CHEST publishes select peer-reviewed, accepted manuscripts Online First each week. The media embargo is lifted on the date of Online First publication. Final, edited versions will appear in a numbered issue of CHEST and may contain substantive changes. We encourage readers to check back for the final article. Online First papers are indexed in PubMed and by search engines, but the information, including the final title and author list, may be updated on final publication.

original research 
José M. Porcel, MD, FCCP; Marina Pardina, MD; Silvia Bielsa, MD; Antonio González, MD; Richard W. Light, MD, FCCP
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Background:  Chest computed tomography (CT) has become an integral part of the work-up for undiagnosed pleural effusions. We aimed to develop a CT scan-based scoring system for differentiating between benign and malignant pleural effusions.

Methods:  A number of chest CT abnormalities were compared between 228 patients with benign and 115 with malignant effusions (derivation cohort). A logistic regression analysis was used to identify the independent predictors of malignancy and generate CT scores, with more points assigned to those findings associated with higher β-coefficient values. The diagnostic accuracy of the CT scoring system was calculated for the derivation cohort and further evaluated in two independent populations (n=80 and 42, respectively) by two radiologists.

Results:  CT scores predicting malignancy included any pleural lesion (i.e., nodule, mass or thickening) ≥ 1 cm (5 points), the presence of liver metastases, an abdominal mass, or a lung mass or nodule ≥ 1 cm (3 points each), and the absence of either pleural loculations, pericardial effusions or cardiomegaly (2 points each). In the first validation cohort, a sum score of ≥7 yielded a sensitivity of 88% (95% CI, 73-95%), specificity of 94% (95% CI, 83-98%), likelihood ratio positive of 13.8 (95% CI, 4.6-41.5), likelihood ratio negative of 0.13 (95% CI, 0.05-0.33), and AUC of 0.919 (95% CI, 0.849-0.990). Moreover, 69% of 42 patients with pathologically unconfirmed malignant effusions from a second independent cohort would have been correctly labeled by the predictive score.

Conclusions:  A simple CT-based scoring system can help physicians to separate malignant from benign pleural effusions.

original research 
Jann-Yuan Wang, Ph.D.; Ming-Chia Lee, M.S.; Chin-Chung Shu, M.D.; Chih-Hsin Lee, Ph.D.; Li-Na Lee, Ph.D.; Kun-Mao Chao, Ph.D.; Feng-Yee Chang, Ph.D.
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Introduction:  Diabetes mellitus (DM) increases the risk of tuberculosis (TB) recurrence. This study investigated whether nine-month anti-TB treatment is associated with a lower risk of TB recurrence within two years after complete treatment than six-month treatment in DM patients with an emphasis on the impact of directly observed therapy, short course (DOTs).

Methods:  Patients with pulmonary but not extra-pulmonary TB receiving treatment for 173-277 days between 2002 and 2010 were identified from the National Health Insurance Research Database of Taiwan. DM patients were then selected and classified into two groups based on anti-TB treatment duration (9 months vs. 6 months). Factors predicting two-year TB recurrence were explored using Cox regression analysis.

Results:  Among 12688 DM and 43195 non-DM patients, the two-year TB recurrence rate was 2.20% and 1.38%, respectively (p<0.001). Of the DM patients, recurrence rate decreased from 3.54% to 1.19% after implementation of DOTs (p<0.001). A total of 4506 (35.5%) were classified into 9-month anti-TB treatment group. Although a 9-month anti-TB treatment was associated with a lower recurrence rate (HR 0.76 [0.59-0.97]), the benefit disappeared (HR 0.69 [0.43-1.11]) under DOTs. Other predictors of recurrence included older age, male sex, malignancy, earlier TB diagnosis year, culture positivity after 2 months of anti-TB treatment, and anti-TB treatment being ≤80% consistent with standard regimen.

Conclusions:  The two-year TB recurrence rate is higher in diabetic population in Taiwan and can be reduced by treatment supervision. Extending the anti-TB treatment by three months may also decrease the recurrence rate when treatment is not supervised.

original research 
Wan-Jie Gu, MSc; Fei Wang, MD; Lu Tang, MD; Jing-Chen Liu, MD
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Background:  The effect of single-dose etomidate on mortality in patients with sepsis remains controversial. We systematically reviewed the literature to investigate whether a single-dose etomidate for rapid sequence intubation increased mortality in patients with sepsis.

