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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 
William W. Busse; Stephen T. Holgate; Sally W. Wenzel; Paul Klekotka; Yun Chon; JingYuan Feng; Edward Ingenito; Ajay Nirula
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Background:  High bronchodilator reversibility (HR) in adult asthma is associated with distinct clinical characteristics. This analysis compares lung function, biomarker profiles and disease control in HR and low reversibility (LR) asthma patients.

Methods:  A retrospective analysis was performed with data from 2 completed clinical trials of similar design (NCT01018550 and NCT01199289). Patients were divided into HR and LR subgroups based on their response to bronchodilators (HR = ΔFEV1 post-bronchodilator ≥ +20%). Serum IgE, blood eosinophils, and exhaled nitric oxide (FeNO), biomarkers commonly used to stratify patients into Th2-high vs. Th2-low phenotypes, were measured in “not well controlled” (1.5 ≤ ACQ ≤ 2.143) and “very poorly controlled” (ACQ > 2.143) patients.

Results:  The majority of patients in HR and LR subgroups displayed Th2-low biomarker profiles and very poor disease control. HR was more frequently associated with Th2-high biomarkers (40.1% vs. 29.4%; p=0.006), lower lung function (FEV1: 63.5±7.7% vs. 67.9±8.4% pred; p<0.001), and atopy (93.7% vs. 86.5%; p=0.005).

Conclusions:  HR is a physiological indicator of reduced lung function, and is more often associated with elevations in Th2 biomarkers than LR in moderate-to-severe asthma. However, the majority of HR and LR patients in this analysis displayed a Th2-low biomarker profile. Moreover, a Th2-high biomarker profile was not associated with worse disease control.

original research 
Eleni Papakonstantinou; Ioannis Klagas; Michael Roth; Michael Tamm; Daiana Stolz
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Background:  Acute exacerbations in chronic obstructive pulmonary disease (AE-COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. In this study, we investigated if AE-COPD are associated with differential expression of glycosaminoglycans in bronchoalveolar lavage (BAL) in a large cohort of 97 COPD patients.

Methods:  COPD patients, undergoing diagnostic bronchoscopy, with either stable disease (n=53) or AE-COPD (n=44), matched for their demographics and lung function parameters were included in this study. Levels of heparan sulfate, chondroitin sulfate, dermatan sulfate and matrix metalloproteinases (MMPs) in BAL were measured by ELISA.

Results:  Heparan sulfate and chondroitin sulfate were significantly increased in BAL of patients at exacerbation. Levels of heparan sulfate were higher in the BAL of patients with microbial infections. Chondroitin sulfate was negatively correlated with FEV1% predicted but not with DLCO% predicted, indicating that chondroitin sulfate is associated with airway remodeling leading to obstruction rather than to emphysema. Furthermore, heparan sulfate and chondroitin sulfate were significantly correlated with MMP-9, MMP-2 and MMP-12 in BAL, indicating that they were cleaved from their respective proteoglycans by MMPs and subsequently washed out in BAL.

Conclusions:  During AE-COPD there is increased expression of heparan sulfate and chondroitin sulfate in BAL. These molecules are significantly correlated with MMPs in BAL, indicating that they may be associated with airway remodeling and may lead to lung function decline during exacerbations of COPD.

original research 
Eleni Papakonstantinou, MD, PhD; Michael Roth, PhD; Ioannis Klagas, PhD; George Karakiulakis, MD, PhD; Michael Tamm, MD; Daiana Stolz, MD
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Background:  Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation and remodeling, with serious modifications of the extracellular matrix (ECM). Hyaluronic acid (HA) is an abundant ECM molecule in the lung with various biological functions that are depended on its molecular weight (MW). High-MW HA exhibits anti-inflammatory and immune-suppressive effects, while low-MW HA is pro-inflammatory. In this study, we investigated whether acute exacerbations of COPD (AECOPD), which affect quality of life and survival of COPD patients, are associated with altered HA turnover in bronchoalveolar lavage (BAL).

Methods:  We used bronchoalveolar lavage (BAL) from COPD patients, with stable disease (n=53) or at AECOPD (n=44), matched for their demographics and clinical characteristics, and BAL from controls (n=15). HA, HA-synthase-1 (HAS-1) and hyaluronidase (HYAL) were determined by ELISA and HYAL activity by HA zymography. The MW of HA was analyzed by agarose electrophoresis.

