Current Issue


Chest. 2017;151(6):1199-1200. doi:10.1016/j.chest.2017.01.008

Overwhelming inflammation and oxidative stress contribute to the high morbidity and mortality of sepsis by causing vasoplegia, capillary leakage, and organ failure. This provided the strong rationale for Paul Marik’s group to target both uncontrolled inflammation and oxidative stress in an attempt to improve patient outcome. In their provocative before and after study, they administered a combination of IV vitamin C, hydrocortisone, and thiamine in the early phase of severe sepsis and found a considerable decrease in organ failure and mortality. Results are reported in this issue of CHEST.

Chest. 2017;151(6):1201-1203. doi:10.1016/j.chest.2016.11.034

Infection remains a daily challenge in the care of critically ill patients. Point prevalence studies suggest that nearly 50% of patients in ICUs globally suffer from acute infection., Pneumonia accounts for more than half of these infections and therefore serves as the major reason for antibiotic use. Concurrently, antibiotic therapy for pneumonia represents a key driver of antimicrobial resistance. Every day the vicious cycle ensues wherein we use broad-spectrum agents to avoid providing inadequate antimicrobial therapy but risk creating further resistance. Although the need for initially appropriate antibiotic therapy is clearly recognized as the main determinant of outcome in severe infection, clinicians struggle to find ways to balance the need to get it right the first time against the cost of promoting further resistance., In essence, the dilemma places the needs of the patient requiring immediate care against the needs of potential future patients.

Topics: antibiotics , pneumonia , wind
Chest. 2017;151(6):1204-1206. doi:10.1016/j.chest.2016.12.027

Bronchiectasis (from the Greek “bronkhos,” meaning wind pipe or latterly bronchial tubes, and “ektasis,” meaning stretching out, extension, or dilation) refers to both a radiological appearance usually evaluated by CT imaging and a disease characterized by cough, sputum production, and exacerbations. It is associated with a number of infectious, autoimmune, congenital, and allergic disorders. The disease is associated with neutrophilic inflammation and chronic airway infection.

Chest. 2017;151(6):1207-1208. doi:10.1016/j.chest.2017.04.161

Treatment of latent TB infection (LTBI) is increasingly seen as an important component of TB control and elimination programs, particularly in low-prevalence countries such as the United States and in western Europe.,, However, the burden of latent infection in the world is enormous, estimated at some 1.7 billion persons. Even in the United States, a country with a very low prevalence of TB, it is estimated that there are roughly 11 million persons with LTBI. It will be difficult or impossible to treat all these persons under any circumstances. However, if treatment of LTBI was targeted at those most likely to experience active disease, the challenge might become more manageable. How are such persons best identified?

Giants in Chest Medicine

Chest. 2017;151(6):1209-1212. doi:10.1016/j.chest.2016.11.056

Editorials: Point and Counterpoint

Chest. 2017;151(6):1213-1215. doi:10.1016/j.chest.2016.11.057

Modern primary care continues to evolve as a specialty with a broad agenda. What began as a profession focused on day-to-day problem identification and management now includes disease prevention and health promotion. The physician fee schedule issued annually by the Centers for Medicare & Medicaid Services provides payment for these added responsibilities. For Medicare patients, the Initial Preventive Physical Examination (also known as the “Welcome to Medicare” visit) and the Annual Wellness Visits were specifically designed to provide physician payment to complete the full medical history and determine appropriate screening, vaccination, and lifestyle recommendations. Most recently, the Medicare Access and CHIP Reauthorization Act establishes a value-based paradigm based, in part, on the premises of disease prevention and health promotion.

Chest. 2017;151(6):1215-1217. doi:10.1016/j.chest.2016.11.055

The National Lung Screening Trial, the largest randomized controlled lung cancer screening study ever performed, showed a 20% relative decrease in lung cancer mortality and a 7% decrease in overall mortality in high-risk individuals who were screened with LDCT scanning of the chest vs those screened with chest radiographs., LDCT screening may cause harm, an important concern given that most individuals undergoing screening do not have cancer and therefore cannot benefit from screening. Moreover, LDCT screening is a complex process requiring careful coordination. The process begins with selecting appropriate candidates for screening and discussing screening tradeoffs with patients, includes annual screening LDCT scans, and extends through evaluation of suspicious findings and treatment of screen-detected cancers.

Chest. 2017;151(6):1217-1218. doi:10.1016/j.chest.2016.11.054

If the professional community is to fully embrace lung cancer screening, then we have work to do. As Dr Powell correctly points out, the PCP workforce has diminished to well below the crisis level. I would add, as a cautionary note, that the cognitive specialties outside of primary care, including pulmonology, face similar workforce deficiencies. Embracing LDCT screening has implications far beyond the medical rationale. With limited resources, there is the real risk that an expanded screening agenda will further stress our depleted workforce. We simply cannot continue adding new expectations without addressing the root cause for the decline of the cognates. Medicare’s physician fee schedule, with inappropriately undervalued evaluation and management service codes, must be corrected.,,

Chest. 2017;151(6):1218-1219. doi:10.1016/j.chest.2016.11.053

Dr Goodson convincingly establishes the importance of integrating screening services within an ongoing comprehensive provider-patient relationship that continuously evaluates and prioritizes the provision of screening services while taking into account patients’ comorbidities, values, and preferences. It is an attractive proposition that represents a preferred approach for key steps of the lung cancer screening process that include assessment of eligibility and performance of a shared medical decision-making visit.

