Chest. 2013;143(5):1193-1195. doi:10.1378/chest.12-3108

Despite advancements in screening, diagnostics, and treatment, lung cancer remains the leading cause of cancer death in men and women in the United States with a 16% overall 5-year survival rate.1 The third edition of the American College of Chest Physicians (ACCP) Lung Cancer Guidelines, which accompanies this issue of CHEST (http://journal.publications.chestnet.org/issue.aspx?volume=143&issue=5_suppl), reflect a new era in screening, diagnostic, and staging modalities, treatment based on histology and mutation analysis, and novel approaches like stereotactic body radiotherapy (SBRT). Ideally, pulmonologists will help guide these endeavors and seize opportunities to improve patient outcomes, answer old questions, and address new challenges. While the guidelines comprehensively address screening, diagnostic, and treatment, some of the most notable are described as follows.

Chest. 2013;143(5):1195-1196. doi:10.1378/chest.12-2729

The widespread use of antibiotics has been paralleled by the development of resistance in bacteria. It is, thus, necessary for us to use antibiotics wisely and appropriately. Getting therapy right the first time has been crucial in improving outcomes in severe infections, reducing all-cause 30-day mortality and hospital length of stay. Knowing your local organisms and susceptibilities is crucial to getting it right the first time.1 This will largely determine your antibiotic choices. In turn, overuse of antibiotics will drive more resistance.

Chest. 2013;143(5):1196-1198. doi:10.1378/chest.12-2776

Occupational asthma (OA) resulting from sensitization at work has implications for the patient that include not only medical management but also changes at work to completely avoid further exposure to the causal agent and optimize asthma outcome.1-4 Occasionally, the workplace can remove the causative sensitizing agent, but often, this is not considered feasible. In a large company, the affected worker may be moved to a different location, to a job with no further exposure. However, in many cases, especially within smaller companies, OA results in the worker leaving the workplace. Despite support from workers’ compensation systems, OA has been associated with a significant negative psychosocioeconomic impact.5,6

Chest. 2013;143(5):1198-1199. doi:10.1378/chest.12-2884

In this issue of CHEST (see page 1277), Bazan and colleagues1 examine the link between obstructive sleep apnea (OSA) and recurrent atrial arrhythmias in patients undergoing catheter ablation for the treatment of typical right atrial flutter (AF). All subjects underwent a sleep-study evaluation after a cavotricuspid isthmus ablation; 82% had OSA. CPAP was initiated in those with the highest apnea-hypopnea index (AHI), involving about one-half of the patients. Atrial fibrillation (AFib) was noted in 38% of patients during follow-up in the first year postablation, with less than one-half being “new” diagnoses of AFib. The authors demonstrated that CPAP treatment of OSA did not reduce the overall AFib rate but was associated with lower rates of new-onset AFib in these patients postablation.

Second Opinion

Chest. 2013;143(5):1200. doi:10.1378/chest.143.5.1200

Point/Counterpoint Editorials

Chest. 2013;143(5):1201-1203. doi:10.1378/chest.13-0217

Every year, roughly 400 Americans experience a spinal cord injury (SCI) that requires long-term invasive mechanical ventilation. Their cost of care is ≥ $100,000 (US) per year, and their life expectancy is 50% less than their counterparts who do not require invasive mechanical ventilation.1

Chest. 2013;143(5):1203-1206. doi:10.1378/chest.13-0219

The incidence of long-term ventilator assistance in patients with spinal cord injury (SCI) has increased from 1990, rising to 43,700 cases per year in 1998 likely because of better available treatment plans.1 More than $8 billion per year is spent on SCI care in the United States after the first year of injury, and respiratory complications comprise the number one cause of morbidity and mortality in SCI.2 The majority of patients with SCI are male, aged <30 years, and, as expected, the leading causes of death are pneumonia, pulmonary emboli, and septicemia. As of February 2011, the National Spinal Cord Injury Statistical Center3 estimated that 232,000 to 316,000 patients in the United States are living with SCI. Of the 12,000 new cases per year, >2,700 patients with tetraplegia will require extended ventilator support. Ultimately, 2,000 will wean from ventilators, and 500 high tetraplegic injuries will result in permanent mechanical ventilator dependency.

Chest. 2013;143(5):1206. doi:10.1378/chest.13-0218

Dr Gay1 has shared some interesting points. Many of his arguments hinge on the assumption that all patients with tracheostomy and spinal cord injury (SCI) have the option of using an alternative to either mechanical ventilation or diaphragm pacing support (DPS). This alternative would be noninvasive ventilation (NIV) and aggressive airway clearance, including mechanical cough assist. In reality, those patients with SCI who do not require invasive mechanical ventilation are not even considered candidates for DPS. If even 4 h of spontaneous breathing is possible, DPS is excluded,2 and 24-h NIV when there is no use of hands is possible but may not be practical. Dr Gay1 also states that mechanical ventilation with a Passy-Muir valve (Passy-Muir Inc) provides completely normal speech, but the use of a Passy-Muir valve may not be safe in all patients because of secretions that may obstruct the valve, and speech without the valve is unnatural because it occurs mainly during inhalation. In addition, many patients have an intolerance to the added resistance of the Passy-Muir valve, and fenestrated tubes are not an adequate compensation because they may promote aggressive leak compensation, even risking respiratory alkalosis and seizure. In the best of situations, leak speech using mechanical ventilation does not produce adequate speech.3

Chest. 2013;143(5):1206-1207. doi:10.1378/chest.13-0220

Dr Wolfe1 and I2 have discussed whether a diaphragm pacing support (DPS) system is the treatment of choice for patients with spinal cord injury (SCI) in terms of technical aspects, costs, safety, ethics, and, most importantly, data to answer the primary question of what is the treatment of choice. We will further examine these arguments, beginning with the technical issues, but the emphasis must be on the available data and whether treatment outcome issues are completely clarified to this date. I again contend that they are not at this time, but like most debates, the truth is not always black and white.


Chest. 2013;143(5):1208-1213. doi:10.1378/chest.12-2881

For 2 decades, long-acting β-agonists (LABAs) have been associated with increased asthma-related death risks in several randomized trials, even when added to inhaled corticosteroids (ICSs). In reaction, the US Food and Drug Administration (FDA) recently mandated that the manufacturers of LABAs conduct five large, noninferiority, randomized trials of the LABA+ICS combination in 53,000 patients with asthma. Three methodologic issues in these trials could lead to masking of or falsely detecting elevated risks. First, the effect of LABA discontinuation among the many patients already using these drugs at enrollment can result in an underestimation of the relative risk by a factor of around 20%. This effect will bias downward the upper bound of the resulting CI away from the preset noninferiority margin of 2.0 for the relative risk, artificially making it more difficult to detect a risk increase. Second, the composite asthma outcome will be dominated by asthma hospitalization, possibly dwarfing an increased risk of asthma-related death, with differences as wide as seven deaths under the LABA+ICS combination vs one death under ICS alone remaining statistically uncertain. Finally, because of the multiple identical trials being requested from the different manufacturers of LABAs, even if each trial is powered at 90%, there is a 41% likelihood that at least one of the trials will not rule out a risk increase when, in truth, there is no risk increase. In view of these impediments, the FDA should preempt such complexities by establishing decision rules regarding the interpretation of the results from these momentous safety trials before their completion, expected in 2017.

Chest. 2013;143(5):1214-1218. doi:10.1378/chest.13-0066

In 2013, the outpatient hospital payment from Medicare for a transbronchial needle aspiration more than doubled. At the same time, the recently updated American College of Chest Physicians guidelines for the diagnosis and management of lung cancer now recommend needle techniques, such as transbronchial needle aspiration, over surgical staging. The convergence of these two events will accelerate the existing forces of technology and economics that have been influencing both the practices of outpatient bronchoscopy and mediastinoscopy and the management of patients with lung cancer over the past 20 years.

Original Research: Critical Care

Chest. 2013;143(5):1219-1225. doi:10.1378/chest.12-1361

Background:  Comatose patients present a high risk of early-onset ventilator-associated pneumonia (EO-VAP) for which antibiotic prophylaxis has been proposed. Comatose patients were studied to evaluate the efficacy of a single-dose of antibiotic prophylaxis at intubation against EO-VAP.

