk factor for recurrent symptomatic VTE.

Chest. 2016;149(5):1252-1260. doi:10.1016/j.chest.2015.11.015

Background  Patients with pulmonary arterial hypertension (PAH) are routinely instructed to avoid performing the Valsalva maneuver for fear of syncope or sudden cardiac death. The mechanism of this action has not been elucidated. We conducted a case-control trial of nine patients with PAH and 15 healthy control subjects to determine if systemic hemodynamic changes during the Valsalva maneuver in these patients invoke greater susceptibility to syncope than healthy control subjects. Metrics commonly employed in autonomic testing were used to assess the degree of autonomic failure.

Methods  Common Valsalva parameters, including adrenergic baroreflex sensitivity, pressure recovery time, systolic BP (SBP) recovery, diastolic BP (DBP) recovery, mean arterial pressure recovery, and the Valsalva ratio, were calculated. Mann-Whitney U tests were used to compare continuous variables. The primary end point was adrenergic baroreflex sensitivity.

Results  Patients with PAH had lower adrenergic baroreflex sensitivity (9.7 ± 4.6 mm Hg/s vs 18.8 ± 9.2 mm Hg/s; P = .005), longer pressure recovery time (3.6 ± 2.5 s vs 1.7 ± 0.8 s; P = .008), similar SBP recovery (–13 ± 11 mm Hg vs –12 ± 23 mm Hg; P = .640), less DBP recovery (–1 ± 12 mm Hg vs 13 ± 14 mmHg; P = .025), less mean arterial pressure recovery (–5 ± 11 mm Hg vs 5 ± 17 mm Hg; P = .048), and a decreased Valsalva ratio (1.25 ± 0.11 vs 1.60 ± 0.22; P < .001) compared with healthy control subjects.

Conclusions  Compared with healthy control subjects, patients with PAH are more susceptible to syncope during the Valsalva maneuver because of autonomic dysfunction causing cerebral hypoperfusion. These study patients with PAH exhibited a degree of susceptibility to syncope similar to a spectrum of patients with intermediate autonomic failure who typically experience a SBP drop of 10 to 30 mm Hg with standing.

Chest. 2016;149(5):1261-1268. doi:10.1378/chest.15-0819

Background  One of the foremost diagnostic challenges in clinical pulmonary hypertension is discriminating between pulmonary arterial hypertension (group 1) and heart failure with preserved ejection fraction (group 2.2). Group 2.2 is defined as a normal left ventricular ejection fraction (> 50%) and a pulmonary arterial wedge pressure (PAWP) > 15 mm Hg. We aimed to determine whether patient history, demographics, and noninvasive measures could predict PAWP before to right heart catheterization.

Methods  Data were prospectively collected on 350 consecutive patients at a single tertiary care medical center; of these patients, 151 met criteria for entry into our study (88 in group 1 and 63 in group 2.2). Data included historical features, demographics, and results of a transthoracic echocardiogram. A multivariate regression model was developed to predict PAWP > 15 mm Hg.

Results  Univariate predictors of PAWP > 15 mm Hg included older age, higher BMI and weight, systemic systolic BP and pulse pressure, more features of the metabolic syndrome, presence of hypertension and left atrial enlargement, absence of right ventricular enlargement, and lower glomerular filtration rate and 6-min walk distance. The optimal model for predicting PAWP > 15 mm Hg was composed of age (> 68 years), BMI (> 30 kg/m2), absence of right ventricular enlargement, and presence of left atrial enlargement (area under the curve, 0.779).

Conclusions  Clinical characteristics obtained before diagnostic right heart catheterization accurately predict the probability of elevation of PAWP > 15 mm Hg in patients with preserved ejection fraction. These combined clinical characteristics can be used a priori to predict the likelihood of group 2.2 pulmonary hypertension.

Original Research: Pulmonary Procedures

Chest. 2016;149(5):1269-1275. doi:10.1016/j.chest.2015.12.024

Background  This study explored the sensitivity and specificity of ultrasound for diagnosing transient tachypnea of the newborn (TTN).