Methods:  PubMed, Embase, and CENTRAL were searched for randomized controlled trials (RCTs) and observational studies regarding the effect of single-dose etomidate on mortality in adults with sepsis. The primary outcome was all-cause mortality. The Mantel-Haenszel method with random effects model was used to calculate pooled relative risks (RRs) and 95% confidence intervals (CIs).

Results:  Eighteen studies (two RCTs and sixteen observational studies), involving 5552 patients, were included. Pooled analysis suggested that single-dose etomidate was not associated with increased mortality in patients with sepsis, both in RCTs (RR, 1.20; 95% CI, 0.84 to 1.72; P = 0.31; I2 = 0%) and observational studies (RR, 1.05; 95% CI, 0.97 to 1.13; P = 0.23; I2 = 25%). When only adjusted RRs were pooled in five observational studies, RR for mortality was 1.05 (95% CI, 0.79 to 1.39; P = 0.748; I2= 71.3%). These findings also were consistent across all subgroup analyses for observational studies. Single-dose etomidate increased the risk of adrenal insufficiency in patients with sepsis (eight studies; RR, 1.42; 95% CI, 1.22 to 1.64; P < 0.00001).

Conclusions:  Current evidence indicates that single-dose etomidate does not increase mortality in patients with sepsis. However, this finding largely relies on data from observational studies, potentially subject to selection bias, and hence high-quality and adequately powered RCTs are warranted.

original research 
Yongyue Wei, PhD; Zhaoxi Wang, PhD; Li Su, BSc; Feng Chen, PhD; Paula Tejera, PhD; Ednan K. Bajwa, MD; Mark M. Wurfel, MD, PhD; Xihong Lin, PhD; David C. Christiani, MD, FCCP
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Background:  Platelets are thought to be critical in pulmonary-origin acute respiratory distress syndrome (ARDS) as mediators of endothelial damage through their interactions with fibrinogen and multiple signal transduction pathways. A prior meta-analysis identified 5 loci for platelet count (PLT): BAD, LRRC16A, CD36, JMJD1C and SLMO2. This study aims to validate the quantitative trait loci (QTLs) of PLT within BAD, LRRC16A, CD36, JMJD1C, and SLMO2 among critically ill patients and to investigate the associations of these QTLs with ARDS risk that may be mediated through PLT.

Methods:  ARDS cases and at-risk controls were recruited from the Intensive Care Unit of the Massachusetts General Hospital. Exome-wide genotyping data of 629 ARDS cases and 1,026 at-risk controls, and genome-wide gene expression profiles of 18 at-risk controls were generated for analysis.

Results:  Single-nucleotide polymorphism (SNP) rs7766874 within LRRC16A was a significant locus for PLT among at-risk controls [β =-13.00, 95% confidence interval (95%CI) =-23.22∼-2.77, p =0.013]. This association was validated using LRRC16A gene expression data from at-risk controls (β =77.03 per 1 standard-deviation increase of log2-transformed expression, 95%CI =27.26∼126.80, p =0.005). Further, rs7766874 was associated with ARDS risk conditioned on PLT [odds ratio (OR) =0.68, 95%CI =0.51∼0.90, p =0.007], interacting with PLT (OR =1.15 per effect allele per 100×103/µL of PLT, 95%CI =1.03∼1.30, p =0.015), and mediated through PLT (ORIndirect =1.045, 95%CI =1.007∼1.085, p =0.021).

Conclusions:  Our findings support the role of LRRC16A in platelet formation, and suggest the importance of LRRC16A in ARDS pathophysiology by interacting with, and being mediated through, platelet.

original research 
Philip H. Quanjer, MD, PhD; Masaru Kubota, MD, PhD; Hirosuke Kobayashi, MD, PhD, FJSIM, FCCP; Hisamitsu Omori, MD, PhD; Koichiro Tatsumi, MD, PhD, FCCP; Minoru Kanazawa, MD, PhD; Sanja Stanojevic, PhD; Janet Stocks, PhD; Tim J. Cole, ScD
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Background:  Most but not all data from different ethnic groups fit the Global Lung Function Initiative (GLI) spirometric reference model. This study investigates to what extent discrepancies are caused by secular changes in body proportions.