Commentary: Ahead of the Curve

Chest. 2017;151(6):1220-1228. doi:10.1016/j.chest.2017.02.018

Ex vivo lung perfusion (EVLP) promises to be a comprehensive platform for assessment, reconditioning, and preservation of donor lungs and has been dramatically changing the face of clinical lung transplantation. Besides its increasing role in lung transplantation, EVLP has also been recognized as a useful tool for translational research involving the lungs. Based on recent remarkable evidence and experience using EVLP in lung transplantation, there is growing interest in, and expectations for, the use of EVLP beyond the field of lung transplantation. By combining EVLP with advances in regenerative medicine, stem cell biology, and oncology, the evolving technology of EVLP has tremendous potential to advance pulmonary medicine and science. In this review, we revisit recent advances in EVLP technology and research and discuss the future translation of EVLP applications into life-changing medicine.

Original Research: Critical Care

Chest. 2017;151(6):1229-1238. doi:10.1016/j.chest.2016.11.036

Background  The global burden of sepsis is estimated as 15 to 19 million cases annually, with a mortality rate approaching 60% in low-income countries.

Methods  In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome.

Results  There were 47 patients in both treatment and control groups, with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04-0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group (P < .001).

Conclusions  Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock. Additional studies are required to confirm these preliminary findings.

Chest. 2017;151(6):1239-1246. doi:10.1016/j.chest.2016.11.026

Background  Clinical failures in ventilator-associated pneumonia (VAP) caused by gram-negative bacteria are common and associated with substantial morbidity, mortality, and resource utilization.

Methods  We assessed the safety and efficacy of the amikacin fosfomycin inhalation system (AFIS) for the treatment of gram-negative bacterial VAP in a randomized double-blind, placebo-controlled, parallel group, phase 2 study between May 2013 and March 2016. We compared standard of care in each arm plus 300 mg amikacin/120 mg fosfomycin or placebo (saline), delivered by aerosol twice daily for 10 days (or to extubation if < 10 days) via the investigational eFlow Inline System (PARI GmbH). The primary efficacy end point was change from baseline in the Clinical Pulmonary Infection Score (CPIS) during the randomized course of AFIS/placebo, using the subset of patients with microbiologically proven baseline infections with gram-negative bacteria.

Results  There were 143 patients randomized: 71 to the AFIS group, and 72 to the placebo group. Comparison of CPIS change from baseline between treatment groups was not different (P = .70). The secondary hierarchical end point of no mortality and clinical cure at day 14 or earlier was also not significant (P = .68) nor was the hierarchical end point of no mortality and ventilator-free days (P = .06). The number of deaths in the AFIS group was 17 (24%) and 12 (17%) in the placebo group (P = .32). The AFIS group had significantly fewer positive tracheal cultures on days 3 and 7 than placebo.

Conclusions  In this trial of adjunctive aerosol therapy compared with standard of care IV antibiotics in patients with gram-negative VAP, the AFIS was ineffective in improving clinical outcomes despite reducing bacterial burden.

Trial Registry  ClinicalTrials.gov; No.: NCT01969799; URL: www.clinicaltrials.gov

Original Research: Bronchiectasis

Chest. 2017;151(6):1247-1254. doi:10.1016/j.chest.2016.12.024

Background  This study assessed if bronchiectasis (BR) and rheumatoid arthritis (RA), when manifesting as an overlap syndrome (BROS), were associated with worse outcomes than other BR etiologies applying the Bronchiectasis Severity Index (BSI).

Methods  Data were collected from the BSI databases of 1,716 adult patients with BR across six centers: Edinburgh, United Kingdom (608 patients); Dundee, United Kingdom (n = 286); Leuven, Belgium (n = 253); Monza, Italy (n = 201); Galway, Ireland (n = 242); and Newcastle, United Kingdom (n = 126). Patients were categorized as having BROS (those with RA and BR without interstitial lung disease), idiopathic BR, bronchiectasis-COPD overlap syndrome (BCOS), and “other” BR etiologies. Mortality rates, hospitalization, and exacerbation frequency were recorded.

Results  A total of 147 patients with BROS (8.5% of the cohort) were identified. There was a statistically significant relationship between BROS and mortality, although this relationship was not associated with higher rates of BR exacerbations or BR-related hospitalizations. The mortality rate over a mean of 48 months was 9.3% for idiopathic BR, 8.6% in patients with other causes of BR, 18% for RA, and 28.5% for BCOS. Mortality was statistically higher in patients with BROS and BCOS compared with those with all other etiologies. The BSI scores were statistically but not clinically significantly higher in those with BROS compared with those with idiopathic BR (BSI mean, 7.7 vs 7.1, respectively; P < .05). Patients with BCOS had significantly higher BSI scores (mean, 10.4), Pseudomonas aeruginosa colonization rates (24%), and previous hospitalization rates (58%).

Conclusions  Both the BROS and BCOS groups have an excess of mortality. The mechanisms for this finding may be complex, but these data emphasize that these subgroups require additional study to understand this excess mortality.

Chest. 2017;151(6):1255-1262. doi:10.1016/j.chest.2016.11.024

Background  Bronchiectasis is frequent in smokers with COPD; however, there are only limited data on objective assessments of this process. The objective was to assess bronchovascular morphology, calculate the ratio of the diameters of bronchial lumen and adjacent artery (BA ratio), and identify those measurements able to discriminate bronchiectasis.