Methods  Ultrasound was performed by one export. Patients were placed in a supine, lateral recumbent, or prone position. The probe was placed perpendicular or parallel to the ribs, and each region of the lung was scanned. The scan results were compared with conventional chest radiographic results.

Results  A total of 1,358 infants were included in this study. We identified 412 cases without pulmonary diseases, 228 TTN cases, 358 respiratory distress syndrome (RDS) cases, 85 meconium aspiration syndrome (MAS) cases, 215 infectious pneumonia cases, and 60 other cases. The primary ultrasonic characteristic of TTN was pulmonary edema. “White lung” or a “compact B-line” were only observed in severe cases, whereas TTN primarily presented as pulmonary interstitial syndrome or “double lung point.” Furthermore, double lung point could appear during the recovery period of severe TTN or RDS, MAS, and pneumonia. Lung consolidation with air bronchograms was not observed in TTN patients. The results showed that white lung or a compact B-line exhibited a sensitivity of 33.8% and a specificity of 91.3% in diagnosing TTN, whereas double lung point exhibited a sensitivity of 45.6% and a specificity of 94.8% in diagnosing severe TTN.

Conclusions  Pulmonary edema, alveolar-interstitial syndrome, double lung point, white lung, and compact B-line are the primary ultrasound characteristics of TTN. Ultrasonic diagnosis of TTN based on these findings is accurate and reliable. TTN can be ruled out in the presence of lung consolidation with air bronchograms.

Chest. 2016;149(5):1276-1284. doi:10.1378/chest.14-3042

Background  Endobronchial ultrasonography (EBUS) facilitates a lung cancer diagnosis. However, qualitative tissue characterization of lung tumors is difficult using EBUS. Integrated backscatter (IBS) is an ultrasound technique that calculates the power of the ultrasound signal to characterize tissue components in coronary arteries. We hypothesized that qualitative diagnosis of lung tumors is possible using the IBS technique. The aim of the present study was to elucidate whether the IBS technique can be used in lung tissue diagnoses.

Methods  Thirty-five consecutive patients who underwent surgery for lung cancer were prospectively enrolled. Surgical specimens of the lung and the tumor tissue were obtained, and the IBS values were measured within 48 h after surgery. Histologic images of lung and tumor tissues were compared with IBS values, and the relative interstitial area according to results of Masson’s trichrome staining were determined by using an imaging processor.

Results  The IBS values in tumor tissue were significantly lower than those in normal lung tissue (–50.9 ± 2.6 dB and –47.6 ± 2.6 dB, respectively; P < .001). The IBS values of adenocarcinomas associated with a good 5-year survival rate were higher than those of non-adenocarcinomas (–48.1 ± 1.6 dB and –52.6 ± 1.4 dB; P < .001). There were significant correlations between the IBS values and the relative interstitial area or micro air area in tumor (r = 0.53 and r = 0.67; P < .01). After combining normal lung tissue and adenocarcinomas with a good prognosis, the sensitivity and specificity for establishing the presence of lung tumors were 84% and 85%.

Conclusions  Qualitative diagnosis of lung tumors was possible, with a sensitivity of 84% and a specificity of 85%, using the ultrasound IBS technique.

Original Research: Chest Infections

Chest. 2016;149(5):1285-1293. doi:10.1378/chest.15-0543

Background  Mycobacterium avium complex (MAC) lung disease requires prolonged treatment with multiple antibiotics. Drug intolerances and interactions are common with the current recommended treatment. There is limited information on outcomes with alternative medications.

Methods  Retrospective review including adult patients with MAC lung disease who were treated and monitored for at least 6 months posttreatment. The aim was to evaluate the clinical and microbiologic outcomes in patients treated with regimens including clofazimine and/or rifampin.