Methods:  Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) from 20,336 healthy Japanese subjects (13,492 females) aged 17–95 years were compared with GLI-2012 reference values for Europeans. Data on the sitting height/standing height ratio (Cormic index) in 17 year old students, collected from 1949-2012 in successive birth cohorts, were used to assess secular changes in body frame. The cohort-specific Cormic index was utilized to assess how variation in body frame affected pulmonary function.

Results:  FEV1 and FVC were lower than GLI-2012 reference values, with values progressively falling until age 35-40 years and then rising to European levels in the elderly. The Cormic index rose until 1942, then fell with a nadir in the 1970s, before rising again until 1995. Nearly half of the spirometric variability from predicted values could be explained by differences in the Cormic index between birth cohorts.

Conclusions:  In low income countries improving health conditions are likely to drive increases in height and changes in relative leg length similar to those observed in Japan, and thus to a change in body frame. This implies that height based prediction equations for such populations will need to be periodically updated.

commentary  FREE TO VIEW
Bruce L. Davidson, MD, MPH
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Direct thrombin inhibitor (anti-factor IIa) anticoagulants, now established for treatment and prevention of cardiac and venous thromboembolism, have been repeatedly associated with a significantly increased frequency of thrombosis on abnormal cardiac endothelium when compared head-to-head with indirectly-acting therapeutic anticoagulants in studies of sufficient patient number and duration. Although there is uncertainty as to mechanism, the weight of evidence as a class effect warrants prescribing effective anticoagulants other than direct thrombin inhibitors.

original research 
Henry T. Stelfox, MD, PhD, FRCPC; Dan Lane, MSc; Jamie M. Boyd, BA; Simon Taylor, BSc; Laure Perrier, MEd, MLIS; Sharon Straus, MD, MSc, FRCPC; David Zygun, MD, MSc, FRCPC; Danny J. Zuege, MD, MSc, FRCPC
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Background:  We conducted a scoping review to systematically review the literature reporting patient discharge from intensive care units (ICU), identify facilitators and barriers to high quality care and describe tools developed to improve care.

Methods:  We searched Medline, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials. Data were extracted on the article type, study details for research articles, patient population, phase of care during discharge, and dimensions of healthcare quality.

Results:  From 8,154 unique publications we included 224 articles. Of these, 131 (58%) articles were original research predominantly case series (23%) and cohort (16%) studies while 12% were narrative reviews and 11% were guidelines/policies. Common themes included patient and family needs/experiences (29% of articles) and the importance of complete and accurate information (26%). Facilitators of high quality care included provider-patient communication (30%), provider-provider communication (25%) and the use of guidelines/policies (29%). Patient and family anxiety (21%) and limited availability of ICU and ward resources (26%) were reported barriers to high quality care. A total of 47 tools to facilitate patient discharge from ICU were identified and focused on patient evaluation for discharge (29%), discharge planning and teaching (47%) and optimized discharge summaries (23%).

Conclusions:  Common themes, facilitators and barriers related to patient and family needs/experiences, communication and the use of guidelines/policies to standardize patient discharge from ICU transcend the literature. Candidate tools to improve care are available, comparative evaluation is needed prior to broad implementation, and could be tested through local quality improvement programs.

original research 
Christopher Austin, M.D.; Khadija Alassas, M.D.; Charles Burger, M.D.; Robert Safford, M.D., P.h.D.; Ricardo Pagan, M.D.; Katherine Duello, M.D.; Preetham Kumar, M.D.; Tonya Zeiger, R.R.T; Brian Shapiro, M.D.
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Background:  Elevated mean right atrial pressure (RAP) measured by cardiac catheterization is an independent risk factor for mortality. Prior studies have demonstrated a modest correlation with invasive and noninvasive echocardiographic right atrial pressure (eRAP), but the prognostic impact of eRAP has not been previously evaluated in pulmonary arterial hypertension (PAH) patients.

Methods:  A retrospective analysis of 121 consecutive patients with PAH based on right heart catheterization and echocardiography was performed. The eRAP was calculated by inferior vena cava (IVC) diameter and collapse using 2005 and 2010 American Society of Echocardiography (ASE) definitions. Accuracy and correlation of eRAP to RAP was assessed. Kaplan-Meier survival analysis by eRAP, right atrial area and Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) risk criteria as well as univariate and multivariate analysis of echocardiographic findings was performed.