Results:  HA, HAS-1 and HYAL were significantly increased in BAL of COPD patients at a stable state and at exacerbation, as compared to controls. HYAL activity was significantly increased in BAL of AECOPD patients, resulting in an increase of low-MW HA during exacerbations. In AECOPD patients, we also observed a significant negative correlation of HA and HYAL levels with FEV1% predicted, but not with DLCO% predicted, indicating that increased HA degradation may be associated with airway obstruction than with emphysema.

Conclusions:  AECOPD are associated with increased HYAL activity in BAL and subsequent degradation of HA which may contribute to airway inflammation and subsequent lung function decline during exacerbations.

original research 
Dario Prais, MD; Eytan Kaplan, MD; Gil Klinger, MD; Huda Mussaffi, MD; Meir Mei-Zahav, MD; Ephraim Bar-Yishay, PhD; Patrick Stafler, MD; Guy Steuer, MD; Lea Sirota, MD; Hannah Blau, MBBS
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Background:  Palivizumab reduces the severity of respiratory syncytial virus (RSV) infection in premature infants, but whether there is a protective effect beyond pre-school age is unknown. This study sought to assess the short- and long-term effects of palivizumab immunization on respiratory morbidity and pulmonary function at school age in children born extremely prematurely.

Methods:  Infants born before 29 weeks’ gestation in 2000-2003 were assessed at school age by parental questionnaire, hospital chart review, and lung function tests. Children born immediately before the introduction of routine palivizumab prophylaxis were compared to age-matched children who received palivizumab prophylaxis during the first RSV season.

Results:  Sixty-three children of mean age 8.9 years were included: 30 had received palivizumab and 33 had not (controls). The groups were similar for gestational age, birth weight, need for mechanical ventilation and oxygen supplementation. Fifty-three percent of the palivizumab compared to 39% of the control group had BPD (P=0.14). Wheezing occurred in the first 2 years of life in 27% of the palivizumab group and 70% of controls (P=0.008); respective hospitalization rates were 33% and 70% (P=0.001). At school age, rates of hyper-responsiveness (PC20 <1mg/ml) were 33% and 48%, respectively (P=0.38). Spirometry, lung volumes, diffusion, and exhaled nitric oxide were within normal limits, with no significant differences between groups.

Conclusion:  Palivizumab prophylaxis was associated with reduced wheezing episodes and hospitalizations during the first 2 years of life in children born extremely prematurely. However, it does not affect pulmonary outcome at school age.

original research 
Harneet K. Walia, MD; Sandra D. Griffith, PhD; Nancy Foldvary-Schaefer, DO, MS; George Thomas, MD; Emmanuel L. Bravo, MD; Douglas E. Moul, MD, MPH; Reena Mehra, MD, MS
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Background:  Clinic-based effectiveness studies of sleep disordered breathing (SDB) treatment in reducing blood pressure (BP) in resistant hypertension (RHTN) versus non-RHTN are sparse. We hypothesize that continuous positive airway pressure (CPAP) use in SDB reduces BP significantly in RHTN and non-RHTN in a large clinic-based cohort.

Methods:  Electronic medical records were reviewed in patients with SDB and comorbid RHTN and non-RHTN for CPAP therapy initiation (baseline) and subsequent visits. We estimated generalizable BP changes from multivariable mixed-effects linear models for systolic, diastolic, and mean arterial blood pressures (SBP, DBP, MAP), adjusting for RHTN status, age, sex, race, body mass index (BMI), cardiac history, and diabetes, and repeated measure correlation.

Results:  Of 894 patients, 130 (15%) had RHTN at baseline (age: 58 ±12 years, 52 % male, BMI: 36 ± 9 kg/m2). RHTN patients had significantly higher BP overall (p<0.001), most notably for systolic BP (6.9 mmHg, 95%CI: 3.84, 9.94). In the year following CPAP initiation, improvements in BP indices did not generally differ based on RHTN status in which RHTN status was a fixed effect. However, there was a significant decrease in SBP (3.08 mmHg, 95% CI: 1.79, 4.37), DBP (2.28, 95%CI: 1.56, 3.00), and MAP (2.54 mmHg, 95% CI: 1.73, 3.36) in both groups.