Results  One hundred and seven patients were included (79% were female; mean age, 67 years). Sputum samples were smear positive in 54% of patients. The majority (84%) were treated with clofazimine in combination with a macrolide and ethambutol. Fourteen patients (13%) were treated with rifampin, macrolide, and ethambutol. Most patients (95%) converted from positive to negative sputum culture results in an average of 4.5 ± 4.2 months (range, 0-30 months). A significantly greater proportion of patients treated with clofazimine converted to negative culture results compared with those treated with rifampin (100% vs 71%; P = .0002). Microbiologic relapse occurred in 52 of 107 patients (49%). Thirty-six percent of patients required retreatment. There was no difference in microbiologic relapse or re-treatment rates between the two treatment groups.

Conclusions  The majority of patients with MAC lung disease achieve negative sputum culture results. Re-treatment is needed in approximately one-third of patients. In this cohort, both initial outcomes and re-treatment rates were at least as good in patients treated with clofazimine-containing regimens as in patients receiving rifampin-containing regimens. Clofazimine should be considered as an alternative drug for the treatment of MAC lung disease.

Original Research: Pulmonary Manifestations of Systemic Disease

Chest. 2016;149(5):1294-1301. doi:10.1016/j.chest.2015.11.004

Background  Acquired hemophagocytic lymphohistiocytosis (HLH) is a life-threatening event that usually occurs as a complication of immunodeficiency. Lung involvement in HLH has received little attention. This article describes lung involvement in HLH and assesses whether it affects the prognosis.

Methods  We retrospectively studied 219 patients with HLH admitted to a national reference center over a 14-year period, including 118 (54%) with lung involvement.

Results  Dyspnea and cough were the most common onset symptoms. Radiographs revealed interstitial infiltrates with centrilobular nodules, ill-defined consolidation, or localized ground-glass opacities. Pleural effusions and mediastinal lymphadenopathies were found in approximately one-half of the patients. One or more causes of lung involvement were documented in 91 of 118 patients (77.1%) and included infection (n = 52), pulmonary edema (n = 34), and malignancies (n = 22 [mostly lymphoma]). HLH-specific treatment combined with treatment of the cause of lung involvement improved respiratory function in only 67 of the 188 patients (56.7%). Hospital mortality was higher in patients with lung involvement (52.5% vs 20%). Infection as the cause of lung involvement was the only determinant of death (56% vs 30%; P = .004).

Conclusions  Lung involvement is common and of poor prognosis in patients with HLH. Studies should assess whether specific diagnostic and therapeutic strategies are warranted in patients with HLH and lung involvement.

Translating Basic Research into Clinical Practice

Chest. 2016;149(5):1302-1312. doi:10.1016/j.chest.2015.11.021

COPD is a significant public health challenge, notably set to become the third leading cause of death and fifth leading cause of chronic disability worldwide by the next decade. Skeletal muscle impairment is now recognized as a disabling, extrapulmonary consequence of COPD that is associated with reduced quality of life and premature mortality. Because COPD typically manifests in older individuals, these clinical features may overlie normal age-associated declines in muscle function and performance. Although physical inactivity, oxidative stress, inflammation, hypoxia, malnutrition, and medications all likely contribute to this comorbidity, a better understanding of the underlying mechanism is needed to develop effective therapies. Mitochondrial alterations have been described; these alterations include reductions in density and oxidative enzyme activity, increased mitochondrial reactive oxygen species production, and induction of muscle proteolysis including autophagy. This review focuses on the perspective that mitochondrial alterations contribute to impaired locomotor muscle performance in patients with COPD by reducing oxidative capacity and thus endurance, as well as by triggering proteolysis and thus contributing to atrophy and weakness. We discuss how the potential underlying mechanisms converge on mitochondria by targeting the peroxisome proliferator-activated receptor γ-coactivator-1α signaling pathway (thereby reducing mitochondrial biogenesis and muscle oxidative capacity and potentially increasing fiber atrophy) and how taking advantage of normal muscle plasticity and mitochondrial biogenesis may reverse this pathophysiology. We propose recent therapeutic strategies aimed at increasing peroxisome proliferator-activated receptor γ-coactivator-1α levels, such as endurance training and exercise mimetic drugs, with the strong rationale for increasing mitochondrial biogenesis and function and thus improving the muscle phenotype in COPD.