Methods:  A prospective cohort of comatose patients (Glasgow Coma Score ≤ 8) who were admitted in 2009-2010 and administered a single-dose of antibiotic within 4 h of intubation was compared with comatose patients (admitted ≥ 4 h after intubation in 2009-2010 or admitted in 2007-2008) who did not receive antibiotic prophylaxis. We analyzed the incidence of EO-VAP, late-onset VAP, and ventilator-associated tracheobronchitis in both groups. Propensity scores for receiving antibiotic prophylaxis were derived on the basis of patients’ characteristics (eg, age and severity) to assess its impact on EO-VAP development.

Results:  We included 129 patients (71 in the prophylaxis group and 58 in the control group). The global incidence of VAP and incidence of EO-VAP were lower in the prophylaxis group: 10.8 vs 28.4 episodes/1,000 days on mechanical ventilation (P = .015) and 4.4 vs 23.1 episodes/1,000 days on mechanical ventilation (P = .02), respectively. The incidence of late-onset VAP did not differ. The prophylaxis group tended toward lower incidence of ventilator-associated tracheobronchitis (15.5% vs 25.9%, P = .14). No differences in mortality were found between groups. The propensity-score regression analysis confirmed that a single dose of antibiotic prophylaxis was independently associated with lower incidence of EO-VAP (OR, 0.11; 95% CI, 0.02-0.58; P = .009).

Conclusions:  A single dose of antibiotic prophylaxis at intubation might lower the incidence of EO-VAP. However, a randomized clinical trial should be conducted to confirm our findings.

Chest. 2013;143(5):1226-1234. doi:10.1378/chest.12-2072

Background:  Optimal glucose management in the ICU remains unclear. In 2009, many clinicians at Intermountain Healthcare selected a moderate glucose control (90-140 mg/dL) instead of tight glucose control (80-110 mg/dL). We hypothesized that moderate glucose control would affect patients with and without preexisting diabetes differently.

Methods:  We performed a retrospective cohort analysis of all patients treated with eProtocol-insulin from November 2006 to March 2011, stratifying for diabetes. We performed multivariate logistic regression for 30-day mortality with covariates of age, modified APACHE (Acute Physiology and Chronic Health Evaluation) II score, Charlson Comorbidity score, and target glucose.

Results:  We studied 3,529 patients in 12 different ICUs in eight different hospitals. Patients with diabetes had higher mean glucose (132 mg/dL vs 124 mg/dL) and greater glycemic variability (SD = 41 mg/dL vs 29 mg/dL) than did patients without diabetes (P < .01 for both comparisons). Tight glucose control was associated with increased frequency of moderate and severe hypoglycemia (30.3% and 3.6%) compared with moderate glucose control (14.3% and 2.0%, P < .01 for both). Multivariate analysis demonstrated that the moderate glucose target was independently associated with increased risk of mortality in patients without diabetes (OR, 1.36; 95% CI, 1.01-1.84; P = .05) but decreased risk of mortality in patients with diabetes (OR, 0.65; 95% CI, 0.45-0.93; P = .01).

Conclusions:  Moderate glucose control (90-140 mg/dL) may confer greater mortality in critically ill patients without diabetes compared with tight glucose control (80-110 mg/dL). A single glucose target does not appear optimal for all critically ill patients. These data have important implications for the design of future interventional trials as well as for the glycemic management of critically ill patients.

Chest. 2013;143(5):1235-1242. doi:10.1378/chest.12-2112

Background:  The incidence and outcomes of disseminated intravascular coagulation (DIC) are incompletely defined. Therefore, we aimed to evaluate the trends in incidence and outcomes of critically ill patients with DIC.

Methods:  We conducted a population-based, retrospective cohort study evaluating consecutively admitted adult (≥ 18 years old) critically ill patients with DIC at the Mayo Clinic, Minnesota, from 2004 to 2010. DIC was diagnosed according to the International Society on Thrombosis and Hemostasis’ overt DIC algorithm. Patients given a diagnosis of heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura, Child Pugh class C, or any known congenital or acquired coagulation disorders were excluded.

Results:  Of the 8,089 Olmsted County resident ICU admissions, a total of 154 patients met the DIC inclusion criteria. The overall incidence rate of DIC/100,000 person-years decreased from 26.2 (95% CI, 17.1-38.4) in 2004 to 18.6 (95% CI, 11.3-28.7) in 2010. The incidence rate of DIC increased with age in both men and women and was consistently higher in men, with the exception of the age group 18 to 39 years. The incidence rate/100,000 person-years of DIC in men decreased from 41.6 (95% CI, 25.4-64.2) in 2004 to 21.2 (95% CI, 10.6 37.9) in 2010 (P = .01), whereas in women, it did not change significantly (P = .79). The case fatality rate did not change significantly during the study period.

Conclusions:  The incidence of DIC has decreased over the past decade, significantly in men, although the mortality rate remains the same. This is in agreement with trends in other critical care syndromes and could be attributable to improvements in health care delivery.

Chest. 2013;143(5):1243-1251. doi:10.1378/chest.12-0574

Objective:  Communication is a major issue for patients with tracheostomy who are supported by mechanical ventilation. The use of positive end-expiratory pressure (PEEP) may restore speech during expiration; however, the optimal PEEP level for speech may vary individually. We aimed to improve speech quality with an individually adjusted PEEP level delivered under the patient’s control to ensure optimal respiratory comfort.

Methods:  Optimal PEEP level (PEEPeff), defined as the PEEP level that allows complete expiration through the upper airways, was determined for 12 patients with neuromuscular disease who are supported by mechanical ventilation. Speech and respiratory parameters were studied without PEEP, with PEEPeff, and for an intermediate PEEP level. Flow and airway pressure were measured. Microphone speech recordings were subjected to both quantitative and qualitative assessments of speech, including an intelligibility score, a perceptual score, and an evaluation of prosody determined by two speech therapists blinded to PEEP condition.

Results:  Text reading time, phonation flow, use of the respiratory cycle for phonation, and speech comfort significantly improved with increasing PEEP, whereas qualitative parameters remained unchanged. This resulted mostly from the increase of the expiratory volume through the upper airways available for speech for all patients combined, with a rise in respiratory rate for nine patients. Respiratory comfort remained stable despite high levels of PEEPeff (median, 10.0 cm H2O; interquartile range, 9.5-12.0 cm H2O).

Conclusions:  Patient-controlled PEEP allowed for the use of high levels of PEEP with good respiratory tolerance and significant improvement in speech (enabling phonation during the entire respiratory cycle in most patients). The device studied could be implemented in home ventilators to improve speech and, therefore, autonomy of patients with tracheostomy.

Trial registry:  ClinicalTrials.gov; No.: NCT01479959; URL: clinicaltrials.gov

Chest. 2013;143(5):1252-1260. doi:10.1378/chest.12-2058

Background:  Mechanical ventilation used in patients with acute lung injury can damage pulmonary epithelial cells through production of inflammatory cytokines and excess deposition of the extracellular matrix protein lumican. Lumican participates in macrophage inflammatory protein (MIP)-2 and transforming growth factor-β1 (TGF-β1) signaling during the fibroproliferative phase of acute lung injury, which involves a process of epithelial-mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and lung injury are unclear. We hypothesized that lung damage and EMT by high tidal volume (Vt) mechanical stretch causes upregulation of lumican that modulates MIP-2 and TGF-β1 through the extracellular signal-regulated kinase (ERK) 1/2 pathway.

Methods:  Male C57BL/6 mice (either wild type or lumican null) aged 3 months and weighing between 25 and 30 g were exposed to low Vt (6 mL/kg) or high Vt (30 mL/kg) mechanical ventilation with room air for 2 to 8 h. Nonventilated mice were used as control subjects.

Results:  We found that high Vt mechanical ventilation increased microvascular permeability, neutrophil influx, production of free radicals, MIP-2 and TGF-β1 proteins, positive staining of α-smooth muscle actin and S100A4/fibroblast-specific protein-1, Masson trichrome staining and extracellular collagen, and activation of lumican and ERK1/2 in wild-type mice. Decreased staining of the epithelial marker E-cadherin was also observed. Mechanical stretch-augmented EMT was attenuated with lumican-deficient mice and pharmacologic inhibition of ERK1/2 activity by PD98059.

