Chest. 2013;144(4):1087. doi:10.1378/chest.13-1639

In this issue of CHEST, we are excited to introduce a new series, Giants in Chest Medicine. As its name implies, Giants in Chest Medicine will highlight the achievements of individuals who have made groundbreaking contributions within the fields of pulmonary, critical care, and sleep medicine.

Chest. 2013;144(4):1087-1089. doi:10.1378/chest.13-1166

In this issue of CHEST (see page 1111), Neumann et al1 report that some panelists participating in the development of the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (AT9)2 cast anonymous votes on controversial recommendations when they should have recused themselves because of conflicts of interest (COIs). One might question the wisdom of writing this article, because three of the authors (Gordon H. Guyatt, MD, FCCP; Elie A. Akl, MD, PhD, MPH; and Holgar Schünemann, MD, PhD) bore major responsibilities for birthing AT9, but I applaud them for having the courage to share their findings.

Chest. 2013;144(4):1089-1091. doi:10.1378/chest.13-0659

Signs of obstruction in the small distal airways (< 2 mm) are demonstrated by the pathophysiology of so-called asymptomatic smokers.1 Increased resistance of these airways can be inferred even at this early (mild?) stage.2 The tools currently available for measuring early stages of airways disease each have their own limitations. Even though the FEV3/FVC ratio is not discussed in the American Thoracic Society/European Respiratory Society statement on ways to assess lung function,3 in this issue of CHEST (see page 1117) Morris et al4 present a study that makes the case that it should be routinely reported on in spirometry.

Chest. 2013;144(4):1091-1093. doi:10.1378/chest.13-0775

Pulmonary rehabilitation is a comprehensive intervention based on a thorough patient assessment followed by patient-tailored therapies that include, but are not limited to, exercise training, education, and behavior change, designed to improve the physical and psychologic condition of people with chronic respiratory disease and to promote long-term adherence to health-enhancing behaviors. Exercise performance and health-related quality of life improve following pulmonary rehabilitation in individuals with COPD.1-3 Moreover, health-care use is reduced following pulmonary rehabilitation,4 in particular in individuals starting pulmonary rehabilitation immediately after an exacerbation-related hospitalization.5 Therefore, pulmonary rehabilitation is a very important part of the overall disease management of individuals with COPD.6,7

Chest. 2013;144(4):1093-1094. doi:10.1378/chest.13-0772

Air quality is one of those interesting areas where public health confronts economics and lifestyle. The burning of either fossil fuels or biomass creates the energy that fuels our economy and makes our lives comfortable, but it also pollutes the air of our small planet and harms our health. Ground level ozone is such a pollutant. It is created by reactions between oxides of nitrogen and volatile organic compounds in the presence of sunlight. Major sources of oxides of nitrogen and volatile organic compounds include emissions from industrial facilities, electricity-generating facilities, gasoline and other chemical solvents, and motor vehicle exhaust. Ozone is a powerful oxidizing agent. Ozone exposure leads to the release of proinflammatory mediators from airway cells.1

Second Opinion

Chest. 2013;144(4):1095. doi:10.1378/chest.144.4.1095

Point/Counterpoint Editorials

Chest. 2013;144(4):1096-1098. doi:10.1378/chest.13-0916

Fever is a highly conserved response to infection in animal species. The presence of fever implies immune competence, and although some postulate the ability to mount fever portends survival advantages, the magnitude of fever has been associated with higher mortality in sepsis.1 Unfortunately, the pathophysiologic derangements accompanying septic shock overcome the protective value of fever, and in some cases fever contributes to a cycle of vasodilatory shock, myocardial dysfunction, and organ failure that precedes death. Critical care physicians should strongly consider external cooling to minimize the harmful effects of fever, especially among the most seriously ill patients. We base this position upon the following arguments:

  • 1. A physiologic rationale exists to support fever therapy;

  • 2. Contradictory conclusions in the literature result primarily from heterogeneity of studies (eg, severity of illness, methods of cooling, and timing of interventions); and

  • 3. The strongest clinical trial supports fever treatment.

Chest. 2013;144(4):1098-1101. doi:10.1378/chest.13-0918

Fever is a classic symptom of sepsis in critically ill patients and commonly prompts ICU physicians to evaluate for infection. Despite the frequency with which fevers occur in patients in the ICU, there is surprisingly little consistency among intensivists regarding whether fevers should be treated.1 Certainly, there are subsets of critically ill patients—those with neurologic injury or active myocardial ischemia, for example—who are particularly susceptible to the deleterious effects of fever and should undoubtedly receive antipyretic therapy.2 Sepsis, however, is a complex and heterogeneous disease. Although some patients may benefit from the protective effects of fever control, others may not, depending on the severity of their disease and their degree of end-organ dysfunction. Unfortunately, there are few randomized controlled trials to guide clinical practice. Based on the available evidence, though, our opinion is that fever should not routinely be treated in patients with septic shock.

Chest. 2013;144(4):1101-1102. doi:10.1378/chest.13-0917

In their counterpoint editorial, Drs Drewry and Hotchkiss1 present a well-reasoned argument of why fever may benefit those with life-threatening infections. We agree with several of their points that likely merit little further discussion:

  • 1. Fever is an adaptive response and affords some host protection;

  • 2. Little evidence-based support exists for use of antipyretic medications to improve fever-associated morbidity and/or mortality; and

  • 3. Fever control in life-threatening infection merits further high-quality study.

Chest. 2013;144(4):1102-1103. doi:10.1378/chest.13-0919

We commend Drs Mohr and Doerschug1 on their well-constructed argument in favor of antipyretic therapy for patients with septic shock. However, based on current evidence, we adamantly maintain that fever should not routinely be treated in all patients with septic shock. Although both our groups seem to agree that pharmacologic antipyretic therapy is unlikely to benefit these patients, we differ in our interpretation of the clinical evidence regarding external cooling. Only one large clinical trial specifically designed to investigate the benefit of external cooling in patients with septic shock exists. Schortgen et al2 randomized 200 febrile patients with severe septic shock to 48 h of external cooling or to no fever control. The number of patients with at least a 50% vasopressor dose reduction at 12 h was greater in the group that received external cooling. Although there was a nonsignificant trend toward decreased ICU mortality in the external cooling group, there was no difference in mortality at hospital discharge. Based on these results, Drs Mohr and Doerschug conclude that “febrile patients with septic shock should be cooled using external cooling to normothermia to optimize clinical outcome.”1 We respectfully disagree.

Giants in Chest Medicine

Chest. 2013;144(4):1104-1105. doi:10.1378/chest.13-1591

Alfred Soffer, MD, Master FCCP, served as Editor of CHEST for 25 years from 1968 to 1993 and led the American College of Chest Physicians (ACCP) as its Executive Director for 23 years from 1969 to 1992. His efforts have had a profound impact on the College and on its Journal, CHEST.


Chest. 2013;144(4):1106-1110. doi:10.1378/chest.13-0040

Physicians are moving increasingly from self-employed, private practices to at-will employment relationships. This historic change in the organizational administration of medical services is likely to accelerate as the Affordable Care Act is implemented and as accountable care organizations permeate the medical marketplace. Physicians vow an ascendant oath to safeguard patients’ welfare, but as they become employees, they may sign legal contracts that also oblige obedience to the institutions that hire them. What happens when an employer makes a decision that is not in the best interests of patients and the physicians fulfill their Hippocratic obligation to voice dissent on their patients’ behalf rather than abiding by their contractual obligation to obey their employer? This article explores the philosophical and legal ramifications of this potential collision of obligations to patients and to employers.

Original Research: Education, Research, and Quality Improvement

Chest. 2013;144(4):1111-1116. doi:10.1378/chest.13-0169

Background:  The executive committee of the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (AT9) developed a strategy to limit the impact of conflict of interest (COI) on recommendations. This policy excluded conflicted panelists from voting on recommendations with which they had conflicts. The objective of the study is to explore the compliance of the attendees of the AT9 final conference.

Methods:  We conducted a survey and reviewed public declarations of COI of all the final AT9 conference attendees. For each of the controversies on which voting occurred (nine of 628 total recommendations), we estimated the compliance with COI policy as the proportion of attendees who recused themselves from voting on controversies for which they were conflicted. To evaluate the potential effect of noncompliance, we assumed that every vote cast by an ineligible conference attendee was cast in direction of the majority vote.