Methods  We collected quantitative CT (QCT) measures of BA ratios, peak wall attenuation, wall thickness (WT), wall area, and wall area percent (WA%) at matched fourth through sixth airway generations in 21 ever smokers with bronchiectasis (cases) and 21 never-smoking control patients (control airways). In cases, measurements were collected at both bronchiectatic and nonbronchiectatic airways. Logistic analysis and the area under receiver operating characteristic curve (AUC) were used to assess the predictive ability of QCT measurements for bronchiectasis.

Results  The whole-lung and fourth through sixth airway generation BA ratio, WT, and WA% were significantly greater in bronchiectasis cases than control patients. The AUCs for the BA ratio to predict bronchiectasis ranged from 0.90 (whole lung) to 0.79 (fourth-generation). AUCs for WT and WA% ranged from 0.72 to 0.75 and from 0.71 to 0.75. The artery diameters but not bronchial diameters were smaller in bronchiectatic than both nonbronchiectatic and control airways (P < .01 for both).

Conclusions  Smoking-related increases in the BA ratio appear to be driven by reductions in vascular caliber. QCT measures of BA ratio, WT, and WA% may be useful to objectively identify and quantify bronchiectasis in smokers.

Trial Registry  ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.

Original Research: COPD

Chest. 2017;151(6):1263-1271. doi:10.1016/j.chest.2017.01.003

Background  Guidelines recommend the confirmation of a COPD diagnosis with spirometry. International Classification of Diseases, Ninth Revision, Clinical Modification, diagnostic codes are frequently used to identify patients with COPD for administrative purposes. However, coding the diagnosis of COPD does not require confirmation using spirometry. The purpose of this study was to determine how often the discharge diagnosis of COPD is supported by spirometric measurements in the Veterans Affairs (VA) health system.

Methods  We reviewed records of patients hospitalized for COPD in a VA teaching hospital between 2005 and 2015. Individuals were counted once; rehospitalizations for COPD in the same time frame were excluded. Patient records were assessed for the presence of spirometric measurements and for spirometric evidence of COPD.

Results  There were 1,278 discharges with the principal diagnosis of COPD and allied conditions in the time frame. A total of 826 discharged patients were included. Among them, 21% had no spirometric measurements, 12% were unable to perform the breathing maneuvers correctly, 56% had spirometric evidence of airways obstruction, and 11% had normal prebronchodilator or postbronchodilator FEV1/FVC measurements. Older patients were more likely to fail the spirometry test or have no documented spirometry. Younger patients were more likely to have the first spirometry conducted after their COPD hospitalizations.

Conclusions  Caution must be taken when using the discharge diagnosis database to measure health-care outcomes and determine resource management. Efforts are needed to assure that patients clinically suspected of having COPD are tested with spirometry to improve the accuracy of a COPD diagnosis.

Original Research: Asthma

Chest. 2017;151(6):1272-1278. doi:10.1016/j.chest.2017.03.005

Background  Many people with asthma remain suboptimally controlled despite current treatments. Reasons include comorbidities that could aggravate asthma, including gastroesophageal reflux. We aimed to investigate whether aspiration occurs in patients with asthma and, if so, does it correlate with asthma control?

Methods  Patients had Asthma Control Questionnaire 7 (ACQ-7), fractional exhaled nitric oxide, and spirometry performed to characterize their level of asthma control. Barium swallow with provocation was performed to assess for predisposition to aspiration. Patients underwent bronchoscopic investigation, with BAL pepsin measured as a marker of aspiration.

Results  Seventy-eight patients stratified by disease severity (Global Initiative for Asthma) into mild (35.8%), moderate (21.7%) and severe (42.3%) were studied. Pepsin was detectable in BAL in 46/78 (58.9%). There were no differences between pepsin levels in patients with different disease severity. Furthermore, no significant associations were seen between pepsin level and measures of asthma control, FEV1, ACQ-7 or exacerbation frequency. Similarly no associations were found with adjustments for smoking history, BMI, proton pump inhibitor use, eosinophil count or IgE. When stratified into eosinophilic or neutrophilic asthmatic populations on the basis of BAL, there was no relationship to detected pepsin concentrations. A positive barium swallow (seen in 33/60 patients) did not correlate with BAL pepsin level and we found no significant association between barium swallow result and ACQ-7, Global Initiative for Asthma, exacerbation frequency or FEV1 using either univariate or multivariate analyses.

Conclusions  This study suggests that the importance of aspiration on current asthma symptom control and exacerbation rate may be overstated. However, this study did not address the role of aspiration and future risk of exacerbation.

Original Research: Sleep Disorders

Chest. 2017;151(6):1279-1287. doi:10.1016/j.chest.2017.03.006

Background  Because the interrelationships of objectively ascertained sleep-disordered breathing (SDB), postcardiac surgery atrial fibrillation (PCSAF), and obesity remain unclear, we aimed to further investigate the interrelationships in a clinic-based cohort.

Methods  Patients with polysomnography and cardiac surgery (coronary artery bypass surgery and/or valvular surgery) within 3 years, from January 2009 to January 2014, were identified, excluding those with preexisting atrial fibrillation. Logistic models were used to determine the association of SDB (apnea hypopnea index [AHI] per 5-unit increase) and secondary predictors (central sleep apnea [CSA] [central apnea index ≥ 5] and oxygen desaturation index [ODI]) with PCSAF. Models were adjusted for age, sex, race, BMI, and hypertension. Statistical interaction and stratification by median BMI was performed. ORs and 95% CIs are presented.

