Current Issue

Giants in Chest Medicine

Chest. 2015;148(5):1123-1125. doi:10.1378/chest.15-2005

Saturday rounds in an academic center are generally conducted with the house staff having one eye on the clock and the other on the attending physician, the unspoken thought being, “Can we hurry this along so we can get out of here?” However, this was not the prevailing attitude when John F. Murray, MD, was attending in the medical ICU at San Francisco General Hospital. Dr Murray used Saturday mornings to discuss some aspect of clinical respiratory physiology that was illustrated by a patient in the unit, making the physiologic principles relevant to critically ill patients. The value of these sessions was not lost even on the most sleep-deprived interns and residents, and they were widely regarded as extraordinary learning experiences.

Topics: pulmonology


Chest. 2015;148(5):1126-1127. doi:10.1378/chest.15-1454

The relation between cigarette smoking and the development of emphysema and COPD has been well documented.1,2 Although not all smokers develop disease, among long-term smokers nearly 50% will have evidence of obstruction on spirometry.3 Other forms of smoke inhalation, such as exposure to biomass smoke from cooking or heating, are also linked to the development of COPD.4,5 Although there are several important differences between these exposures, a key one is intent: Cigarette smokers are intentionally exposing themselves to high levels of particulate pollution, whereas those exposed to biomass smoke are not doing this intentionally.

Chest. 2015;148(5):1127-1129. doi:10.1378/chest.15-1010

The interrelationships between OSA and obesity are complex in large part because of the multidirectional nature of not only the association between these two factors, but also their relationships with undesirable cardiovascular health outcomes. Indisputably, obesity serves as a risk factor for OSA not only because of its direct mechanical effects (ie, disadvantageously affecting upper airways critical closing pressure), but also potentially via pathophysiologic pathways involving a reduction in lung volume resulting in a loss of caudal traction of the upper airways and upper airways neuromodulatory effects of adipokines.1

Chest. 2015;148(5):1129-1130. doi:10.1378/chest.15-1041

In this issue of CHEST (see page 1204), Chervin et al1 provide important information that should influence how we treat young children who have OSA syndrome (OSAS). The reported data came from the Childhood Adenotonsillectomy Trial (CHAT), a multicenter research project that included 464 children 5 to 9 years of age who had OSAS.2 Each child underwent polysomnography (PSG), neuropsychologic testing, and symptom scoring using widely accepted questionnaires before being randomly assigned to either an early adenotonsillectomy (AT) group or a watchful waiting group. The protocol called for repeat PSG, neuropsychologic testing, and symptom scoring 7 months later. Of the 397 children who completed CHAT, PSGs normalized in 79% of the AT group and 46% of the watchful waiting group. Symptom scores also improved following AT, but neuropsychologic testing showed no significant improvement in attention or executive function. These findings raised important questions for clinicians about the indications of AT in a child with OSAS. Chervin et al1 present a detailed look at the children who did not have AT.

Point and Counterpoint

Chest. 2015;148(5):1131-1135. doi:10.1378/chest.15-0106

Detection of airway disease by physiologic testing was initially described using spirometry to determine vital capacity and expiratory airflow under maximal effort to distinguish obstructive from restrictive disease processes.1 Subsequently, Dubois and colleagues2 demonstrated direct assessment of airway resistance using plethysmography and in a separate publication described the precursor of the forced oscillation technique to measure respiratory system resistance.3 This review addresses the question of whether direct assessment of resistance by forced oscillation provides diagnostic information equivalent or superior to standard assessment of airflow rates by spirometry.

Chest. 2015;148(5):1135-1137. doi:10.1378/chest.15-1038

Pulmonary physiologists at the Mayo Clinic used a large loudspeaker to measure respiratory system resistance the year I was born (Fig 1).1 My first research project used a forced oscillator to measure bronchodilation during exercise in children with asthma.2 Joe Rodarte, MD, from whom I learned pulmonary physiology at the Mayo Clinic, said about the technique in 1990 that “one man’s noise is another man’s signal.” After five generations and 65 years of improvements in forced oscillation technique (FOT) instrumentation and software, I remain cautiously optimistic that this test will eventually find clinical value.

Chest. 2015;148(5):1137-1138. doi:10.1378/chest.15-1037

We agree that the holy grail of pulmonary physiologists is a test that detects early chronic airway disease. Although Dr Enright1 remains “cautiously optimistic” that forced oscillation technique (FOT) can serve this purpose, there are sufficient data to mitigate his caution.

