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Editorials

Chest. 2013;143(6):1521-1523. doi:10.1378/chest.13-0006

Lactate has been studied for decades as a prognostic marker of resuscitation and patient outcome in shock. While the mechanism for lactate elevation is debatable, it has been known since the 1960s that a lactate value > 4 mM in the critically ill patient is associated with increased mortality.1 Additionally, lactate clearance, or the decrease in lactate level as a goal during resuscitation, has been examined and re-examined for the past 3 decades.

Chest. 2013;143(6):1525-1527. doi:10.1378/chest.12-2993

COPD is the third-leading cause of death in the United States.1 Given its chronicity and morbidity, it imposes a tremendous and increasing burden on public health worldwide; improved therapies are badly needed. COPD encompasses a spectrum of clinical phenotypes, and its underlying pathogenesis is correspondingly complex. However, inflammation seems to be central to many of the injurious cascades thought to initiate and propel the disease.2

Chest. 2013;143(6):1527-1529. doi:10.1378/chest.13-0275

The article by Saji and colleagues1 in this issue of CHEST (see page 1618) is a well-done analysis of the relative effect of lymph node involvement by number vs location in patients undergoing resection of lung cancer. Lung cancer stage classification traditionally is based on the location,2 whereas in some other cancers, it is based on the number of involved nodes. Several authors have questioned this paradigm,3-6 and the study by Saji et al1 is one of only a few such studies to carefully evaluate the relative value of these two approaches.

Chest. 2013;143(6):1529-1531. doi:10.1378/chest.12-3001

Flock worker’s lung disease presents a useful paradigm for identifying new occupational causes of lung disease. It is an unusual interstitial lung disease characterized by lymphocytic bronchiolitis and peribronchiolitis in workers exposed to flock fibers in manufacturing velvet-like fabrics, fuzzy greeting cards and wall papers, and automotive gaskets and glove box surfaces. Flock is made by cutting short synthetic fibers from bundles of parallel monofilaments of nylon or other polymers for application to adhesive-coated substrates. Unlike respirable mineral fibers such as asbestos, synthetic flock is visible, as illustrated in its typical applications. Since 1975, published case reports have raised suspicion of a respiratory hazard associated with various synthetic fibers, including polyester, nylon, and acrylic dust.1-3 With regard to synthetic flock, early reports in 1974 and 1981 of workplace evaluations by National Institute of Occupational Safety and Health (NIOSH) investigators attributed respiratory symptoms among workers to irritant properties of nonrespirable flock fibers on the upper airways but did not pursue the possibility of lung disease associated with flock work.4,5 Systematic workplace investigation of lung disease in workers that flock with synthetic fibers awaited the recognition of case clusters of interstitial disease in small workforces, first in Kingston, Ontario, Canada, and then in Rhode Island, as detailed in the background of the follow-up study by Turcotte et al6 published in this issue of CHEST (see page 1642). Subsequently, additional cases or subclinical morbidity have been found in relation to nylon flock in two Massachusetts plants, to polyethylene flock in Spain, to polypropylene flock in Turkey, and to rayon flock in Kansas.6

Second Opinion

Chest. 2013;143(6):1532. doi:10.1378/chest.143.6.1532
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Point/Counterpoint Editorials

Chest. 2013;143(6):1533-1536. doi:10.1378/chest.13-0296

It is often said that perfect is the enemy of good. A disease screening procedure can never be perfect and almost always represents a balance between positive and negative predictive values while factoring in patient risk and costs to society. Although physicians are taught to strive for perfect, when balancing the aforementioned, we must strive for good enough.

Chest. 2013;143(6):1536-1539. doi:10.1378/chest.13-0297

Widely available, noninvasive diagnostic modalities are understandably attractive to both physicians and patients but can also be as equally dangerous as they are easy to order. Indeed, such dangers have been realized in the field of pulmonary hypertension (PH), seemingly correlating with the increased popularity and accessibility of Doppler echocardiography (DE). However, prior to delving into the complexities of this topic, careful consideration and review of important PH-related nomenclature is needed to put into the proper perspective this clinically relevant question of whether DE estimates of systolic pulmonary artery pressures (sPAPs) can be relied on in the accurate diagnosis of PH.

Chest. 2013;143(6):1539-1540. doi:10.1378/chest.13-0305

I congratulate Dr Rich for his comprehensive review of the pitfalls of echocardiography in estimating pulmonary pressures.1 In all literature and texts, echocardiography is said to provide just that: an estimate. Given that the current definition of pulmonary hypertension (PH) is predicated on a measure obtained by right-sided heart catheterization (RHC), echocardiography cannot be used to diagnose PH, but it can certainly provide an estimate of systolic pulmonary artery pressure (sPAP) as well as many other clues to PH that are not appreciated if one only has tracings obtained through the tip of a fluid-filled catheter.

Chest. 2013;143(6):1540-1541. doi:10.1378/chest.13-0298

While some may accept that “perfect is the enemy of good,”1 when it comes to the care of patients with potentially fatal diseases such as pulmonary arterial hypertension (PAH), to strive for anything less than perfect, or to “strive for good enough,”1 is a prescription for failure. First, let us begin with the emotional side of a PAH diagnosis. With a mortality rate comparable to that of many advanced malignancies, the anguish and mental strife associated with being falsely diagnosed with PAH is gut wrenching for both the patient and the family and is occurring at an alarming rate. Consider the published hospital discharge data from the Centers for Medicare & Medicaid Services, which placed the number of hospitalized patients with pulmonary hypertension (PH) from all causes at 240,000 in 2002; this figure rose dramatically to 560,000 in 2005 largely because of the ease and availability of Doppler echocardiography (DE).2

Commentary

Chest. 2013;143(6):1542-1547. doi:10.1378/chest.12-2491

Linking health-care quality improvement to payment appears straightforward. Improve the care that one provides to one’s patients, and one is rewarded financially. Should one fail to improve care, then one is financially penalized. However, this strategy assumes that health-care workers and administrators possess the necessary tools and knowledge to improve care and that the metrics being measured have been rigorously tested. Although health-care workers and hospitals are publically committed to reducing inappropriate care, improving patient safety, achieving better health outcomes, and holding down costs, many are unsure how to do this effectively. We present the case that it is not usually the people who create the problems in our health system; rather, it is the processes of the care-delivery system that require change. Incentivizing performance improvement using simple metrics is unlikely to work before using compensation strategies to incentivize behavior change in clinical systems. But prior to even doing this, leaders and physicians must first create accurate performance measures and understand improvement science.

Original Research: Critical Care

Chest. 2013;143(6):1548-1553. doi:10.1378/chest.12-0878

Background:  We sought to compare the association of whole-blood lactate kinetics with survival in patients with septic shock undergoing early quantitative resuscitation.

Methods:  This was a preplanned analysis of a multicenter, ED-based, randomized, controlled trial of early sepsis resuscitation. Inclusion criteria were suspected infection, two or more systemic inflammation criteria, either systolic BP< 90 mm Hg after a fluid bolus or lactate level > 4 mM, two serial lactate measurements, and an initial lactate level > 2.0 mM. We calculated the relative lactate clearance, rate of lactate clearance, and occurrence of early lactate normalization (decline to < 2.0 mM in the first 6 h). Area under the receiver operating characteristic curve (AUC) and multivariate logistic regression were used to determine the lactate kinetic parameters that were the strongest predictors of survival.

Results:  The analysis included 187 patients, of whom 36% (n = 68) normalized their lactate level. Overall survival was 76.5% (143 of 187 patients), and the AUC of initial lactate to predict survival was 0.64. The AUCs for relative lactate clearance and lactate clearance rate were 0.67 and 0.58, respectively. Lactate normalization was the strongest predictor of survival (adjusted OR, 5.2; 95% CI, 1.7-15.8), followed by lactate clearance ≥ 50% (OR, 4.0; 95% CI, 1.6-10.0). Lactate clearance ≥ 10% (OR, 1.6; 95% CI, 0.6-4.4) was not a significant independent predictor in this cohort.