Conclusions:  In this clinic-based effectiveness study involving patients closely followed for BP control, a significant reduction of BP measures (strongest for SBP) was observed in response to CPAP which was similar in RHTN and non-RHTN groups thus informing expected clinical CPAP treatment response.

original research 
Matthew D. Krasowski, MD, PhD; Johanna Savage, MD; Alexandra Ehlers, BS; Jon Maakestad, BS; Gregory A. Schmidt, MD, FCCP; Sonia L. La’ulu, BS; Natalie N. Rasmussen, BS; Frederick G. Strathmann, PhD; Jonathan R. Genzen, MD, PhD
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BACKGROUND:  Serum angiotensin converting enzyme (ACE) levels may be decreased by use of ACE inhibitor (ACEI) medication. In this study, we determined how often ACE levels were performed in patients receiving ACEI therapy.

METHODS:  ACE levels analyzed over a 54 month “pre-intervention” time period at an academic medical center were reviewed retrospectively for tests performed during ACEI therapy. This data was compared with a large, de-identified dataset of ACE levels performed at a national reference laboratory, in vitro studies of ACEI inhibition, and liquid chromatography-time-of-flight mass spectrometry (LC-TOF-MS) detection of lisinopril in a subset of clinical specimens.

RESULTS:  Over a 54 month period, 1,292 patients had ACE levels performed, with 108 patients (8.4%) on ACEI therapy at time of testing. ACE levels performed for patients on ACEI therapy were substantially lower. In general, clinical teams did not recognize medication effect on ACE levels. Introduction of a warning prompt in the electronic health record reduced ordering of ACE levels in patients on ACEIs by more than 60% in a seventeen month “post-intervention” time period. The de-identified dataset of ACE levels at a reference laboratory showed a bimodal distribution, with a peak of very low ACE levels. Using LC-TOF-MS, the presence of lisinopril was confirmed in a subset of specimens with low ACE activity. In vitro studies of two different ACE assays showed significant inhibition of activity at clinically relevant concentrations.

CONCLUSIONS:  Assessment of ACE activity is often performed for patients on ACEIs, potentially leading to low ACE concentrations and inaccurate interpretations.

recent advances in chest medicine 
Pamela J. McShane, MD; Jeffrey Glassroth, MD
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Since pulmonary nontuberculous mycobacterial lung disease (PNTM) was last reviewed in Chest in 2008, new information has emerged spanning multiple domains including: epidemiology; transmission and pathogenesis; clinical presentation; diagnosis; and treatment. The overall prevalence of PNTM is increasing and in the U.S., areas of highest prevalence are clustered in distinct geographic locations with common environmental and socioeconomic factors. While the accepted paradigm for transmission continues to be inhalation from the environment, provocative reports suggest that person to person transmission may occur. A panoply of host factors have been investigated in effort to elucidate why ostensibly immune-competent patients develop infection from this bacteria, and there has been clarification that immune-competent patients exhibit different histopathology than immunocompromised patients when infected by nontuberculous mycobacteria. It is now evident that M. abscessus, an increasingly prevalent cause of PNTM, can be classified into three separate subspecies, with differing genetic susceptibility or resistance to macrolides. Recent publications also raise the possibility of improved control of PNTM via enhanced adherence to current treatment guidelines as well as new approaches to treatment and even prevention. These and other recent developments and insights that may inform our approach to PNTM are reviewed and discussed.

contemporary reviews in sleep medicine 
Pierre Mayer; Raphael Heinzer; Gilles Lavigne
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Sleep bruxism (SB) consists of involuntary episodic and repetitive jaw muscle activity characterized by occasional tooth grinding or jaw clenching during sleep. Prevalence decreases from 20% to 14% in childhood to 8% to 3% in adults. Although the causes and mechanisms of idiopathic-primary SB are unknown, putative candidates include psychological risk factors (e.g., anxiety, stress due to life events, hypervigilance) and sleep physiological reactivity (e.g., sleep arousals with autonomic activity and/or breathing events). Whereas certain neurotransmitters (serotonin, dopamine, noradrenalin, histamine) have been proposed to play an indirect role in SB, their exact contribution to rhythmic masticatory muscle activity (RMMA; the electromyography marker of SB) genesis remains undetermined. No specific gene is associated with SB, and familial environmental influence plays a significant role. To date, no single explanation can account for the SB mechanism. Secondary SB with sleep comorbidities that should be clinically assessed includes insomnia, periodic limb movements during sleep, sleep-disordered breathing (e.g., apnea-hypopnea), gastroesophageal reflux disease, and neurological disorders (e.g., sleep epilepsy, REM behavior disorder). SB is currently quantified by scoring RMMA recordings in parallel with brain, respiratory, and heart activity recordings in a sleep laboratory or home setting. RMMA confirmation with audio-video recordings is recommended for better diagnostic accuracy in the presence of neurological conditions. The management strategy (diagnostic tests and treatment) should be tailored to the patient’s phenotype and comorbidities. In the presence of sleep-disordered breathing, a mandibular advancement appliance or continuous positive airway pressure (CPAP) treatment is preferred over single occlusal splint therapy on the upper jaw.