Recent Advances in Chest Medicine

Chest. 2016;149(5):1313-1324. doi:10.1016/j.chest.2015.11.016

Sickle cell disease (SCD), the most common genetic hemolytic anemia worldwide, affects 250,000 births annually. In the United States, SCD affects approximately 100,000 individuals, most of African descent. Hemoglobin S (HbS) results from a glutamate-to-valine mutation of the sixth codon of the β-hemoglobin allele; the homozygous genotype (HbSS) is associated with the most prevalent and severe form of the disease. Other SCD genotypes include HbSC, composed of one HbS allele and one HbC (glutamate-to-lysine mutation) allele; and HbS-β-thalassemia0 or HbS-β-thalassemia+, composed of one HbS allele and one β-thalassemia allele with absent or reduced β-chain production, respectively. Despite advances in care, median survival remains in the fifth decade, due in large part to chronic complications of the disease. Chronic pulmonary complications in SCD are major contributors to this early mortality. Although our understanding of these conditions has improved much over the past 10 to 15 years, there remains no specific treatment for pulmonary complications of SCD. It is unclear whether conventional treatment regimens directed at non-SCD populations have equivalent efficacy in patients with SCD. This represents a critical research need. In this review, the authors review the state-of-the-art understanding of the following pulmonary complications of SCD: (1) pulmonary hypertension; (2) venous thromboembolic disease; (3) sleep-disordered breathing; (4) asthma and recurrent wheezing; and (5) pulmonary function abnormalities. This review highlights the advances as well as the knowledge gaps in this field to update clinicians and other health care providers and to garner research interest from the medical community.

Contemporary Reviews in Critical Care Medicine

Chest. 2016;149(5):1325-1331. doi:10.1016/j.chest.2015.12.014

Recent literature has implicated severe neurologic injuries, such as aneurysmal subarachnoid hemorrhage, as a cause of cardiac dysfunction, impaired hemodynamic function, and poor outcomes. Mechanistic links between the brain and the heart have been explored in detail over the past several decades, and catecholamine excess, neuroendocrine dysfunction, and unchecked inflammation all likely contribute to the pathophysiologic process. Although cardiac dysfunction has also been described in other disease paradigms, including septic shock and thermal injury, there is likely a common underlying pathophysiology. In this review, we will examine the pathophysiology of cardiac dysfunction after neurologic injury, discuss the evidence surrounding cardiac dysfunction after different neurologic injuries, and suggest future research goals to gain knowledge and improve outcomes in this patient population.

Contemporary Reviews in Sleep Medicine

Chest. 2016;149(5):1332-1339. doi:10.1378/chest.15-0605

Insomnia in children is complex and frequently multifactorial. This review discusses the major categories of insomnia as well as common causes. The consequences of insomnia, including issues with mood, behavior, and cognition, are discussed. Sleep disorders are much more prevalent in certain pediatric populations, such as children with autism spectrum disorders. The evaluation of insomnia in children includes a focused history and examination and occasionally actigraphy or polysomnography. Behavioral and pharmacological therapies are discussed, as are future directions for research and clinical practice.

Topics: pediatrics , insomnia , sleep

Topics in Practice Management

Chest. 2016;149(5):1340-1344. doi:10.1016/j.chest.2015.11.020

Asthma is characterized by chronic airway inflammation. Fractional exhaled nitric oxide (Feno) has emerged as a marker of T-helper cell type 2-mediated allergic airway inflammation. Recent studies suggest a role for Feno testing as a point-of-care tool in the management of patients with asthma. This Topics in Practice Management article reviews current coverage and reimbursement issues related to Feno testing and provides an overview of pertinent recent studies.