Results  There were 190 patients who comprised the analytic sample (mean age, 60.6 ± 11.4 years; 36.1% women; 80% white; BMI, 33.3 ± 7.5 kg/m2; 93.2% had an AHI ≥ 5; 30% had PCSAF). Unlike unadjusted analyses (OR, 1.06; 95% CI, 1.01-1.1), in the adjusted model, increasing AHI was not significantly associated with increased odds of PCSAF (OR, 1.04; 95% CI, 0.98-1.1). Neither CSA nor ODI was associated with PCSAF. A significant interaction with median BMI was noted (P = .015). Effect modification by median BMI was observed; those with a higher BMI > 32 kg/m2 had 15% increased odds of PCSAF (OR, 1.15; 95% CI, 1.05-1.26; P < .003).

Conclusions  SDB was significantly associated with PCSAF in unadjusted analyses, but not after taking into account obesity; those with both SDB and obesity may represent a vulnerable subgroup to target to reduce PCSAF and its associated morbidity.

Original Research: Signs and Symptoms of Chest Diseases

Chest. 2017;151(6):1288-1294. doi:10.1016/j.chest.2017.02.001

Background  Cough is produced by the same neuronal pool implicated in respiratory rhythm generation, and antitussive drugs acting at the central level, such as opioids, may depress ventilation. Levodropropizine is classified as a nonopioid peripherally acting antitussive drug that acts at the level of airway sensory nerves. However, the lack of a central action by levodropropizine remains to be fully established. We set out to compare the effects of levodropropizine and the opioid antitussive agent dihydrocodeine on the respiratory responses to a conventional CO2 rebreathing test in patients with chronic cough of any origin.

Methods  Twenty-four outpatients (aged 39-70 years) with chronic cough were studied. On separate runs, each patient was randomly administered 60 mg levodropropizine, 15 mg dihydrocodeine, or a matching placebo. Subsequently, patients breathed a mixture of 93% oxygen and 7% CO2 for 5 min. Fractional end-tidal CO2 (Fetco2) and inspiratory minute ventilation (i) were continuously monitored. Changes in breathing pattern variables were also assessed.

Results  At variance with dihydrocodeine, levodropropizine and placebo did not affect respiratory responses to hypercapnia (P < .01). The ventilatory increases by hypercapnia were mainly accounted for by a rise in the volume components of the breathing pattern.

Conclusions  The results are consistent with a peripheral action by levodropropizine; the assessment of ventilatory responses to CO2 may represent a useful tool to investigate the central respiratory effects of antitussive agents.

Trial Registry  European Union Clinical Trials Register (EudraCT No.: 2013-004735-68); URL: https://www.clinicaltrialsregister.eu/

Original Research: Pulmonary Procedures

Chest. 2017;151(6):1295-1301. doi:10.1016/j.chest.2017.02.003

Background  Acute dyspnea is a common symptom in the ED. The standard approach to dyspnea often relies on radiologic and laboratory results, causing excessive delay before adequate therapy is started. Use of an integrated point-of-care ultrasonography (PoCUS) approach can shorten the time needed to formulate a diagnosis, while maintaining an acceptable safety profile.

Methods  Consecutive adult patients presenting with dyspnea and admitted after ED evaluation were prospectively enrolled. The gold standard was the final diagnosis assessed by two expert reviewers. Two physicians independently evaluated the patient; a sonographer performed an ultrasound evaluation of the lung, heart, and inferior vena cava, while the treating physician requested traditional tests as needed. Time needed to formulate the ultrasound and the ED diagnoses was recorded and compared. Accuracy and concordance of the ultrasound and the ED diagnoses were calculated.

Results  A total of 2,683 patients were enrolled. The average time needed to formulate the ultrasound diagnosis was significantly lower than that required for ED diagnosis (24 ± 10 min vs 186 ± 72 min; P = .025). The ultrasound and the ED diagnoses showed good overall concordance (κ = 0.71). There were no statistically significant differences in the accuracy of PoCUS and the standard ED evaluation for the diagnosis of acute coronary syndrome, pneumonia, pleural effusion, pericardial effusion, pneumothorax, and dyspnea from other causes. PoCUS was significantly more sensitive for the diagnosis of heart failure, whereas a standard ED evaluation performed better in the diagnosis of COPD/asthma and pulmonary embolism.

Conclusions  PoCUS represents a feasible and reliable diagnostic approach to the patient with dyspnea, allowing a reduction in time to diagnosis. This protocol could help to stratify patients who should undergo a more detailed evaluation.

Original Research: Diffuse Lung Disease

Chest. 2017;151(6):1302-1310. doi:10.1016/j.chest.2017.01.033

Background  Animal and cellular studies support the importance of autophagy inhibition in lymphangioleiomyomatosis (LAM). In a cohort of subjects with LAM, we tested the hypothesis that treatment with sirolimus and hydroxychloroquine (an autophagy inhibitor) at two different dose levels is safe and well tolerated. Secondary end points included changes in lung function.

Methods  This 48-week, two-center phase I trial evaluated the safety of escalating oral hydroxychloroquine doses (100-200 mg) given twice a day in combination with sirolimus to eligible patients ≥ 18 years old with LAM. Subjects received combination therapy for 24 weeks followed by an observation phase without taking study drugs for an additional 24 weeks.

Results  Fourteen patients provided written informed consent. Thirteen were treated in cohorts of three patients each with escalating hydroxychloroquine doses (200 and 400 mg) and an extension phase at the 400-mg dose. The most common adverse events were mucositis, headache, and diarrhea. No drug-related serious adverse events were reported. Secondary end points showed improvement in lung function at 24 weeks, with a decrease in lung function at the 48-week time point. When the higher dose of hydroxychloroquine was analyzed separately, FEV1 and FVC remained stable at 48 weeks, but the 6-min walk distance showed a decrease toward baseline.