original research 
Takaya Maruyama, M.D., Ph.D.; Takao Fujisawa, M.D., Ph.D.; Shigeru Suga, M.D., Ph.D.; Haruna Nakamura, M.D.; Mizuho Nagao, M.D., Ph.D.; Kiyosu Taniguchi, M.D., Ph.D.; Kiyoyuki Tsutsui, M.D., Ph.D.; Toshiaki Ihara, M.D., Ph.D.; Michael S. Niederman, M.D.
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Background:  In Japan, routine use of early antiviral therapy for patients with influenza is standard.

Methods:  Multicenter prospective cohort evaluation of hospitalized patients with laboratory-confirmed influenza to identify prognostic factors among patients receiving antiviral therapy.

Results:  The population included 1345 influenza patients ( 766 pediatric and 579 adult), and excluding those < age 1(not approved for anti-viral therapy) , 97.7% (1224/1253) received antiviral therapy. Among 579 adult patients, 24 (4.1%) died within 30 days , while none of the 766 pediatric patients died. 528 of the adult patients (91.2%) had influenza A, 509 (87.9%) had a chronic underlying illness, 211 (36.4%) had radiographically confirmed pneumonia . 20 of the 24 patients who died, had pneumonia , and the etiologies were: Streptococcus pneumoniae (12.3%), Staphylococcus aureus (10.9%), including methicillin-resistant S. aureus (MRSA) (3.3%), Enterobacteriaceae (8.1%), and Pseudomonas aeruginosa (3.3%). Of these, 151 were classified as community-acquired pneumonia (CAP), and 60 as healthcare-associated pneumonia (HCAP). Inappropriate therapy was more common in HCAP than CAP ( 15.2% vs. 2%, p=0.001). Potential multidrug-resistant (MDR) pathogens were more common ( 21.7%vs 2.6%, p<0.001) in HCAP patients, particularly MRSA (10% vs 0.7%, p=0.002) and Pseudomonas aeruginosa (8.3% vs 1.3%, p=0.021). Using Cox proportional hazards modeling with prescribed independent variables, male gender, severity score, serum albumin (malnutrition), and pneumonia were associated with survival 30 -days from the onset of influenza.

Conclusions:  Among the prognostic factors, malnutrition and pneumonia are amenable to medical intervention. There is an opportunity to improve empiric therapy for patients with HCAP and influenza.

Trial registration:  Japan Medical Association Center for Clinical Trials JMA-IIA00123.

original research 
MAJ David C. Hostler, MD, MPH; Elizabeth S. Marx, MD; COL Lisa K. Moores, MD; CPT Sarah Petteys, MD; MAJ Jordanna Mae Hostler, MD; MAJ Joshua D. Mitchell, MD; Paul R. Holley, MS; LTC Jacob F. Collen, MD; CPT Brian Foster, DO; LTC Aaron B. Holley, MD

Objectives:  Recent guidelines recommend assessing medical inpatients for bleeding risk prior to providing chemical prophylaxis for venous thromboembolism (VTE). The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding risk score (BRS) was derived from a well defined population of medical inpatients but it has not been externally validated. We sought to externally validate the IMPROVE BRS.

Methods:  We prospectively collected characteristics on admission and VTE prophylaxis data each hospital day on all patients admitted for a medical illness to the Walter Reed Army Medical Center (WRAMC) over an 18 month period. We calculated the IMPROVE BRS for each patient using admission data and reviewed medical records to identify bleeding events.

Results:  From September 2009 through March 2011 there were 1668 inpatients who met the IMPROVE inclusion criteria. Bleeding events occurred during 45 (2.7%) separate admissions; 31 (1.9%) events were major and 14 (0.8%) were non-major but clinically relevant. 256 (20.7%) patients had an IMPROVE BRS ≥ 7.0. Kaplan-Meier curves showed a higher cumulative incidence of major (p=0.02) and clinically important (major plus clinically relevant non-major) (p=0.06) bleeding within 14 days in patients with an IMPROVE BRS ≥ 7.0. An IMPROVE BRS ≥ 7.0 was associated with major bleeding in Cox-regression analysis adjusted for administration of chemical prophylaxis (OR 2.6, 95% CI: 1.1-5.9; p=0.03); there was a trend toward significant association with clinically important bleeding (OR 1.9, 95% CI: 0.9-3.7; p=0.07).