Results:  Sixty-three panelists voted in at least one controversy at the final conference; the percentage of conflicted panelists varied from 6% to 39% for eight controversies. The compliance with the COI policy was 14 of 14 (100%) for one controversy, and varied from one of 19 (5%) to one of three (33%) in the remaining seven. In two of the eight controversies (“Compression device plus aspirin vs low-molecular-weight heparin in tromboprophylaxis in orthopedic surgery” and “Low-molecular-weight heparin vs vitamin K antagonists for treatment”), the low compliance may have affected the final recommendations.

Conclusions:  The low compliance raises concerns about implementation of COI restrictions in the context of anonymous voting.

Original Research: COPD

Chest. 2013;144(4):1117-1123. doi:10.1378/chest.12-2816

Background:  The FEV3/FVC ratio is not discussed in the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for lung function interpretation in spite of narrow confidence limits of normal and its association with smoking. We sought to determine whether a reduction in only the FEV3/FVC ratio was associated with physiologic changes compared with subjects with normal FEV1/FVC and FEV3/FVC ratios.

Methods:  Lung volumes and diffusion were studied in individuals with concomitant spirometry. Patients with restriction on total lung capacity (TLC) were excluded, as were repeat tests on the same patient. A total of 13,302 subjects were divided into three groups: (1) normal FEV1/FVC and FEV3/FVC (n = 7,937); (2) only a reduced FEV3/FVC (n = 840); and (3) reduced FEV1/FVC (n = 4,525).

Results:  Subjects with only a reduced FEV3/FVC compared with those with normal FEV1/FVC and FEV3/FVC ratios had higher mean % predicted TLC (99.1% vs 97.1%, P < .001), residual volume (RV) (109.4% vs 102.3%, P < .001), and RV/TLC ratio (110.1% vs 105.4%, P < .001). They had lower mean % predicted FEV1 (82.6% vs 90.2%, P < .001), inspiratory capacity (94.5% vs 98.2%, P < .001), and diffusing capacity of lung for carbon monoxide (Dlco) (78.3% vs 81.9%, P < .001). Their mean BMI was lower (30.8 vs 31.5, P < .005), they were older (61.2 vs 57.2, P < .001), and more likely male (52.0% vs 40.4%, P < .001), with no racial differences. Comparing this group to those with a reduced FEV1/FVC, similar but greater differences were noted in all of the previous measurements, though mean age and sex were not significantly different.

Conclusions:  The FEV3/FVC ratio should be routinely reported on spirometry. An isolated reduction may indicate an early injury pattern of hyperinflation, air trapping, and loss of Dlco.

Chest. 2013;144(4):1124-1133. doi:10.1378/chest.12-2421

Background:  The success of pulmonary rehabilitation (PR) is established, but how to sustain benefits over the long term is less clear. The aim of this systematic review was to determine the effect of supervised exercise programs after primary PR on exercise capacity and health-related quality of life (HRQL) in individuals with COPD.

Methods:  Randomized controlled trials of postrehabilitation supervised exercise programs vs usual care for individuals with COPD were identified after searches of six databases and reference lists of appropriate studies. Two reviewers independently assessed study quality. Standardized mean differences (SMDs) with 95% CIs were calculated using a fixed-effect model for measures of exercise capacity and HRQL.

Results:  Seven randomized controlled trials, with a total of 619 individuals with moderate to severe COPD, met the inclusion criteria. At 6-month follow-up there was a significant difference in exercise capacity in favor of the postrehabilitation interventions (SMD, −0.20; 95% CI, −0.39 to −0.01), which was not sustained at 12 months (SMD, −0.09; 95% CI, −0.29 to 0.11). There was no difference between postrehabilitation interventions and usual care with respect to HRQL at any time point.

Conclusions:  Supervised exercise programs after primary PR appear to be more effective than usual care for preserving exercise capacity in the medium term but not in the long term. In this review, there was no effect on HRQL. The small number of studies precludes a definitive conclusion as to the impact of postrehabilitation exercise maintenance on longer-term benefits in individuals with COPD.

Chest. 2013;144(4):1134-1142. doi:10.1378/chest.13-0488

Background:  Community-acquired pneumonia (CAP) is a frequent event in patients with COPD, although it is not currently considered an acute exacerbation of COPD (AECOPD). To our knowledge, no studies have compared the inflammatory response of patients with COPD who develop CAP or AECOPD. The aim of our study was to compare clinical and evolutive manifestations and biologic signaling of AECOPD and CAP + COPD.

Methods:  Prospective data were collected from 249 consecutively hospitalized patients with COPD. Comparative analyses were performed in patients with AECOPD (n = 133) and patients with CAP + COPD (n = 116). Measures of clinical characteristics, blood biomarkers, and evolution were recorded on admission, after 3 and 30 days, and in a follow-up period of 30 days, 90 days, and 1 year.

Results:  Patients with CAP + COPD had higher FEV1 compared with patients with COPD without pneumonia. In-hospital and long-term outcomes (1 year) were similar for both populations. However, patients with AECOPD had more readmissions, and patients with CAP had more prior episodes of pneumonia. At day 1 and day 3, patients with CAP + COPD had significantly (P < .001) higher serum levels of C-reactive protein (CRP), procalcitonin, tumor necrosis factor-α, and IL-6. Repetition of the analyses after stratifying patients based on severity of disease, current inhaled pharmacotherapy, and noninfectious AECOPD cause confirmed higher levels of the same biomarkers in patients with CAP + COPD. Chills, pleuritic pain, sputum purulence, and CRP levels at day 1 were independent clinical predictors of CAP + COPD.

Conclusions:  Our study confirms that two different clinical and inflammatory profiles exist in hospitalized patients with COPD in response to CAP (stronger response) and AECOPD, although with similar short-term and long-term outcomes.

Chest. 2013;144(4):1143-1151. doi:10.1378/chest.13-0183

Background:  COPD and heart failure with preserved ejection fraction overlap clinically, and impaired left ventricular (LV) filling is commonly reported in COPD. The mechanism underlying these observations is uncertain, but may include upstream pulmonary dysfunction causing low LV preload or intrinsic LV dysfunction causing high LV preload. The objective of this study is to determine if COPD and emphysema are associated with reduced pulmonary vein dimensions suggestive of low LV preload.

Methods:  The population-based Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers aged 50 to 79 years who were free of clinical cardiovascular disease. COPD was defined by spirometry. Percent emphysema was defined as regions < −910 Hounsfield units on full-lung CT scan. Ostial pulmonary vein cross-sectional area was measured by contrast-enhanced cardiac magnetic resonance and expressed as the sum of all pulmonary vein areas. Linear regression was used to adjust for age, sex, race/ethnicity, body size, and smoking.

Results:  Among 165 participants, the mean (± SD) total pulmonary vein area was 558 ± 159 mm2 in patients with COPD and 623 ± 145 mm2 in control subjects. Total pulmonary vein area was smaller in patients with COPD (−57 mm2; 95% CI, −106 to −7 mm2; P = .03) and inversely associated with percent emphysema (P < .001) in fully adjusted models. Significant decrements in total pulmonary vein area were observed among participants with COPD alone, COPD with emphysema on CT scan, and emphysema without spirometrically defined COPD.

Conclusions:  Pulmonary vein dimensions were reduced in COPD and emphysema. These findings support a mechanism of upstream pulmonary causes of underfilling of the LV in COPD and in patients with emphysema on CT scan.

Chest. 2013;144(4):1152-1162. doi:10.1378/chest.13-0161

Background:  The new GOLD (Global Initiative for Chronic Obstructive Lung Disease) strategy recommends use of the COPD Assessment Test (CAT) or modified Medical Research Council (mMRC) scale to assess symptoms in COPD against “risk” as assessed by spirometry or exacerbation frequency. We aimed to determine the concordance between CAT and mMRC scale in assessing risk in patients with α1-antitrypsin deficiency (AATD) and the CAT threshold for risk assessment at which similar proportions of patients are assigned into the risk categories.

Methods:  Distribution of 309 patients (protease inhibitor Z phenotype) in four GOLD categories (A, B, C, and D) was compared. Using CAT for symptoms, we compared patient distribution using scores between 10 and 15 to ascertain the CAT threshold at which the distribution of patients in each group is proportional.