Conclusions:  In patients in the ED with a sepsis diagnosis, early lactate normalization during the first 6 h of resuscitation was the strongest independent predictor of survival and was superior to other measures of lactate kinetics.

Trial registry:  ClinicalTrials.gov; No.: NCT00372502; URL: clinicaltrials.gov

Chest. 2013;143(6):1554-1561. doi:10.1378/chest.12-2115

Background:  Obese patients are at risk for developing atelectasis and ARDS. Prone position (PP) may reduce atelectasis, and it improves oxygenation and outcome in severe hypoxemic patients with ARDS, but little is known about its effect in obese patients with ARDS.

Methods:  Morbidly obese patients (BMI ≥ 35 kg/m2) with ARDS (Pao2/Fio2 ratio ≤ 200 mm Hg) were matched to nonobese (BMI < 30 kg/m2) patients with ARDS in a case-control clinical study. The primary end points were safety and complications of PP; the secondary end points were the effect on oxygenation (Pao2/Fio2 ratio at the end of PP), length of mechanical ventilation and ICU stay, nosocomial infections, and mortality.

Results:  Between January 2005 and December 2009, 149 patients were admitted for ARDS. Thirty-three obese patients were matched with 33 nonobese patients. Median (25th-75th percentile) PP duration was 9 h (6-11 h) in obese patients and 8 h (7-12 h) in nonobese patients (P = .28). We collected 51 complications: 25 in obese and 26 in nonobese patients. The number of patients with at least one complication was similar across groups (n = 10, 30%). Pao2/Fio2 ratio increased significantly more in obese patients (from 118 ± 43 mm Hg to 222 ± 84 mm Hg) than in nonobese patients (from 113 ± 43 mm Hg to 174 ± 80 mm Hg; P = .03). Length of mechanical ventilation, ICU stay, and nosocomial infections did not differ significantly, but mortality at 90 days was significantly lower in obese patients (27% vs 48%, P < .05).

Conclusions:  PP seems safe in obese patients and may improve oxygenation more than in nonobese patients. Obese patients could be a subgroup of patients with ARDS who may benefit the most of PP.

Original Research: Sleep Disorders

Chest. 2013;143(6):1562-1568. doi:10.1378/chest.12-1524

Background:  Systemic symptoms are common in sarcoidosis and are associated with a decreased quality of life. Excessive daytime sleepiness (EDS) often is associated with obstructive sleep apnea (OSA) but may be a systemic symptom independently associated with sarcoidosis. The aim of this study was to assess the relationship between sarcoidosis and EDS.

Methods:  In a retrospective analysis, we used Epworth Sleepiness Scale scores to compare sleepiness in 62 patients with sarcoidosis with 1,005 adults without sarcoidosis referred for polysomnography for suspicion of OSA. Linear regression models controlled for covariates. In a subgroup analysis of patients with sarcoidosis, sleepiness scores and polysomnograms were compared between those with normal and those with abnormal pulmonary function based on total lung capacity.

Results:  EDS was more common in patients with sarcoidosis than in those without, and sarcoidosis remained an independent predictor of increased sleepiness after controlling for covariates. Compared with control patients referred for polysomnography, fewer patients with sarcoidosis had clinically significant OSA. However, among patients with sarcoidosis, OSA was more severe in those with abnormal lung function.

Conclusions:  Sarcoidosis is independently associated with EDS. Sleepiness may contribute to the morbidity of sarcoidosis and should be followed even after treating for potentially coexisting OSA or depression. Abnormal lung function in sarcoidosis may contribute to OSA, although the mechanisms for this are not known.

Chest. 2013;143(6):1569-1575. doi:10.1378/chest.12-2174

Background:  The Epworth Sleepiness Scale (ESS) is a simple, self-administered questionnaire that provides a measurement of the subject’s level of daytime sleepiness, and is widely used for patients with obstructive sleep apnea (OSA). Some works undermined its accuracy. The aim of this study was to compare self-administered ESS scores to physician-administered scores in a sample of patients with suspicion of OSA.

Methods:  Patients were randomly divided into two groups: group 1, or the self-administered group (n = 113); and group 2, or the physician-administered group (n = 112). Patients in group 1 were asked to complete the ESS in the traditional way; in group 2, the ESS was administered by a sleep-medicine physician. Subjects in both groups underwent diagnostic in-laboratory portable monitoring (PM) within 1 week’s time.

Results:  The percentage of questionnaires properly completed was significantly different between groups: 77% (87 of 113) in the group 1 vs 100% (112 of 112) in the group 2 (P = .00). Scores obtained when a physician administered the questionnaire (ESSp) were higher than those when the ESS was self administered (ESSs) (ESSp:12.09 ± 4.1 vs ESSs:10.37 ± 5.49; P = .01). The ESSp was more highly correlated with apnea-hypopnea index and oxygen desaturation index than the ESSs.

Conclusions:  Our results lead us to consider the physician-administered ESS to be more accurate than the traditional ESS; thus, our suggestion is to validate this new method of administration.

Chest. 2013;143(6):1576-1583. doi:10.1378/chest.12-2606

Background:  Pediatric obstructive sleep apnea (OSA) is associated with cognitive dysfunction, suggesting altered neurotransmitter function. We explored overnight changes in neurotransmitters in the urine of children with and without OSA.

Methods:  Urine samples were collected from children with OSA and from control subjects before and after sleep studies. A neurocognitive battery assessing general cognitive ability (GCA) was administered to a subset of children with OSA. Samples were subjected to multiple enzyme-linked immunosorbent assays for 12 neurotransmitters, and adjusted for creatinine concentrations.

Results:  The study comprised 50 children with OSA and 20 control subjects. Of the children with OSA, 20 had normal GCA score (mean ± SD) (101.2 ± 14.5) and 16 had a reduced GCA score (87.3 ± 13.9; P < .001). Overnight increases in epinephrine, norepinephrine, and γ-aminobutyric acid (GABA) levels emerged in children with OSA; taurine levels decreased. Using combinatorial approaches and cutoff values for overnight changes of these four neurotransmitters enabled prediction of OSA (area under the curve [AUC]: 0.923; P < .0001). Furthermore, GABA and taurine alterations, as well as overnight reductions in phenylethylamine, were more prominent in children with OSA and low GCA than in children with OSA and normal GCA (P < .001), and they reliably discriminated GCA status (AUC: 0.977; P < .0001).

Conclusions:  Pediatric OSA is associated with overnight increases in urinary concentrations of catecholamines indicative of heightened sympathetic outflow. Increases in GABA levels and decreases in taurine levels could underlie mechanisms of neuronal excitotoxicity and dysfunction. Combinatorial approaches using defined cutoffs in overnight changes in concentrations of selected neurotransmitters in urine may not only predict OSA but also the presence of cognitive deficits. Larger cohort studies appear warranted to confirm these findings.

Chest. 2013;143(6):1584-1589. doi:10.1378/chest.12-1652

Background:  There is growing evidence from animal models that intermittent hypoxemia (IH) may induce dyslipidemia. Altered lipid metabolism may contribute to the increased cardiovascular risk observed in obstructive sleep apnea (OSA). In this multisite, cross-sectional study, we tested the hypothesis that there is an independent association between nocturnal IH and dyslipidemia in OSA.

Methods:  Fasting serum lipid levels were measured in 2,081 patients (638 women) undergoing nocturnal recording for clinical suspicion of OSA. Multivariate regression analyses were performed to evaluate the independent associations between oxygen desaturation index (ODI) and lipid profile after adjustment for potential confounders, including components of the metabolic syndrome (MS) or the MS itself. Adjusted OR for metabolic dyslipidemia (triglycerides [TG] ≥ 150 mg/dL and high-density lipoprotein cholesterol [HDL-C] ≤ 50 mg/dL for women and ≤ 40 mg/dL for men) according to quartiles of ODI were determined by logistic regression.