Conclusions:  The IMPROVE BRS calculated at admission predicts major bleeding in medical inpatients. This model may help assess relative risks of bleeding and VTE before chemoprophylaxis is administered.

original research 
Roland W. Esser; M. Cornelia Stoeckel, PhD; Anne Kirsten, MD; Henrik Watz, MD; Karin Taube, MD; Kirsten Lehmann; Sibylle Petersen, PhD; Helgo Magnussen, MD; Andreas von Leupoldt, PhD
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Background:  Patients with Chronic Obstructive Pulmonary Disease (COPD) suffer from chronic dyspnea, which is commonly perceived as highly aversive and threatening. Moreover, COPD is often accompanied by disease-specific fears and avoidance of physical activity. However, little is known about structural brain changes in COPD patients and respective relations with disease duration and disease-specific fears.

Methods:  This study investigated structural brain changes in COPD patients and their relation with disease duration, fear of dyspnea, and fear of physical activity. We used voxel-based morphometric analysis of MRI images to measure differences in generalized cortical degeneration and regional gray matter between 30 patients with moderate-to-severe COPD and 30 matched healthy control subjects. Disease-specific fears were assessed by the COPD anxiety questionnaire.

Results:  COPD patients showed no generalized cortical degeneration, but decreased gray matter in posterior cingulate cortex (whole brain analysis) as well as in anterior and mid cingulate cortex, hippocampus, and amygdala (regions-of-interest analyses). Patients’ reductions in gray matter in anterior cingulate cortex were negatively correlated with disease duration, fear of dyspnea, and fear of physical activity. Mediation analysis revealed that the relation between disease duration and reduced gray matter of the anterior cingulate was mediated by fear of physical activity.

Conclusions:  COPD patients demonstrated gray matter decreases in brain areas relevant for the processing of dyspnea, fear, and antinociception. These structural brain changes were partly related to longer disease duration and greater disease-specific fears, which might contribute to a less favorable course of the disease.

original research 
Thomas K. Aldrich, MD; Pragya Gupta, MD; Sean Stoy, MD; Anthony Carlese, DO; Daniel J. Goldstein, MD
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Background:  Pulse oximetry fails when pulsations are weak or absent, common in patients with continuous flow left ventricular assist devices (LVADs). We developed a method to measure arterial oxygenation (SaO2) noninvasively in pulseless LVAD patients.

Methods:  The technique involves 5-10 second occlusions of radial and ulnar arteries on one hand. A fingertip is transilluminated alternately with LEDs emitting 660nm (red,R) and 905nm (infrared,IR). During the ∼1 second after release of occlusion, changing absorbance of each wavelength is measured and their ratio (R/IR) calculated.We studied five normal subjects breathing hyperoxic, normoxic, or hypoxic gas mixtures to establish a calibration curve, using standard pulse oximetry as gold standard. We also studied seven pulseless LVAD patients (two studied twice) at clinically-determined oxygenation.

Results:  Normal subject data showed close correlation of SpO2 with R/IR, [SpO2 =111-(26.7 x R/IR), R2=0.975]. For LVAD patients, predicted SaO2 (from the calibration curve) tended to underestimate measured SaO2 (from arterial blood) by a clinically-insignificant 1.1±1.6 percentage points (mean±SD), maximum 3.4 percentage points.

Conclusions:  Preliminary results in a small number of patients demonstrate that pulseless oximetry can be used to estimate arterial saturation with acceptable accuracy.

Clinical Implications:  A noninvasive oximeter that does not rely on pulsatile flow would be a valuable advance in assessing oxygenation in patients with LVADs, for whom the only current option is arterial puncture, which is painful, risks arterial injury, and only provides a snapshot evaluation of oxygenation.

original research 
Gurinder Singh, MD; Wei Zhang, MS; Yong-Fang Kuo, PhD; Gulshan Sharma, MD, MPH
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Background:  There is a growing understanding of the prevalence and impact of psychological disorders on chronic obstructive pulmonary disease (COPD). However, the role of these disorders in early readmission is unclear.