Pectoriloquy

Chest. 2016;149(5):1345. doi:10.1016/j.chest.2015.09.006
FREE TO VIEW

    Train technology on a labyrinth of ductwork
    and cul de sacs, strain the broth of suggestion.
    We sail under the white flag of Percocet,
    lie on the wrong side of the bed to make room.
    Real and unreal crossover.

    The Minotaur wears a buffalo robe
    and steel-toed boots that double clunk
    on the floor. Bedsprings howl as it wedges
    between us. Coarse hooves paw the comforter,
    ruck the sheets into tangles. Conceived of pain
    and unknown, it torments innocent flesh, demands tribute.

    The Minotaur's ears twitch as fat carrion flies
    land on its sticky muzzle. Picking flesh
    from its teeth, it snorts clouds of fetid breath.
    Finally subdued by feathered darts of narcotic,
    cool hand comes to rest between twisted horns.

    Divinity more palatable than pathology,
    put fear in a back closet, lay a careful hand
    where pain leaves sharp edges beneath the skin.
    The thinnest thread connects frayed edges.
    We will find our way back.

Chest. 2016;149(5):1346. doi:10.1016/j.chest.2015.09.014
FREE TO VIEW

    My home is dead to me.

    I must pretend to fit
    my new environment.
    I have to drug the locals,

    soldiers of immunity,
    to let me live.
    This comes with risk:

    they are the sole defense
    against invading
    enemies.

    The key is balance,
    balance to survive,
    but at a cost.

    Why don’t I change
    my antigens
    and end the war?

    I wear them for identity.
    I can’t fit in,
    I won’t fit in,
    I must be me.

    I must display the flags
    that are my own,
    and beat my lonely drum
    throughout the night.

Chest. 2016;149(5):1347. doi:10.1016/j.chest.2015.09.023
FREE TO VIEW

    Even though I’m a young doctor,
    already I’ve lost so many.
    Sometimes I can see the writing
    on the wall, the proverbial
    foot in the grave from the very
    beginning and I know there is
    nothing I can do to save them.
    The hardest ones to lose are those
    that start off at first glance healthy,
    brimming with possibility,
    only to choke, aspirate, then
    linger for a few weeks, flat-lined.

    In either case, when it’s clear that
    the end is near, my poet-self
    sits down my doctor-self and says:

    I have some bad news. Your poem
    is dying. It’s not going to
    make it. It’s only a matter
    of time. I’m sorry for your loss.
    I can imagine how you feel.
    It’s never easy to let go.
    I did my best, I tried every
    revision I could to save it.
    Your poem has suffered so much.
    Now it won’t suffer any more.
    And neither will any reader.

Correspondence

Chest. 2016;149(5):1348. doi:10.1016/j.chest.2016.02.673
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In the CHEST (January 2016) article “Practice Patterns and Outcomes of Treatments for Atrial Fibrillation During Sepsis: A Propensity-Matched Cohort Study,” Walkey et al used a propensity-matched retrospective database-derived cohort of adult patients with atrial fibrillation (AF) who were initially admitted with sepsis to compare mortality outcomes between patients receiving different AF treatments. The authors concluded that β-blockers (BBs) were associated with a superior survival advantage in all subgroups analyzed, and that their findings provide a strong rationale for randomized controlled trials comparing the effectiveness of AF treatments in sepsis.