Results:  Total cholesterol and low-density lipoprotein cholesterol were not associated with ODI. In contrast, nocturnal IH and OSA severity were associated with higher TG levels and lower HDL-C levels after adjustment for confounding factors. The association between ODI and TG and HDL-C levels was independent of the MS. Adjusted OR (95% CIs) for metabolic dyslipidemia were 1 (reference), 1.56 (1.24-1.96), 1.72 (1.29-2.29), and 1.93 (1.55-2.41) for ODI ≤ 7, > 7 to ≤ 18, > 18 to ≤ 38, and > 38, respectively (P < .0001 for linear trend).

Conclusions:  Nocturnal IH is independently associated with metabolic dyslipidemia, which may predispose patients with OSA to a higher risk of cardiovascular disease.

Original Research: COPD

Chest. 2013;143(6):1590-1598. doi:10.1378/chest.12-2094

Background:  COPD is a devastating disease affecting millions worldwide. As disease pathogenesis includes both chronic pulmonary and systemic inflammation, antiinflammatory effects of systemically administered mesenchymal stem cells (MSCs) may decrease inflammation, resulting in improved lung function and quality of life. The goal of this study was to assess safety and to perform an initial evaluation of the potential efficacy of systemic MSC administration to patients with moderate to severe COPD.

Methods:  Sixty-two patients at six sites were randomized to double-blinded IV infusions of either allogeneic MSCs (Prochymal; Osiris Therapeutics Inc) or vehicle control. Patients received four monthly infusions (100 × 106 cells/infusion) and were subsequently followed for 2 years after the first infusion. End points included comprehensive safety evaluation, pulmonary function testing (PFT), and quality-of-life indicators including questionnaires, 6MWT, and assessments of systemic inflammation.

Results:  All study patients completed the full infusion protocol, and 74% completed the 2-year follow-up. There were no infusional toxicities and no deaths or serious adverse events deemed related to MSC administration. There were no significant differences in the overall number of adverse events, frequency of COPD exacerbations, or worsening of disease in patients treated with MSCs. There were no significant differences in PFTs or quality-of-life indicators; however, an early, significant decrease in levels of circulating C-reactive protein (CRP) was observed in patients treated with MSCs who had elevated CRP levels at study entry.

Conclusions:  Systemic MSC administration appears to be safe in patients with moderate to severe COPD and provides a basis for subsequent cell therapy investigations.

Trial registry:  ClinicalTrials.gov; No.: NCT00683722; URL: www.clinicaltrials.gov

Chest. 2013;143(6):1599-1606. doi:10.1378/chest.12-1499

Background:  Although COPD affects large sections of the population, its effects on postoperative outcomes have not been rigorously studied. The objectives of this study were to describe the prevalence of COPD in patients undergoing surgery and to analyze the associations between COPD and postoperative morbidity, mortality, and hospital length of stay.

Methods:  Patients with COPD who underwent surgery were identified from the National Surgical Quality Improvement Program database (2007-2008). Univariate and multivariate analyses were performed on this multicenter, prospective data set (N = 468,795).

Results:  COPD was present in 22,576 patients (4.82%). These patients were more likely to be older, men, white, smokers, and taking corticosteroids and had a lower BMI (P < .0001 for each). Median length of stay was 4 days for patients with COPD vs 1 day in those without COPD (P < .0001). Thirty-day morbidity rates were 25.8% and 10.2% for patients with and without COPD, respectively (P < .0001). Thirty-day death rates were 6.7% and 1.4% for patients with and without COPD, respectively (P < .0001). After controlling for > 50 comorbidities through logistic regression modeling, COPD was independently associated with higher postoperative morbidity (OR, 1.35; 95% CI, 1.30-1.40; P < .0001) and mortality (OR, 1.29; 95% CI, 1.19-1.39; P < .0001). Multivariate analyses with each individual postoperative complication as the outcome of interest showed that COPD was associated with increased risk for postoperative pneumonia, respiratory failure, myocardial infarction, cardiac arrest, sepsis, return to the operating room, and renal insufficiency or failure (P < .05 for each).

Conclusions:  COPD is common among patients undergoing surgery and is associated with increased morbidity, mortality, and length of stay.

Chest. 2013;143(6):1607-1617. doi:10.1378/chest.12-1616

Background:  CT scanning is increasingly used to characterize COPD. Although it is possible to obtain CT scan-measured lung lobe volumes, normal ranges remain unknown. Using COPDGene data, we developed reference equations for lobar volumes at maximal inflation (total lung capacity [TLC]) and relaxed exhalation (approximating functional residual capacity [FRC]).

Methods:  Linear regression was used to develop race-specific (non-Hispanic white [NHW], African American) reference equations for lobar volumes. Covariates included height and sex. Models were developed in a derivation cohort of 469 subjects with normal pulmonary function and validated in 546 similar subjects. These cohorts were combined to produce final prediction equations, which were applied to 2,191 subjects with old GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage II to IV COPD.

Results:  In the derivation cohort, women had smaller lobar volumes than men. Height positively correlated with lobar volumes. Adjusting for height, NHWs had larger total lung and lobar volumes at TLC than African Americans; at FRC, NHWs only had larger lower lobes. Age and weight had no effect on lobar volumes at TLC but had small effects at FRC. In subjects with COPD at TLC, upper lobes exceeded 100% of predicted values in GOLD II disease; lower lobes were only inflated to this degree in subjects with GOLD IV disease. At FRC, gas trapping was severe irrespective of disease severity and appeared uniform across the lobes.

Conclusions:  Reference equations for lobar volumes may be useful in assessing regional lung dysfunction and how it changes in response to pharmacologic therapies and surgical or endoscopic lung volume reduction.

Original Research: Lung Cancer

Chest. 2013;143(6):1618-1625. doi:10.1378/chest.12-0750

Background:  We previously reported the prognostic impact of the number of involved lymph nodes (LNs) on survival in non-small cell lung cancer (NSCLC). However, it remains unknown whether the total number or anatomic location of involved LNs is a superior prognostic factor.

Methods:  A total of 689 patients with NSCLC who underwent complete resection involving dissection of the hilar and mediastinal LNs with curative intent of ≥ 10 LNs were enrolled. The association between the total number of LNs (nN) involved and survival was assessed by comparison with the anatomic location of LN involvement (pathologic lymph node [pN]), the present nodal category.

Results:  We classified the patients into five categories according to the combined pN and nN status as follows: pN0-nN0, pN1-nN1-3, pN1-nN4−, pN2-nN1-3, and pN2-nN4. Although there was no statistically significant difference between the pN1-nN4− and pN2-nN1-3 categories, pN2-nN1-3 had better prognoses than pN1-nN4−. On multivariate analysis, the nN category was an independent prognostic factor for overall survival and disease-free survival (vs nN4−; the hazard ratios of nN0 and nN1-3 for overall survival were 0.223 and 0.369, respectively, P < .0001 for all), similar to the pN category. We propose a new classification based on a combination of the pN and nN categories: namely, N0 becomes pN0-nN0, the N1 category becomes pN1-nN1-3, the N2a category becomes pN2-nN1-3 + pN1-nN4−, and the N2b category becomes pN2-nN4. Each survival curve was proportional and was well distributed among the curves.

Conclusions:  A combined anatomically based pN stage classification and numerically based nN stage classification is a more accurate prognostic determinant in patients with NSCLC, especially in the prognostically heterogeneous pN1 and pN2 cases. Further large-scale international cohort validation analyses are warranted.

Chest. 2013;143(6):1626-1634. doi:10.1378/chest.12-1717

Objective:  The objective of this study was to identify the clinicopathologic factors influencing postrecurrence survival (PRS) in and the effect of postrecurrence therapy (PRT) on patients with completely resected stage I non-small cell lung cancer (NSCLC).

Methods:  We reviewed the data of 919 patients in whom complete resection of stage I NSCLC had been performed.