Methods:  We analyzed data from 5% fee-for-service Medicare beneficiaries diagnosed with COPD (ICD-9 code 491.xx, 492.xx,493.xx and 496.xx) between 2001 and 2011 who were hospitalized with a primary discharge diagnosis of COPD or a primary discharge diagnosis of respiratory failure (518.xx and 799.1) with secondary diagnosis for COPD. We hypothesized that such psychological disorders as depression, anxiety, psychosis, alcohol abuse and drug abuse are independently associated with an increased risk of 30-day readmission in patients hospitalized for COPD.

Results:  Between 2001 and 2011, 135,498 hospitalizations occurred for COPD in 80,088 fee-for-service Medicare beneficiaries. Of these, 30,218 (22.30%) patients had one or more psychological disorders. In multivariate analyses, odds of 30-day readmission were higher in patients with COPD who had depression [Odds Ratio (OR) 1.34, 95% Confidence Interval (CI), 1.29 - 1.39], anxiety (OR 1.43, 95% CI 1.37-1.50), psychosis (OR 1.18, 95% CI 1.10-1.27), alcohol abuse (OR 1.30, 95% CI 1.15-1.47) and drug abuse (OR 1.29, 95% CI 1.11-1.50) compared to those who did not have these disorders. These psychological disorders increased amount of variation in 30-day readmission attributed to patient characteristics by 37%.

Conclusion:  Psychological disorders like depression, anxiety, psychosis, alcohol abuse and drug abuse are independently associated with higher all cause 30-day readmission rates for Medicare beneficiaries with COPD.

original research 
Melissa A. Lyle, MD; Eric R. Fenstad, MD, MSc; Michael D. McGoon, MD; Robert P. Frantz, MD; Michael J. Krowka, MD; Garvan C. Kane, MD, PhD; Karen L. Swanson, DO
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Background:  A subset of patients with Hereditary Hemorrhagic Telangiectasia (HHT) develops pulmonary hypertension (PH) by mechanisms including pulmonary arterial hypertension, high flow, and elevated pulmonary arterial wedge pressure (PAWP). We aimed to describe echocardiographic and hemodynamic characteristics of patients with coexisting HHT and PH.

Methods:  Single center cohort study of patients with confirmed HHT who underwent right heart catheterization (RHC) and transthoracic 2D echocardiography for suspected PH between 6/1/2003-9/1/2013 at Mayo Clinic Rochester.

Results:  Of 38 patients with confirmed HHT who underwent RHC and echocardiography, 28 (74%) had a MPAP ≥ 25 mmHg. Of those 28, 12 (43%) had pulmonary arterial hypertension. Two patients had normal PAWP and PVR, with PH secondary to either an atrial septal defect or high cardiac flow. Fourteen patients (50%) had elevated PAWP (≥ 15 mmHg), nine with evidence of high flow. RHC in all 28 patients demonstrated a MPAP of 41 ± 11 mmHg, PAWP of 17 ± 10 mmHg, and PVR of 4.5 ± 4.2 Wood Units. Echocardiography demonstrated moderate/severe right ventricular dysfunction in nine (32%) patients. The presence of PH trended towards worse survival (p = 0.06).

Conclusions:  PH in patients with HHT occurs by different mechanisms, and there is a trend towards worse survival in patients that develop PH despite the mechanism. The equal predilection towards all subtypes of PH illustrates the necessity of RHC to clarify the hemodynamics.

original research 
Elizabeth L. Salsgiver, MPH; Aliza K. Fink, DSc; Emily A. Knapp, BA; John J. LiPuma, MD; Kenneth N. Olivier, MD; Bruce C. Marshall, MD; Lisa Saiman, MD, MPH
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Background:  Monitoring potential changes in the epidemiology of cystic fibrosis (CF) pathogens furthers our understanding of the potential impact of interventions.

Methods:  We performed a retrospective analysis using data reported to the CF Foundation Patient Registry (CFFPR) from 2006-2012 to determine the annual percent changes in the prevalence and incidence of selected CF pathogens. Pathogens included P. aeruginosa, methicillin-susceptible S. aureus (MSSA), MRSA, Haemophilus influenzae, B. cepacia complex, Stenotrophomonas maltophilia and Achromobacter xylosoxidans. Changes in nontuberculous mycobacteria (NTM) prevalence were assessed from 2010-2012 when the CFFPR collected NTM species.