Results:  Using CAT 10 and spirometry for risk assessment, 6.1% of patients were in group A (low symptoms/low risk), 39.2% in B (high symptoms/low risk), 2.3% in C (low symptoms/high risk), and 52.4% in D (high symptoms/high risk). Using mMRC scale and spirometry for risk produced a significantly different distribution from that using CAT (P < .0001). Using CAT 13 as a symptom threshold and spirometry for risk resulted in a more proportional distribution of patients, which was similar using CAT and exacerbation history (P > .0001) and mMRC scale and spirometry and/or exacerbation history for risk (P > .0001).

Conclusions:  In patients with AATD, using either the mMRC scale 0 to 1 or CAT 10 scores to determine symptoms results in a significant difference in patient distribution. However, CAT 13 as the threshold for assessing symptoms results in a similar proportion of patients being categorized into the risk categories.

Chest. 2013;144(4):1163-1178. doi:10.1378/chest.12-2847

Background:  Cardiovascular disease (CVD) is common among patients with COPD. However, it is not clear whether this is due to shared risk factors or if COPD increases the risk for CVD independently. This study aimed to provide a systematic review of studies that investigated the association between COPD and CVD outcomes, assessing any effect of confounding by common risk factors.

Methods:  A search was conducted in MEDLINE (via PubMed) for observational studies published between January 1990 and March 2012 reporting cardiovascular comorbidity in patients with COPD (or vice versa).

Results:  Of the 7,322 citations identified, 25 studies were relevant for this systematic review. Twenty-two studies provided an estimate for CVD risk in COPD, whereas four studies provided estimates of COPD risk in CVD. The crude prevalence for the aggregate CVD category ranged from 28% to 70%, likely due to differences in populations studied and CVD definitions; unadjusted rate ratio (RR) estimates of unspecified CVD among patients with COPD compared with patients without COPD ranged from 2.1 to 5.0. The association between COPD and CVD persisted after adjustment for shared risk factors in the majority of the studies. Two studies found a relationship between the severity of airflow limitation and CVD risk. Increased RRs were observed for individual CVD types, but their estimates varied considerably for congestive heart failure, coronary heart disease, arrhythmias, stroke, arterial hypertension, and peripheral arterial disease.

Conclusions:  Available observational data support the hypothesis that COPD is associated with an increased risk of CVD.

Chest. 2013;144(4):1179-1185. doi:10.1378/chest.12-2674

Background:  Most current classification schemes for COPD use lung function as the primary way of classifying disease severity and monitoring disease progression. This approach misses important components of the disease process.

Methods:  We evaluated existing data to develop a classification scheme for COPD using measures beyond lung function, including respiratory symptoms, exacerbation history, quality-of-life assessment, comorbidity, and BMI. We then applied this scheme to data from the Lung Health Study, calculating a score for study subjects in year 1 and year 5 of the study, along with the difference between year 1 and year 5.

Results:  We developed a four-point scale ranging from 1.00 (mild) to 4.00 (very severe). In year 1 of the study, the mean COPD score was 1.76; in year 5 it was 1.82. The mean difference from year 1 to year 5 was an increase (worsening) of 0.06 and a range from −1.0 to 1.6. The COPD score at year 1, year 5, and the difference between these scores were all predictive of mortality at follow-up. For example, the 14.0% of subjects whose score improved by at least 0.25 between year 1 and 5 had decreased mortality compared with those with stable scores (between −0.25 and 0.25; hazard ratio, 0.6; 95% CI, 0.4, 0.8).

Conclusions:  A COPD severity score that includes components in addition to lung function and allows for both improvement and worsening of disease may provide additional guidance to COPD classification, management, and prognosis.

Original Research: Genetic and Developmental Disorders

Chest. 2013;144(4):1186-1192. doi:10.1378/chest.12-2414

Background:  Tropospheric oxidant pollutants may injure the respiratory tract. Cystic fibrosis (CF) respiratory disease involves significant inflammation and excessive oxidative stress, and exposure to air pollutants can magnify the lung damage. The objective of this study was to investigate the association between the short-term variation in the concentration of air pollutants in metropolitan São Paulo, Brazil, and the occurrence of respiratory exacerbations in children and adolescents with CF.

Methods:  A longitudinal panel of repeated measurements was obtained from 103 patients attending the outpatient center of our institution from September 6, 2006 through September 4, 2007. Daily concentrations of inhaled particulate matter, sulfur dioxide, nitrogen dioxide, ozone (O3), carbon monoxide, and meteorologic variables, such as the minimum temperature and relative humidity, were evaluated. The generalized estimation equation model for binomial distribution was used to assess the impact of these measurements on the occurrence of acute respiratory exacerbations.

Results:  In total, 103 patients with CF (median age, 8.9 years) made 408 visits, with a mean ± SD of 4 ± 1.74 visits per patient (range, 2-9). A respiratory disease exacerbation was diagnosed on 142 visits (38.4%). An interquartile range increase in the O3 concentration (45.62 μg/m3) had a positive, delayed (2 days after exposure) effect on the risk of a respiratory exacerbation (relative risk = 1.86; 95% CI, 1.14-3.02).

Conclusions:  This study demonstrates that exposure to short-term air pollution in a large urban center increases the risk of a pulmonary exacerbation in patients with CF.

Chest. 2013;144(4):1193-1198. doi:10.1378/chest.12-2589

Objective:  The aim of this study was to determine whether assessment of early CT scan-detected bronchiectasis in young children with cystic fibrosis (CF) depends on lung volume.

Methods:  This study, approved by the hospital ethics committee, included 40 young children with CF from a newborn screened population contributing paired volume-controlled inspiratory and expiratory volumetric chest CT scans acquired under general anesthesia while clinically stable. Bronchiectasis was assessed with a semiquantitative CT scan score in inspiration and expiration, and the sensitivity of the expiratory CT scan to detect bronchiectasis was compared with the inspiratory CT scan by sensitivity and intraclass correlation coefficient analysis and Bland-Altman plots. Matched inspiratory and expiratory airway-vessel measurements were obtained in a subset of 10 children, and the relationship between lung volume and airway:vessel ratio after adjusting for age and vessel size was examined with the use of a linear regression model with generalized estimating equations. The number of visible airways in inspiration and expiration was compared in all 40 children by Wilcoxon signed rank test.

Results:  Expiratory scans had poor sensitivity (0.46) to detect bronchiectasis, underestimating disease extent (P < .001). Airway:vessel ratios were consistently higher in inspiration, independent of age and vessel size (P < .001), with significantly more airways visible in inspiration than in expiration, independent of age (median, 71 vs 28, respectively; P < .001).

Conclusions:  In young children with CF, radiologic assessment of early bronchiectasis with chest CT scan depends on lung volume; thus, expiratory scans may not be appropriate for evaluating bronchiectasis in this population. Lung volume during CT image acquisition should be standardized to evaluate airway dimensions in young children.

Chest. 2013;144(4):1199-1206. doi:10.1378/chest.13-0811

Background:  Neuroendocrine cell hyperplasia of infancy (NEHI) is a childhood diffuse lung disease of unknown etiology. We investigated the mechanism for lung disease in a subject whose clinical, imaging, and lung biopsy specimen findings were consistent with NEHI; the subject’s extended family and eight other unrelated patients with NEHI were also investigated.

Methods:  The proband’s lung biopsy specimen (at age 7 months) and serial CT scans were diagnostic of NEHI. Her mother, an aunt, an uncle, and two first cousins had failure to thrive in infancy and chronic respiratory symptoms that improved with age. Genes associated with autosomal-dominant forms of childhood interstitial lung disease were sequenced.

Results:  A heterozygous NKX2.1 mutation was identified in the proband and the four other adult family members with histories of childhood lung disease. The mutation results in a nonconservative amino acid substitution in the homeodomain in a codon extensively conserved through evolution. None of these individuals have thyroid disease or movement disorders. NKX2.1 mutations were not identified by sequence analysis in eight other unrelated subjects with NEHI.

Conclusions:  The nature of the mutation and its segregation with disease support that it is disease-causing. Previously reported NKX2.1 mutations have been associated with “brain-thyroid-lung” syndrome and a spectrum of more severe pulmonary phenotypes. We conclude that genetic mechanisms may cause NEHI and that NKX2.1 mutations may result in, but are not the predominant cause of, this phenotype. We speculate that altered expression of NKX2.1 target genes other than those in the surfactant system may be responsible for the pulmonary pathophysiology of NEHI.