Chest. 2015;148(5):1138-1139. doi:10.1378/chest.15-1039

Several years ago while working with Drs Berger, Goldring, and Oppenheimer evaluating people who were exposed to World Trade Center (WTC) dust and fumes, I found them to be excellent pulmonary physiologists, and I appreciate the high quality of their research using pulmonary function tests, such as forced oscillometry technique (FOT). Studies showing that an FOT index is abnormal more often than spirometry in smokers or people exposed to respiratory hazards in the workplace may merely mean that the false positive rate for oscillometry is higher than that for spirometry. An up-to-date review referenced by Dr Berger and colleagues1 regarding the diagnostic value of FOT concluded that “it is unclear whether any of these measures of airway resistance contribute clinically important information to the traditional measures derived from spirometry (FEV1, FVC, and FEV1/FVC).”2


Chest. 2015;148(5):1140-1147. doi:10.1378/chest.15-0634

In recent years, the potentially adverse role of sleep-disordered breathing in cancer incidence and outcomes has emerged. In parallel, animal models of intermittent hypoxia (IH) and sleep fragmentation (SF) emulating the two major components of OSA have lent support to the notion that OSA may enhance the proliferative and invasive properties of solid tumors. Based on several lines of evidence, we propose that OSA-induced increases in sympathetic outflow and alterations in immune function are critically involved in modifying oncologic processes including angiogenesis. In this context, we suggest that OSA, via IH (and potentially SF), promotes changes in several signaling pathways and transcription factors that coordinate malignant transformation and expansion, disrupts host immunologic surveillance, and consequently leads to increased probability of oncogenesis, accelerated tumor proliferation, and invasion, ultimately resulting in adverse outcomes.

Commentary: Ahead of the Curve

Chest. 2015;148(5):1148-1155. doi:10.1378/chest.15-0706

Institutional review boards (IRBs) or research ethics committees provide a core protection for human research participants through advance and periodic independent review of the ethical acceptability of proposals for human research. IRBs were codified in US regulation just over three decades ago and are widely required by law or regulation in jurisdictions globally. Since the inception of IRBs, the research landscape has grown and evolved, as has the system of IRB review and oversight. Evidence of inconsistencies in IRB review and in application of federal regulations has fueled dissatisfaction with the IRB system. Some complain that IRB review is time-consuming and burdensome without clear evidence of effectiveness at protecting human subjects. Multiple proposals have been offered to reform or update the current IRB system, and many alternative models are currently being tried. Current focus on centralizing and sharing reviews requires more attention and evidence. Proposed changes to the US federal regulations may bring more changes. Data and resourcefulness are needed to further develop and test review and oversight models that provide adequate and respectful protections of participant rights and welfare and that are appropriate, efficient, and adaptable for current and future research.

Original Research: COPD

Chest. 2015;148(5):1156-1163. doi:10.1378/chest.15-0236

BACKGROUND:  Inhalation/smoking has become the most common method of recreational opiate consumption in the United Kingdom and other countries. Although some heroin smokers appear to develop COPD, little is known about the association.

METHODS:  We present data from a cohort of 73 heroin smokers with clinician-diagnosed and spirometrically confirmed COPD, seen within our clinical service, where symptoms developed before the age of 40 years.

RESULTS:  The whole group mean age at diagnosis was 41 years, subjects had smoked heroin for 14 years, and mean FEV1 was 1.08 L (31.5% predicted), with mean FEV1/FVC of 0.4. No subject was found to have severe α1-antitrypsin deficiency. Forty-four subjects had either a high-resolution CT (HRCT) scan (32) or measurement of lung diffusion (12). Overall HRCT scan emphysema score averaged across the upper, middle, and lower part of the lung was 2.3 (5%-25% emphysema), with 47% subjects having an upper lobe emphysema score ≥ 3 (25%-50% emphysema). Median diffusing capacity of the lung for carbon monoxide was 48% of predicted value.

CONCLUSIONS:  Recreational smoking of heroin appears to lead to early onset COPD with a predominant emphysema phenotype. This message is important to both clinicians and the public, and targeted screening and education of this high-risk population may be justified.

Chest. 2015;148(5):1164-1176. doi:10.1378/chest.14-3138

BACKGROUND:  Statins have immunomodulatory properties that may provide beneficial effects in the treatment of COPD. We investigated whether a statin improves the IL-17/IL-10 imbalance in patients with COPD, as has previously been demonstrated in patients with asthma.

METHODS:  Thirty patients with stable COPD were recruited to a double-blind, randomized, controlled, crossover trial comparing the effect of simvastatin, 20 mg po daily, with that of a matched placebo on sputum inflammatory markers and airway inflammation. Each treatment was administered for 4 weeks separated by a 4-week washout period. The primary outcome was the presence of T-helper 17 cytokines and indoleamine 2,3-dioxygenase (IDO) in induced sputum. Secondary outcomes included sputum inflammatory cells, FEV1, and symptoms using the COPD Assessment Test (CAT).

RESULTS:  At 4 weeks, there was a significant reduction in sputum IL-17A, IL-22, IL-6, and CXCL8 concentrations (mean difference, −16.4 pg/mL, P = .01; −48.6 pg/mL, P < .001; −45.3 pg/mL, P = .002; and −190.9 pg/mL, P = .007, respectively), whereas IL-10 concentrations, IDO messenger RNA expression (fold change), and IDO activity (kynurenine to tryptophan ratio) were markedly increased during simvastatin treatment compared with placebo treatment periods (mean difference, 24.7 pg/mL, P < .001; 1.02, P < .001; and 0.47, P < .001, respectively). The absolute sputum macrophage count, proportion of macrophages, and CAT score were reduced after simvastatin compared with placebo (mean difference, −0.16 × 106, P = .004; −14.1%, P < .001; and −3.2, P = .02, respectively). Values for other clinical outcomes were similar between the simvastatin and placebo treatments.