Results:  Elevation of eRAP was associated with decreased survival time compared to lower eRAP (p<0.001, RR=7.94 for eRAP > 15 mmHg vs. eRAP ≤ 5 mmHg). Univariate analysis of echocardiographic parameters including eRAP > 15 mmHg, right atrial area > 18 cm2, presence of pericardial effusion, right ventricular fractional area change < 35% and at least moderate tricuspid regurgitation was predictive of poor survival. However, multivariate analysis revealed that only eRAP > 15 mmHg was the only echocardiographic risk factor that was predictive of mortality (HR=2.28, p=0.037).

Conclusions:  Elevation of eRAP by echocardiography at baseline assessment was strongly associated with increased risk of death or transplant in patients with PAH. This measurement may represent an important prognostic component in the comprehensive echocardiographic evaluation of PAH.

original research 
Ho-Cheol Kim, MD; Wonjun Ji, MD; Mi Young Kim, MD, PhD; Thomas V. Colby, MD, PhD; Se Jin Jang, MD, PhD; Chang-Keun Lee, MD, PhD; Seung Bong Han, PhD; Dong Soon Kim, MD, PhD
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Background:  Undifferentiated connective tissue disease (UCTD) involves conditions characterized by both having symptoms of connective tissue disease (CTD) and autoantibodies but they do not fulfill the criteria of a specific CTD. The frequency or prognosis of the usual interstitial pneumonia (UIP) pattern in UCTD is unknown, which may be confused with idiopathic pulmonary fibrosis (IPF). This study aimed to investigate the frequency of the UIP pattern in interstitial pneumonia related to UCTD and compare its prognosis with that of IPF and UCTD-nonspecific interstitial pneumonia (UCTD-NSIP).

Methods:  The medical records of 788 patients presumptively diagnosed with idiopathic interstitial pneumonia (IIP) at Asan Medical Center from January 2005 to December 2012 were retrospectively reviewed. UCTD was diagnosed according to the criteria by Corte et al1 and the prognoses were compared between UCTD-UIP and UCTD-NSIP and between UCTD-UIP and IPF.

Results:  Among 105 UCTD patients (13.3% of total subjects), 44 had an UIP pattern (by surgical lung biopsy: 24; by high-resolution computed tomography: 20), 29 had an NSIP pattern (by surgical lung biopsy), and 9 had an organizing pneumonia pattern (by biopsy). The overall survival of the UCTD-UIP group was shorter than that of the UCTD-NSIP group (P=0.021) but significantly better than that of the IPF group (P=0.042).

Conclusions:  A UIP pattern, which seems to be frequent in UCTD, showed a poorer prognosis than that of UCTD-NSIP. However, the prognosis of UCTD-UIP was significantly better than that of IPF, highlighting the importance of searching for underlying UCTD in suspected IPF cases.

original research 
Maria Cristina Vedovati, MD; Federico Germini, MD; Giancarlo Agnelli, MD; Cecilia Becattini, MD, PhD
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Background  Direct oral anticoagulants (DOA) have been shown to be as effective and at least as safe as conventional anticoagulation for the prevention of recurrences in patients with venous thromboembolism (VTE). Whether this is the case in patients with cancer-associated VTE remains undefined.

Methods  We performed a meta-analysis of randomized controlled trials with the aim of assessing the efficacy and safety of DOA in patients with VTE and cancer. MEDLINE, EMBASE and CENTRAL were searched up to December 2013 with no language restriction. The primary outcome of the analysis was recurrent VTE. Data on major (MB) and clinically relevant non-major bleedings were analyzed. Data were pooled and compared by odds ratios (ORs) and 95% confidence intervals (CIs).

Results  Overall, 10 studies comparing DOA with conventional anticoagulation for treatment of VTE including patients with cancer were included in the review. Six studies were included in the meta-analysis (2 with dabigatran, 2 rivaroxaban, 1 edoxaban and 1 apixaban), accounting for a total of 1132 patients. VTE recurred in 23 of 595 (3.8%) and in 32 of 537 (5.9%) cancer patients treated with DOA and conventional treatment, respectively (OR 0.63, 95% CI 0.37 to 1.10; I-squared 0%). MB occurred in 3.2 and 4.2% of patients receiving DOA and conventional treatment, respectively (OR 0.77, 95% CI 0.41 to 1.44; I-squared 0%).