Chest. 2016;149(5):1348-1349. doi:10.1016/j.chest.2016.02.674
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We thank Dr Patel for interest in our article in CHEST. Dr Patel raises important questions regarding the possibility of unmeasured confounding in observational comparative effectiveness research and potential mechanisms for improved outcomes with use of β-blockade during sepsis. We agree that etiological associations cannot generally be inferred from a single observational study, and advocate for care in description of results from observational comparative effectiveness research. Hence, we explicitly described our findings regarding β-blockers in terms of “associated with outcome” rather than “improving outcome,” we discussed the possibility of unmeasured confounding as a limitation of our findings, we did not make treatment recommendations, we used both propensity score and instrumental variable-based methods to address potential confounding, and called for trials to evaluate the effectiveness of atrial fibrillation treatments during sepsis. As suggested by Dr Patel, APACHE and SOFA severity of illness scores are not a panacea for unmeasured confounding; the moderate discriminative ability of severity of illness scores for predicting mortality is similar to that of models derived from enhanced administrative databases such as the one used in our study., For many of the reasons raised by Dr Patel and discussed in our article, we respectfully submit that the difference in outcomes observed between patients who received β-blockers and those who received calcium channel blockers may be less susceptible to confounding by unmeasured severity of illness than the results for digoxin or amiodarone. Finally, multiple potentially beneficial mechanisms of β-blockade during sepsis have been proposed, including improved hemodynamics and immunomodulatory effects. We encourage further investigation of optimal methods to treat atrial fibrillation during sepsis.

Chest. 2016;149(5):1349-1350. doi:10.1016/j.chest.2016.02.671
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We read with interest the recent Point and Counterpoint between Rapoport and Punjabi published in CHEST (January 2016), on the clinical significance of apnea-hypopnea index (AHI) as the measure of the severity of sleep-disordered breathing. In particular, we share Punjabi’s viewpoint that the AHI is a crude and imprecise metric and that any measure of OSA severity should capture the pathophysiologic diversity of the disease process.

Chest. 2016;149(5):1350-1351. doi:10.1016/j.chest.2016.02.684
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In an article recently published in CHEST (April 2016), Mongodi et al investigated the fascinating hypothesis that, as in community-acquired pneumonia, thoracic ultrasonography (TUS) could also be a reliable complementary diagnostic tool in ventilator-associated pneumonia (VAP).

Chest. 2016;149(5):1351-1352. doi:10.1016/j.chest.2015.10.058
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I note that in the interesting counterpoint article by Gillespie and DeCamp discussing the use of small-bore pleural catheters in the management of malignant pleural effusions in CHEST (July 2015), the authors commented on how best to ablate the pleural space to prevent reaccumulation of pleural fluid (pleurodesis). This reflects the widespread view that successful pleurodesis requires obliteration of the pleural space.

Erratum

Chest. 2016;149(5):1353. doi:10.1016/j.chest.2016.03.014
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The authors have reported to CHEST that a reference error appears in the text in “Treatment of Unexplained Chronic Cough: CHEST Guideline and Expert Panel Report” (Chest 2016; 149(1):27-44). The error appears in line 11 of the first paragraph in the right-hand column on page 37.

Chest. 2016;149(5):1353. doi:10.1016/j.chest.2016.03.029
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The authors have reported to CHEST that an error appeared in “Vessels of the Central Airways: A Bronchoscopic Perspective” (Chest 2016; 149(3):869-881). The legends for Figure 3A and B are marked erroneously. Figure 3A is the right bronchus and Figure 3B is the left bronchus. The authors wish to apologize to the readers for the mistake.

Selected Reports

Chest. 2016;149(5):e127-e131. doi:10.1016/j.chest.2015.10.001

Baclofen, a gamma-aminobutyric acid-B agonist with muscle-relaxant properties, is widely used in patients with severe spasticity. In animals, baclofen has been shown to decrease respiratory drive. In humans, however, use of baclofen at the standard dose did not significantly impair sleep-disordered breathing in a susceptible population of snorers. Recently, there has been increasing interest in the role of baclofen for the treatment of alcohol dependence. We describe severe central sleep apnea (CSA) in four patients with none of the conditions commonly associated with CSA who were receiving chronic baclofen therapy for alcohol withdrawal. In one patient, baclofen withdrawal was associated with a complete resolution of CSA. Three patients were treated by adaptive servo-ventilation while continuing their treatment with baclofen. Given the increasing number of patients receiving baclofen for alcohol withdrawal treatment, physicians should be aware that these patients might be affected by severe CSA. Future studies are required to determine the mechanisms, prevalence, and treatment modalities of sleep-disordered breathing associated with baclofen usage.