Results:  Of the 919 patients, 170 (18.5%) had recurrent disease. Initial PRT was performed in 118 patients (69.1%) (surgery in eight, chemotherapy in 79, radiotherapy in 10, and chemoradiotherapy in 21). On multivariate analyses, PRT (hazard ratio [HR], 0.542; 95% CI, 0.344-0.853; P = .008), female sex (HR, 0.487; 95% CI, 0.297-0.801; P = .005), and differentiation (HR, 1.810; 95% CI, 1.194-2.743; P = .005) demonstrated a statistically significant association with favorable PRS. Bone metastasis (HR, 3.288; 95% CI, 1.783-6.062; P < .001), liver metastasis (HR, 4.518; 95% CI, 1.793-11.379; P = .001), chemotherapy (HR, 0.478; 95% CI, 0.236-0.975; P = .040), epidermal growth factor receptor-tyrosine kinase inhibitors treatment (EGFR-TKIs) (HR, 0.460; 95% CI, 0.245-0.862; P = .015), and nonadenocarcinoma (HR, 2.136; 95% CI, 1.273-3.585; P = .004) were independently and significantly associated with PRS in the 118 patients who underwent any PRT. Subgroup analysis with a combination of these five PRS factors in the patients who underwent any PRT revealed median PRS times of 42.4 months for 20 patients lacking all five risk factors and 18.8 months for 98 patients with at least one of these risk factors (P = .001).

Conclusions:  PRT, sex, and differentiation were independently associated with PRS. In the patients who underwent any PRT, PRS was related to EGFR-TKIs, chemotherapy, histology, and initial recurrence sites. One challenge for the future will be to create systematic treatment strategies for recurrent NSCLC according to the risk factor status of individual patients.

Chest. 2013;143(6):1635-1641. doi:10.1378/chest.12-1691

Background:  Radiopaque markers (otherwise known as fiducials) are used clinically to mark sites of biopsy or resection, which aids with targeting of local therapy, including surgery and radiation therapy. We performed a human cadaveric imaging series with a novel, injectable, radiopaque, absorbable hydrogel marker to demonstrate its potential in the management of thoracic malignancies.

Methods:  Baseline CT imaging was performed on three unfixed cadaveric specimens. Hydrogel marker implants were placed in the submucosa of the esophagus, the mediastinum, and lung parenchyma by an endoscopic approach with real-time endobronchial and esophageal ultrasound guidance. Subpleural implants in peripheral lung parenchyma were also performed through an anterolateral thoracotomy. Postimplant simulation CT imaging, T2-weighted MRI, and cone-beam CT imaging were performed. Gross dissection of the lung parenchyma was used to evaluate localization of the hydrogel.

Results:  Transthoracic and endoscopic marker placement was readily achieved. The hydrogel appeared hyperechoic by ultrasound, hyperenhancing on T2-weighted MRI, and demonstrated radiopacity of ~300 Hounsfield Units in simulation CT imaging and cone-beam CT imaging. Gross dissection of the lung revealed well-localized blebs of hydrogel marker within lung parenchyma.

Conclusions:  This cadaveric series demonstrates the excellent visibility of a radiopaque injectable hydrogel marker in the human thorax by multiple common imaging techniques. The hydrogel marker forms a well-localized bleb within tissue, which can assist with triangulation of disease during minimally invasive thoracic surgery. Esophageal applications include radiographic delineation of tumor defined by endoscopy and image guidance for radiotherapy. Future in vivo studies are warranted because radiopaque injectable compounds are promising alternatives to metal fiducials.

Original Research: Occupational And Environmental Lung Diseases

Chest. 2013;143(6):1642-1648. doi:10.1378/chest.12-0920

Background:  The natural history of flock worker’s lung (FWL) and longitudinal lung function changes in nylon flock-exposed workers have not been well characterized.

Methods:  Symptoms, pulmonary function testing, and chest radiographs from five index cases, subsequent case referrals, and screened employees of a flocking plant in Kingston, Ontario, Canada, were compared and analyzed for changes over time (variable follow-up intervals between 1991 and 2011).

Results:  Nine cases and 30 flock-exposed workers without FWL were identified. Four cases had persistent interstitial lung disease despite three having left the workplace. Two developed hypoxemic respiratory failure and secondary pulmonary hypertension and died of complications 18 and 20 years after diagnosis, respectively. Five cases resolved after leaving the workplace. Compared with resolved cases, persistent cases had lower diffusing capacity of the lung for carbon monoxide at presentation (P < .05) and follow-up (P < .05). Among exposed workers employed for 14.5 ± 4.7 years, five had abnormal chest radiographs vs none at baseline (P = .001) over 14.8 ± 4.6 years of follow-up. The prevalence of wheeze increased (P = .001), and FEV1/FVC decreased (P < .001). FEV1 % predicted was significantly lower at follow-up (P = .05). Average FEV1 decline was 46 mL/year (range, −27 to 151 mL/y). Seventy-seven percent of exposed workers were current or former smokers.

Conclusions:  The natural history of FWL includes the following patterns: complete resolution of symptoms; radiographic and pulmonary function abnormalities; permanent, but stable symptoms and restrictive pulmonary function deficits; and progressive decline in pulmonary function, causing death from respiratory failure and secondary pulmonary hypertension. A low baseline diffusing capacity of the lung for carbon monoxide is associated with the persistence and progression of FWL.

Original Research: Asthma

Chest. 2013;143(6):1649-1655. doi:10.1378/chest.12-2289

Background:  Data from long-term follow-up studies of patients with well-characterized asthma are limited. We studied all-cause and cause-specific mortality and risk factors in a large cohort of adults with asthma.

Methods:  A total of 1,075 adult patients with asthma were recruited consecutively from an outpatient clinic from 1974 to 1990 and followed up until the end of 2011. Subjects were classified as having allergic or nonallergic asthma on the basis of a detailed history, spirometric tests, tests for IgE-mediated allergy (skin prick tests and radioallergosorbent test), and bronchial challenge tests. Information on vital status and cause of death were obtained from the Danish Death Register and the Danish National Board of Health. All-cause mortality was also studied in an age- and sex-matched group of subjects without asthma.

Results:  All-cause mortality was increased significantly among patients with asthma compared with control subjects (261 cases vs 124 control subjects; relative risk (RR), 2.1; 95% CI, 1.4-3.0; P < .001). The excess mortality was primarily due to death from obstructive lung disease (95 deaths). Subsequent death from asthma was significantly associated with age (P < .001), level of FEV1 % predicted (P < .001), bronchodilator reversibility (P < .01), peripheral eosinophil count (P < .0001), and previous acute hospital contacts for asthma (P = .002) at enrollment. No significant association was found between smoking habits or self-reported symptom severity, and subsequent death from asthma. After adjusting for age and level of FEV1 % predicted, nonallergic asthma was associated with a higher risk of death from asthma (RR, 1.9; 95% CI, 1.1-3.2; P = .001).

Conclusion:  This 25-year prospective study of a large cohort of adults with well-characterized asthma showed an excess mortality compared with matched control subjects, to a large extent explained by death from obstructive lung disease.

Chest. 2013;143(6):1656-1666. doi:10.1378/chest.12-1187
OPEN ACCESS

Background:  The airway epithelium plays a central role in wound repair and host defense and is implicated in the immunopathogenesis of asthma. Whether there are intrinsic differences between the synthetic capacity of epithelial cells derived from subjects with asthma and healthy control subjects and how this mediator release is modulated by antiinflammatory therapy remains uncertain. We sought to examine the synthetic function of epithelial cells from different locations in the airway tree from subjects with and without asthma and to determine the effects of antiinflammatory therapies upon this synthetic capacity.

Methods:  Primary epithelial cells were derived from 17 subjects with asthma and 16 control subjects. The release of 13 cytokines and chemokines from nasal, bronchial basal, and air-liquid interface differentiated epithelial cells before and after stimulation with IL-1β, IL-1β and interferon-γ, or Poly-IC (Toll-like receptor 3 agonist) was measured using MesoScale discovery or enzyme-linked immunosorbent assay, and the effects of prednisolone and an inhibitor of nuclear factor κ-B2 (IKK2i) were determined.