Conclusions  DOA seems to be as effective and safe as conventional treatment for prevention of VTE in cancer patients. Further clinical trials in patients with cancer-associated VTE should be performed to confirm these results.

original research 
Eun Sun Kim, MD; Sun Mi Choi, MD; Jinwoo Lee, MD; Young Sik Park, MD; Chang-Hoon Lee, MD; Jae-Joon Yim, MD; Chul-Gyu Yoo, MD; Young Whan Kim, MD; Sung Koo Han, MD; Sang-Min Lee, MD
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Background:  No study has determined whether the risk of mortality predicted by the gender, age, and physiological variables (GAP) model matches the observed mortality from idiopathic pulmonary fibrosis (IPF) in non-Western populations. We evaluated the clinical course of IPF and validated the GAP model in Korean IPF patients.

Methods:  We included 268 patients who had been diagnosed with IPF at Seoul National University Hospital between 2005 and 2009. For each patient, demographics and clinical data such as lung physiological parameters at the diagnosis of IPF were evaluated. And, we validated the GAP model using discrimination and calibration to predict the risk of death in Korean IPF patients.

Results:  The study population comprised 181 men and 87 women, with a mean age of 65.9 years. The mean baseline percent predicted functional vital capacity (FVC) was 77 and percent predicted carbon monoxide diffusing capacity (DLCO) was 65.9. 157 (58.6%) deaths occurred during the follow-up, and the median time to death was 4.64 years. The observed cumulative mortality rates at 1, 2, and 3 years were 10.4%, 20.9%, and 31.0%, respectively. The GAP model produced estimates of 1-year mortality risk consistent with the observed data (c-statistic: GAP calculator 0.74 and GAP index and staging system 0.72, P < 0.29). However, calibration of the GAP model at 3 years was not satisfactory.

Conclusion:  The GAP model showed similar discrimination power compared with the original cohort. But it did not predict the 3-year risk of death accurately. Further multinational validation study will be needed.

original research 
Christophe Dooms, PhD; Kurt G. Tournoy, PhD; Olga Schuurbiers, PhD; Herbert Decaluwe, MD; Frédéric De Ryck, MD; Ad Verhagen, MD; Roel Beelen, MD; Erik van der Heijden, PhD; Paul De Leyn, PhD
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Background:  Patients with clinical N1 (cN1) lung cancer based on imaging are at risk for malignant mediastinal nodal involvement (N2-disease). Endosonography with a needle technique is suggested over surgical staging as a best first test for preoperative invasive mediastinal staging. The addition of a confirmatory mediastinoscopy seems questionable in patients with a normal mediastinum on imaging. This prospective multicenter trial investigated the sensitivity of preoperative linear endosonography and mediastinoscopy for mediastinal nodal staging of cN1 lung cancer.

Methods:  Consecutive patients with operable and resectable cN1 non-small cell lung cancer underwent a lobe-specific mediastinal nodal staging by endosonography. The primary study outcome was sensitivity to detect N2-disease. The secondary endpoints were the prevalence of N2-disease, the negative predictive value (NPV) of both endosonography and endosonography with confirmatory mediastinoscopy, and the number of patients needed to detect one additional N2-disease with mediastinoscopy.

Results:  Of the 100 patients with cN1 on imaging, 24 patients were diagnosed with N2-disease. Invasive mediastinal nodal staging with endosonography alone has a sensitivity of 38%, which can be increased to 73% by adding a mediastinoscopy. Its NPV was 81% and 91%, respectively. Ten mediastinoscopies are needed to detect one additional N2-disease missed by endosonography.

Conclusions:  Endosonography alone has an unsatisfactory sensitivity to detect mediastinal nodal metastasis in cN1 lung cancer, and the addition of a confirmatory mediastinoscopy is of added value. [clinicaltrials.gov NCT01456429]

original research 
A. Whitney Brown, MD; Chelsea P. Fischer; Oksana A. Shlobin, MD; Russell G. Buhr, MD; Shahzad Ahmad, MD; Nargues A. Weir, MD; Steven D. Nathan, MD
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Background:  The outcomes of IPF patients who undergo hospitalization have not been well characterized. We sought to evaluate the frequency and impact of all-cause as well as respiratory-related hospitalizations on the subsequent course and survival of patients with IPF.

Methods:  The records of IPF patients evaluated at a tertiary center were examined for cause and duration of hospitalization. Data on subsequent patient outcomes was collated.