CONCLUSIONS:  Simvastatin reversed the IL-17A/IL-10 imbalance in the airways and reduced sputum macrophage but not neutrophil counts in patients with COPD.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT01944176; www.clinicaltrials.gov

Chest. 2015;148(5):1177-1183. doi:10.1378/chest.15-0627

BACKGROUND:  The widespread use of inhaled corticosteroids (ICSs) for COPD treatment has been questioned. Recent studies of weaning some patients with COPD off ICSs found little or no adverse consequences compared with long-acting bronchodilators. It is unclear, however, whether discontinuation of ICSs reduces the elevated risk of pneumonia associated with these drugs.

METHODS:  Using the Quebec health insurance databases, we formed a new-user cohort of patients with COPD treated with ICSs during 1990 to 2005 and followed through 2007 or until a serious pneumonia event, defined as a first hospitalization for or death from pneumonia. A nested case-control analysis of the cohort was used to estimate the rate ratio of serious pneumonia associated with discontinuation of ICS use compared with continued use, adjusted for age, sex, respiratory disease severity, and comorbidity.

RESULTS:  The cohort included 103,386 users of ICSs, of whom 14,020 had a serious pneumonia event during 4.9 years of follow-up (incidence rate, 2.8/100/y). Discontinuation of ICSs was associated with a 37% decrease in the rate of serious pneumonia (rate ratio [RR], 0.63; 95% CI, 0.60-0.66). The risk reduction was rapidly evident, going from 20% in the first month to 50% by the fourth month after discontinuation. The risk reduction was particularly marked with fluticasone (RR, 0.58; 95% CI, 0.54-0.61) but less so with budesonide (RR, 0.87; 95% CI, 0.78-0.97).

CONCLUSIONS:  Discontinuation of ICS use in COPD is associated with a reduction in the elevated risk of serious pneumonia, particularly so with fluticasone.

Chest. 2015;148(5):1184-1192. doi:10.1378/chest.15-0261

BACKGROUND:  COPD is the third most frequent cause of death globally, with much of this burden attributable to household biomass smoke exposure in developing countries. As biomass smoke exposure is also associated with cardiovascular disease, lower respiratory infection, lung cancer, and cataracts, it presents an important target for public health intervention.

METHODS:  Lung function in Guatemalan women exposed to wood smoke from open fires was measured throughout the Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) stove intervention trial and continued during the Chronic Respiratory Effects of Early Childhood Exposure to Respirable Particulate Matter (CRECER) cohort study. In RESPIRE, early stove households received a chimney woodstove at the beginning of the 18-month trial, and delayed stove households received a stove at trial completion. Personal exposure to wood smoke was assessed with exhaled breath carbon monoxide (CO) and personal CO tubes. Change in lung function between intervention groups and as a function of wood smoke exposure was assessed using random effects models.

RESULTS:  Of 306 women participating in both studies, acceptable spirometry was collected in 129 early stove and 136 delayed stove households (n = 265), with a mean follow-up of 5.6 years. Despite reduced wood smoke exposures in early stove households, there were no significant differences in any of the measured spirometric variables during the study period (FEV1, FVC, FEV1/FVC ratio, and annual change) after adjustment for confounding.

CONCLUSIONS:  In these young Guatemalan women, there was no association between lung function and early randomization to a chimney stove or personal wood smoke exposure. Future stove intervention trials should incorporate cleaner stoves, longer follow-up, or potentially susceptible groups to identify meaningful differences in lung function.

Original Research: Sleep Disorders

Chest. 2015;148(5):1193-1203. doi:10.1378/chest.14-3016

BACKGROUND:  Obesity is an important risk factor for OSA. This study aimed to assess the effect of weight reduction through a lifestyle modification program (LMP) on patients with moderate to severe OSA.

METHODS:  This was a parallel group, randomized controlled trial. Altogether, 104 patients with moderate to severe OSA diagnosed on portable home sleep monitoring were randomized to receive a dietician-led LMP or usual care for 12 months. The primary outcome was reduction of apnea-hypopnea index (AHI) at 12 months as assessed by portable home sleep monitoring.

RESULTS:  In the intention-to-treat analysis (ITT), LMP (n = 61) was more effective in reducing AHI from baseline (16.9% fewer events in the LMP group vs 0.6% more events in the control group, P = .011). LMP was more effective in reducing BMI (−1.8 kg/m2, 6.0% of the initial BMI; −0.6 kg/m2, 2.0% of the initial BMI in control group; P < .001). The reduction in daytime sleepiness as assessed by Epworth Sleepiness Scale was not significant in ITT but was more in the LMP group (−3.5 in the LMP group vs −1.1 in the control group, P = .004) by treatment per protocol analysis. There was modest improvement in mental health in the Short Form Health Survey. Eating behavior was improved with increased intake of protein and fiber. These changes were observed 4 months after the initial intensive diet counseling and persisted at 12 months.