Conclusions  The combination of sirolimus and hydroxychloroquine is well tolerated, with no dose-limiting adverse events observed at 200 mg twice a day. Potential effects on lung function should be explored in larger trials.

Trial Registry  ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov

Original Research: Chest Infections

Chest. 2017;151(6):1311-1319. doi:10.1016/j.chest.2017.01.005

Background  The burden of pneumococcal disease is measured only through patients with invasive pneumococcal disease. The urinary antigen test (UAT) for pneumococcus has exhibited high sensitivity and specificity. We aimed to compare the pneumococcal pneumonias diagnosed as invasive disease with pneumococcal pneumonias defined by UAT results.

Methods  A prospective observational study of consecutive nonimmunosuppressed patients with community-acquired pneumonia was performed from January 2000 to December 2014. Patients were stratified into two groups: invasive pneumococcal pneumonia (IPP) defined as a positive blood culture or pleural fluid culture result and noninvasive pneumococcal pneumonia (NIPP) defined as a positive UAT result with negative blood or pleural fluid culture result.

Results  We analyzed 779 patients (15%) of 5,132, where 361 (46%) had IPP and 418 (54%) had NIPP. Compared with the patients with IPP, those with NIPP presented more frequent chronic pulmonary disease and received previous antibiotics more frequently. Patients with IPP presented more severe community-acquired pneumonia, higher levels of inflammatory markers, and worse oxygenation at admission; more pulmonary complications; greater extrapulmonary complications; longer time to clinical stability; and longer length of hospital stay compared with the NIPP group. Age, chronic liver disease, mechanical ventilation, and acute renal failure were independent risk factors for 30-day crude mortality. Neither IPP nor NIPP was an independent risk factor for 30-day mortality.

Conclusions  A high percentage of confirmed pneumococcal pneumonia is diagnosed by UAT. Despite differences in clinical characteristics and outcomes, IPP is not an independent risk factor for 30-day mortality compared with NIPP, reinforcing the importance of NIPP for pneumococcal pneumonia.

Original Research: Genetic and Developmental Disorders

Chest. 2017;151(6):1320-1328. doi:10.1016/j.chest.2017.01.019

Background  Lung transplantation (LTx) is frequently considered for patients with cystic fibrosis (CF) when the FEV1 reaches < 30%. This study estimated transplant-free survival for patients with CF and an FEV1 < 30% and identified predictors of death without LTx.

Methods  We conducted a retrospective cohort study using the CF Foundation Patient Registry from January 1, 2003 to December 31, 2013. Adult patients (≥ 18 years) with FEV1 < 30% prior to LTx were included. We performed Kaplan-Meier survival estimates censored at LTx. Multivariable Cox proportional hazard regression identified predictors of mortality.

Results  There were 3,340 patients with an FEV1 < 30%. Death without LTx occurred in 1,250 patients (37.4%); 951 patients (28.5%) underwent LTx; 918 patients (27.5%) remained alive without LTx at the end of follow-up; and 221 patients (6.6%) were lost to follow-up. Median transplant-free survival after FEV1 < 30% was 6.6 years (95% CI, 5.9-7.0). Adjusted predictors of death without LTx included supplemental oxygen use (hazard ratio [HR], 2.1; 95% CI, 1.7-2.6), Burkholderia cepacia infection (HR, 1.8; 95% CI, 1.3-2.6), BMI ≤ 18 (HR, 1.6; 95% CI, 1.3-1.9), female sex (HR, 1.6; 95% CI, 1.2-2.0), CF-related diabetes in patients receiving insulin (HR, 1.4; 95% CI, 1.2-1.8), and ≥ one exacerbation per year (HR, 1.7; 95% CI, 1.3-2.2 vs. 0 exacerbations).

Conclusions  Median survival was > 6.5 years for patients with CF and an FEV1 < 30%, exceeding prior survival estimates. There was substantial heterogeneity in survival, with some patients with CF dying soon after reaching this lung function threshold and others living for many years. For this reason, we conclude that FEV1 < 30% remains an important marker of disease severity for patients with CF. Patients with a supplemental oxygen requirement or frequent exacerbations should have prompt referral because of their increased risk of death.

Original Research: Pulmonary Physiology

Chest. 2017;151(6):1329-1337. doi:10.1016/j.chest.2017.01.009

Background  Cardiac output () is a key parameter in the assessment of cardiac function, its measurement being crucial for the diagnosis, treatment, and prognostic evaluation of all heart diseases. Until recently, determination at peak exercise has been possible through invasive methods, so that normal values were obtained in studies based on small populations.

Methods  Nowadays, peak can be measured noninvasively by means of the inert gas rebreathing (IGR) technique. The present study was undertaken to provide reference values for peak in the normal general population and to obtain a formula able to estimate peak exercise from measured peak oxygen uptake (o2).

Results  We studied 500 normal subjects (age, 44.9 ± 1.5 years; range, 18-77 years; 260 men, 240 women) who underwent a maximal cardiopulmonary exercise test with peak measurement by IGR. In the overall study sample, peak was 13.2 ± 3.5 L/min (men, 15.3 ± 3.3 L/min; women, 11.0 ± 2.0 L/min; P < .001) and peak o2 was 95% ± 18% of the maximum predicted value (men, 95% ± 19%; women, 95% ± 18%). Peak o2 and peak progressively decreased with age (R2, 0.082; P < .001; and R2, 0.144; P < .001, respectively). The o2-derived formula to measure at peak exercise was (4.4 × peak o2) + 4.3 in the overall study cohort, (4.3 × peak o2) + 4.5 in men, and (4.9 × peak o2) + 3.6 in women.