Results:  The IPF cohort consisted of 592 patients, 25.3% of whom were hospitalized subsequent to their IPF diagnosis. A respiratory-related etiology accounted for 77.3% of these hospitalizations. The median transplant-free survival for all patients was 23.3 [IQR:7.6-63.6] months from time of consultation. Transplant-free survival after hospital admission was much worse for patients with a respiratory hospitalization compared to a non-respiratory hospitalization (median survival: 2.8 [IQR: 0.63-16.2] vs. 27.7 [IQR: 7.4-59.6] months, p=0.0004). Multivariate analyses demonstrated that both all-cause and respiratory-related hospitalizations were strongly associated with mortality after adjusting for baseline demographics. Among patients with a respiratory hospitalization, 22.4% died while in the hospital while 16.4% eventually went onto lung transplantation.

Conclusions:  Hospitalizations are common events in IPF patients. Most hospitalizations are respiratory-related and are associated with high in-hospital mortality and limited survival beyond discharge. Both all-cause hospitalization and respiratory hospitalization are associated with mortality, and therefore either could be utilized as an endpoint in IPF clinical trials.

original research 
Sergio Caravita, MD; Andrea Faini, MSc, PhD; Carolina Lombardi, MD, PhD; Mariaconsuelo Valentini, MD; Francesca Gregorini, MSc; Jessica Rossi, MD; Paolo Meriggi, MSc, PhD; Marco Di Rienzo, MSc, PhD; Grzegorz Bilo, MD, PhD; Piergiuseppe Agostoni, MD, PhD; Gianfranco Parati, MD, PhD
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Background.  Nocturnal periodic breathing occurs more frequently in males than in females in various clinical and pathophysiological conditions. The mechanisms accounting for this gender-related difference are not completely understood. Acetazolamide effectively counteracts nocturnal periodic breathing, but it has been investigated almost exclusively in males.Our aim was to explore possible determinants of nocturnal periodic breathing in a high-altitude setting. We hypothesized that: increased hypoxic chemosensitivity in males could be associated with development of nocturnal periodic breathing at altitude more frequently than in females; and that acetazolamide, by left-shifting the CO2 ventilatory response, could improve nocturnal periodic breathing at altitude in a gender-independent manner.

Methods.  44 healthy lowlanders (21 females), randomized to acetazolamide or placebo, underwent cardiorespiratory sleep studies at sea-level off treatment and under treatment on the first night after arrival at 4559m altitude. Hypoxic and hypercapnic chemosensitivities were assessed at sea-level.

Results.  Males exhibited increased hypoxic chemosensitivity, and displayed nocturnal periodic breathing at altitude more frequently than females. Acetazolamide leftward-shifted the CO2 set-point and, at altitude, improved oxygenation and reduced periodic breathing in both genders, but to a larger extent in males. Hypoxic chemosensitivity directly correlated with the number of apneas/hypopneas at altitude in the placebo group, but not in acetazolamide group.

Conclusions.  The greater severity of periodic breathing during sleep displayed by males at altitude could be attributed to their increased hypoxic chemosensitivity. Acetazolamide counteracted the occurrence of periodic breathing at altitude in both genders, modifying the apneic threshold and improving oxygenation.

Clinical Trial Registration.  EudraCT code-number 2010-019986-27

original research 
Mehdi Mirsaeidi, MD, MPH; Roberto F. Machado, MD; Dean Schraufnagel, MD; Nadera J. Sweiss, MD; Robert P. Baughman, MD
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Background.  The clinical presentation and outcome of sarcoidosis varies by race. However, the race difference in mortality outcome remains largely unknown.

Methods.  We studied mortality related to sarcoidosis from 1999 through 2010 by examining multiple-cause-of-death data from the National Center for Health Statistics. We compared the comorbid conditions between sarcoidosis related deaths with who died from car accidents (previously healthy control) and rheumatoid arthritis (chronic disease control) in both African Americans and Caucasians.

Results.  From 1999 through 2010, sarcoidosis was reported as an immediate cause of death in 10,348 people in the United States with a combined overall mean age-adjusted mortality rate of 2.8 per 1,000,000 person-years. Of these, 6,285 were African American and 3,984 Caucasian. The age adjusted mortality rate for African Americans was 12 times higher than Caucasians. African Americans died at an earlier age than Caucasians. African Americans living in the District of Columbia and North Carolina and Caucasians living in Vermont had higher mortality rates. Although the total sarcoidosis age-adjusted mortality rate has not changed in the last 12 years, this rate was increasing for Caucasians (R=0.747, P=0.005) but not African Americans. Compared to control groups, pulmonary hypertension was significantly more common in individuals with sarcoidosis.