Results:  The pattern of release of cytokines and chemokines was significantly different between nasal, bronchial basal, and differentiated epithelial cells but not between health and disease. Stimulation of the epithelial cells caused marked upregulation of most mediators, which were broadly corticosteroid unresponsive but attenuated by IKK2i.

Conclusion:  Synthetic capacity of primary airway epithelial cells varied between location and degree of differentiation but was not disease specific. Activation of epithelial cells by proinflammatory cytokines and toll-like receptor 3 agonism is attenuated by IKK2i, but not corticosteroids, suggesting that IKK2i may represent an important novel therapy for asthma.

Original Research: Pulmonary Procedures

Chest. 2013;143(6):1667-1670. doi:10.1378/chest.12-1963

Background:  Interventional pulmonology (IP) is an emerging subspecialty with a dedicated 12 months of additional training after traditional pulmonary and critical care fellowships with fellowships across the country. A multiple-choice question (MCQ) examination was developed to measure didactic knowledge acquired in IP fellowships.

Methods:  Interventional pulmonologists from 10 academic centers developed a MCQ-based examination on a proposed curriculum for IP fellowships. The 75 multiple-choice question examination was proctored, time limited (120 min), and computer-based. The examination was administered to IP faculty, IP fellows in their last month of fellowship, graduating pulmonary and critical care fellows in their last month of training, and incoming first-year pulmonary and critical care fellows.

Results:  The mean score for IP faculty was 87% (range, 83%-94%), 74% for IP fellows (range, 61%-81%, SD 5.09, median 76%), 62% for graduating pulmonary and critical care fellows (range 52% to 73%), and 50% for incoming pulmonary/critical care fellows (range, 35%-65%). There was a graduated increase in mean scores with level of IP training. Scores differed significantly across the four groups (P = .001).

Conclusion:  A validated MCQ examination can measure IP knowledge. There is a difference in IP knowledge based on IP training exposure.

Original Research: Diffuse Lung Disease

Chest. 2013;143(6):1671-1678. doi:10.1378/chest.12-0161

Background:  Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that causes shortness of breath, hypoxemia, and impaired health-related quality of life (HRQL). Whether St. George’s Respiratory Questionnaire (SGRQ), a respiratory-specific HRQL instrument, captures longitudinal changes in HRQL in patients with LAM is unknown.

Methods:  Using data from the Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus trial, we performed analyses to examine associations between SGRQ scores and values for four external measures (anchors). Anchors included (1) FEV1, (2) diffusing capacity of the lung for carbon monoxide, (3) distance walked during the 6-min walk test, and (4) serum vascular endothelial growth factor-D.

Results:  SGRQ scores correlated with the majority of anchor values at baseline, 6 months, and 12 months. Results from longitudinal analyses demonstrated that SGRQ change scores tracked changes over time in values for each of the four anchors. At 12 months, subjects with the greatest improvement from baseline in FEV1 experienced the greatest improvement in SGRQ scores (Symptoms domain, −13.4 ± 14.6 points; Activity domain, −6.46 ± 8.20 points; Impacts domain, −6.25 ± 12.8 points; SGRQ total, −7.53 ± 10.0 points). Plots of cumulative distribution functions further supported the longitudinal validity of the SGRQ in LAM.

Conclusions:  In LAM, SGRQ scores are associated with variables used to assess LAM severity. The SGRQ is sensitive to change in LAM severity, particularly when change is defined by FEV1, perhaps the most clinically relevant and prognostically important variable in LAM. The constellation of results here supports the validity of the SGRQ as capable of assessing longitudinal change in HRQL in LAM.

Chest. 2013;143(6):1679-1684. doi:10.1378/chest.12-1917

Background:  Pulmonary Langerhans cell histiocytosis is a localized proliferation of Langerhans cells in the lung that presents without systemic manifestations as bilateral nodular lung disease in adult cigarette smokers. The molecular basis for this proliferation is unknown.

Methods:  Twenty-two concurrent nodules in five patients were microdissected from formalin-fixed paraffin-embedded tissue and analyzed by next-generation sequencing for mutations in 46 cancer genes with the Ion AmpliSeq Cancer Panel on an Ion PGM (Personal Genome Machine) Sequencer (Life Technologies Corporation). Mutation confirmation was performed by conventional Sanger sequencing or by sensitive coamplification at lower denaturation polymerase chain reaction/fluorescence melting curve analysis.

Results:  Small amounts of DNA (10 ng) isolated from nodules were sufficient for successful interrogation of 740 mutational hot spots in 46 cancer genes by the Ion PGM Sequencer, with an average depth of coverage of 2,783 reads per hot spot and with uniformity of coverage of 92%. BRAF V600E mutation was detected in all concurrent nodules studied in two of the five patients, whereas in three of the five patients, no oncogene mutations were found.

Conclusions:  Pulmonary Langerhans cell histiocytosis appears to be a clonal proliferation that may or may not have BRAF V600E mutations. For those with BRAF V600E mutations, new targeted therapies, such as vemurafenib, may be used in progressive cases.

Chest. 2013;143(6):1685-1691. doi:10.1378/chest.12-1359

Background:  [18F]-2-fluoro-2-deoxyglucose (FDG)-PET scan uptake is increased in areas of fibrosis and honeycombing in patients with idiopathic pulmonary fibrosis (IPF). Glucose transporter-1 (Glut-1) is known to be the main transporter for FDG. There is a paucity of data regarding the distribution of Glut-1 and the cells responsible for FDG binding in fibrotic lung diseases.

Methods:  We applied immunofluorescence to localize Glut-1 in normal, IPF, and Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis lung tissue specimens as well as an array of 19 different lung neoplasms. In addition, we investigated Glut-1 expression in inflammatory cells from BAL fluid (BALF) from healthy volunteers, subjects with IPF, and subjects with HPS pulmonary fibrosis.

Results:  In normal lung tissue, Glut-1 immunoreactivity was seen on the surface of erythrocytes. In tissue sections from fibrotic lung diseases (IPF and HPS pulmonary fibrosis), Glut-1 immunoreactivity was present on the surface of erythrocytes and inflammatory cells. BALF inflammatory cells from healthy control subjects showed no immunoreactivity; BALF cells from subjects with IPF and HPS pulmonary fibrosis showed Glut-1 immunoreactivity associated with neutrophils and alveolar macrophages.

Conclusions:  Glut-1 transporter expression in normal lung is limited to erythrocytes. In fibrotic lung, erythrocytes and inflammatory cells express Glut-1. Together, these data suggest that FDG-PET scan uptake in IPF could be explained by enhanced inflammatory and erythrocytes uptake due to neovascularization seen in IPF and not an upregulation of metabolic rate in pneumocytes. Thus, FDG-PET scan may detect inflammation and neovascularization in lung fibrosis.

Chest. 2013;143(6):1692-1698. doi:10.1378/chest.12-1368

Background:  The course of idiopathic pulmonary fibrosis (IPF) is characterized by variable patterns of disease progression. The red cell distribution width (RDW) is a parameter that is routinely reported with all CBC counts. We sought to test the prognostic usefulness of this parameter in a well-defined cohort of patients with IPF.

Methods:  CBCs, demographics, and pulmonary function data from patients with IPF evaluated between January 1997 and June 2011 were collated. Patient outcomes were ascertained from the program’s database and the Social Security Death Index.

Results:  There were 319 patients with IPF evaluated in whom baseline CBCs were available. The range in the RDW was 11.9 to 21.9 (median 14.1). There were 228 subjects with RDW values ≤ 15 (normal) and 91 patients with RDW values > 15. Patients with normal RDW values had a median survival of 43.1 months compared with 16.3 months for those whose RDW was > 15 (P = .001). There were 198 patients with available serial RDW data. Those patients who had a change in the RDW of less or greater than +0.010/mo had median survivals of 43.0 and 23.9 months, respectively (P = .0246).