Conclusions:  The data suggest that lumican promotes high Vt mechanical ventilation-induced lung injury and EMT through the activation of the ERK1/2 pathway.

Original Research: Asthma

Chest. 2013;143(5):1261-1268. doi:10.1378/chest.12-1983

Background:  Specific inhalation challenges (SICs) with occupational agents are used to establish the diagnosis and etiology of occupational asthma. The aim of this study was to assess the frequency and determinants of severe asthmatic reactions induced by various occupational agents during SICs performed using realistic methods of exposure.

Methods:  The SIC records of 335 consecutive subjects with a positive SIC (ie, ≥ 20% fall in FEV1) due to various occupational agents were reviewed. Asthmatic reactions were graded as moderate when requiring repeated administration of an inhaled short-acting β2-agonist (SABA) and severe when requiring repeated SABA and systemic corticosteroids.

Results:  Overall, 68 of the 335 subjects (20%) required an inhaled SABA during the SICs. The multivariate logistic regression analysis showed that the need for an inhaled SABA increased when the SIC involved a low-molecular-weight agent (LMW) (OR, 2.47; 95% CI, 1.43-4.28) and marginally so when the subjects required regular treatment with an inhaled corticosteroid (OR, 1.62; 95% CI, 0.93-2.80). The severity of asthmatic reactions was graded as moderate in 12% and severe in 3% of the subjects. Of the 10 severe reactions, five developed after exposures ≤ 5 min. Multivariate logistic regression analysis showed that challenging subjects with a LMW agent was the only significant determinant for the development of moderate/severe reactions (OR, 3.05; 95% CI, 1.62-5.73).

Conclusions:  Challenges with LMW agents are associated with a higher risk of an asthmatic reaction requiring pharmacologic treatment. This study may provide useful guidelines for further improving the safety of SICs.

Chest. 2013;143(5):1269-1276. doi:10.1378/chest.12-1374

Background:  Fractional exhaled nitric oxide measured at expiratory flow of 50 mL/s (Feno50), a biomarker of airway inflammation, is affected by changes in airway caliber. Whether a lower Feno50 level during bronchoconstriction is only an artifact due to the strong flow dependence of this parameter is controversial.

Methods:  We aimed to evaluate the dynamics of airway and alveolar nitric oxide (NO) during acute bronchoconstriction induced by methacholine. Exhaled NO was measured at expiratory flows of 10, 50, 100, 150, and 250 mL/s before and after metacholine in 26 responders to methacholine and 37 nonresponders. Flow-independent parameters (airway wall NO flux, airway NO diffusing capacity, airway wall NO concentration, alveolar NO concentration) were calculated using a two-compartment model, and correction for NO axial back diffusion was applied.

Results:  Bronchoconstriction in responders was associated with a decrease in Feno50 (−28%, P < .0001), in airway wall NO flux (−34%, P < .0001), and in airway NO diffusing capacity (−15%, P < .05). In contrast, alveolar NO concentration was not affected by bronchoconstriction. Postmethacholine changes in Feno50 were more strictly related to the ventilation distribution, assessed by single-breath carbon monoxide uptake, than to larger airways caliber, assessed by FEV1. When bronchoconstriction was reversed by salbutamol, airway wall NO flux and airway NO diffusing capacity returned to values comparable to those measured premethacholine.

Conclusions:  The changes in airway caliber induced by noninflammatory stimuli alter NO transport in the lung. The changes in NO dynamics are limited to conductive airways and are characterized by a reduction of NO flow to luminal space.

Original Research: Sleep Disorders

Chest. 2013;143(5):1277-1283. doi:10.1378/chest.12-0697

Background:  The clinical yield of cavotricuspid isthmus (CTI) radiofrequency ablation of atrial flutter (AF) is limited by a high incidence of atrial fibrillation (AFib) in the long term. Among other acknowledged variables, the association of obstructive sleep apnea (OSA) could favor incomplete arrhythmia control in this setting. We assessed the impact of CPAP in reducing the occurrence of AFib after CTI ablation.

Methods:  Consecutive patients with AF who were undergoing CTI ablation were screened for OSA. Relationship of the following variables with the occurrence of AFib during follow-up (12 months) was investigated: CPAP initiation, hypertension, BMI, underlying structural heart disease, left atrial diameter, and AFib documentation prior to ablation.

Results:  We prospectively included 56 patients (mean age: 66 (± 11) years; 12 female patients), of whom 46 (82%) had OSA and 25 (45%) had severe OSA. Twenty-one patients (38%) had AFib during follow-up after CTI ablation. Both freedom from AFib prior to ablation and CPAP initiation in those patients without previously documented AFib at inclusion were associated with a reduction of AFib episodes during follow-up (P = .019 and P = .025, respectively). Inversely, CPAP was not protective from AFib recurrence when this arrhythmia was documented prior to ablation (P = .25).

Conclusions:  OSA is a prevalent condition in patients with AF. Treatment with CPAP is associated with a lower incidence of newly diagnosed AFib after CTI ablation. Screening for OSA in patients with AF appears to be a reasonable clinical strategy.

Chest. 2013;143(5):1284-1293. doi:10.1378/chest.12-1132

Background:  The STOP-Bang questionnaire is a validated screening tool for the identification of surgical patients with obstructive sleep apnea (OSA). A STOP-Bang score ≥ 3 is highly sensitive but only moderately specific. Apnea/hypopnea during sleep can lead to intermittent hypercapnia and may result in serum bicarbonate (HCO3) retention. The addition of serum HCO3 level to the STOP-Bang questionnaire may improve its specificity.

Methods:  Four thousand seventy-seven preoperative patients were approached for consent and screened by the STOP-Bang questionnaire. Polysomnography was performed and preoperative HCO3 level was collected in 384 patients. Study participants were randomly assigned to a derivation or validation cohort. Predictive parameters (sensitivity, specificity, positive and negative predictive values) for STOP-Bang score and serum HCO3 level were calculated.

Results:  In the derivation cohort, with a STOP-Bang score ≥ 3, the specificity for all OSA, moderate/severe OSA, and severe OSA was 37.0%, 30.4%, and 27.7%, respectively. HCO3 level of 28 mmol/L was selected as a cutoff for analysis. With the addition of HCO3 level ≥ 28 mmol/L to the STOP-Bang score ≥ 3, the specificity for all OSA, moderate/severe OSA, and severe OSA improved to 85.2%, 81.7%, and 79.7%, respectively. Similar improvement was observed in the validation cohort.

Conclusion:  Serum HCO3 level increases the specificity of STOP-Bang screening in predicting moderate/severe OSA. We propose a two-step screening process. The first step uses a STOP-Bang score to screen patients, and the second step uses serum HCO3 level in those with a STOP-Bang score ≥ 3 for increased specificity.

Chest. 2013;143(5):1294-1301. doi:10.1378/chest.12-1930

Background:  Sleep-disordered breathing (SDB) may promote an increase in cardiac workload early after acute myocardial infarction (AMI). We tested the hypothesis that in the early phase after AMI, SDB is associated with increased 24-h arterial BP, heart rate (HR), and, thus, cardiac workload.

Methods:  In this prospective study, 55 consecutive patients with AMI and subsequent percutaneous coronary intervention (78% men; mean age, 54 ± 10 y; mean BMI, 28.3 ± 3.6 kg/m2; mean left ventricular ejection fraction [LVEF], 47% ± 8%) underwent polysomnography and 24-h ambulatory BP and heart rate monitoring within 5 days after MI. Cardiac workload was calculated as systolic BP multiplied by HR. The presence of SDB was defined as ≥ 10 apneas and hypopneas per hour of sleep.