Conclusions.  This nationwide population-based study exposes a significant difference in ethnicity and gender among those dying of sarcoidosis in the United States. Pulmonary hypertension investigation should be considered in all patients with sarcoidosis, especially African Americans.

original research 
Kathleen O. Lindell, PhD, RN; Zhan Liang, MSN, RN; Leslie A. Hoffman, PhD, RN, FAAN; Margaret Q. Rosenzweig, PhD, FNP-BC, AOCNP; Melissa I. Saul, MS; Joseph M. Pilewski, MD; Kevin F. Gibson, MD; Naftali Kaminski, MD
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Rationale:  Palliative care, integrated early, may reduce symptom burden in patients with idiopathic pulmonary fibrosis (IPF). However, limited information exists on timing and clinical practice. The purpose of this study was to describe the time course of events prior to death in patients with IPF managed at a specialty center with a focus on location of death and timing of referral for palliative care.

Methods:  Data were retrospectively extracted from the health system’s data repository and obituary listings. The sample included all decedents, excluding lung transplant recipients, who had their first visit to the center between 2000 and 2012.

Results:  Median survival for 404 decedents was 3 years from diagnosis and 1 year from first center visit. Of 277 decedents whose location of death could be determined, over half died in the hospital (57%). Only 38 (13.7%) had a formal palliative care referral and the majority (71%) was referred within one month of their death. Decedents who died in the academic medical center ICU were significantly younger than those who died in a community hospital floor (p=0.04) or hospice (p=0.001).

Conclusion:  The majority of IPF patients died in a hospital setting and only a minority received a formal palliative care referral. Referral to palliative care occurred late in the disease. These findings indicate the need to study adequacy of end-of-life management in IPF and promote earlier discussion and referral to palliative care.

original research 
Kimberly Fisher, M.D.; Mihaela Stefan, M.D.; Chad Darling, M.D.; Darleen Lessard, MS; Robert J. Goldberg, Ph.D.
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Background:  Chronic obstructive pulmonary disease(COPD) is a common co-morbidity in patients with heart failure, yet little is known about the impact of this condition in patients with acute decompensated heart failure (ADHF), especially from a more generalizable, community-based perspective. The primary objective of this study was to describe the in-hospital and post discharge mortality and treatment of patients hospitalized with ADHF according to COPD status.

Methods:  The study population consisted of patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 4 study years: 1995, 2000, 2002, and 2004. Patients were followed through 2010 for determination of their vital status.

Results:  Of the 9,748 patients hospitalized with ADHF during the years under study, 35.9% had a history of COPD. The average age of this population was 76.1 years, 43.9% were men, and 93.3% were white. At the time of hospital discharge, patients with COPD were less likely to have received evidence-based heart failure medications, including beta-blockers and ACE inhibitors/angiotensin receptor blockers, than patients without COPD. Multivariable adjusted in-hospital death rates were similar for patients with and without COPD. However, among patients who survived to hospital discharge, patients with COPD had a significantly higher risk of dying at 1 (adjusted RR 1.10; 95% CI 1.06, 1.14) and 5-years (adjusted RR 1.40; 95% CI 1.28, 1.42) after hospital discharge than patients who were not previously diagnosed with COPD.

Conclusions:  COPD is a common co-morbidity in patients hospitalized with ADHF and is associated with a worse long-term prognosis. Further research is required to understand the complex interactions of these diseases and ensure that patients with ADHF and COPD receive optimal treatment modalities.

original research 
José M. Porcel, MD, FCCP; Paula Hernández, MD; Montserrat Martínez-Alonso, BSc Stats; Silvia Bielsa, MD; Antonieta Salud, MD
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Background  The role of FDG-PET imaging for diagnosing malignant pleural effusions is not well defined. The aim of this study was to summarize the evidence for its use in ruling in or out the malignant origin of a pleural effusion and/or thickening.