CONCLUSIONS:  LMP was effective in reducing the severity of OSA and daytime sleepiness. The beneficial effect was sustained in 12 months.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT01384760; URL: www.clinicaltrials.gov

Chest. 2015;148(5):1204-1213. doi:10.1378/chest.14-2873

BACKGROUND:  Adenotonsillectomy (AT) is commonly performed for childhood OSA syndrome (OSAS), but little is known about prognosis without treatment.

METHODS:  The Childhood Adenotonsillectomy Trial (CHAT) randomized 50% of eligible children with OSAS to a control arm (watchful waiting), with 7-month follow-up symptom inventories, physical examinations, and polysomnography. Polysomnographic and symptomatic resolution were defined respectively by an apnea/hypopnea index (AHI) <2 and obstructive apnea index (OAI) <1 and by an OSAS symptom score (Pediatric Sleep Questionnaire [PSQ]) < 0.33 with ≥ 25% improvement from baseline.

RESULTS:  After 194 children aged 5 to 9 years underwent 7 months of watchful waiting, 82 (42%) no longer met polysomnographic criteria for OSAS. Baseline predictors of resolution included lower AHI, better oxygen saturation, smaller waist circumference or percentile, higher-positioned soft palate, smaller neck circumference, and non-black race (each P < .05). Among these, the independent predictors were lower AHI and waist circumference percentile < 90%. Among 167 children with baseline PSQ scores ≥ 0.33, only 25 (15%) experienced symptomatic resolution. Baseline predictors were low PSQ and PSQ snoring subscale scores; absence of habitual snoring, loud snoring, observed apneas, or a household smoker; higher quality of life; fewer attention-deficit/hyperactivity disorder symptoms; and female sex. Only lower PSQ and snoring scores were independent predictors.

CONCLUSIONS:  Many candidates for AT no longer have OSAS on polysomnography after 7 months of watchful waiting, whereas meaningful improvement in symptoms is not common. In practice, a baseline low AHI and normal waist circumference, or low PSQ and snoring score, may help identify an opportunity to avoid AT.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00560859; URL: www.clinicaltrials.gov.

Chest. 2015;148(5):1214-1223. doi:10.1378/chest.15-0171

BACKGROUND:  Despite the increasing aging population and the high prevalence of OSA in elderly adults, little is known about cognitive effects of OSA and the effectiveness of CPAP treatment. Therefore, this study investigated whether elderly patients with OSA present cognitive deficits and functional and structural alterations of the brain that could be improved by CPAP treatment.

METHODS:  This randomized, evaluator-blinded, parallel-group, single-center pilot study involved patients aged ≥ 65 years with newly-diagnosed severe OSA syndrome. Thirty-three patients were assigned to receive either conservative care (CC) or CPAP plus CC for 3 months. At baseline and 3 months after treatment, patients underwent a neuropsychologic evaluation and a functional and structural MRI study of connectivity within the default mode network (DMN) and of cortical thickness.

RESULTS:  Neuropsychologic evaluation revealed no differences in cognitive performance between OSA groups at baseline. By contrast, after CPAP treatment, patients showed a significant improvement in episodic (between-group difference in change, 7.60; 95% CI, 1.66-13.55; P = .014) and short-term memory (between-group difference in change, 1.06; 95% CI, 0.10-2.01; P = .032) and in executive function (speed of mental processing, 5.74; 95% CI, 1.69-9.79; P = .007; mental flexibility, −47.64; 95% CI, −81.83 to −13.45; P = .008), whereas no changes were observed in the CC group. Neuroimaging revealed an increase in the connectivity in the right middle frontal gyrus after 3 months of CPAP treatment and a higher percentage of cortical thinning in the CC group. No association was seen between cognition and brain functional connectivity changes within the DMN.

CONCLUSIONS:  Elderly patients with severe OSA who present with cognitive difficulties could benefit from CPAP treatment. Moreover, CPAP treatment increases the connectivity of the DMN and attenuates cortical thinning.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT01826032; URL: www.clinicaltrials.gov

Original Research: Critical Care

Chest. 2015;148(5):1224-1230. doi:10.1378/chest.15-0287

BACKGROUND:  Prospective studies on the incidence of VTE during severe sepsis and septic shock remain absent, hindering efficacy assessments regarding VTE prevention strategies in sepsis.

METHODS:  We prospectively studied 113 consecutively enrolled patients in the ICU with severe sepsis and septic shock at three hospitals. All patients provided informed consent. VTE thromboprophylaxis was recorded for all patients. Patients underwent ultrasonography and were followed for VTE prior to ICU discharge. All-cause 28-day mortality was recorded. Variables from univariate analyses that were associated with VTE (including central venous catheter [CVC] insertion, age, length of stay, and mechanical ventilation) were included in a multivariable logistic regression analysis using backward stepwise elimination to determine VTE predictors.