Original Research: Critical Care

Chest. 2013;144(4):1207-1215. doi:10.1378/chest.13-0121

Background:  Thrombocytopenia is the most common hemostatic disorder in critically ill patients. The objective of this study was to describe the incidence, risk factors, and outcomes of thrombocytopenia in patients admitted to medical-surgical ICUs.

Methods:  Three thousand seven hundred forty-six patients in 67 centers were enrolled in a randomized trial in which unfractionated heparin was compared with low-molecular-weight heparin (LMWH) for thromboprophylaxis. Patients who had baseline platelet counts < 75 × 109/L or severe coagulopathy at screening were excluded. We analyzed the risk of developing mild (100-149 × 109/L), moderate (50-99 × 109/L), and severe (< 50 × 109/L) thrombocytopenia during an ICU stay. We also assessed independent and time-varying predictors of thrombocytopenia and the effect of thrombocytopenia on major bleeding, transfusions, and death.

Results:  The incidences of mild, moderate, and severe thrombocytopenia were 15.3%, 5.1%, and 1.6%, respectively. The predictors of each category of thrombocytopenia were APACHE (Acute Physiology and Chronic Health Evaluation) II score, use of inotropes or vasopressors, and renal replacement therapy. The risk of moderate thrombocytopenia was lower in patients who received LMWH thromboprophylaxis but higher in surgical patients and in patients who had liver disease. Each category of thrombocytopenia was associated with subsequent bleeding and transfusions. Moderate and severe thrombocytopenia were associated with increased ICU and hospital mortality.

Conclusion:  A high severity of illness, prior surgery, use of inotropes or vasopressors, renal replacement therapy, and liver dysfunction are associated with a higher risk of thrombocytopenia developing in the ICU, whereas LMWH thromboprophylaxis is associated with a lower risk. Patients who develop thrombocytopenia in the ICU are more likely to bleed, receive transfusions, and die.

Trial registry:  ClinicalTrials.gov; No.: NCT00182143; URL: www.clinicaltrials.gov

Chest. 2013;144(4):1216-1221. doi:10.1378/chest.12-2906

Background:  The factors that limit primary care providers (PCPs) from intervening for adults with evolving, acute, severe illness are less understood than the increasing frequency of management by acute care providers.

Methods:  Rates of prehospital patient management by a PCP and of communication with acute care teams were measured in a multicenter, cross-sectional, descriptive study conducted in all four of the adult medical ICUs of the three hospitals in central Massachusetts that provide tertiary care. Rates were measured for 390 critical care encounters, using a validated instrument to abstract the medical record and conduct telephone interviews.

Results:  PCPs implemented prehospital management for eight episodes of acute illness among 300 encounters. Infrequent prehospital management by PCPs was attributed to their lack of awareness of the patient’s evolving acute illness. Only 21% of PCPs were aware of the acute illness before their patient was admitted to an ICU, and 33% were not aware that their patient was in an ICU. Rates of PCP involvement were not appreciably different among provider groups or by patient age, sex, insurance status, hospital, ICU, or ICU staffing model.

Conclusions:  We identified lack of PCP awareness of patients’ acute illness and high rates of PCP referral to acute care providers as the most frequent barriers to prehospital management of evolving acute illness. These findings suggest that implementing processes that encourage early patient-PCP communication and increase rates of prehospital management of infections and acute exacerbations of chronic diseases could reduce use of acute care services.

Original Research: Asthma

Chest. 2013;144(4):1222-1229. doi:10.1378/chest.13-0178

Background:  The combination of fluticasone furoate (FF), a novel inhaled corticosteroid (ICS), and vilanterol (VI), a long-acting β2 agonist, is under development as a once-daily treatment of asthma and COPD. The aim of this study was to compare the efficacy of FF/VI with fluticasone propionate (FP)/salmeterol (SAL) in patients with persistent asthma uncontrolled on a medium dose of ICS.

Methods:  In a randomized, double-blind, double-dummy, parallel group study, 806 patients received FF/VI (100/25 μg, n = 403) once daily in the evening delivered through ELLIPTA (GlaxoSmithKline) dry powder inhaler, or FP/SAL (250/50 μg, n = 403) bid through DISKUS/ACCUHALER (GlaxoSmithKline). The primary efficacy measure was 0- to 24-h serial weighted mean (wm) FEV1 after 24 weeks of treatment.

Results:  Improvements from baseline in 0- to 24-h wmFEV1 were observed with both FF/VI (341 mL) and FP/SAL (377 mL); the adjusted mean treatment difference was not statistically significant (−37 mL; 95% CI, −88 to 15, P = 0.162). There were no differences between 0- to 4-h serial wmFEV1, trough FEV1, and asthma control and quality-of-life questionnaire scores. There was no difference in reported exacerbations between treatments. Both treatments were well tolerated, with no clinically relevant effect on urinary cortisol excretion or vital signs and no treatment-related serious adverse events.

Conclusions:  The efficacy of once-daily FF/VI was similar to bid FP/SAL in improving lung function in patients with persistent asthma. No safety issues were identified.

Trial registry:  ClinicalTrials.gov; No.: NCT01147848; URL: www.clinicaltrials.gov

Chest. 2013;144(4):1230-1237. doi:10.1378/chest.13-0367

Background:  Lung cytotoxic mechanisms trigger the release of perforin and granzymes, causing oxidative DNA damage that ultimately leads to apoptosis. These effects, although demonstrated in COPD, have not been investigated in patients with asthma and in particular in patients with asthma who smoke. Our aim was to measure perforin, granzyme A, granzyme B, and 8-OHdG expression in sputum from smoking and nonsmoking patients with asthma, compared with smoking and nonsmoking control subjects.

Methods:  Perforin, granzyme A, granzyme B, and 8-OHdG expression levels were detected by enzyme-linked immunosorbent assays in induced sputum specimens.

Results:  Perforin expression was increased in 40% of smokers and 45% of smoking patients with asthma and in only 7% of nonsmoking patients with asthma (P = .004), compared with control subjects’ values. In contrast, granzymes A and B levels were increased in > 40% of patients in all three groups vs control subjects. Finally, 8-OHdG levels were elevated in 35% of smoking patients with asthma, in 20% of smokers, and in only 10% of nonsmoking patients with asthma. Statistical analysis revealed a positive correlation between granzyme A (P < .001) and granzyme B (P = .006) expression levels and the number of pack-years in smoking patients with asthma.

Conclusions:  Asthma cytotoxic immune response is mainly represented by granzymes A and B, whereas in smoking patients with asthma perforin and 8-OHdG are additionally involved, resembling the immune response in COPD.

Original Research: Lung Cancer

Chest. 2013;144(4):1238-1244. doi:10.1378/chest.12-3034

Background:  Patients with lung cancer often present with recurrence, even after resection. The identification of risk factors for recurrence after resection is useful.

Methods:  Among 1,338 patients with lung cancer who underwent a complete resection, 277 developed recurrences post surgery. Data regarding the TNM factors, histologic subtype, and presence/absence of vessel invasion were analyzed retrospectively using the survival tree method to identify groups with a high risk of recurrence after resection.

Results:  The results revealed that the T factor, the N factor, and lymphatic (ly) and blood (v) vessel invasion were related to the risk of recurrence, and six combinations of these factors were identified using the survival tree method: group A: v = 0, T ≤ 1b, ly = 0; group B: v = 0, T ≤ 1b, ly ≥ 1; group C: v = 0, T ≥ 2a; group D: v ≥ 1, N ≤ 1, T ≤ 2b; group E: v ≥ 1, N ≤ 1, T ≥ 3; and group F: v ≥ 1, N ≥ 2. The six groups were then further classified into three groups: a low-risk group (group A), a moderate-risk group (groups B, C, and D), and a high-risk group (groups E and F). The 5-year recurrence-free survival rate was approximately 98% for the low-risk group, 75% for the moderate-risk group, and 30% for the high-risk group.

Conclusions:  Combining the T, N, v, and ly factors allowed the precise identification of a group with a high risk of recurrence after resection.

Chest. 2013;144(4):1245-1252. doi:10.1378/chest.12-2986

Background:  Suicide rates among patients with lung cancer are higher than the general population. This study aims to identify patient and disease characteristics associated with suicide in patients with lung cancer.

Methods:  We conducted an analysis of subjects with primary lung cancer diagnosed between 1973 and 2008 recorded in the Surveillance, Epidemiology and End Results database.