Results:  Fifty-five percent of the patients had SDB, of which 40% was predominantly central in nature. Patients with SDB had higher 24-h HR and systolic and diastolic BP compared with those without SDB (115 vs 108 mm Hg, P = .029; 71 vs 67 mm Hg, P = .034; 69 vs 64 beats/min, P = .050, respectively). Use of antihypertensive medication and β-receptor blockers was similar in both groups. In a multivariate linear regression analysis, SDB was significantly associated with an increased 24-h cardiac workload (β-coefficient, 0.364; 95% CI, 0.071-0.657; P = .016), independently of age, sex, BMI, LVEF, and antihypertensive medication.

Conclusion:  Patients with AMI and SDB have significantly increased 24-h BP, HR, and cardiac workload. Treatment of SDB may be a valuable nonpharmacologic approach to lower cardiac workload in these patients.

Original Research: COPD

Chest. 2013;143(5):1302-1311. doi:10.1378/chest.12-1489

Background:  COPD exacerbations are associated with increased morbidity and mortality and can accelerate disease progression. The best predictor of future exacerbations is a history of previous exacerbations, which helps identify a frequent exacerbator phenotype. This post hoc analysis evaluated the effect of roflumilast, a drug known to reduce the COPD exacerbation rate, on exacerbation status.

Methods:  Pooled data from two 1-year, placebo-controlled, roflumilast (500 μg once daily) studies in patients with symptomatic COPD and severe airflow obstruction were evaluated (studies M2-124 and M2-125, ClinicalTrials.gov identifiers NCT00297102 and NCT00297115). A total of 3,091 patients were included in this analysis (62.5% with GOLD [Global Initiative for Chronic Obstructive Lung Disease] III COPD and 29.2% with GOLD 4 COPD). Based on their exacerbation frequency status in the previous year, patients were classified as frequent (two or more events) or infrequent (fewer than two events) exacerbators. Exacerbation frequency was analyzed at baseline and at year 1.

Results:  Among frequent exacerbators treated with roflumilast, 32.0% still had frequent exacerbations at year 1 compared with 40.8% of placebo-treated patients (risk ratio, 0.799; P = .0148). Among infrequent exacerbators, 17.5% of roflumilast-treated patients became frequent exacerbators at year 1 compared with 22.9% of those taking placebo (risk ratio, 0.768; P = .0018). The reduction in severe exacerbations leading to hospitalization/death was similar between subgroups and occurred independently of concomitant long-acting β2-agonists or previous inhaled corticosteroid treatment. When analyzed by severity of airflow limitation, 26.4% of roflumilast-treated frequent exacerbators with GOLD III COPD remained frequent exacerbators at year 1 compared with 38.9% of those taking placebo (P = .0042).

Conclusions:  Treatment with roflumilast shifts patients from the frequent to the more stable infrequent exacerbator state.

Trial registry:  ClinicalTrials.gov; No.: NCT00297102 and NCT00297115; URL: www.clinicaltrials.gov

Chest. 2013;143(5):1312-1320. doi:10.1378/chest.12-1770

Background:  COPD and hypertension both increase the risk of congestive heart failure (CHF). Current clinical trials do not inform the selection of combination antihypertensive therapy among patients with COPD. We performed a comparative effectiveness study to investigate whether choice of dual agent antihypertensive therapy is associated with risk of hospitalization for CHF among patients with these two conditions.

Methods:  We identified a cohort of 7,104 patients with COPD and hypertension receiving care within Veterans Administration hospitals between January 2001 and December 2006, with follow-up through April 2009. We included only patients prescribed two antihypertensive medications. We used Cox proportional hazard models for statistical analysis.

Results:  Compared with β-blockers plus an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, patients prescribed a thiazide diuretic plus a β-blocker (adjusted hazard ratio [HR], 0.49; 95% CI, 0.32-0.75), a thiazide plus an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (adjusted HR, 0.50; 95% CI, 0.35-0.71), and a thiazide plus a calcium channel blocker (adjusted HR, 0.55; 95% CI, 0.35-0.88) had a significantly lower risk of hospitalization for CHF. After stratification by history of CHF, we found that this association was isolated to patients without a history of CHF. Adjustment for patient characteristics and comorbidities had a small effect on risk of hospitalization. Choice of antihypertensive medication combination had no significant association with risk of COPD exacerbation.

Conclusions:  Among patients with comorbid hypertension and COPD requiring two antihypertensive agents, combination therapy that includes a thiazide diuretic was associated with a significantly lower risk of hospitalization for CHF among patients without a history of CHF.

Chest. 2013;143(5):1321-1329. doi:10.1378/chest.12-0034

Background:  Partial volume averaging and tilt relative to the scan plane on transverse images limit the accuracy of airway wall thickness measurements on CT scan, confounding assessment of the relationship between airway remodeling and clinical status in COPD. The purpose of this study was to assess the effect of partial volume averaging and tilt corrections on airway wall thickness measurement accuracy and on relationships between airway wall thickening and clinical status in COPD.

Methods:  Airway wall thickness measurements in 80 heavy smokers were obtained on transverse images from low-dose CT scan using the open-source program Airway Inspector. Measurements were corrected for partial volume averaging and tilt effects using an attenuation- and geometry-based algorithm and compared with functional status.

Results:  The algorithm reduced wall thickness measurements of smaller airways to a greater degree than larger airways, increasing the overall range. When restricted to analyses of airways with an inner diameter < 3.0 mm, for a theoretical airway of 2.0 mm inner diameter, the wall thickness decreased from 1.07 ± 0.07 to 0.29 ± 0.10 mm, and the square root of the wall area decreased from 3.34 ± 0.15 to 1.58 ± 0.29 mm, comparable to histologic measurement studies. Corrected measurements had higher correlation with FEV1, differed more between BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index scores, and explained a greater proportion of FEV1 variability in multivariate models.

Conclusions:  Correcting for partial volume averaging improves accuracy of airway wall thickness estimation, allowing direct measurement of the small airways to better define their role in COPD.

Original Research: Pulmonary Vascular Diseases

Chest. 2013;143(5):1330-1336. doi:10.1378/chest.12-0528

Background:  Pulmonary arterial hypertension (PAH) is a rare disease with a predilection for young women that is associated with right ventricular failure and premature death. PAH can complicate pregnancy with hemodynamic instability or sudden death during parturition and postpartum. Our aim was to examine the impact of PAH on pregnancy outcomes in the modern era.

Methods:  We conducted a retrospective evaluation of pregnant patients with PAH managed between 1999 and 2009 at five US medical centers. Patient demographics, medical therapies, hemodynamic measurements, manner of delivery, anesthetic administration, and outcomes were assessed.

Results:  Among 18 patients with PAH, 12 continued pregnancy and six underwent pregnancy termination. Right ventricular systolic pressure in patients managed to parturition was 82 ± 5 mm Hg and in patients with pregnancy termination was 90 ± 16 mm Hg. Six patients underwent pregnancy termination at mean gestational age of 13 ± 1.0 weeks with no maternal deaths or complications. Twelve patients elected to continue their pregnancy and were hospitalized at 29 ± 1.4 weeks. PAH-specific therapy was administered to nine (75%) at time of delivery consisting of sildenafil, IV prostanoids, or combination therapy. All parturients underwent Cesarean section at 34 weeks with one in-hospital death and one additional death 2 months postpartum for maternal mortality of 16.7%.

Conclusions:  Compared with earlier reports, maternal morbidity and mortality among pregnant women with PAH was reduced, yet maternal complications remain significant and patients should continue to be counseled to avoid pregnancy.

Chest. 2013;143(5):1337-1342. doi:10.1378/chest.12-1446

Background:  Recently, endogenous glucocorticoid excess has been identified as a risk factor for VTE. Whether exogenous use of glucocorticoids is associated with an increased risk of VTE is unclear. We aimed to quantify the risk of symptomatic pulmonary embolism (PE) in patients using corticosteroids.

Methods:  A case-control study using the PHARMO Record Linkage System, a Dutch population-based pharmacy registry, was conducted. Cases were 4,495 patients with a first hospital admission for PE between 1998 and 2008. Control subjects were 16,802 sex- and age-matched subjects without a history of PE. International Classification of Diseases codes for hospitalization were used to retrieve information on underlying conditions.