RESULTS:  Mean APACHE (Acute Physiology and Chronic Health Evaluation) II score was 18.2 ± 7.0, and age was 50 ± 18 years. Despite all patients receiving guideline-recommended thromboprophylaxis, the incidence of VTE was 37.2% (95% CI, 28.3-46.8). Most VTE events were clinically significant (defined as pulmonary embolism, proximal DVT, and/or symptomatic distal DVT) and associated with an increased length of stay (18.2 ± 9.9 days vs 13.4 ± 11.5 days, P < .05). Mortality was higher in patients with acute VTE but did not reach statistical significance. Insertion of a CVC and longer mechanical ventilation duration were significant VTE risk factors. VTE incidence did not differ by thromboprophylaxis type.

CONCLUSIONS:  To our knowledge this is the first multicenter prospective study to identify a high incidence of VTE in patients with severe sepsis and septic shock, despite the use of universal, guideline-recommended thromboprophylaxis. Our findings suggest that the systemic inflammatory milieu of sepsis may uniquely predispose patients with sepsis to VTE. More effective VTE prevention strategies are necessary in patients with sepsis.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT02353910; URL: www.clinicaltrials.gov

Chest. 2015;148(5):1231-1241. doi:10.1378/chest.15-0525

BACKGROUND:  Delirium is frequent in patients in the ICU, but its association with the outcome of weaning from mechanical ventilation has not been assessed. Circadian rhythm alteration may favor delirium. In the current study, we assessed the impact of delirium during weaning and associated alterations in the circadian rhythm of melatonin excretion.

METHODS:  This was a substudy of 70 participants of the B-type Natriuretic Peptide for the Fluid Management of Weaning trial, comparing two fluid management strategies during weaning. Patients with or without delirium (as assessed using the Confusion Assessment Method for the ICU) were compared in terms of baseline characteristics and outcomes and the circadian rhythm of melatonin excretion using the 24-h excretion of its urinary metabolite 6-sulfatoxymelatonin (aMT6s).

RESULTS:  Among the 70 patients included, 43 (61.4%) experienced delirium at the initiation of weaning. Delirium at the initiation of weaning was associated with more alcohol consumption, a greater severity of illness, and medication use before weaning (including neuromuscular blockade, antibiotics, sedatives, and narcotics). Delirium at the initiation of weaning was associated with more respiratory and neurologic complications and a reduced probability of successful extubation (Cox multivariate model hazard ratio of successful extubation = 0.54; 95% CI, 0.30-0.95; P = .03). Delirium was also associated with a significant reduction in peak, mean, amplitude, and total values of aMT6s urinary excretion during the first 24 h of weaning (general linear model F statistic = 5.81, P = .019).

CONCLUSIONS:  Delirium is frequent at the initiation of ventilator weaning. It is associated with a prolongation of weaning and an alteration in the circadian rhythm of melatonin excretion.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT00473148; URL: www.clinicaltrials.gov

Chest. 2015;148(5):1242-1250. doi:10.1378/chest.15-0576

BACKGROUND:  Although the benefits of early tracheostomy in patients dependent on ventilators are well established, the reasons for variation in time from intubation to tracheostomy remain unclear. We identified clinical and demographic disparities in time to tracheostomy.

METHODS:  We performed a level 3 retrospective prognostic study by querying the University HealthSystem Consortium (2007-2010) for adult patients receiving a tracheostomy after initial intubation. Time to tracheostomy was designated early (< 7 days) or late (> 10 days). Cohorts were stratified by time to tracheostomy and compared using univariate tests of association and multivariable adjusted models.

RESULTS:  A total of 49,191 patients underwent tracheostomy after initial intubation: 42% early (n = 21,029) and 58% late (n = 28,162). On both univariate and multivariable analyses, women, blacks, Hispanics, and patients receiving Medicaid were less likely to receive an early tracheostomy. Patients in the early group also experienced lower rates of mortality (OR, 0.84; 95% CI, 0.79-0.88).

CONCLUSIONS:  Early tracheostomy was associated with increased survival. Yet, there were still significant disparities in time to tracheostomy according to sex, race, and type of insurance. Application of evidence-based algorithms for tracheostomy may reduce unequal treatment and improve overall mortality rates. Additional research into this apparent bias in referral/rendering of tracheostomy is needed.

Original Research: Asthma

Chest. 2015;148(5):1251-1258. doi:10.1378/chest.15-0098

BACKGROUND:  Endotoxin exposure is associated with airway inflammation. Children spend 6 to 8 h/d in school, yet the effect of school-specific endotoxin exposure on asthma morbidity is not well understood.

METHODS:  In this longitudinal cohort study, 248 students with asthma, from 38 inner-city schools, underwent baseline phenotyping and follow-up. Clinical outcomes were evaluated throughout the academic school year and linked to classroom-specific dust and air endotoxin levels as well as home dust endotoxin levels. The primary outcome was maximum asthma symptom-days per 2-week period.