Conclusions:  The RDW is a readily available laboratory test result that may provide important, independent prognostic information at baseline and follow-up in patients with IPF. Further studies are warranted to validate this as a biomarker for IPF outcomes, as well as to define the biologic basis for this association.

Chest. 2013;143(6):1699-1708. doi:10.1378/chest.12-1594

Background:  Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with pulmonary vasculopathy.

Objective:  The purpose of this study was to determine whether sildenafil improves 6-min walk distance (6MWD) in subjects with IPF and right ventricular dysfunction.

Methods:  The IPFnet, a network of IPF research centers in the United States, conducted a randomized trial examining the effect of sildenafil on 6MWD in patients with advanced IPF, defined by carbon monoxide diffusing capacity < 35% predicted. A substudy examined 119 of 180 randomized subjects where echocardiograms were available for independent review by two cardiologists. Right ventricular (RV) hypertrophy (RVH), right ventricular systolic dysfunction (RVSD), and right ventricular systolic pressure (RVSP) were assessed. Multivariable linear regression models estimated the relationship between RV abnormality, sildenafil treatment, and changes in 6MWD, St. George’s Respiratory Questionnaire (SGRQ), the EuroQol instrument, and SF-36 Health Survey (SF-36) from enrollment to 12 weeks.

Results:  The prevalence of RVH and RVSD were 12.8% and 18.6%, respectively. RVSP was measurable in 71 of 119 (60%) subjects; mean RVSP was 42.5 mm Hg. In the subgroup of subjects with RVSD, subjects treated with sildenafil experienced less decrement in 6MWD (99.3 m; P = .01) and greater improvement in SGRQ (13.4 points; P = .005) and EuroQol visual analog scores (17.9 points; P = .04) than subjects receiving placebo. In the subgroup with RVH, sildenafil was not associated with change in 6MWD (P = .13), but was associated with greater relative improvement in SGRQ (14.8 points; P = .02) vs subjects receiving placebo. Sildenafil treatment in those with RVSD and RVH was not associated with change in SF-36.

Conclusions:  Sildenafil treatment in IPF with RVSD results in better preservation of exercise capacity as compared with placebo. Sildenafil also improves quality of life in subjects with RVH and RVSD.

Original Research: Disorders of the Pleura

Chest. 2013;143(6):1709-1716. doi:10.1378/chest.12-2221

Background:  In individual patients, especially those who are hospitalized, several conditions often coexist that may be responsible for the development of a pleural effusion and may affect the pleural fluid analysis (PFA). The objective of this study was to investigate the effects of end-stage renal disease and pneumonia on PFA in patients with hydrostatic pleural effusion.

Methods:  In a retrospective analysis of 1,064 consecutive patients who underwent thoracentesis at a university hospital, cell counts and pleural fluid protein, lactate dehydrogenase, pH, and glucose levels were examined in those (n = 300) with clinical evidence of hydrostatic pleural effusion.

Results:  The 300 patients (28.1%) with pleural effusions had congestive heart failure (CHF), circulatory overload (CO), or both. Expert consensus was achieved in 66 (22%) for CHF as the sole diagnosis (SCHF), 30 (10%) for CHF and coexisting pneumonia (PCHF), and 26 (8.7%) for end-stage renal disease (ESRD) with coexisting CO or CHF. The remaining 178 patients were excluded because of complicating conditions. There were minor, but statistically significant differences in pleural fluid/serum protein ratios in patients with ESRD with coexisting CO or CHF compared with SCHF. Compared with SCHF, there were statistically significant tendencies for higher protein and lactate dehydrogenase concentrations and lower pH levels in those with PCHF. The total nucleated cell count and the absolute neutrophil count were significantly higher in PCHF.

Conclusions:  ESRD in patients with hydrostatic pleural effusions has a minimal effect on the PFA. Coexisting pneumonia most often results in an exudative effusion in patients with CHF.

Original Research: Transplantation

Chest. 2013;143(6):1717-1724. doi:10.1378/chest.12-2107

Background:  Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies.

Methods:  We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients.

Results:  A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection.

Conclusions:  These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists.

Trial registry:  ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov

Original Research: Chest Infections

Chest. 2013;143(6):1725-1732. doi:10.1378/chest.12-2051

Background:  Sputum samples from patients with non-multidrug-resistant (non-MDR) pulmonary TB may remain smear-positive for acid-fast bacilli (AFB) at the fifth month of anti-TB treatment. However, its significance remains unknown.

Methods:  From January 2004 to April 2009, there were 5,403 patients with culture-confirmed pulmonary TB from four hospitals in Taiwan. Among them, 116 patients (2.2%) with non-MDR TB whose sputum samples were smear-positive by concentration smear method at the fifth month of treatment were evaluated.

Results:  Sputum culture yielded Mycobacterium tuberculosis in 10 patients (8.6%, MTB group), nontuberculous mycobacteria in 23 (19.8%, NTM group), and no growth in the remaining 83 (71.6%, no-growth group). The relapse rate (22%) was higher in the MTB group (P = .01). Four predictors, smear grading ≥ 3+ at the fifth month (“S”) (OR, 10.73; 95% CI, 2.67-43.17), no sputum culture conversion on the second month (“C”) (OR, 7.16; 95% CI, 1.45-35.44), lack of directly observed therapy (“O”) (OR, 6.40; 95% CI, 1.54-26.56), and no radiographic improvement at the fifth month (“R”) (OR, 4.18; 95% CI, 1.02-17.10), were associated with viable M tuberculosis (MTB group). An integrated “SCOR” index of 1 point for each positive factor had the best discriminatory power for predicting culture results at the fifth month. If the SCOR index was 0, all smear-positive sputum was culture-negative for M tuberculosis.

Conclusions:  Positive sputum smears by a concentrated smear method at the fifth month of treatment in patients with non-MDR TB, especially those with a low SCOR index, may be due to nonviable bacilli and NTM. Careful review of the quality of patient supervision, bacteriologic data, and chest radiography is crucial.

Original Research: Tobacco Cessation and Prevention

Chest. 2013;143(6):1733-1739. doi:10.1378/chest.12-1033

Background:  Cigarette smoking can lead to systemic endothelial dysfunction. Since the airway circulation is exposed to a high concentration of cigarette smoke constituents, we reasoned that airway vascular endothelial dysfunction could be present in healthy smokers without systemic endothelial dysfunction.

Objectives:  The purpose of this study was to compare airway and systemic endothelial function and measure markers of systemic inflammation in lung-healthy current smokers. Since endothelial dysfunction in smokers has been related to systemic inflammation, we also investigated its response to an inhaled glucocorticosteroid (ICS).

Methods:  Fifteen healthy, current smokers and 17 healthy, lifetime nonsmokers were enrolled. Smokers were randomly assigned to 3-week treatments with inhaled fluticasone propionate or placebo in a crossover design. Vascular endothelial function was assessed in the airway by the airway blood-flow response to inhaled albuterol (ΔQaw) and in the extrapulmonary circulation by brachial arterial flow-mediated vasodilation (FMD). Venous blood was collected for C-reactive protein and IL-6.

Results:  Baseline parameters did not differ between groups except for ΔQaw, which was greater in nonsmokers (45% ± 12%) than smokers (1% ± 12%) (P = .001). In the smokers, ICS treatment increased Qaw to 41% ± 7% (P < .001), but had no effect on FMD or inflammatory markers. There was an inverse relationship between baseline and ICS-induced changes in ΔQaw.

Conclusions:  Healthy smokers with no signs of systemic inflammation or endothelial dysfunction display impaired airway vascular endothelial function, possibly preceding systemic endothelial dysfunction. Airway endothelial function was restored with an ICS, and the response was directly related to the severity of endothelial dysfunction.

Original Research: Signs and Symptoms of Chest Diseases

Chest. 2013;143(6):1740-1744. doi:10.1378/chest.12-1837

Background:  Vital signs are critical data in the care of hospitalized patients, but the accuracy with which respiratory rates are recorded in this population remains uncertain. We used a novel flash mob research approach to evaluate the accuracy of recorded respiratory rates in inpatients.