Methods  Meta-analysis of diagnostic accuracy studies published in the Cochrane library, PubMed and Embase (inception to June 2013) without language restrictions. Two investigators selected studies that had evaluated the performance of FDG-PET in patients with pleural effusions and/or thickening, using pleural cyto- or histopathology as the reference standard for malignancy. Subgroup analyses were conducted according to FDG-PET imaging interpretation (qualitative or semi-quantitative), PET equipment (PET vs integrated PET-CT) and/or target population (known lung cancer or malignant pleural mesothelioma). Study quality was assessed using QUADAS-2. We used a bivariate random-effects model for the analysis and pooling of diagnostic performance measures across studies.

Results  Fourteen non-high risk of bias studies, comprising 407 patients with malignant and 232 with benign pleural conditions met the inclusion criteria. Semi-quantitative PET readings had a significantly lower sensitivity for diagnosing malignant effusions than visual assessments (82% vs 91%, p=0.026). The pooled test characteristics of integrated PET-CT systems using semi-quantitative interpretations for identifying malignant effusions were: sensitivity 81%, specificity 74%, positive LR 3.22, negative LR 0.26, and AUC 0.838. Resultant data were heterogeneous, and spectrum bias should be considered when appraising FDG-PET operating characteristics.

Conclusions  The moderate accuracy of PET-CT using semi-quantitative readings precludes its routine recommendation for discriminating malignant from benign pleural effusions.

Systematic Review Registration Number  International Prospective Register of Systematic Reviews (PROSPERO) Identifier: CRD42011001392. http://www.crd.york.ac.uk/prospero/

evidence-based medicine  FREE TO VIEW
Brendan J. Canning, PhD; Anne B. Chang, MBBS, PhD, MPH; Donald C. Bolser, PhD; Jaclyn A. Smith, MB ChB, MRCP, PhD; Stuart B. Mazzone, PhD, FCCP; Lorcan McGarvey, MD on behalf of the CHEST Expert Cough Panel
Topics: , , ,

Bronchopulmonary C-fibers and a subset of mechanically sensitive, acid-sensitive myelinated sensory nerves play essential roles in regulating cough. These vagal sensory nerves terminate primarily in the larynx, trachea, carina and large intrapulmonary bronchi. Other bronchopulmonary sensory nerves, sensory nerves innervating other viscera as well as somatosensory nerves innervating the chest wall, diaphragm and abdominal musculature regulate cough patterning and cough sensitivity. The responsiveness and morphology of the airway vagal sensory nerve subtypes and the extrapulmonary sensory nerves that regulate coughing are described. The brainstem and higher brain control systems that process this sensory information are complex, but our current understanding of them is considerable and increasing. The relevance of these neural systems to clinical phenomena, such as urge to cough and psychological methods for treatment of dystussia, is high and modern imaging methods have revealed potential neural substrates for some features of cough in the human.

original research 
Giampietro Marchetti; Alberto Valsecchi; Davide Indellicati; Sabrina Arondi; Marco Trigiani; Valentina Pinelli
Topics: , ,

Background  Medical Thoracoscopy (MT) is a diagnostic and therapeutic procedure, which permits to study the pleural space. The presence of pleural adhesions is the most important contraindication to performing MT. Lesions of the pleura in absence of pleural effusion are usually studied in video-assisted thoracoscopic surgery (VATS) with preoperative ultrasound evaluation. No data are available about ultrasound guided MT in the absence of pleural effusion.

Methods  From January 2007 to June 2013, 622 consecutive MT were performed under US guide, without inducing a pneumothorax. A retrospective cohort of 29 patients affected by pleural diseases with no liquid was reviewed. The 5th-6th intercostals spaces along the midaxillary line with a good echographic 'sliding sign' and a normal appearance of the pleural line were chosen as the entry site. Pleural cavity was explored and biopsies were performed.

Results  The mean age of the patient cohort was 62.8 years, 20 male and 9 female. Pleural adherence were avoided, an adequate number of pleural biopsies were performed. We never incurred in parenchymal lung injuries, bleeding or hematoma. 17 patients had a completely free pleural cavity, 4 cases a single pleural adhesion and 8 multiple pleural adhesions but in all cases endoscopic exploration was possible and biopsy adequate. The most frequent histhopathological diagnosis was malignant pleural mesothelioma.

Conclusion  We have shown that thoracic ultrasound is accurate in identify intrathoracic adhesions and in experienced hands can guide medical thoracoscopy access, replacing VATS approach, even in the complete absence of pleural effusion.

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