RESULTS:  Classrooms had higher settled dust endotoxin levels compared with homes (14.3 endotoxin unit/mg vs 11.3 endotoxin unit/mg; P = .02). Airborne endotoxin levels exceeding recommended occupational exposure limits for adults were recorded in 22.0% of classrooms. Classroom air endotoxin levels were independently associated with increased maximum symptom-days in children with nonatopic asthma, but not in those with atopic asthma (interaction P = .03). Adjusting for home exposures, classroom endotoxin exposure was independently associated with a dose-dependent increase in asthma symptom-days for children with nonatopic asthma (adjusted incidence rate ratio, 1.16 [95% CI, 1.03-1.31]; P = .02). In these subjects, maximum symptom-days increased by 1.3 days for each 14-day period when comparing students in classrooms with the lowest endotoxin levels compared with average measured levels.

CONCLUSIONS:  Inner-city children with asthma are exposed to high levels of airborne endotoxin at school, resulting in increased asthma symptoms in children with nonatopic asthma. Mitigation of school-related exposures may represent a strategy to decrease asthma morbidity in this population.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT01756391; URL: www.clinicaltrials.gov

Original Research: Signs and Symptoms of Chest Diseases

Chest. 2015;148(5):1259-1267. doi:10.1378/chest.15-0138

BACKGROUND:  The intensity of cough is an important determinant of cough severity. Few studies have quantified cough intensity in patients with chronic cough with objective measures. We investigated the intensity of voluntary, induced, and spontaneous cough in patients with chronic cough and healthy control subjects.

METHODS:  Patients with chronic cough and control subjects underwent physiologic assessment of the intensity of maximum voluntary, capsaicin-induced, and spontaneous cough. Assessments included measurement of gastric pressure (Pga) and esophageal pressure (Pes) during cough, peak cough flow (PCF), expiratory muscle strength (twitch gastric pressure [TwPga]), and cough compression phase duration (CPD). Subjective perception of cough intensity was assessed using a visual analog scale (VAS).

RESULTS:  Pes, Pga, and PCF during maximum voluntary cough were significantly greater in patients with chronic cough compared with control subjects (P = .003-.042). There was no difference in TwPga between patients and control subjects. CPD was increased in female patients compared with control subjects (mean ± SD, 0.50 ± 0.22 s vs 0.28 ± 0.17 s; P = .007). Mean ± SD Pes during spontaneous cough was comparable to induced cough (128 ± 28 cm H2O vs 122 ± 37 cm H2O, P = .686) but less than maximum voluntary cough (170 ± 46 cm H2O, P = .020). Median within-subject correlation coefficients between cough intensity VAS and Pes, Pga, and PCF were r = 0.82 to 0.86.

CONCLUSIONS:  Maximum voluntary cough intensity was increased in patients with chronic cough compared with control subjects. There was no significant difference in expiratory muscle contractility. Further studies should evaluate the compressive phase of cough in more detail. Physiologic measures of cough intensity correlated strongly with subjective perception of intensity in patients with chronic cough and may be relevant objective outcome measures for clinical studies.

Topics: cough

Original Research: Diffuse Lung Disease

Chest. 2015;148(5):1268-1275. doi:10.1378/chest.15-0003

BACKGROUND:  Mortality risk prediction tools have been developed in idiopathic pulmonary fibrosis, however, it is unknown whether these models accurately estimate mortality in systemic sclerosis-associated interstitial lung disease (SSc-ILD).

METHODS:  Four baseline risk prediction models—the Composite Physiologic Index, the Interstitial Lung Disease-Gender, Age, Physiology Index, the du Bois index, and the modified du Bois index—were calculated for patients recruited from a specialized SSc-ILD clinic. Each baseline model was assessed using logistic regression analysis with 1-year mortality as the outcome variable. Discrimination was quantified using the area under the receiver operating characteristic curve. Calibration was assessed using the goodness-of-fit test. The incremental prognostic ability of additional predictor variables was determined by adding prespecified variables to each baseline model.

RESULTS:  The 156 patients with SSc-ILD completed 1,294 pulmonary function tests, 725 6-min walk tests, and 637 echocardiograms. Median survival was 15.0 years from the time of SSc-ILD diagnosis. All baseline models were significant predictors of 1-year mortality in SSc-ILD. The modified du Bois index had an area under the receiver operating characteristic curve of 0.84, compared with 0.77 to 0.81 in the other models. Calibration was acceptable for the modified du Bois index, but was poor for the other models. All baseline models include FVC and 6-min walk distance was identified as an additional independent predictor of 1-year mortality.

CONCLUSIONS:  The modified du Bois index has good discrimination and calibration for the prediction of 1-year mortality in SSc-ILD. FVC and 6-min walk distance are important independent predictors of 1-year mortality in SSc-ILD.

Original Research: Chest Infections

Chest. 2015;148(5):1276-1284. doi:10.1378/chest.15-0289

BACKGROUND:  To better understand clinical and epidemiologic patterns of blastomycosis, we report on a large series of blastomycosis in Indiana.

METHODS:  All microbiologically and histopathologically confirmed cases of blastomycosis from four hospitals serving Central Indiana from 1985 to 2014 were identified. Available data were collected. Data on population estimates, annual precipitation, and construction in Indiana were evaluated for correlations with incidence rates of blastomycosis.