Results:  From 871,230 people diagnosed with lung cancer, 1,184 cases of suicide were identified. The rate of suicide did not change considerably over time, with 8.83 compared with 7.17 suicides per 10,000 person-years in 1973 to 1979 and 2000 to 2009, respectively. The standardized mortality ratio (SMR) of the entire cohort was 4.95, with an SMR of 13.4 within 3 months of a cancer diagnosis. Despite most subgroups having a higher SMR than the general population, a wide variation in suicide risk was seen among different subgroups, including histologic type (SMR 1.58 vs 7.28 in bronchoalveolar and small cell carcinoma, respectively). The highest SMRs were found in patients with the following characteristics: male, older age, higher-grade tumor, and metastatic disease, and in patients who did not receive or refused treatment. Despite the higher SMR among patients with metastatic disease, > 50% of suicides occurred in those with locoregional and potentially curable disease.

Conclusions:  Patients with lung cancer have a higher risk for suicide compared with the general US population, especially within 3 months of diagnosis. Despite the higher SMR among patients with a poorer prognosis, a concerning proportion of suicides occurs in potentially curable patients, highlighting the need for effective screening strategies to avoid this preventable cause of death.

Chest. 2013;144(4):1253-1260. doi:10.1378/chest.13-0073

Background:  The non-small cell lung cancer (NSCLC) staging system (published in 2009 in the seventh edition of the cancer staging manuals of the Union for International Cancer Control and American Joint Commission on Cancer) did not include any changes to current N descriptors for NSCLC. However, the prognostic significance of the extent of lymph node (LN) involvement (including the LN zones involved [hilar/interlobar or peripheral], cancer-involved LN ratios [LNRs], and the number of involved LNs) remains unknown. The aim of this report is to evaluate the extent of LN involvement and other prognostic factors in predicting outcome after definitive surgery among Chinese patients with stage II-N1 NSCLC.

Methods:  We retrospectively reviewed the clinicopathologic characteristics of 206 patients with stage II (T1a-T2bN1M0) NSCLC who had undergone complete surgical resection at Shanghai Chest Hospital from June 1999 to June 2009. Overall survival (OS) and disease-free survival (DFS) were compared using Kaplan-Meier statistical analysis. Stratified and Cox regression analyses were used to evaluate the relationship between the LN involvement and survival.

Results:  Peripheral zone LN involvement, cancer-involved LNR, smaller tumor size, and squamous cell carcinoma were shown to be statistically significant indicators of higher OS and DFS by univariate analyses. Visceral pleural involvement was also shown to share a statistically significant relationship with DFS by univariate analyses. Multivariate analyses showed that tumor size and zone of LN involvement were significant predictors of OS.

Conclusions:  Zone of N1 LN, LN ratios, and tumor size were found to provide independent prognostic information in patients with stage II NSCLC. This information may be used to stratify patients into groups by risk for recurrence.

Original Research: Pulmonary Procedures

Chest. 2013;144(4):1261-1268. doi:10.1378/chest.13-0534

Background:  Solitary pulmonary nodules (SPNs) frequently require transbronchial needle aspiration (TBNA) or biopsy to determine malignant potential, but have variable diagnostic yields. Confirming needle placement within SPNs during TBNA could significantly increase diagnostic yield. Optical coherence tomography (OCT) provides nondestructive, high-resolution, microstructural imaging with potential to distinguish SPN from parenchyma. We have developed needle-based OCT probes compatible with TBNA. Before OCT can play any significant role in guiding clinical TBNA, OCT interpretation criteria for differentiating SPN from lung parenchyma must be developed and validated.

Methods:  OCT of SPN and parenchyma was performed on 111 ex vivo resection specimens. OCT criteria for parenchyma and SPN were developed and validated in a blinded assessment. Six blinded readers (two pulmonologists, two pathologists, and two OCT experts) were trained on imaging criteria in a 15-min training session prior to interpreting the validation data set.

Results:  OCT of lung parenchyma displayed evenly spaced signal-void alveolar spaces, signal-intense backreflections at tissue-air interfaces, or both. SPNs lacked both of these imaging features. Independent validation of OCT criteria by the six blinded readers demonstrated sensitivity and specificity of 95.4% and 98.2%, respectively.

Conclusions:  We have developed and validated OCT criteria for lung parenchyma and SPN with sensitivity and specificity > 95% in this ex vivo study. We anticipate that OCT could be a useful complementary imaging modality to confirm needle placement during TBNA to potentially increase diagnostic yield.

Original Research: Antithrombotic Therapy

Chest. 2013;144(4):1269-1275. doi:10.1378/chest.12-2712

Background:  Heparin-induced thrombocytopenia (HIT) is diagnosed using clinical criteria and detection of platelet-activating anti-platelet factor 4/heparin (anti-PF4/H) antibodies, usually through a surrogate enzyme-linked immunosorbent assay (ELISA). The high false-positive rate (FPR) of this ELISA prompted us to reexamine its interpretation.

Methods:  We analyzed anti-PF4/H ELISA results from a previously published dataset of 1,958 patients, using clinical suspicion and serotonin-release assay (SRA) to diagnose HIT. We performed receiver operating characteristic (ROC) analysis using stratum-specific likelihood ratios (SSLRs) and used Bayes theorem to construct a clinical decision-support algorithm.

Results:  The most discriminant single cutoff by anti-PF4/H ELISA for the diagnosis of HIT was found to be 0.8 optical density (OD) units, not 0.4 OD (currently accepted practice). This change reduced the FPR from 31% to 6% (95% CI, 5%-8%). ELISA results were grouped into five strata, which yielded SSLRs ranging from 0.02 (strongly ruling HIT out) to 104.4 (strongly ruling HIT in). Comparison of ROC curves demonstrated that this five-strata approach is statistically more accurate than current accepted practice at discriminating whether patients have HIT or not (area under the ROC curve, 0.97 [95% CI, 0.93-1.00] vs 0.83 [95% CI, 0.80-0.89]). Our decision-support algorithm incorporated clinical assessment into this stratified model and clarified HIT diagnosis with a high degree of certainty and without the need for SRA testing in approximately 90% of patients.

Conclusions:  Diagnostic accuracy of the anti-PF4/H ELISA can be optimized by using a higher cutoff and a stratified interpretation of the results. Our algorithm should significantly reduce overdiagnosis of HIT and the need for SRA testing.

Original Research: Pulmonary Vascular Disease

Chest. 2013;144(4):1276-1281. doi:10.1378/chest.13-0267

Background:  VTE is a common complication of hospitalization and is associated with significant morbidity and mortality. The use of appropriate thromboprophylaxis can significantly reduce the risk of VTE but remains underutilized. In England, a comprehensive approach to VTE prevention was launched in 2010. This study aimed to evaluate the impact of the implementation of the national program in a single center.

Methods:  A prospective quality improvement program was established at King’s College Hospital NHS Foundation Trust in 2010. The multidisciplinary thrombosis team launched mandatory documented VTE risk assessment and updated thromboprophylaxis guidance. Root cause analysis of hospital-associated thrombosis (HAT) was implemented to identify system failures, enable outcome measurement, and facilitate learning to improve VTE prevention practice. The key outcomes were the incidence of HAT and the proportion of events preventable with appropriate thromboprophylaxis.

Results:  Documented VTE risk assessment improved from <40% to > 90% in the first 9 months. Four hundred twenty-five episodes of HAT were identified over 2 years. A significant reduction in the incidence of HAT was observed following sustained achievement of 90% risk assessment (risk ratio, 0.88; 95% CI, 0.74-0.98; P = .014). The proportion of HAT attributable to inadequate thromboprophylaxis fell significantly from 37.5% to 22.4% (P = .005).

Conclusions:  Mandatory VTE risk assessment can significantly reduce preventable HAT and thereby improve patient safety.

Chest. 2013;144(4):1282-1290. doi:10.1378/chest.12-0653

Background:  The impact of modern therapy on survival in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc) is not clear. We sought to determine associations among commonly used clinical and hemodynamic variables, treatment, and long-term survival in PAH associated with SSc compared with PAH defined as idiopathic, familial, or associated with anorexigens.

Methods:  The observation period (1996-2010) included the option for epoprostenol and the availability of oral agents in 2002 (modern era of endothelin antagonists and phosphodiesterase-5 inhibitors). Primary outcome was all-cause mortality.