Conclusions  The simultaneous measurement of and o2 at peak exercise in a large sample of healthy subjects provided an equation to predict peak from peak o2 values.

Translating Basic Research Into Clinical Practice

Chest. 2017;151(6):1338-1344. doi:10.1016/j.chest.2016.10.042

The interaction between the airway epithelium and the inhaled environment is crucial to understanding the pathobiology of asthma. Several studies have identified an important role of airway epithelial-derived cytokines, IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) in asthma pathogenesis. These cytokines have been described as epithelial-derived alarmins that activate and potentiate the innate and humoral arms of the immune system in the presence of actual or perceived damage. Each of the three epithelial-derived alarmins has been implicated in the pathobiology of inhaled allergen-induced airway responses. The best evidence to date exists for TSLP, in that a human monoclonal antibody, which binds TSLP and prevents its engagement with its receptor, resolves airway inflammation in patients with allergic asthma and attenuates allergen-induced airway responses. Better understanding the roles that the epithelial-derived alarmins play and how they influence airway immune response may allow the development of novel therapeutics for asthma treatment.

Recent Advances in Chest Medicine

Chest. 2017;151(6):1345-1355. doi:10.1016/j.chest.2016.07.035

During the past decade, there has been increasing evidence that the small airways (ie, airways < 2 mm in internal diameter) contribute substantially to the pathophysiologic and clinical expression of asthma and COPD. The increased interest in small airways is, at least in part, a result of innovation in small-particle aerosol formulations that better target the distal lung and also advanced physiologic methods of assessing small airway responses. Increasing the precision of drug deposition may improve targeting of specific diseases or receptor locations, decrease airway drug exposure and adverse effects, and thereby increase the efficiency and effectiveness of inhaled drug delivery. The availability of small-particle aerosols of corticosteroids, bronchodilators, or their combination enables a higher total lung deposition and better peripheral lung penetration and provides added clinical benefit, compared with large-particle aerosol treatment. However, a number of questions remain unanswered about the pragmatic approach relevant for clinicians to consider the role of small airways directed therapy in the day-to-day management of asthma and COPD. We thus have tried to clarify the dilemmas, confusion, and misconceptions related to small airways directed therapy. To this end, we have reviewed all studies on small-particle aerosol therapy systematically to address the dilemmas, confusion, and misconceptions related to small airways directed therapy.

Special Features

Chest. 2017;151(6):1356-1374. doi:10.1016/j.chest.2016.12.033

CT scanning of the chest is one of the most important imaging modalities available to a pulmonologist. The advent of high-resolution CT scanning of the chest has led to its increasing use. Although chest radiographs are still useful as an initial test, their utility is limited in the diagnosis of lung diseases that depend on higher resolution images such as interstitial lung diseases and pulmonary vascular diseases. Several metaphoric chest CT scan signs have been described linking abnormal imaging patterns to lung diseases. Some of these are specific to a disease, whereas others help narrow the differential diagnosis. Recognizing these imaging patterns and CT scan signs are thus vitally important. In the present article, we describe a comprehensive list of the commonly encountered metaphoric chest CT scan signs and their clinical relevance.

Contemporary Reviews in Sleep Medicine

Chest. 2017;151(6):1375-1386. doi:10.1016/j.chest.2017.01.002

Sleep abnormalities are clearly recognized as a distinct clinical symptom of concern in neurodegenerative disorders. Appropriate management of sleep-related symptoms has a positive impact on quality of life in patients with neurodegenerative disorders. This review provides an overview of mechanisms that are currently being considered that tie sleep with neurodegeneration. It appraises the literature regarding specific sleep changes seen in common neurodegenerative diseases, with a focus on Alzheimer disease and synucleinopathies (ie, Parkinson disease, dementia with Lewy bodies, multiple system atrophy), that have been better studied. Sleep changes may also serve as markers to identify patients in the preclinical stage of some neurodegenerative disorders. A hypothetical model is postulated founded on the conjecture that specific sleep abnormalities, when noted to increase in severity beyond that expected for age, could be a surrogate marker reflecting pathophysiological processes related to neurodegenerative disorders. This provides a clinical strategy for screening patients in the preclinical stages of neurodegenerative disorders to enable therapeutic trials to establish the efficacy of neuroprotective agents to prevent or delay the development of symptoms and functional decline. It is unclear if sleep disturbance directly impacts neurodegenerative processes or is a secondary outcome of neurodegeneration; this is an active area of research. The clinical importance of recognizing and managing sleep changes in neurodegenerative disorders is beyond doubt.

Topics in Practice Management

Chest. 2017;151(6):1387-1393. doi:10.1016/j.chest.2017.02.024

Advanced respiratory diseases progress over time and often lead to death. As the condition worsens, patients may lose medical decision-making ability. Advance care planning (ACP) is a process in which patients receive information about their diagnosis and prognosis; discuss values, goals, and fears; articulate preferences about life-sustaining treatments and end-of-life care; and appoint a surrogate medical decision maker. This process may result in written documentation of patient preferences or the appointment of a health-care power of attorney (HCPOA). ACP discussions have multiple benefits for patients and their surrogate decision makers, including ensuring that the care provided is aligned with the patient’s goals and preferences and decreasing stress, anxiety, and burden in surrogates. Time and provider comfort are often cited barriers to ACP, so it may be necessary for clinicians to gain experience in conversations and identify the patients most likely to benefit from ACP discussions. Two new Current Procedural Terminology (CPT) codes, 99497 and 99498, have been recognized by the Centers for Medicare and Medicaid Services (CMS) as of January 1, 2016 and are intended to incentivize clinicians to engage in ACP discussions with their patients earlier and with more frequency. This manuscript reviews the benefits and barriers to ACP in patients with advanced respiratory disease and provides guidance on the use of the new CPT codes for reimbursement of these conversations.