Results:  In 2012, the pathogens of highest prevalence and incidence were MSSA and P. aeruginosa, followed by MRSA. The prevalence of A. xylosoxidans and B. cepacia complex were relatively low. From 2006-2012, the annual percent change in overall (as well as in most age strata) prevalence and incidence significantly decreased for P. aeruginosa and B. cepacia complex, but significantly increased for MRSA. From 2010-2012, the annual percent change in overall prevalence of NTM and M. avium complex increased.

Conclusions:  The epidemiology of CF pathogens continues to change. The causes of these observations are most likely multifactorial and include improvements in clinical care and infection prevention and control. Data from this study will be useful to evaluate the impact of new therapies on CF microbiology.

original research 
Marla K. Beauchamp, PhD; Samantha L. Harrison, PhD; Roger S. Goldstein, MD; Dina Brooks, PhD

Background:  Balance deficits and an increased fall risk are well documented in individuals with COPD. Despite evidence that balance training can improve performance on clinical balance tests their Minimal Clinically Important Difference (MCID) is unknown. The aim of this study was to determine the MCID of the Berg Balance Scale (BBS), Balance Evaluation Systems Test (BESTest) and Activities-specific Balance Confidence Scale (ABC) in COPD patients undergoing pulmonary rehabilitation.

Methods:  We performed a secondary analysis of data from two studies of balance training in COPD (n=55). The MCID for each balance measure was estimated using the following anchor and distribution-based approaches: 1) mean change scores on a patient-reported global change in balance scale; 2) optimal cut-point from receiver operating curves (ROC); and 3) the minimal detectable change with 95% confidence (MDC95).

Results:  Data from 55 patients with COPD (mean age 71.2 ± 7.1; mean FEV1 39.2 ± 15.8 percent predicted) were used in the analysis. The smallest estimate of MCID was from the ROC curve method. Anchor-based estimates of the MCID ranged from 3.5 to 7.1 for the BBS, 10.2 to 17.4 for the BESTest and 14.2 to 18.5 for the ABC scale; their MDC95 values were 5.0, 13.1 and 18.9, respectively.

Conclusion:  Among COPD patients undergoing pulmonary rehabilitation, a change of 5 to 7 points for the BBS, 13 to 17 points for the BESTest and 19 points for the ABC scale is required to be both perceptible to patients and beyond measurement error.

original research 
Emir Festic, MD, MS; Jose Soto Soto, MD; Lisa A. Pitre, MS; Marilu Leveton, MS; Danielle M. Ramsey, ARNP; William D. Freeman, MD; Michael G. Heckman, MS; Augustine S. Lee, MD, MS
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Background:  There is a need for improved clinical identification of hospitalized patients at risk of aspiration. We evaluated our novel phonetic test in a broad spectrum of intensive or intermediate care unit patients at risk for aspiration.

Methods:  We prospectively enrolled 60 hospitalized patients with aspiration risk, between December 2009 and September 2011, who subsequently underwent audio-recorded 3-component phonetic bedside evaluation. The recordings were scored by two blinded speech-language pathologists. The institutional “Dysphagia Admission Screening Test” was performed by a bedside nurse. The primary outcomes, dysphagia and aspiration, were assessed by videofluoroscopic swallowing study and/or fiberoptic endoscopic evaluation of swallowing. We assessed the short and long-term clinical outcomes (length of stay, subsequent aspiration pneumonia and respiratory failure, survival), and how these associated with the phonetic and swallow assessments.

Results:  Statistically significant linear associations with dysphagia were noted for all three individual phonetic components. Also, there were statistically significant linear associations with aspiration for diadochokinesis (P=0.050) and Consensus Auditory-Perceptual Evaluation of voice (P=0.025). Diadochokinesis alone predicted dysphagia (AUC: 0.74, P=0.001) and aspiration (AUC: 0.67, P=0.012). Its predictive ability improved when combined with normalized dysphagia admission screening test results (AUC: 0.79, P=0.001). The short and long-term clinical outcomes were adversely affected by the worse phonetic/swallowing scores, though not statistically different.