Methods:  This was a single-day, resident-led, prospective observational study of recorded vs directly observed vital signs in nonventilated patients not in the ICU on internal medicine teaching services at six large tertiary-care centers across the United States.

Results:  Among the 368 inpatients included, the median respiratory rate was 16 breaths/min for the directly observed values and 18 breaths/min for the recorded values, with a median difference of 2 breaths/min (P < .001). Respiratory rates of 18 or 20 breaths/min accounted for 71.8% (95% CI, 67.1%-76.4%) of the recorded values compared with 13.0% (95% CI, 9.5%-16.5%) of the directly observed measurements. For individual patients, there was less agreement between the recorded and the directly observed respiratory rate compared with pulse rate.

Conclusions:  Among hospitalized patients across the United States, recorded respiratory rates are higher than directly observed measurements and are significantly more likely to be 18 or 20 breaths/min.

Chest. 2013;143(6):1745-1749. doi:10.1378/chest.12-2870

Background:  Cough is a pervasive and disabling symptom of idiopathic pulmonary fibrosis (IPF) and is an independent predictor of disease progression. The Cough Quality-of-Life Questionnaire (CQLQ) is a validated measure of cough-specific quality of life that could be used as an outcome measure in therapeutic trials for IPF. This study aimed to assess the reliability and validity of the CQLQ in individuals with IPF.

Methods:  The CQLQ was administered as an outcome within a previously published 27-week, placebo-controlled, crossover trial of thalidomide for cough in IPF. Participants were adults with IPF and chronic cough. A cough visual analog scale (VAS) and the St. George’s Respiratory Questionnaire (SGRQ) were administered to establish concurrent validity of the CQLQ.

Results:  Internal consistency was high (Cronbach α > .70) for the CQLQ total and four of six subscale scores. The CQLQ total score demonstrated concurrent validity through significant correlations with scores on the cough VAS and SGRQ total and subscale scores (r range, 0.63-0.81; P < .05). The intraclass correlation coefficient for the CQLQ completed at baseline and after a therapeutic washout period at week 15 was 0.87, indicating very good test-retest reliability.

Conclusions:  This study supports the use of the CQLQ as a valid and reliable instrument in IPF and should be used to assess cough-specific quality of life in therapeutic trials.

Translating Basic Research into Clinical Practice

Chest. 2013;143(6):1750-1757. doi:10.1378/chest.12-2413

In healthy individuals, billions of cells die by apoptosis each day. Clearance of these apoptotic cells, termed “efferocytosis,” must be efficient to prevent secondary necrosis and the release of proinflammatory cell contents that disrupt tissue homeostasis and potentially foster autoimmunity. During inflammation, most apoptotic cells are cleared by macrophages; the efferocytic process actively induces a macrophage phenotype that favors tissue repair and suppression of inflammation. Several chronic lung diseases, particularly airways diseases such as chronic obstructive lung disease, asthma, and cystic fibrosis, are characterized by an increased lung burden of uningested apoptotic cells. Alveolar macrophages from individuals with these chronic airways diseases have decreased efferocytosis relative to alveolar macrophages from healthy subjects. These two findings have led to the hypothesis that impaired apoptotic cell clearance may contribute causally to sustained lung inflammation and that therapies to enhance efferocytosis might be beneficial. This review of the English-language scientific literature (2006 to mid-2012) explains how such existing therapies as corticosteroids, statins, and macrolides may act in part by augmenting apoptotic cell clearance. However, efferocytosis can also impede host defenses against lung infection. Thus, determining whether novel therapies to augment efferocytosis should be developed and in whom they should be used lies at the heart of efforts to differentiate specific phenotypes within complex chronic lung diseases to provide appropriately personalized therapies.

Recent Advances in Chest Medicine

Chest. 2013;143(6):1758-1765. doi:10.1378/chest.12-1605

Patients who suffer adverse events on the wards, such as cardiac arrest and death, often have vital sign abnormalities hours before the event. Early warning scores have been developed with the aim of identifying clinical deterioration early and have been recommended by the National Institute for Health and Clinical Excellence. In this review, we discuss recently developed and validated risk scores for use on the general inpatient wards. In addition, we compare newly developed systems with more established risk scores such as the Modified Early Warning Score and the criteria used in the Medical Early Response Intervention and Therapy (MERIT) trial in our database of > 59,000 ward admissions. In general we found the single-parameter systems, such as the MERIT criteria, to have the lowest predictive accuracy for adverse events, whereas the aggregate weighted scoring systems had the highest. The Cardiac Arrest Risk Triage (CART) score was best for predicting cardiac arrest, ICU transfer, and a composite outcome (area under the receiver operating characteristic curve [AUC], 0.83, 0.77, and 0.78, respectively), whereas the Standardized Early Warning Score, VitalPAC Early Warning Score, and CART score were similar for predicting mortality (AUC, 0.88). Selection of a risk score for a hospital or health-care system should be guided by available variables, calculation method, and system resources. Once implemented, ensuring high levels of adherence and tying them to specific levels of interventions, such as activation of a rapid response team, are necessary to allow for the greatest potential to improve patient outcomes.

Special Features

Chest. 2013;143(6):1766-1773. doi:10.1378/chest.12-1854

The past century witnessed a rapid development of respiratory medicine in China. The major burden of respiratory disease has shifted from infectious diseases to chronic noninfectious diseases. Great achievements have been made in improving the national standard of clinical management of various respiratory diseases and in smoking control. The specialty of respiratory medicine is expanding into pulmonary and critical care medicine. Nevertheless, respiratory diseases remain a major public health problem, with new challenges such as air pollution and nosocomial infections. This review describes the history, accomplishments, new challenges, and opportunities in respiratory medicine in China.

Medical Ethics: Interface of Law and Medicine

Chest. 2013;143(6):1774-1783. doi:10.1378/chest.12-2161

Physicians may encounter medical emergencies outside a hospital or clinical setting, such as on an airplane or at a sporting event. Physicians, particularly critical care physicians, should feel a call of duty to assist in a medical emergency and may do so without complete knowledge of existing laws for protection. The intent of this article is to encourage physicians to have a detailed awareness of Good Samaritan laws in the United States. The authors reviewed and summarized the Aviation Medical Assistance Act (AMAA) as well as the Good Samaritan laws and external defibrillator laws in 50 states and the District of Columbia. Physicians have an ethical duty to provide appropriate emergency care outside hospital or clinical settings and, therefore, should be aware of applicable protective laws. On airplanes, the AMAA provides protection to those physicians acting in Good Samaritan roles on airlines registered in the United States. On the ground, physicians should understand that statutes exist in all jurisdictions to protect Good Samaritans from liability in medical emergencies and in the use of defibrillators. Although there are common elements, each state has its own unique statutory language protecting physicians licensed in that state. All states except Kentucky have statutory language providing immunity to physicians licensed in any other state as well. Some states have interesting statutes relative to other aspects of medical emergency care. A physician entrusted to practice medicine by society and law should be willing to provide appropriate medical care wherever needed.

Topics in Practice Management

Chest. 2013;143(6):1784-1790. doi:10.1378/chest.12-2580

Lung cancer remains the leading cause of death worldwide. Because many patients with non-small cell lung cancer are elderly and have multiple comorbid conditions, many with potentially curable disease are unfit to undergo definitive surgical resection. Stereotactic body radiation therapy (SBRT) is increasingly being used to treat patients with medically inoperable stage I non-small cell lung cancer. SBRT combines reproducible and accurate anatomic targeting with the delivery of a very high dose per fraction of radiation to a target. Planning and delivery of SBRT is a coordinated effort between the radiation oncology team and consulting services. Clinical outcomes, toxicity profiles, treatment delivery, and indications for SBRT are reviewed. Services currently billed during planning and treatment of SBRT are detailed. This article introduces to consulting specialists and subspecialists a new Current Procedural Terminology code that has been proposed to more accurately reflect work performed during SBRT by these consulting providers. This code is described, and its implications for patient care are discussed.