Results:  The risk of PE was highest in the first 30 days of glucocorticoid exposure (adjusted OR, 5.9; 95% CI, 2.3-3.9) and gradually decreased with increasing duration of use (OR, 1.9; 95% CI, 1.3-2.9) for long-term users (> 1 year). Low-dose glucocorticoid use (prednisolone daily dose equivalent < 5 mg) carried a twofold increased risk of PE (OR, 1.8; 95% CI, 1.3-2.4), whereas a 10-fold increased risk was observed for the highest dose of glucocorticoids (prednisolone > 30 mg) (OR, 9.6; 95% CI, 4.3-20.5). Stratification for both duration and dose of glucocorticoid showed the highest risk of PE in recently started users compared with long-term users at the time of PE, irrespective of the dose.

Conclusion:  Patients treated with oral glucocorticoids may be at an increased risk of PE, especially during the first month of exposure. This hypothesis requires confirmation in future studies.

Chest. 2013;143(5):1343-1350. doi:10.1378/chest.12-1880

Background:  The mean pulmonary artery pressure (mPAP) replaces mean systolic ejection pressure (msePAP) in the classic formula of right ventricular stroke work (RVSW) = (mPAP − RAP) × stroke volume, where RAP is mean right atrial pressure. Only the steady work is thus taken into account, not the pulsatile work, whereas pulmonary circulation is highly pulsatile. Our retrospective, high-fidelity pressure study tested the hypothesis that msePAP was proportional to mPAP, and looked at the implications for RVSW.

Methods:  Eleven patients with severe, precapillary pulmonary hypertension (PH) (six patients with idiopathic pulmonary arterial hypertension and five with chronic thromboembolic PH; mPAP = 57 ± 10 mm Hg) were studied at rest and during mild to moderate exercise. Eight non-PH control subjects were also studied at rest (mPAP = 16 ± 2 mm Hg). The msePAP was averaged from end diastole to dicrotic notch.

Results:  In the full data set (53 pressure-flow points), mPAP ranged from 14 to 99.5 mm Hg, cardiac output from 2.38 to 11.1 L/min, and heart rate from 53 to 163 beats/min. There was a linear relationship between msePAP and mPAP (r2 = 0.99). The msePAP matched 1.25 mPAP (bias, −0.5 ± 2.6 mm Hg). Results were similar in the resting non-PH group and in resting and the exercising PH group. This implies that the classic formula markedly underestimates RVSW and that the pulsatile work may be a variable 20% to 55% fraction of RVSW, depending on RAP and mPAP. At rest, RVSW in patients with PH was twice as high as that of the non-PH group (P < .05), but pulsatile work fraction was similar between the two groups (26 ± 4% vs 24 ± 1%) because of the counterbalancing effects of high RAP (11 ± 5 mm Hg vs 4 ± 2 mm Hg), which increases the fraction, and high mPAP, which decreases the fraction.

Conclusions:  Our study favored the use of an improved formula that takes into account the variable pulsatile work fraction: RVSW = (1.25 mPAP − RAP) × stroke volume. Increased RAP and increased mPAP have opposite effects on the pulsatile work fraction.

Original Research: Genetic and Developmental Disorders

Chest. 2013;143(5):1351-1357. doi:10.1378/chest.12-1363

Background:  The recovery of Aspergillus and Candida from the respiratory secretions of patients with cystic fibrosis (CF) is common. Their relationship to the development of allergic sensitization and effect on lung function has not been established. Improved techniques to detect these organisms are needed to increase knowledge of these effects.

Methods:  A 2-year prospective observational cohort study was performed. Fifty-five adult patients with CF had sputum monitored for Aspergillus by culture and real-time polymerase chain reaction and Candida by CHROMagar and carbon assimilation profile (API/ID 32C). Skin prick tests and ImmunoCAP IgEs to a panel of common and fungal allergens were performed. Lung function and pulmonary exacerbation rates were monitored over 2 years.

Results:  Sixty-nine percent of patient sputum samples showed chronic colonization with Candida and 60% showed colonization with Aspergillus. There was no association between the recovery of either organism and the presence of specific IgE responses. There was no difference in lung function decline for patients with Aspergillus or Candida colonization compared with those without (FEV1 percent predicted, P = .41 and P = .90, respectively; FVC % predicted, P = .87 and P = .37, respectively). However, there was a significantly greater decline in FEV1 and increase in IV antibiotic days for those sensitized to Aspergillus (FEV1 decline, P = .03; IV antibiotics days, P = .03).

Conclusions:  Allergic sensitization is not associated with recovery of Candida or Aspergillus from the sputum of patients with CF. Aspergillus but not Candida sensitization is associated with greater lung function decline and pulmonary exacerbations.

Chest. 2013;143(5):1358-1364. doi:10.1378/chest.12-2022

Background:  Determining prognosis and predicting outcomes in cystic fibrosis (CF) is a complex issue, and there have been very few clinically applicable models for this. The aim was to create a simple, practical outcome prediction tool for CF.

Methods:  Forty-nine consecutive patients with CF from a single center were studied over an 84-month period (2004-2010). All baseline clinical parameters were gathered, and FEV1 measurements were analyzed over the study period. Using patterns of FEV1 decline, a tipping point of 52.8% predicted was identified. Other clinical variables were analyzed and correlated with outcome. Poor outcome was defined as death or transplantation. Using age, BMI, lung function (ie, FEV1), and number of exacerbations in the past 3 months, the CF-ABLE score was created. The score was validated for data from 370 patients from the national Cystic Fibrosis Registry of Ireland.

Results:  The ABLE score uses clinical parameters that are measured at every clinic visit and scored on a scale from 0 to 7. If FEV1 is < 52%, then 3.5 points are added; if the number of exacerbations in the past 3 months is > 1, then 1.5 points are added; if BMI is < 20.1 kg/m2 or age < 24 years, each receive 1 point.

Conclusions:  Patients with a low score have a very low risk of death or lung transplantation within 4 years; however, as the score increases, the risk significantly increases. Patients who score > 5 points have a 26% risk of poor outcome within 4 years. This score is simple and applicable and better predicts outcome than FEV1 alone.

Original Research: Lung Cancer

Chest. 2013;143(5):1365-1377. doi:10.1378/chest.12-0710

Objective:  An increasing proportion of patients with stage I non-small cell lung cancer (NSCLC) is undergoing sublobar resection (L−). However, there is little information about the risks and correlates of local recurrence (LR) after such surgery, especially compared with patients undergoing lobectomy (L+).

Methods:  Ninety-three and 318 consecutive patients with stage I NSCLC underwent L− and L+, respectively, from 2000 to 2006. Median follow-up was 34 months.

Results:  In the L− group, the LR rates at 2, 3, and 5 years were 13%, 24%, and 40%, respectively. The risk of LR was significantly associated with tumor grade, tumor size, and T stage. The crude risk of LR was 33.8% (21 of 62) for patients whose tumors were grade ≥ 2. In the L+ group, the LR rates at 2, 3, and 5 years were 14%, 19%, and 24%, respectively. The risk of LR significantly increased with increasing tumor size, length of hospital stay, and the presence of diabetes. The L− group experienced a significant increase in failure in the bronchial stump/staple line compared with the L+ group (10% vs 3%; P = .04) and nonsignificant trends toward increased ipsilateral hilar and subcarinal failure rates.

Conclusions:  Patients with stage I NSCLC who undergo L− have an increased risk of LR compared with patients undergoing L+, particularly when they have tumors grade ≥ 2 or tumor size > 2 cm. If L− is considered, additional local therapy should be considered to reduce this risk of LR, especially with tumors grade ≥ 2 or size > 2 cm.

Original Research: Signs and Symptoms of Chest Diseases

Chest. 2013;143(5):1378-1385. doi:10.1378/chest.12-1541

Background:  Although opioid receptors are expressed broadly in the CNS and in peripheral sensory nerve endings including bronchioles and alveolar walls of the respiratory tract, it is unknown whether the modulatory effect of endogenous opioids on breathlessness occurs in the CNS or in the peripheral nervous system. The purpose of this investigation was to examine whether increased blood levels of β-endorphin modify breathlessness by a putative effect of binding to peripheral opioid receptors in the respiratory tract.