Chest. 2017;151(6):1394. doi:10.1016/j.chest.2016.10.051

    “Oh God, someone help. My husband…”
    “Code Blue, room nine.”
    “He's in here. Hurry, hurry. Please help him.”
    “Get her out of here.”
    “Someone start compressions. You, get over here, push on his chest.”
    “Where's the epi? Get me some epi.”
    “V. tach, wait…he’s going into v. fib…shock him. Everybody clear.”
    “Leukemia, pancytopenic. MI three days ago.”
    “Who’s his doc?”
    “Jones, we’ve paged him.”
    “Stop compressions. We got a rhythm. He have a pulse?”
    “No pulse.”
    “Start compressions again. Get the ET tube in. The vent here yet?”
    “I can’t see…damn it, I can’t see his cords.”
    “Call anesthesia, we need a tube in…now!”
    “Keep the compressions going. You tired? She’s tired, someone relieve her.”
    “Come on, get anesthesia here, we need an airway.”
    “Doctor, there’s a…”
    “Where the hell is anesthesia?”
    “V. fib again. Stand clear.”
    “…red sticker!”
    “Oh damn! He’s DNR?”

Chest. 2017;151(6):1395. doi:10.1016/j.chest.2016.12.020

    I sat within the tethered wheel
    Propelled by ancient fears
    That sprung from saddened residues
    Collected through the years

    The crumbling words that tumbled out
    Proclaimed my dissipation
    While tempting me with offerings
    Of unforeseen salvation

    Then buoyed by waves of swirling rage
    That swelled throughout the night
    I cast my darkest thoughts aside
    And hid them from the light

    But when the wheel lurched back again
    It spun me through the air
    Then plunged my heart into the ground
    Demolished by despair


Chest. 2017;151(6):1396-1397. doi:10.1016/j.chest.2017.01.044

We read with interest the recent publication in CHEST (June 2017) by Wu et al analyzing the spirometric results from two large databases of patients admitted to the hospital with COPD exacerbation as the primary cause of admission. By matching two databases, admissions and spirometric results, the authors identify cases of COPD exacerbation based on International Classification of Diseases, Ninth Revision, Clinical Modification codes and are able to provide valuable information on the disagreement between clinical and spirometric diagnoses of COPD, finding a considerable number of misdiagnosed cases.

Chest. 2017;151(6):1397-1398. doi:10.1016/j.chest.2017.02.031

We appreciate the interest and observations of Dr Lopez-Campos et al regarding our article recently published in CHEST on spirometric confirmation of COPD in patients hospitalized for COPD exacerbation.

Chest. 2017;151(6):1398-1399. doi:10.1016/j.chest.2017.03.022

We read with interest the article by Ungprasert et al published in CHEST (February 2017). In it, the authors use data from the Olmsted County population to show that sarcoidosis portends an increased risk of VTE. We congratulate the authors on this very important and well-performed study. However, due to a low prevalence of sarcoidosis, the number of VTE events in their study is very small, reflected by the large CIs. Thus, although the authors clearly show that the risk of VTE is increased in patients with sarcoidosis, the effect size of this risk is less clear.

Chest. 2017;151(6):1399. doi:10.1016/j.chest.2017.03.021

We would like to thank Dr Yaqoob et al for their interest in our study. They performed an analysis to assess the association between sarcoidosis VTE using diagnostic codes from a large electronic medical record database. A significant association between the two conditions was observed at a magnitude similar to that in our report.

Chest. 2017;151(6):1399-1400. doi:10.1016/j.chest.2017.02.033

In issuing a conditional recommendation in favor of inspiratory pressure augmentation during spontaneous breathing trials (SBTs) in a recent issue of CHEST (January 2017), Ouellete et al noted that the available evidence informing the recommendation is at serious risk of bias. We highlight here some additional limitations and address other key issues to consider when evaluating the best technique for conducting SBTs.

Chest. 2017;151(6):1400-1401. doi:10.1016/j.chest.2017.03.051

We thank Goligher et al for their interest in our manuscript. They raise concerns about our conditional recommendation in favor of using pressure augmentation (PA) during a spontaneous breathing trial (SBT) compared with T-piece/CPAP.

Chest. 2017;151(6):1401-1402. doi:10.1016/j.chest.2017.02.034

The literature does not support routine practice of chest radiography following thoracentesis for evaluation of pneumothorax, yet this remains the standard of care amongst community pulmonary physicians. The thoracentesis procedure has evolved such that ultrasound guidance is common practice for preprocedural identification and characterization of pleural effusion. With a nominal increase in time expenditure and training, the use of ultrasound can be further expanded to rule out pneumothorax. This is particularly valuable as ultrasound has demonstrated superiority over chest radiography for evaluation of pneumothorax identification in multiple studies.