Results:  Eighty-three patients had SSc (mean age, 59 years), and 120 had PAH (mean age, 51 years) (P < .0001, > 80% were functional class III or IV in both groups). Compared with PAH, SSc had a lower mean pulmonary artery pressure (48 mm Hg vs 58 mm Hg, P < .0001) and pulmonary vascular resistance (10 resistance units vs 15 resistance units, P < .0001), and a higher cardiac index (2.3 L/min/m2 vs 1.8 L/min/m2, P < .0001). PAH was more often treated with prostacyclin (71% vs 44%, P < .0001), but there were no differences in the use of monotherapy or combination oral therapy. SSc had a twofold-higher mortality over the 14 years. The 5-year survival in the modern era for PAH was 87%, compared with 51% for SSc (P < .001).

Conclusions:  Despite an improvement in clinical status, unlike in PAH, mortality in SSc has not improved since the introduction of epoprostenol.

Original Research: Imaging

Chest. 2013;144(4):1291-1299. doi:10.1378/chest.12-2987

Background:  Little is known about the histopathology and prognosis of persistent pure ground-glass opacity nodules (GGNs) of ≥ 10 mm in diameter. We aimed to compare the morphologic features of persistent pure GGNs of ≥ 10 mm in diameter at thin-section CT (TSCT) scan with histopathology and patient prognosis.

Methods:  A total of 46 resected GGNs that were evaluated with TSCT scan and followed up for ≥ 3 years were included in this study. Correlations between histopathology (adenocarcinoma in situ [AIS], minimally invasive adenocarcinoma [MIA], and invasive adenocarcinoma) and CT scan characteristics were examined. CT scan and clinicodemographic data were investigated by univariate and multivariate analyses to identify features that helped distinguish invasive adenocarcinoma from AIS or MIA. Disease recurrence was also evaluated.

Results:  The nodules included 19 AISs (41%), nine MIAs (20%), and 18 invasive adenocarcinomas (39%). On univariate analysis, the presence of air bronchogram (P = .012), size of nodule (P = .032, cutoff = 16.4 mm in diameter), and mass of nodule (P = .040, cutoff = 0.472 g) were significant factors that differentiated invasive adenocarcinoma from AIS or MIA. On multivariate analysis, size (P = .010) and mass of nodule (P = .016) were significant determinants for invasive adenocarcinoma. There were no cases of recurrence during a follow-up period of ≥ 3 years after surgical resection.

Conclusions:  In persistent pure GGNs of ≥ 10 mm in diameter, the size and mass of the nodule are determinants of invasive adenocarcinoma, for which surgical resection leads to excellent prognosis.

Chest. 2013;144(4):1300-1310. doi:10.1378/chest.12-2597

Background:  Fluorine-enhanced MRI is a relatively inexpensive and straightforward technique that facilitates regional assessments of pulmonary ventilation. In this report, we assess its suitability through the use of perfluoropropane (PFP) in a cohort of human subjects with normal lungs and subjects with lung disease.

Methods:  Twenty-eight subjects between the ages of 18 and 71 years were recruited for imaging and were classified based on spirometry findings and medical history. Imaging was carried out on a Siemens TIM Trio 3T MRI scanner using two-dimensional, gradient echo, fast low-angle shot and three-dimensional gradient echo, volumetric, interpolated, breath-hold examination sequences for proton localizers and PFP functional scans, respectively. Respiratory waveforms and physiologic signals of interest were monitored throughout the imaging sessions. A region-growing algorithm was applied to the proton localizers to define the lung field of view for analysis of the PFP scans.

Results:  All subjects tolerated the gas mixture well with no adverse side effects. Images of healthy lungs demonstrated a homogeneous distribution of the gas with sufficient signal-to-noise ratios, while lung images from asthmatic and emphysematous lungs demonstrated increased heterogeneity and ventilation defects.

Conclusions:  Fluorine-enhanced MRI using a normoxic PFP gas mixture is a well-tolerated, radiation-free technique for regionally assessing pulmonary ventilation. The inherent physical characteristics and applicability of the gaseous agent within a magnetic resonance setting facilitated a clear differentiation between normal and diseased lungs.

Original Research: Cardiovascular Disease

Chest. 2013;144(4):1311-1322. doi:10.1378/chest.13-0675

Background:  Clinical studies have suggested an association between bisphosphonate use and the onset of atrial fibrillation (AF). However, data on the risk of developing AF, stroke, and cardiovascular mortality with the use of bisphosphonate are conflicting. The objective of this study was to evaluate the risk of serious AF (events that required hospital admission), stroke, and cardiovascular mortality with the use of bisphosphonates through a systematic review of the literature.

Methods:  We searched the PubMed, CENTRAL, and EMBASE databases for observational studies and randomized controlled trials (RCTs) on the use of bisphosphonates from 1966 to April 2012 that reported the number of patients who developed serious AF, stroke, and cardiovascular mortality at follow-up. The random-effects Mantel-Haenszel test was used to evaluate relative risk-adverse cardiovascular outcomes with the use of bisphosphonates.

Results:  Six observational studies (n = 149,856) and six RCTs (n = 41,375) were included for analysis. On pooling observational studies, there was an increased risk of AF (OR, 1.27; 95% CI, 1.16-1.39) among bisphosphonate users. Further, analysis of RCTs revealed a statistically significant increase in the risk of serious AF (OR, 1.40; 95% CI, 1.02-1.93) and no increase in the risk of stroke (OR, 1.07; 95% CI, 0.85-1.34) or cardiovascular mortality (OR, 0.92; 95% CI, 0.68-1.26) with the use of bisphosphonates.

Conclusions:  Evidence from RCTs and observational studies suggests a significantly increased risk of AF requiring hospitalization, but no increase in risk of stroke or cardiovascular mortality, with the use of bisphosphonate.

Original Research: Occupational and Environmental Lung Diseases

Chest. 2013;144(4):1323-1329. doi:10.1378/chest.12-1569

Background:  The contribution of environmental tobacco smoke (ETS) exposure to pulmonary morbidity in children with sickle cell anemia (SCA) is poorly understood. We tested the hypothesis that children with SCA and ETS exposure would have an increased prevalence of obstructive lung disease and respiratory symptoms compared with children with SCA and no ETS exposure.

Methods:  Parent reports of ETS and respiratory symptom frequency were obtained for 245 children with SCA as part of a multicenter prospective cohort study. One hundred ninety-six children completed pulmonary function testing. Multivariable regression models were used to evaluate the associations between ETS exposure at different time points (prenatal, infant [birth to 2 years], preschool [2 years to first grade], and current) and lung function and respiratory symptoms.

Results:  Among the 245 participants, a high prevalence of prior (44%) and current (29%) ETS exposure was reported. Of the 196 children who completed pulmonary function testing, those with parent-reported infant and current ETS exposure were more likely to have airway obstruction (defined as an FEV1/FVC ratio below the lower limit normal) compared with unexposed children (22.0% vs 3.1%, P < .001). Those with ETS exposure also had a lower forced expiratory flow, midexpiratory phase/FVC ratio (0.82 vs 0.97, P = .001) and were more likely to have evidence of bronchodilator responsiveness (23% vs 11%, P = .03). Current and prior ETS exposure and in utero smoke exposure were associated with increased frequency of respiratory symptoms.

Conclusions:  ETS exposure is associated with evidence of lower airway obstruction and increased respiratory symptoms in SCA.

Original Research: Pulmonary Physiology

Chest. 2013;144(4):1330-1339. doi:10.1378/chest.12-3022

Background:  Alterations in respiratory mechanics predispose healthy obese individuals to low lung volume breathing, which places them at risk of developing expiratory flow limitation (EFL). The high ventilatory demand in endurance-trained obese adults further increases their risk of developing EFL and increases their work of breathing. The objective of this study was to investigate the prevalence and magnitude of EFL in fit obese (FO) adults via measurements of breathing mechanics and ventilatory dynamics during exercise.

Methods:  Ten (seven women and three men) FO (mean ± SD, 38 ± 5 years, 38% ± 5% body fat) and 10 (seven women and three men) control obese (CO) (38 ± 5 years, 39% ± 5% body fat) subjects underwent hydrostatic weighing, pulmonary function testing, cycle exercise testing, and the determination of the oxygen cost of breathing during eucapnic voluntary hyperpnea.