Methods:  Twenty patients with COPD (10 women and 10 men; age, 70 ± 8 years) inspired through resistances during practice sessions to identify an individualized target load that caused ratings of intensity and unpleasantness of breathlessness ≥ 50 mm on a 100-mm visual analog scale. At two interventions, blood levels of β-endorphin and adrenocorticotropic hormone (ACTH) were measured, ketoconazole (600 mg) or placebo was administered orally, and patients rated the two dimensions of breathlessness each minute during resistive load breathing (RLB).

Results:  By inhibiting cortisol synthesis, ketoconazole led to significant increases in β-endorphin (mean change, 20% ± 4%) and ACTH (mean change, 21% ± 4%) compared with placebo. The intensity and unpleasantness ratings of breathlessness and the endurance time during RLB were similar in the two interventions.

Conclusions:  The previously demonstrated modulatory effect of endogenous opioids on breathlessness appears to be mediated by binding to receptors within the CNS rather than to peripheral opioid receptors in the respiratory tract. An alternative explanation is that the magnitude of the β-endorphin response is inadequate to affect peripheral opioid receptors.

Trial Registry:  ClinicalTrials.gov; No.: NCT01378520; URL: www.clinicaltrials.gov

Original Research: Pulmonary Rehabilitation

Chest. 2013;143(5):1386-1394. doi:10.1378/chest.12-1442

Background:  Studies of the impact of respiratory muscle training (RMT) on central neurodegenerative pathologies have been aimed at improving pulmonary function. However, there is no certainty about the effectiveness of RMT in patients affected by these groups of disorders. The purpose of this review was to assess the evidence regarding the efficacy of inspiratory muscle training (IMT) and expiratory muscle training (EMT) on respiratory function in patients with neurodegenerative disorders of the CNS.

Methods:  A comprehensive search from 1990 to September 2012 on MEDLINE, Physiotherapy Evidence Database (PEDro), PubMed, Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases was made. Studies reporting on IMT and EMT in patients with neurodegenerative diseases were included. The selected studies were abstracted using a standardized data collection instrument and were assessed by a quality checklist created and adapted from CONSORT (Consolidated Standards for Reporting Trials) and TREND (Transparent Reporting of Evaluation with Nonrandomized Designs).

Results:  Twenty-four studies were identified by the search strategy. Only 19 studies met the criteria for full review. Ten studies met all the inclusion criteria and were included in the final analysis. Of the 16 parameters present in the quality assessment checklist, only six were achieved for the studies analyzed.

Conclusions:  There is some evidence that RMT improves a number of respiratory function parameters in patients with Parkinson disease and multiple sclerosis; however, the number of studies and their quality are not sufficient to conclude whether IMT or EMT is effective in improving respiratory function in patients with neurodegenerative disorders of the CNS.

Original Research: Pulmonary Physiology

Chest. 2013;143(5):1395-1406. doi:10.1378/chest.12-1135

Background:  National spirometric surveillance data in the United States were last collected during 1988-1994. The objective of this study was to provide current estimates for obstructive and restrictive impairment of lung function and to examine changes since 1988-1994.

Methods:  We used data from 14,360 participants aged 20 to 79 years from the National Health and Nutrition Examination Survey (NHANES) III (1988-1994) and 9,024 participants from NHANES 2007-2010. Spirometry was conducted using the same spirometers and generally similar protocols.

Results:  During 2007-2010, 13.5% (SE, 0.6) of participants had evidence of airway obstruction (FEV1/FVC < 0.70): 79.9% of adults had normal lung function, 6.5% had a restrictive impairment, 7.5% had mild obstruction, 5.4% had moderate obstruction, and 0.7% had severe obstruction. Although the overall age-adjusted prevalence of any obstruction did not change significantly from 1988-1994 (14.6%) to 2007-2010 (13.5%) (P = .178), significant decreases were noted for participants aged 60 to 79 years and for Mexican Americans. The prevalence of current smoking remained high among participants with moderate (48.4%) and severe (37.9%) obstructive impairments. A significant decline in current smoking occurred only among those with normal lung function (P < .05).

Conclusion:  Spirometry revealed little change in the prevalence of any obstructive and restrictive impairment in lung function during 2007-2010, compared with 1988-1994.

Original Research: Allergy and Airway

Chest. 2013;143(5):1407-1413. doi:10.1378/chest.12-1860

Background:  Airway pepsin has been increasingly used as a potentially sensitive and quantifiable biomarker for gastric-to-pulmonary aspiration, despite lack of validation in normal control subjects. This study attempts to define normal levels of airway pepsin in adults and distinguish between pepsin A (exclusive to stomach) and pepsin C (which can be expressed by pneumocytes).

Methods:  We performed a prospective study of 51 otherwise healthy adult patients undergoing elective extremity orthopedic surgery at a single tertiary-care academic medical center. Lower airway samples were obtained immediately following endotracheal intubation and just prior to extubation. Total pepsin and pepsin A concentrations were directly measured by an enzymatic activity assay, and pepsin C was subsequently derived. Pepsinogen/pepsin C was confirmed by Western blot analyses. Baseline characteristics were secondarily compared.

Results:  In all, 11 (22%; 95% CI = 9.9%-33%) had detectable airway pepsin concentrations. All 11 positive specimens had pepsin C, without any detectable pepsin A. Pepsinogen/pepsin C was confirmed by Western blot analyses. In a multivariate logistic regression, men were more likely to have airway pepsin (OR, 12.71, P = .029).

Conclusions:  Enzymatically active pepsin C, but not the gastric-specific pepsin A, is frequently detected in the lower airways of patients who otherwise have no risk for aspiration. This suggests that nonspecific pepsin assays should be used and interpreted with caution as a biomarker of gastropulmonary aspiration, as pepsinogen C potentially expressed from pneumocytes may be detected in airway samples.

Original Research: Chest Infections

Chest. 2013;143(5):1414-1421. doi:10.1378/chest.12-1784

Background:  Pulmonary aspergillomas may cause life-threatening hemoptysis. The treatment of this condition is problematic because poor pulmonary function often precludes definitive surgical resection.

Methods:  We retrospectively reviewed all patients hospitalized at our institution for hemoptysis associated with an aspergilloma over an 8-year period and who underwent percutaneous intracavitary instillation of amphotericin B (ICAB). ICAB consisted of catheter placement into the aspergilloma cavity with subsequent instillation of 50 mg amphotericin B in 20 mL 5% dextrose solution daily for 10 days.

Results:  ICAB was attempted for 23 distinct episodes of severe hemoptysis in 20 individual patients. Catheter placement was successful in 21 of the 23 episodes (91%), and of these, ICAB instillation was successfully completed in 20 episodes (95%). In these 20 episodes, hemoptysis ceased by hospital discharge in 17 of 20 patients (85%) and in all 18 who survived until a follow-up visit 1-month after treatment. Pneumothorax occurred in six of 23 (26%) catheter placement attempts without long-term complications. Recurrence of serious hemoptysis occurred after six of 18 episodes for which follow-up was available. Potential risk factors associated with severe, recurrent hemoptysis were a size increase or reappearance of the aspergilloma on a chest CT scan (P = .001), bleeding diathesis (P = .08), and lack of bronchial artery embolization during index hospitalization (P = .07).

Conclusions:  Our data suggest that ICAB is an effective short-term treatment to control severe hemoptysis caused by pulmonary aspergilloma. The long-term benefit of this procedure is unknown. We identified several potential risk factors for recurrent hemoptysis after ICAB that could be examined prospectively in future trials.

Original Research: Diffuse Lung Disease

Chest. 2013;143(5):1422-1429. doi:10.1378/chest.11-2735

Background:  Because of the variable course of idiopathic pulmonary fibrosis (IPF), it is important to generate an accurate prognosis at the time of diagnosis. The aim of this study was to investigate the prognostic value of blood biomarkers in IPF.

Methods:  The plasma level of the biomarkers, matrix metalloproteinase-7 (MMP-7), Krebs von den Lungen-6 antigen, and surfactant protein (SP)-A and SP-D were retrospectively compared with the clinical course of 118 patients with IPF, 68 of whom had biopsy-proven IPF.