RESULTS:  A total of 114 patients were identified. The mean age was 44.4 years; 27% had diabetes mellitus, and 16% were immunosuppressed. Most presented with pneumonia (90%); 48% had extrapulmonary disease (CNS involvement in 9%), and 15% developed ARDS. Cultures, cytopathology, and histopathology were positive in 86%, 27%, and 85% of the sample, respectively, and fungal antigen was positive in 76%. Amphotericin B was administered in 49%, and 87% received an azole. Total mortality was 12%. Immunosuppression (OR = 3.0), diabetes mellitus (OR = 2.9), and multilobar pneumonia (OR = 2.9) were associated with increased likelihood of ICU admission. There was a significant increase in incidence over time in Marion County. There was no correlation with amount of precipitation, but the rise in incidence coincided with a 2005 state initiative to expand Indiana’s highway infrastructure.

CONCLUSIONS:  The incidence of blastomycosis in Central Indiana may be on the rise. Physicians in endemic areas should be aware of the potentially fulminant consequences of the disease.

Topics: blastomycosis

Original Research: Cardiovascular Disease

Chest. 2015;148(5):1285-1292. doi:10.1378/chest.15-0852

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 h and started just before anesthesia induction. The primary end point was the incidence of postoperative atrial fibrillation. The secondary end points were perioperative hemodynamics and levels of BNP, WBC 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 < .001). Patients in the olprinone group showed significantly lower BNP, WBC 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 REGISTRY:  Japan Primary Registries Network; No.: JPRN-UMIN2404; URL: http://www.umin.ac.jp/ctr/

Original Research: Occupational and Environmental Lung Disease

Chest. 2015;148(5):1293-1299. doi:10.1378/chest.15-0118

BACKGROUND:  A large body of evidence demonstrates dose-response relationships of cumulative coal mine dust exposure with lung function impairment and with small-opacity profusion. However, medical literature generally holds that simple coal worker’s pneumoconiosis (CWP) is not associated with lung function impairment. This study examines the relationship between small-opacity profusion and lung function in US underground coal miners with simple CWP.

METHODS:  Miners were examined during 2005 to 2013 as part of the Enhanced Coal Workers’ Health Surveillance Program. Work histories were obtained, and chest radiographs and spirometry were administered. Lung parenchymal abnormalities consistent with CWP were classified according to International Labor Organization guidelines, and reference values for FEV1 and FVC were calculated using reference equations derived from the third National Health and Nutrition Examination Survey. Differences in lung function were evaluated by opacity profusion, and regression models were fit to characterize associations between profusion and lung function.

RESULTS:  A total of 8,230 miners were eligible for analysis; 269 had category 1 or 2 simple CWP. Decrements in FEV1 % predicted were nearly consistent across profusion subcategories. Clear decrements in FVC % predicted and FEV1/FVC were also observed, although these were less consistent. Controlling for smoking status, BMI, and mining tenure, each 1-unit subcategory increase in profusion was associated with decreases of 1.5% (95% CI, 1.0%-1.9%), 1.0% (95% CI, 0.6%-1.3%), and 0.6% (95% CI, 0.4%-0.8%) in FEV1 % predicted, FVC % predicted, and FEV1/FVC, respectively.

CONCLUSIONS:  We observed progressively lower lung function across the range of small-opacity profusion. These findings address a long-standing question in occupational medicine and point to the importance of medical surveillance and respiratory disease prevention in this workforce.

Translating Basic Research Into Clinical Practice

Chest. 2015;148(5):1300-1306. doi:10.1378/chest.15-1029

Pathophysiologic gaps in the actions of currently available treatments for asthma and COPD include neutrophilic inflammation, airway remodeling, and alveolar destruction. All of these processes can be modulated by cyclic adenosine monophosphate-elevating prostaglandins E2 and I2 (also known as prostacyclin). These prostanoids have long been known to elicit bronchodilation and to protect against bronchoconstriction provoked by a variety of stimuli. Much less well known is their capacity to inhibit inflammatory responses involving activation of lymphocytes, eosinophils, and neutrophils, as well as to attenuate epithelial injury and mesenchymal cell activation. This profile of actions identifies prostanoids as attractive candidates for exogenous administration in asthma. By contrast, excessive prostanoid production and signaling might contribute to both the increased susceptibility to infections that drive COPD exacerbations and the inadequate alveolar repair that characterizes emphysema. Inhibition of endogenous prostanoid synthesis or signaling, thus, has therapeutic potential for these types of patients. By virtue of their pleiotropic capacity to modulate numerous pathophysiologic processes relevant to the expression and natural history of airway diseases, prostanoids emerge as attractive targets for therapeutic manipulation.