Results:  There were no differences in functional residual capacity (43% ± 6% vs 40% ± 9% total lung capacity [TLC]), residual volume (21% ± 4% vs 21% ± 4% TLC), or FVC (111% ± 13% vs 104% ± 15% predicted) between FO and CO subjects, respectively. FO subjects had higher FEV1 (111% ± 13% vs 99% ± 11% predicted), TLC (106% ± 14% vs 94% ± 7% predicted), peak expiratory flow (123% ± 14% vs 106% ± 13% predicted), and maximal voluntary ventilation (128% ± 15% vs 106% ± 13% predicted) than did CO subjects. Peak oxygen uptake (129% ± 16% vs 86% ± 15% predicted), minute ventilation (128 ± 35 L/min vs 92 ± 25 L/min), and work rate (229 ± 54 W vs 166 ± 55 W) were higher in FO subjects. Mean inspiratory (4.65 ± 1.09 L/s vs 3.06 ± 1.21 L/s) and expiratory (4.15 ± 0.95 L/s vs 2.98 ± 0.76L/s) flows were greater in FO subjects, which yielded a greater breathing frequency (51 ± 8 breaths/min vs 41 ± 10 breaths/min) at peak exercise in FO subjects. Mechanical ventilatory constraints in FO subjects were similar to those in CO subjects despite the greater ventilatory demand in FO subjects.

Conclusion:  FO individuals achieve high ventilations by increasing breathing frequency, matching the elevated metabolic demand associated with high fitness. They do this without developing meaningful ventilatory constraints. Therefore, endurance-trained obese individuals with higher lung function are not limited by breathing mechanics during peak exercise, which may allow healthy obese adults to participate in vigorous exercise training.

Translating Basic Research into Clinical Practice

Chest. 2013;144(4):1340-1345. doi:10.1378/chest.13-0326

COPD is an important global health problem. In addition to pulmonary impairment, systemic inflammation, musculoskeletal abnormalities, and cardiovascular comorbidity influence disease burden and mortality risk. Body weight and body composition are important discriminants in classifying disease heterogeneity. The rationale for and efficacy of caloric supplementation in preventing and treating involuntary weight loss is currently well established. For maintenance of muscle and bone tissue, appropriately timed, high-quality protein intake and addressing vitamin D deficiency must be considered. Specific nutrients (eg, n-3 polyunsaturated fatty acids and polyphenolic compounds) may have the pharmacologic potential to boost decreased muscle mitochondrial metabolism and enhance impaired physical performance, particularly when the metabolic stimulus of physical activity alone is limited. At this stage, evidence is insufficient to support an intake of high doses of single nutritional supplements to modulate respiratory pathology, but some small studies have identified micronutrient modulation via the diet as a promising intervention.

Recent Advances in Chest Medicine

Chest. 2013;144(4):1346-1356. doi:10.1378/chest.12-2396

Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc) and affects up to 12% of all patients with SSc, with a 50% mortality rate within 3 years of PAH diagnosis. Compared with the idiopathic form of PAH (IPAH), patients with SSc-associated PAH (SSc-PAH) have a threefold increased risk of death and may receive a diagnosis late in the course of disease because of insidious onset and the high prevalence of cardiac, musculoskeletal, and pulmonary parenchymal comorbidities. Treatment with conventional forms of PAH therapy often yield poor results compared with IPAH cohorts; unfortunately, the exact reasons behind this remain poorly understood but likely include variations in the pathologic mechanisms, differences in cardiovascular response to increasing afterload, and inadequate strategies to detect and treat SSc-PAH early in its course. Current methods for screening and longitudinal evaluation of SSc-PAH, such as the 6-min walk test, transthoracic echocardiography, and MRI, each have notable advantages and disadvantages. We provide an up-to-date, focused review of SSc-PAH and how it differs from IPAH, including pathogenesis, appropriate screening for disease onset, and new approaches to treatment and longitudinal assessment of this disease.

Special Features

Chest. 2013;144(4):1357-1367. doi:10.1378/chest.12-2438

The goals of management of COPD include reducing exposure to risk factors; improving lung function, exercise tolerance, and quality of life; and decreasing exacerbations and mortality. Pharmacologic treatments, such as inhaled β2-agonists, anticholinergics, and inhaled corticosteroids, are widely used to help achieve these goals. In addition to efficacy, medication safety is an important consideration in selecting COPD treatments. Clinical trials conducted in support of the regulatory review and approval process establish the general efficacy and tolerability of pharmacologic treatments for COPD, and these data are reflected in product labeling. Following approval, further research continues to provide more data with longer follow-up and in broader settings than feasible in clinical trials. These data add to our knowledge of the efficacy of medications. Understanding medication safety requires assessment of the quality and appropriateness of study design, as well as knowledge of study findings, and is of paramount importance in making sound clinical judgments in the treatment of patients with COPD. In recent years, a wealth of data on COPD medications has been published from different sources, including randomized clinical trials, meta-analyses, systematic reviews, and observational studies. This review discusses important considerations in interpreting data from different types of studies, summarizes the tolerability profile of COPD medications established in preapproval studies, and discusses new findings from more recent postapproval data.

Topics in Practice Management

Chest. 2013;144(4):1368-1375. doi:10.1378/chest.12-2508

The high costs of American health care, the related problem of the uninsured, and the grim fiscal prognosis of Medicare and Medicaid are among the most pressing challenges facing the United States today. A solution to the cost problem that does not reduce access or quality is sought by those at all points on the political spectrum. This article discusses the experience of an independent practice association that has collaborated with a related business partner and a health plan to improve the quality of care of 16,000 Medicare Advantage beneficiaries while substantially reducing hospitalization rates and overall service use. The capacity to reduce service use frees funds that are used to support the infrastructure for high-value care and to reward those who provide it. Higher performing primary care, supported by changes in payment, has driven a sustainable business model that preserves the option of independent practice for physicians. We are now testing competencies developed for Medicare Advantage in the Pioneer Accountable Care Organization program, which preserves the broad patient choice that is an important feature of traditional Medicare.

Selected Reports

Chest. 2013;144(4):1376-1378. doi:10.1378/chest.13-0239

The cystic fibrosis (CF) protein forms an anion channel in epithelial cells, and the absence or defective function of this channel results in the clinical manifestations of CF. CF is an autosomal recessive disorder, and its many disease-causing mutations divide into five or six classes. There are 10 known class 3 gating mutations, the most common of which is G551D. Ivacaftor is a drug that in vitro increases open time and transepithelial chloride transport in all 10 gating mutations, but it is approved for use only in patients with the G551D mutation. We report complete normalization of sweat chloride concentration and rapid clinical improvement over 6 weeks of treatment with ivacaftor in a patient with CF with the gating mutation S549N. The findings suggest that ivacaftor should be considered for use in patients with any of the known gating mutations.

Chest. 2013;144(4):1378-1380. doi:10.1378/chest.12-2950

A protocol was originally designed to study breathing control during and following cardiac arrest in humans, taking advantage of the period of pulseless ventricular fibrillation (PVF) produced while testing a newly implanted cardioverter-defibrillator device. A patient aged in his 60s with New York Heart Association class III heart failure (HF) (left ventricular ejection fraction of 25%) who was originally part of this study displayed permanent periodic breathing (PB) and was then excluded from the final data analysis; his response is presented in this report. The 8- to 9-s PVF was incidentally produced during the ascending phase of a PB cycle, followed by another 12-s recovery period of low BP. PVF and its recovery had no effect on PB characteristics (period or amplitude). This occurred despite a profound change in Paco2, cerebral blood flow, and perfusion of the carotid bodies. It is concluded that PB in patients with HF could be produced by primary oscillations originating from the central pattern generator.