Results:  The median follow-up period was 24 months. Multivariate Cox analysis showed MMP-7 (HR, 1.056; P = .0063) and SP-A (HR, 1.011; P = .0001) were significant predictors of survival along with age, FVC, and extent of honeycombing. The patients with high levels of both MMP-7 (≥ 12.1 ng/mL) and SP-A (≥ 80.3 ng/mL) had shorter survival (1-year survival rate: 59%) and higher frequency (42%) of lung function decline (> 10% reduction in FVC in 6 months) compared with those with high levels of one biomarker (1-year survival rate: 81%; FVC decline: 27%) or low levels of both (1-year survival rate: 83.3%; FVC decline: 9%). Multivariate models demonstrated marginal improvement in the prediction of mortality (concordance index [C-index]: 0.731; P = .061) when MMP-7 and SP-A were included and compared with standard clinical predictors only (C-index: 0.686); however, it became significant with addition of MMP-7, SP-A, and Krebs von den Lungen-6 antigen (C-index: 0.730; P = .037).

Conclusions:  Our retrospective study suggested that at least three biomarkers are necessary to improve predictability of mortality in IPF compared with clinical parameters. Further study in a greater number of patients is warranted.

Original Research: Transplantation

Chest. 2013;143(5):1430-1435. doi:10.1378/chest.12-0354

Background:  The presence of interstitial pneumonitis (IP) on surveillance lung biopsy specimens in lung transplant recipients is poorly described, and its impact on posttransplant outcomes is not established. The following study assessed the association of posttransplant IP with the development of bronchiolitis obliterans syndrome (BOS).

Methods:  We examined all recipients of primary cadaveric lung transplants at our institution between January 1, 2000, and December 31, 2007 (N = 145). Patients had bronchoscopies with BAL, and transbronchial biopsies performed for surveillance during posttransplant months 1, 3, 6, and 12 as well as when clinically indicated. Patients were given a diagnosis of IP if, in the absence of active infection and organizing pneumonia, they showed evidence of interstitial inflammation and fibrosis on two or more biopsy specimens.

Results:  IP was a significant predictor of BOS (OR, 7.84; 95% CI, 2.84-21.67; P < .0001) and was significantly associated with time to development of BOS (hazard ratio, 3.8; 95% CI, 1.93-7.39; P = .0001) within the first 6 years posttransplant. The presence of IP did not correlate with a significantly higher risk of mortality or time to death. There was no association between the presence of IP and the development of or time to acute rejection.

Conclusions:  The presence of IP on lung transplant biopsy specimens suggests an increased risk for BOS, which is independent of the presence of acute cellular rejection.

Translating Basic Research into Clinical Practice

Chest. 2013;143(5):1436-1443. doi:10.1378/chest.12-1766

The increase in total cross-sectional area in the distal airways of the human lung enhances the mixing of each tidal breath with end-expiratory gas volume by slowing bulk flow and increasing gas diffusion. However, this transition also favors the deposition of airborne particulates in this region because they diffuse 600 times slower than gases. Furthermore, the persistent deposition of toxic airborne particulates stimulates a chronic inflammatory immune cell infiltration and tissue repair and remodeling process that increases the resistance in airways <2 mm in diameter four to 40-fold in COPD. This increase was originally attributed to lumen narrowing because it increases resistance in proportion to the change in lumen radius raised to the fourth power. In contrast, removal of one-half the number of tubes arranged in parallel is required to double their resistance, and approximately 90% need to be removed to explain the increase in resistance measured in COPD. However, recent reexamination of this problem based on micro-CT imaging indicates that terminal bronchioles are both narrowed and reduced to 10% of the control values in the centrilobular and 25% in the panlobular emphysematous phenotype of very severe (GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade IV) COPD. These new data indicate that both narrowing and reduction in numbers of terminal bronchioles contribute to the rapid decline in FEV1 that leads to severe airway obstruction in COPD. Moreover, the observation that terminal bronchiolar loss precedes the onset of emphysematous destruction suggests this destruction begins in the very early stages of COPD.

Recent Advances in Chest Medicine

Chest. 2013;143(5):1444-1454. doi:10.1378/chest.12-1801

COPD is a leading cause of morbidity and mortality worldwide and is now the third leading cause of death in the United States. Acute exacerbations of COPD (AECOPDs) are common events that often lead to hospitalization, and their frequency worsens with disease progression. AECOPDs are associated with worsened quality of life, increased health-care costs, and increased mortality. Accordingly, there is great interest in preventing AECOPDs to improve outcomes. Both pharmacologic and nonpharmacologic interventions alter the frequency of AECOPDs and COPD-related hospitalizations. To examine the best available evidence, we restricted this review to include studies that used randomized controlled designs lasting at least 6 months. Pharmacologic interventions discussed include inhaled corticosteroids, long-acting β-agonists, long-acting antimuscarinic agents, macrolide antibiotics, and phosphodiesterase-4 inhibitors. The nonpharmacologic interventions discussed include lung volume reduction surgery, pulmonary rehabilitation, and disease management programs.

Special Features

Chest. 2013;143(5):1455-1459. doi:10.1378/chest.12-2384

Climate change is a health threat no less consequential than cigarette smoking. Increased concentrations of greenhouse gases, and especially CO2, in the earth’s atmosphere have already warmed the planet substantially, causing more severe and prolonged heat waves, temperature variability, air pollution, forest fires, droughts, and floods, all of which put respiratory health at risk. These changes in climate and air quality substantially increase respiratory morbidity and mortality for patients with common chronic lung diseases such as asthma and COPD and other serious lung diseases. Physicians have a vital role in addressing climate change, just as they did with tobacco, by communicating how climate change is a serious, but remediable, hazard to their patients.

Chest. 2013;143(5):1460-1471. doi:10.1378/chest.12-1384

Chronic pulmonary thromboembolism (CPE) is a challenging diagnosis for clinicians. It is an often-forgotten diagnosis and can be difficult to detect and easily misdiagnosed. The radiologic features on CT pulmonary angiography are subtle and can be further compounded by pathologic mimics and unusual findings observed with disease progression. Diagnosis is important because CPE can lead to progressive pulmonary hypertension, morbidity, and mortality. Moreover, chronic thromboembolic pulmonary hypertension is the only category of pulmonary hypertension with an effective curative treatment in the form of pulmonary endarterectomy. Therefore, CPE must be considered and recognized early. The features of chronic pulmonary emboli on CT scans can be categorized into vascular or parenchymal findings. Endoluminal signs include totally or partially occlusive thrombi and webs and bands. Parenchymal features such as mosaic attenuation and pulmonary infarction are also noted, in addition to features of pulmonary artery hypertension. Additional findings have been noted, including cavitation of infarcts, microbial colonization of cavities, and bronchopleural fistulae. As CPE can be diagnosed at different stages of its disease pathway, such findings may not necessarily arouse suspicion toward a causative diagnosis of chronic embolism. To aid diagnosis for clinicians, this article describes the characteristic vascular and parenchymal CT scan features of chronic emboli, as well as important ancillary findings. We also provide an illustrative case series focusing on CT pulmonary angiography specifically as an imaging modality to highlight the progressive nature of CPE and its sequelae, as well as important radiologic mimics to consider in the differential diagnosis.

Topics in Practice Management

Chest. 2013;143(5):1472-1477. doi:10.1378/chest.12-1969

Hospitals are required to have a medical director of respiratory care as a condition of their participation in the Federal Medicare and Medicaid programs. This gives physicians opportunities to improve the quality of care for the patients in their community, to diversify income streams, and to assist hospitals to meet regulatory requirements for quality. The contracts for these positions are usually provided by the hospital, so it is imperative that physicians know how to protect their interests, what is expected of them, if they are being paid fairly, and that the contract is compliant with all regulatory issues. The directorship relationship with the hospital that provides designated health services and the “stand in the shoes” definition of direct compensation also gives physicians and physician practices guidance to determine if their group and individual physicians are compliant with Stark and antikickback regulations. This article guides physicians through the process of reviewing a contract for medical directorship or service line management services. Information on compensation in the directorship market can be found in at least two standard surveys. Duties and compensation vary among entities and frequently include incentive-based compensation for improving quality measures and operations. Directorships are evolving to service line management as more of the hospital’s reimbursement is linked to clinical quality and patient satisfaction. This article does not offer legal advice, nor is it meant to be all inclusive. Physicians should consult a health-care attorney for any questions before signing any contract.