Selected Reports

Chest. 2013;143(6):1791-1795. doi:10.1378/chest.12-1571

Pill aspiration represents a unique type of foreign body aspiration requiring a distinct diagnostic and therapeutic approach. In many cases, the “foreign body” itself may no longer be present, whereas the airway manifestations may persist for months to years. Limited data exist to guide management decisions. We report two cases of severe airway injury secondary to pill aspiration and provide a review of the literature. Endobronchial surveillance may be important to identify impending airway obstruction via secretions, edema, granulation tissue, or fibrotic stricture. In many cases, the airway sequelae of pill aspiration can be effectively managed with bronchoscopy.

Chest. 2013;143(6):1795-1798. doi:10.1378/chest.12-2071

Histoplasma capsulatum infection demonstrates a broad spectrum of acute and chronic clinical manifestations. Unlike the acute reaction to proliferating organisms, the chronic complications are often the result of excessive or prolonged host response with a paucity of organisms. Lung nodules (histoplasmomas) may be noted decades after initial infection and present a challenging clinical problem, as they can be difficult to distinguish from malignancy or tuberculomas. Typically, histoplasmomas are small (<1 cm), asymptomatic, and may be stable in size or slowly enlarge over time. Here we report three patients with unusually large, or giant, histoplasmomas (>3 cm) and describe their extreme phenotype. Importantly, two of the patients presented with subacute symptomatic disease, a presentation that is very atypical for histoplasmoma. The term “buckshot” calcification has been used to describe dozens of small (2-4 mm) calcified nodules, so it may be appropriate to label masses that exceed 3 cm as “cannonball” histoplasmoma.

Postgraduate Education Corner: Contemporary Reviews in Critical Care Medicine

Chest. 2013;143(6):1799-1808. doi:10.1378/chest.12-1849

Alterations in oxygen transport and use are integral to the development of multiple organ failure; therefore, the ultimate goal of resuscitation is to restore effective tissue oxygenation and cellular metabolism. Hemodynamic monitoring is the cornerstone of management to promptly identify and appropriately manage (impending) organ dysfunction. Prospective randomized trials have confirmed outcome benefit when preemptive or early treatment is directed toward maintaining or restoring adequate tissue perfusion. However, treatment end points remain controversial, in large part because of current difficulties in determining what constitutes “optimal.” Information gained from global whole-body monitoring may not detect regional organ perfusion abnormalities until they are well advanced. Conversely, the ideal “canary” organ that is readily accessible for monitoring, yet offers an early and sensitive indicator of tissue “unwellness,” remains to be firmly identified. This review describes techniques available for real-time monitoring of tissue perfusion and metabolism and highlights novel developments that may complement or even supersede current tools.

Postgraduate Education Corner: Contemporary Reviews in Sleep Medicine

Chest. 2013;143(6):1809-1818. doi:10.1378/chest.12-2489

Patients with sleep disorders are most concerned with the impact of these diseases on their quality of life. Patient-reported outcome (PRO) measurement tools, which assess aspects of a patient’s health status that come directly from the patient, are well suited to evaluate quality of life related to sleep disorders. Although PRO data are subjective, they can be quantified, evaluated for reliability and reproducibility, and used to answer questions of clinical and research importance. This article reviews various PRO measure tools used for sleep disorders in clinical and research settings. These instruments may play a role in screening, diagnosis, and monitoring of various sleep disorders.

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

Chest. 2013;143(6):1819-1821. doi:10.1378/chest.12-2433

A 64-year-old man was transferred from an outside hospital for ST elevation myocardial infarction complicated by cardiogenic shock and postinfarction ventricular septal defect (VSD). He was intubated during transfer, admitted to the coronary care unit, and an intraaortic balloon pump was placed. His medical history included obesity, prior coronary artery bypass graft surgery, hypertension, dyslipidemia, and type 2 diabetes mellitus. Medications included aspirin, carvedilol, valsartan, amlodipine, and pravastatin.

Chest. 2013;143(6):1822-1825. doi:10.1378/chest.12-2576

Postgraduate Education Corner: Chest Imaging and Pathology for Clinicians

Chest. 2013;143(6):1826-1829. doi:10.1378/chest.12-1795

Pectoriloquy

Chest. 2013;143(6):1830. doi:10.1378/chest.12-2001
FREE TO VIEW

Oblong rocks skipped creekside,
Late Jonagolds, a bagful.
My morning sport.
He smiled, my grandfather,
Withered though he was
In gentleman’s bedclothes,
Whispered voice, the crab crawling from his lungs.
Black oaks showered acorns,
Pelleted the rooftop
In time with the season.
I, shameful to have drawn contrast
To his invalid’s prison.
I thought his smile hid acceptance of my naivety,
His own cemented decrepitude.
Weeks after his witnessed fall,
Infantile in pose,
Thus unspeakable,
He called us all to that final hour,
To recite our day’s abundance.
A young doctor, minted now
In the façade of maturity,
I am given key to this small family treasure.
Morpheus dreams,
Dram measured, stashed bedside,
Deliberate.
Enough for the job.
Now I recognize that smile
Not of fateful acceptance,
But crooked and wry.
As when as he always did,
He beat me at checkers.
Double jump,
Triumphant.

Chest. 2013;143(6):1830. doi:10.1378/chest.12-2211
FREE TO VIEW

Studying his crooked teeth as he talks,
she scrawls notes
in a shorthand she makes up.
The doctor’s eyes are too kind,
though he is ripping away the camouflage
she’d worn like a Communion veil.
She longs to slip between the office blinds
where dusk beckons,
to lie in the night,
to soften into sleep.
She could grab this man by his starched collar,
his cheerful tie,
whisk him into a dark wood,
commit with him a mortal sin
if he would take back what he said.

Chest. 2013;143(6):1831. doi:10.1378/chest.12-2537
FREE TO VIEW

Some said the lightning came as Raphael died;
pursuing waves of thunder were his knell.
And before the storm could at last subside,
some believed that painting died as well.
Never since have colors seemed so bright
upon the canvases of heavenly themes.
From darkness, his was the purest light,
transforming pagan thoughts to godly dreams.
His carnal ways belied celestial desire,
and placed a demon germ within his veins.
Heroic doctors bled him by candles’ fire,
and with this blood, a final scene was stained.
His was the renaissance of art and grace.
In a century, Medicine would find its place.

Chest. 2013;143(6):1832. doi:10.1378/chest.12-2656
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Gasp he cried with the sound of the breeze
  Hollow and empty as the air swirled.
As bubbles shattered through the calm surface
 So did vivacity through the empty whispers.
 The roar of the lion sang with ferocity
 Muting beeps and concerned whispers.
Ignorant of the pandemonium he growled at last
 As others stood in silence short of breath.

Correspondence

Chest. 2013;143(6):1833. doi:10.1378/chest.13-0209
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Chest. 2013;143(6):1834. doi:10.1378/chest.13-0499
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Chest. 2013;143(6):1835. doi:10.1378/chest.13-0263
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Chest. 2013;143(6):1835-1836. doi:10.1378/chest.13-0473
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Chest. 2013;143(6):1836. doi:10.1378/chest.12-3096
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Chest. 2013;143(6):1836-1837. doi:10.1378/chest.13-0258
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Chest. 2013;143(6):1837. doi:10.1378/chest.13-0579
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Chest. 2013;143(6):1837-1838. doi:10.1378/chest.13-0338
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Chest. 2013;143(6):1838-1839. doi:10.1378/chest.13-0467
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Chest. 2013;143(6):1839. doi:10.1378/chest.13-0376
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Chest. 2013;143(6):1839-1840. doi:10.1378/chest.13-0569
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Chest. 2013;143(6):1840-1841. doi:10.1378/chest.13-0255
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Ultrasound Corner

Chest. 2013;143(6):e1-e4. doi:10.1378/chest.13-0824

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