Postgraduate Education Corner: Contemporary Reviews in Critical Care Medicine

Chest. 2013;144(4):1381-1387. doi:10.1378/chest.13-0395

Increasing numbers of patients survive traumatic brain injury (TBI) and cardiopulmonary arrest and resuscitation and are admitted to the ICU in coma. Some of these patients become brain dead; others regain consciousness. Still others become vegetative or minimally conscious, conditions called chronic disorders of consciousness and ultimately are cared for outside the ICU. Comatose patients lack the wakefulness and awareness that distinguish consciousness from unconsciousness. Vegetative patients are awake in that they manifest sleep-wake cycles, but they are unaware of their environment and cannot respond to stimuli. Minimally conscious patients are awake, aware to a limited extent, and somewhat responsive. The diagnosis of the vegetative and minimally conscious states has been based largely on their behavioral and pathologic features, and it has been believed that vegetative patients remain in that condition permanently. Nevertheless, EEG and neuroimaging studies suggest that the traditional diagnostic approach is imprecise. Moreover, clinical investigations have revealed that some vegetative patients can become minimally conscious and that some minimally conscious patients can gain increased awareness. Few therapies for patients with chronic disorders of consciousness have been subjected to randomized trials. Furthermore, although a small number of patients have improved neurologically with or without treatment, their overall prognosis for neurologic recovery remains poor.

Chest. 2013;144(4):1388-1393. doi:10.1378/chest.13-0428

Increasing numbers of patients survive traumatic brain injury and cardiopulmonary arrest and resuscitation and are admitted to the ICU while in coma. Some of these patients become brain dead; others regain consciousness. Still others become vegetative or minimally conscious, conditions called chronic disorders of consciousness and ultimately can be cared for outside the ICU. Whether these patients would want life-sustaining therapy is difficult to determine because most have not articulated their wishes before becoming comatose. Ethics and law recognize that patients with decision-making capacity have a right to refuse such therapy and that surrogates can exercise this right for them through the principle of substituted judgment as was established by the Supreme Court of New Jersey in the case of Karen Ann Quinlan. In its decision regarding Nancy Cruzan, the US Supreme Court determined that states may require clear and convincing evidence of a vegetative patient’s prior wishes before life-sustaining therapy may be withdrawn; this standard has been applied to minimally conscious patients by state supreme courts in some cases. Nevertheless, cases such as these only come to the legal system because end-of-life decisions are contested, which is unusual, and most end-of-life decisions for specific patients with chronic disorders of consciousness are made by surrogates with recommendations from physicians without court involvement. Recent advances in neuroimaging may influence both end-of-life decision-making and legal deliberations. Targeting vegetative and minimally conscious patients in medical resource allocation remains ethically unacceptable and untested in the law.

Postgraduate Education Corner: Contemporary Reviews in Sleep Medicine

Chest. 2013;144(4):1394-1401. doi:10.1378/chest.12-2963

Air travel is a common mode of transportation in today’s society, particularly for individuals traveling long distances. Sleep disturbances associated with air travel frequently result in cognitive and physiologic impairments that may be detrimental to the traveler’s experience and intent. A primary consequence of air travel is the development of acute sleep deprivation, which may result in reduced attention/vigilance, alteration in mood states, diminished memory processing, and alteration in executive function. Along with and contributing to acute sleep deprivation, circadian rhythm misalignment resulting in jet lag disorder (JLD) is frequently encountered by air travelers traversing multiple time zones. JLD is characterized by insomnia or excessive daytime sleepiness associated with physical or mental impairment associated with travel. This review focuses on the neurocognitive manifestations of acute sleep deprivation and the pathophysiology and treatment of JLD to provide the practicing clinician a greater understanding of the sleep abnormalities manifest in air travelers. Treatment recommendations for the traveler, including the use of light/melatonin therapy, sleep scheduling, and pharmacologic aids for both sleep and alertness, are provided.

Postgraduate Education Corner: Pulmonary, Critical Care, and Sleep Pearls

Chest. 2013;144(4):1402-1405. doi:10.1378/chest.13-0390

A 46-year-old man with no notable medical history presented with a swollen left leg to the ED of a secondary care center. DVT and cellulitis were excluded, and he went home. Several days later, he returned with complaints of dyspnea during exertion, a dry cough, and bilateral lower limb edema. Physical examination showed signs of right-sided congestive heart failure. Subsequent diagnostic assessment excluded pulmonary embolism but demonstrated cephalization of pulmonary vessels, bilateral pleural effusion, hepatic congestion, and elevated N-terminal pro-brain natriuretic peptide levels. Cardiac evaluation demonstrated a normal ECG and no abnormalities on echocardiography, and right-sided heart catheterization was later performed. Meanwhile, the patient had responded well to the initiated loop diuretic with resolution of the dyspnea and pleural effusion. However, the swollen left leg persisted and became painful, which prevented him from going to work. Two months later, the lack of a satisfactory explanation for the clinical picture prompted referral to our tertiary care center.

Chest. 2013;144(4):1406-1409. doi:10.1378/chest.13-0647

Postgraduate Education Corner: Chest Imaging and Pathology for Clinicians

Chest. 2013;144(4):1411-1416. doi:10.1378/chest.12-2642

A 48-year-old woman presented to the ED with headache, nausea, and fever of 2-day duration. She denied any other symptoms, except for some vague malaise and fatigue for several weeks prior to presentation. She denied dyspnea, cough, chest pain, rash, joint swelling, and bruising.

Postgraduate Education Corner: Ultrasound Corner

Chest. 2013;144(4):e1-e4. doi:10.1378/chest.13-0803

A 44-year-old man presented to our ED with progressive shortness of breath and left-sided pleuritic chest pain. His history was remarkable for alcohol and tobacco abuse. On examination, his vital signs were stable except for sinus tachycardia (119 beats/min). Laboratory values for cardiac markers were within normal limits, and chest roentgenogram was notable for a wedge-shaped infiltrate (Fig 1). Acute pulmonary embolism (PE) was suspected, and CT pulmonary angiography (CTPA) was performed. The CTPA showed multiple PEs in segmental branches and wedge-shaped infarcts in the bilateral lower lobes (Fig 2). In addition, a mass was noted near the periphery of the right hepatic lobe, suspicious for a malignancy (Fig 3). The patient was treated for acute PE with heparin and transitioned to warfarin. In addition, investigations were undertaken to further characterize the liver mass. Biopsy of the liver mass was deferred because of the immediate need for anticoagulation and was scheduled to be obtained as an outpatient. The patient was discharged with improvement in his symptoms.


Chest. 2013;144(4):1417. doi:10.1378/chest.13-0403

We talk about the incision line, and how the sutures
will cover the butterfly tattoo she hid from her father at fifteen;
and whether stage three is considered late;
and how the anesthesiologist will help her sleep,
and when the drip stops        how she’ll likely come back
hulling the blue air like wheat.
She counted seven, back from ten; her skin, the color of rain,
      and the blade guttered.

Chest. 2013;144(4):1417. doi:10.1378/chest.13-0416

With her finger touching the pink
and purple diagram, the doc explains
dye will flow through milk ducts
to the Sentinel Lymph Nodes,
making tracer stains
where the scalpel must go.
She doesn’t need to say that cells
are pawns of nature’s lunatic changes,
that no one’s guilty,
nor that years nuzzling those
little packages
wrapped in baby blankets
failed to protect the breast.
Something in you opened,
your cup runneth over
and emptied.
We’re here now, she says,
whatever the past was.
Get dressed. Don’t fret.
And so,
you comb through her brisk words
and find she’s right, death backs off,
while inside, seething, voracious
cells keep eating estrogen,
growing fat from your bruised,
but still intact, breast.


Chest. 2013;144(4):1418. doi:10.1378/chest.13-1320
Chest. 2013;144(4):1418-1419. doi:10.1378/chest.13-1517
Chest. 2013;144(4):1419-1420. doi:10.1378/chest.13-1321
Chest. 2013;144(4):1420-1421. doi:10.1378/chest.13-1350
Chest. 2013;144(4):1421-1422. doi:10.1378/chest.13-1342
Chest. 2013;144(4):1422. doi:10.1378/chest.13-1752
Chest. 2013;144(4):1423. doi:10.1378/chest.13-1332
Chest. 2013;144(4):1423-1424. doi:10.1378/chest.13-1515
Chest. 2013;144(4):1424. doi:10.1378/chest.13-1366
Chest. 2013;144(4):1424-1426. doi:10.1378/chest.13-1728
Chest. 2013;144(4):1426. doi:10.1378/chest.13-1399
Chest. 2013;144(4):1426-1427. doi:10.1378/chest.13-1631


Chest. 2013;144(4):1428. doi:10.1378/chest.13-1892

The article “Prevention of VTE in Nonsurgical Patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (February 2012; 141[2][Suppl]e195S-e226S) contained an error in the rating of the quality of evidence in tables 18 and the online supplementary table S21. The rating should have been low not moderate, due to increased risk of bias and imprecision.

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