Selected Reports

Chest. 2013;143(5):1478-1479. doi:10.1378/chest.12-1604

We report a case of Cryptococcus neoformans pneumonia in a patient taking ruxolitinib, a janus kinase 1,2 inhibitor approved for the treatment of myelofibrosis. We hypothesize that ruxolitinib contributed to this infection through its effects on cell-mediated immunity. Clinicians should be aware of the potential for intracellular or opportunistic infections associated with this novel drug class.

Postgraduate Education Corner: Contemporary Reviews in Critical Care Medicine

Chest. 2013;143(5):1480-1488. doi:10.1378/chest.12-1901

Hemodynamic assessment is a key component of the evaluation of the critically ill patients and has both diagnostic and prognostic utility. This review outlines a general approach to assessment of hemodynamics and perfusion, and then discusses various hemodynamic parameters: heart rate, BP, intravascular (central venous and pulmonary artery) pressures, cardiac output, and myocardial performance, within the context not only of how they are best measured but also how they should be used in a clinical context. Hemodynamics are best assessed using a combination of not only different hemodynamic parameters but also those with the inclusion of clinical indices of perfusion. The benefits of these techniques, as with all medical testing and interventions, must be weighed against any potential risks. Although what to measure and how to measure it is important, what is most important is how to use the information. Evaluating the response to therapeutic interventions is frequently the most useful way to employ hemodynamic monitoring techniques. For the practitioner, learning how to select from a robust set of hemodynamic tools and how to tailor their use to individual clinical settings will allow for optimal patient care.

Postgraduate Education Corner: Contemporary Reviews in Sleep Medicine

Chest. 2013;143(5):1489-1499. doi:10.1378/chest.12-1219

The study of genetics is providing new and exciting insights into the pathogenesis, diagnosis, and treatment of disease. Both normal sleep and several types of sleep disturbances have been found to have significant genetic influences, as have traits of normal sleep, such as those evident in EEG patterns and the circadian sleep-wake cycle. The circadian sleep-wake cycle is based on a complex feedback loop of genetic transcription over a 24-h cycle. Restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) have familial aggregation, and several genes have a strong association with them. Recent genome-wide association studies have identified single nucleotide polymorphisms linked to RLS/PLMS, although none has a definite functional correlation. Narcolepsy/cataplexy are associated with HLA DQB1*0602 and a T-cell receptor α locus, although functional correlations have not been evident. Obstructive sleep apnea is a complex disorder involving multiple traits, such as anatomy of the oropharynx, ventilatory control, and traits associated with obesity. Although there is clear evidence of familial aggregation in the obstructive sleep apnea syndrome, no specific gene or locus has been identified for it. Angiotensin-converting enzyme has been proposed as a risk variant, but evidence is weak. Fatal familial insomnia and advanced sleep phase syndrome are sleep disorders with a definite genetic basis.

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

Chest. 2013;143(5):1500-1503. doi:10.1378/chest.12-2279


Chest. 2013;143(5):1508. doi:10.1378/chest.12-1528

Stained clothes and matted hair, she zig-zagged
   across the mall clutching
      stuffed shopping bags.
Ten o’clock in the air-conditioned night,
   the mall fighting off the humidity of the Mississippi.
My hands were blue and sticky
   from a single scoop Superman,
high off sugar and staying up past my bedtime,
hair in a rushed ponytail from my mother
   to keep out the ice cream.
I knew I wasn’t supposed to stare at her,
   but a purple sequin chain from my souvenir mask
had fallen over my eye
   already cheap and shabby,
the green and yellow feathers
   folding over, tickling my bangs.
She made her way closer,
   the shopkeepers trying to casually shut their gates
   before she got to them.
At Buy You Scoops
   she told the man behind the counter
   that his dog was going to die,
swaying in my vision across the sequins
   like a tightrope master.
We knew it was coming.
My mother shifted her purse into her lap.
My grandmother’s voice
   dropped to a whisper.
she came to our table.
   Stood right next to it.
My dad said hello.
Suddenly turning to me,
she stood unnaturally still,
locked her sharp green eyes to mine.
And no matter how many times later that night my dad explained
the voices she heard, that she wasn’t really talking to me,
   as much as I didn’t know what she meant
       or which detail insulted me more,
   as much as I laugh about it fifteen years later,
the faded mask is still on my dresser.
I never forgot the words:
You little boy, you’re as ugly as your mama.

Chest. 2013;143(5):1509. doi:10.1378/chest.12-1479

In my line of people, especially on my father’s side
There never seems to have been ample blood
Running within the arteries behind our Chinese chests
No matter how warm-hearted we actually are
As in the case of my father, who used to
Accuse me of being an ill-hearted teenager
My heart muscle is imbalanced
As one side is less infused with blood
Than the other, thus causing palpitation
Short breath, and a strong sense of
Tightness, heaviness or tiredness about life
To diagnose my cardiovascular defection
Neither an echo nor a stress test is needed
For I am keenly aware of my own doomed
Arteries that have been clotted
With too many syllables
Voiced or voiceless
And to make all these sounds flow out of my heart
Is already stressful enough
Nevertheless, I will keep pumping out these words
Be they ever so blood-soaked

Chest. 2013;143(5):1510. doi:10.1378/chest.12-1465

I cherish how you kept me warm
Through that long winter of internship
Gallantly steering me through many a storm
While I, the sponge took on water
Sensing I was slow to acquire
The audacity of a Texas swagger
You stood tall with me on Monday mornings
When hindsight’s sagacity ruled the post-call skies
You were my heart’s cloister from the sting
Of lost labors of love for family and the infirm
Your luster undimmed by stains of cheap hospital coffee
Drank with the zest of communion wine to keep eyelids apart
A love this good I’ve learned must end up ephemeral
For while I grew into you, hair whitened & receding,
You shrank from me a size or two down
That separation a penultimate token of love
Bronzed by time’s dust, you still gleam
Crystal and regal with my closet in your pocket
Pock-marked with tattoos from drug rep pens
And threadbare cuffs that mime: you can do it!

Chest. 2013;143(5):1511. doi:10.1378/chest.12-1856

Your servant has examined the remedies
used by physicians for poisonous bites,
and found them to be generally warming.
Some are imbibed with wine,
others with water; if the patient is hot,
vinegar or milk should be used.
The scorpion’s sting chills a person
to the core; in this case ampelos
is the preferred decoction.
For those to whom it is forbidden,
anise will do; like the ethrog seed
it counteracts any fatal toxin.
It is better to avoid being bitten
and if a man is chased by a snake,
he should flee into a sandy place.
A woman, on the other hand,
should make herself naked
and cohabit (with her husband)
in front of the animal. Some say
this will only inflame the serpent’s
instinct. Rather she should
pull out a skein of hair,
gather a pile of nail parings
and hurl them at the attacker,
open her lips and shriek, ‘I am unclean’.
If this fails to deter and the bite is fatal,
the serpent should be put to death
by a court of twenty-three.
But according to Rabbi Akiba,
it should be killed without a trial.


Chest. 2013;143(5):1512. doi:10.1378/chest.12-2997
Chest. 2013;143(5):1512-1513. doi:10.1378/chest.13-0094
Chest. 2013;143(5):1513-1514. doi:10.1378/chest.12-3077
Chest. 2013;143(5):1514. doi:10.1378/chest.13-0557
Chest. 2013;143(5):1514-1515. doi:10.1378/chest.13-0055
Chest. 2013;143(5):1515-1516. doi:10.1378/chest.13-0126
Chest. 2013;143(5):1516. doi:10.1378/chest.13-0111
Chest. 2013;143(5):1516-1517. doi:10.1378/chest.13-0125
Chest. 2013;143(5):1517-1518. doi:10.1378/chest.13-0404
Chest. 2013;143(5):1518. doi:10.1378/chest.13-0087
Chest. 2013;143(5):1518-1519. doi:10.1378/chest.13-0346

Ultrasound Corner

Chest. 2013;143(5):e1-e3. doi:10.1378/chest.13-0107

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