Chest. 2017;151(6):1402-1404. doi:10.1016/j.chest.2017.03.038

Until recently, the annual rate of inferior vena cava (IVC) filter placements has been increasing. The potential inappropriate utilization of IVC filters and its negative consequences have been discussed and highlighted by a US Food and Drug Administration (FDA)-issued advisory in 2010. We analyzed national annual IVC filter placement trends over the past 2 decades to assess for differences in placement rates following updates to societal guidelines, legal events, and governmental communications.

Chest. 2017;151(6):1404-1406. doi:10.1016/j.chest.2017.03.034

With expansion of hospital-based care come increasingly complex needs inviting palliative care (PC), clinical ethics (CE), and spiritual care (SC) collaboration. Commonly encountered situations include withdrawal of life-sustaining therapies, surrogate decision-making, provider conflict, and spiritual/religious distress, all of which overlap among PC, CE, and SC domains of expertise. Nevertheless, although hospitals commonly use these three clinical services, little guidance exists regarding which service to consult, how they might best collaborate, and their effect on quality benchmarks.,,,

Chest. 2017;151(6):1406-1407. doi:10.1016/j.chest.2017.03.052

Recently, we showed in a meta-analysis that in children there is an association between attention-deficit/hyperactivity disorder (ADHD) and atopic diseases, especially asthma. The nature of this relationship is still unknown, although findings suggest links with environmental and/or genetic risk factors contributing to inflammatory mechanisms. Not much is known about this association among adults. The aim of the present study was to investigate associations between the presence of ADHD and the presence and severity of asthma in adults. As a secondary aim we investigated the association between ADHD and the presence of eczema and allergic rhinitis.

Chest. 2017;151(6):1407-1408. doi:10.1016/j.chest.2017.03.044

It is with great interest that we read the article by Zanobetti et al published in this issue of CHEST regarding point-of-care ultrasonography (PoCUS) and its implications in the diagnosis of acute dyspnea in the ED. In this study, the authors found that the average time needed to formulate a diagnosis by using PoCUS was significantly shorter than that of a typical ED diagnosis.

Chest. 2017;151(6):1408-1409. doi:10.1016/j.chest.2017.03.046

We thank Drs Alsolamy and Alrajhi for their thoughtful comments on our article regarding the use of point-of-care ultrasonography (PoCUS) for patients presenting with dyspnea in the ED. In their letter, the colleagues expressed some concerns regarding the effective capability of PoCUS in shortening the diagnostic process, claiming that is often possible to clinically establish a diagnosis during the initial assessment of the patient independent of other test results.


Chest. 2017;151(6):1410. doi:10.1016/j.chest.2017.05.001

The authors have reported to CHEST that an error appeared in the text, Figure 3, and Tables 3 and 4 in “Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Patients With COPD” (Chest. 2017;151(2):340-357).

Ultrasound Corner

Chest. 2017;151(6):e123-e125. doi:10.1016/j.chest.2017.01.040

An African American female in her 20s with sickle cell disease, complicated by previous episodes of acute chest syndrome, was admitted for a planned termination of pregnancy at 18 weeks of gestation. One day post-procedure, in the setting of vaginal bleeding, the patient developed chest pain and hypoxia. Critical care consultation was requested for suspected acute chest syndrome.

Chest. 2017;151(6):e127-e129. doi:10.1016/j.chest.2016.12.036

B. K., a 3-year-old child, without past medical history, was accompanied by his parents to our ED after onset of fever (40°C) and dry cough not responsive to 2 weeks of empirical therapy with amoxicillin/clavulanate.

Pulmonary, Critical Care, and Sleep Pearls

Chest. 2017;151(6):e131-e134. doi:10.1016/j.chest.2016.11.015

Case Presentaion  A 58-year-old man presented with a 6-month history of profound fatigue and a weight loss of 35 to 40 pounds. He reported occasional night sweats and mildly painful knees and elbows without swelling or redness. He denied respiratory symptoms, rashes, or fevers. He had no respiratory symptoms. The patient’s history was significant for rheumatoid arthritis (with arthralgias and joint involvement), paroxysmal atrial fibrillation, and hypothyroidism. His medications included digoxin and metoprolol. He had been taking methotrexate and low-dose prednisone (5 mg) for approximately 10 years but discontinued taking these medications 2 years prior to current presentation. Originally from West Virginia, the patient had relocated to Arizona during the early 1980s. There was no history of international travel or TB. He had no exposure history to birds, bird feathers, or mold; however, he did report exposure to dust at his current job as a home building superintendent. He reported a 10 pack-year history of smoking, having quit 20 years ago. His family history was significant for renal sarcoidosis in his mother.

Chest. 2017;151(6):e135-e139. doi:10.1016/j.chest.2016.11.058

Case presentation  An elderly man presented to the ED from a nursing care facility after transient loss of consciousness. Three weeks previously, the patient had been diagnosed with a high-grade pancreatic neuroendocrine tumor (NET) with metastases to the liver after being hospitalized for weakness. A chest radiograph at that time had revealed a right upper lobe mass that was presumed to represent a metastatic lesion (Fig 1); CT of the chest demonstrated similar findings (Fig 2). The patient had recovered consciousness on arrival to the ED and was diagnosed clinically as having had a syncopal episode from dehydration due to poor intake. On review of systems, the patient reported shortness of breath and a cough productive of scant mucoid sputum of 1 week's duration. He had no complaints of fever but complained of weakness and poor appetite. In addition, his medical history was significant for hypertension, diabetes mellitus, and congestive heart failure with systolic dysfunction. He was a former smoker. Prior to his recent illness and hospitalization, he lived at home with his family and was independent in his activities of daily living.

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