Chest. 2016;149(5):e133-e136. doi:10.1016/j.chest.2015.10.082

To our knowledge, we report the first case of sarcoid-like granulomatous reaction induced by nivolumab, a fully human IgG4 anti-programmed death 1 (PD-1) immune checkpoint inhibitor antibody. A 57-year-old man was treated with nivolumab 3 mg/kg for 2 weeks for a desmoplastic melanoma stage III American Joint Commission on Cancer, with no BRAF, NRAS, and cKit mutations. At 10 months, although melanoma complete response was achieved, he developed sarcoid-like granulomatous reaction in the mediastinal lymph node and skin, which resumed after nivolumab arrest. Melanoma did not relapse after 12 months of follow-up. Considering the recently demonstrated role of activated PD-1/PDL-1 axis in sarcoidosis, granulomatous reaction in the patient seems to be a paradoxical reaction, but similar observations have been reported with ipilimumab, another immune checkpoint inhibitor. Sarcoid-like granulomatous reaction during immunotherapy treatment could be a manifestation of cell-mediated immunity induced by these drugs. Impact of granulomatous reaction induced by immune checkpoint inhibitor on melanoma progression is not known and requires further study. Melanoma patients treated by immunotherapy (anti-cytotoxic T-lymphocyte-associated protein-4/anti-PD-1) should be considered for developing sarcoid-like granulomatous reaction that must not be confused with tumor progression.

Ultrasound Corner

Chest. 2016;149(5):e137-e139. doi:10.1016/j.chest.2015.11.033
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October 9, 2013

Pulmonary, Critical Care, and Sleep Pearls

Chest. 2016;149(5):e141-e145. doi:10.1016/j.chest.2015.12.011

A 28-year-old man of Japanese descent presented to the ED with a 2-month history of dry cough, shortness of breath, and weakness. He did not complain of fever, chest pain, or abdominal symptoms, and had no history of smoking. The patient’s medical history was significant for an episode of ulcerative colitis 6 years previously after presenting with bloody diarrhea, stomach pain, fever, weight loss, and bilateral episcleritis. He had been treated consecutively with mesalazine, azathioprine, infliximab, golimumab, and adalimumab. Concomitant respiratory symptoms had been present during 2 flare-ups of severe ulcerative colitis disease activity and were successfully treated with a course of oral prednisone.

Chest. 2016;149(5):e147-e150. doi:10.1016/j.chest.2015.12.023

An 80-year-old man presented because of superficial head trauma sustained after falling from bed. On review of systems, he reported worsening dyspnea on exertion, nonproductive cough, and weight loss over the preceding 2 to 3 months. There was no report of chest pain or leg swelling. He had a past medical history of hypertension, coronary artery disease, subclinical hypothyroidism, and renal cell carcinoma treated with partial right nephrectomy approximately 1 year before this presentation. Two months earlier he had been evaluated in the dermatology clinic for painful, dystrophic fingernails. At that time he was diagnosed with acropachy with onycholysis and suspected superinfection, and after failing to improve with vinegar soaks and topical antimicrobials, he underwent surgical nail removal on the second and fourth digits of the right hand. Histological examination of the operative specimens revealed dystrophic nails with negative fungal stains. His medications included levothyroxine, hydrochlorothiazide, and clopidogrel. He had never smoked and had done clerical work until retirement. He was originally from Colombia.

Chest. 2016;149(5):e151-e155. doi:10.1016/j.chest.2015.12.031

A 54-year-old man who had undergone bilateral sequential lung transplant for idiopathic pulmonary fibrosis was admitted to the hospital for further evaluation of an abnormal abdominal CT scan. Three months previously a gastrojejunostomy tube had been placed after he was found to have evidence of silent aspiration with oral intake. At a recent clinic visit, he denied abdominal pain or problems with the feeding tube. He described frequent diarrhea since placement of the feeding tube.

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