Conclusions:  Abnormal phonation among intensive and intermediate care unit patients is associated with dysphagia and aspiration. Future investigative efforts should uncover the most effective combination of evaluations for accurate bedside detection of dysphagia and aspiration risk in a broad spectrum of patients.

original research 
Cecilia Becattini, PhD; Alexander T. Cohen, PhD; Giancarlo Agnelli, MD; Luke Howard, PhD; Borja Castejón, MD; Javier Trujillo-Santos, PhD; Manuel Monreal, PhD; Arnaud Perrier, PhD; Roger D. Yusen, MD; David Jiménez, PhD
Topics: , ,

Background:  For patients diagnosed with acute pulmonary embolism (PE), the prognostic significance of concomitant deep vein thrombosis (DVT) lacks clarity.

Methods:  We performed a meta-analysis of studies that enrolled patients with acute PE to assess the prognostic value of concomitant DVT for the primary outcome of 30-day all-cause mortality, and the secondary outcome of 90-day PE-related adverse events. We conducted unrestricted searches of Pubmed and Embase from 1980 through September 30, 2014 and used the terms “deep vein thrombosis”, “pulmonary embolism”, and “prognos*”. We used a random-effects model to pool study results; Begg rank correlation method to evaluate for publication bias; and I2 testing to assess for heterogeneity.

Results:  The meta-analysis included a total of 9 studies (10 cohorts, as one study had 2 cohorts) with 8,859 patients. Of the 7 cohorts with 7,868 participants that had PE and provided results on the primary outcome, 4,379 (56%) had concomitant DVT; 272 of 4,379 (6.2%) patients with concomitant DVT died 30-days after the diagnosis of PE compared with 133 of 3,489 (3.8%) without DVT. Concomitant DVT had a significant association with 30-day all-cause mortality in all patients (7 cohorts; odds ratio [OR], 1.9; 95% CI, 1.5 to 2.4; I2 = 0%). Concomitant DVT was not significantly associated with 90-day PE-related adverse outcomes (5 cohorts; OR, 1.6; 95% CI, 0.8 to 3.4; I2 = 75%).

Conclusions:  In patients diagnosed with acute symptomatic PE, concomitant DVT was significantly associated with an increased risk of death within 30 days of PE diagnosis.

original research 
Takashi Nojiri, MD, PhD; Kazuhiro Yamamoto, MD, PhD, FACC; Hajime Maeda, MD, PhD; Yukiyasu Takeuchi, MD, PhD; Naoko Ose, MD; Yoshiyuki Susaki, MD, PhD; Masayoshi Inoue, MD, PhD; Meinoshin Okumura, MD, PhD
Topics: , , ,

BACKGROUND:  We previously reported that patients with elevated preoperative B-type natriuretic peptide (BNP) levels have an increased risk for postoperative atrial fibrillation following lung cancer surgery. The present study evaluated whether the specific phosphodiesterase III inhibitor olprinone can reduce the incidence of postoperative atrial fibrillation in patients with elevated BNP levels undergoing pulmonary resection for lung cancer.

METHODS:  A prospective randomized study was conducted with 40 patients who had elevated preoperative BNP levels (≥30 pg/mL) and underwent scheduled lung cancer surgery. All patients were in sinus rhythm at surgery. Low-dose olprinone or placebo was continuously infused for 24 hours and started just before anesthesia induction. The primary endpoint was the incidence of postoperative atrial fibrillation. The secondary endpoints were perioperative hemodynamics and levels of BNP, white blood cell counts, and C-reactive protein.

RESULTS:  The incidence of postoperative atrial fibrillation was significantly lower in the olprinone group than in the placebo group (10% vs. 60%, p <0.001). Patients in the olprinone group showed significantly lower BNP, white blood cell counts, and C-reactive protein levels after surgery.

CONCLUSIONS:  Continuous infusion of olprinone during lung cancer surgery was safe and reduced the incidence of postoperative atrial fibrillation following pulmonary resection in patients with elevated preoperative BNP levels.

Trial Registration:  JPRN-UMIN2404

special features 
Paul H. Mayo, MD, FCCP; Mangala Narasimhan, DO, FCCP; Seth Koenig, MD, FCCP
Topics: ,

Critical care transesophageal echocardiography (TEE) has utility in characterizing shock states encountered by intensivists when transthoracic echocardiography (TTE) gives insufficient information, or when more detailed analysis of cardiac structures are needed. It is safe, feasible, easy to learn, and is a recommended component of advanced critical care echocardiography. This article will review critical care TEE in reference to training, equipment, comparison to TTE, indications, safety, and standard views of critical care TEE. It should be considered a companion article to a recent two part series in CHEST that focused on advanced critical care TTE. Included with this article is an online supplement that has a representative series of critical care TEE images with clinical commentary.

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