Recent Advances in Chest Medicine

Chest. 2015;148(5):1307-1322. doi:10.1378/chest.15-0409

Smoking-induced lung diseases were extremely rare prior to the 20th century. With commercialization and introduction of machine-made cigarettes, worldwide use skyrocketed and several new pulmonary diseases have been recognized. The majority of pulmonary diseases caused by cigarette smoke (CS) are inflammatory in origin. Airway epithelial cells and alveolar macrophages have altered inflammatory signaling in response to CS, which leads to recruitment of lymphocytes, eosinophils, neutrophils, and mast cells to the lungs—depending on the signaling pathway (nuclear factor-κB, adenosine monophosphate-activated protein kinase, c-Jun N-terminal kinase, p38, and signal transducer and activator of transcription 3) activated. Multiple proteins are upregulated and secreted in response to CS exposure, and many of these have immunomodulatory activities that contribute to disease pathogenesis. In particular, metalloproteases 9 and 12, surfactant protein D, antimicrobial peptides (LL-37 and human β defensin 2), and IL-1, IL-6, IL-8, and IL-17 have been found in higher quantities in the lungs of smokers with ongoing inflammation. However, many underlying mechanisms of smoking-induced inflammatory diseases are not yet known. We review here the known cellular and molecular mechanisms of CS-induced diseases, including COPD, respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute eosinophilic pneumonia, chronic rhinosinusitis, pulmonary Langerhans cell histiocytosis, and chronic bacterial infections. We also discuss inflammation induced by secondhand and thirdhand smoke exposure and the pulmonary diseases that result. New targeted antiinflammatory therapeutic options are currently under investigation and hopefully will yield promising results for the treatment of these highly prevalent smoking-induced diseases.

Special Features

Chest. 2015;148(5):1323-1332. doi:10.1378/chest.15-0260

Critical care transesophageal echocardiography (TEE) is useful in characterizing shock states encountered by intensivists when transthoracic echocardiography (TTE) gives insufficient information or when more detailed analysis of cardiac structures is needed. It is safe, feasible, and easy to learn and is a recommended component of advanced critical care echocardiography. This article reviews critical care TEE regarding training, equipment, comparison with 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.

Contemporary Reviews in Critical Care Medicine

Chest. 2015;148(5):1333-1345. doi:10.1378/chest.14-2365

The first of this two-part series on critical illness in pregnancy dealt with obstetric disorders. In Part II, medical conditions that commonly affect pregnant women or worsen during pregnancy are discussed. ARDS occurs more frequently in pregnancy. Strategies commonly used in nonpregnant patients, including permissive hypercapnia, limits for plateau pressure, and prone positioning, may not be acceptable, especially in late pregnancy. Genital tract infections unique to pregnancy include chorioamnionitis, group A streptococcal infection causing toxic shock syndrome, and polymicrobial infection with streptococci, staphylococci, and Clostridium perfringens causing necrotizing vulvitis or fasciitis. Pregnancy predisposes to VTE; D-dimer levels have low specificity in pregnancy. A ventilation-perfusion scan is preferred over CT pulmonary angiography in some situations to reduce radiation to the mother’s breasts. Low-molecular-weight or unfractionated heparins form the mainstay of treatment; vitamin K antagonists, oral factor Xa inhibitors, and direct thrombin inhibitors are not recommended in pregnancy. The physiologic hyperdynamic circulation in pregnancy worsens many cardiovascular disorders. It increases risk of pulmonary edema or arrhythmias in mitral stenosis, heart failure in pulmonary hypertension or aortic stenosis, aortic dissection in Marfan syndrome, or valve thrombosis in mechanical heart valves. Common neurologic problems in pregnancy include seizures, altered mental status, visual symptoms, and strokes. Other common conditions discussed are aspiration of gastric contents, OSA, thyroid disorders, diabetic ketoacidosis, and cardiopulmonary arrest in pregnancy. Studies confined to pregnant women are available for only a few of these conditions. We have, therefore, reviewed pregnancy-specific adjustments in the management of these disorders.

Contemporary Reviews in Sleep Medicine

Chest. 2015;148(5):1346-1352. doi:10.1378/chest.14-3090

The Chiari 1 malformation is characterized by > 5-mm herniation of the cerebellar tonsils through the foramen magnum. Consequent compression of the brain stem and nearby neuronal structures involved in respiratory control and maintenance of pharyngeal wall muscle tone may result in respiratory changes during sleep. These changes include respiratory failure and arrest, as well as sleep-related breathing disorders (ie, OSA and central sleep apnea). Although data have accrued on the significance of sleep-related breathing disorders in patients with the Chiari 1 malformation, many management questions remain unanswered. This article reviews the available literature on prevalence and management of sleep-related breathing disorders in patients with the Chiari 1 malformation.

Topics in Practice Management

Chest. 2015;148(5):1353-1360. doi:10.1378/chest.15-0487

After a patient encounter, the physician uses two coding systems to bill for the service rendered to the patient. The Current Procedural Terminology (CPT) code is used to describe the encounter or procedure. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code is used to describe the diagnosis(es) of the patient. On October 1, 2015, ICD-9-CM coding will end, and all physicians will be required to use a new diagnostic coding system, the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). This article describes the new diagnostic coding system and how it differs from the old system. There are resources and costs involved for physicians and physician practices to prepare properly for ICD-10-CM. Similar to other important events, the more thorough the preparation, the more likely a positive outcome will occur. Resource use is very important in preparation for the transition from ICD-9-CM to ICD-10-CM. Greater familiarity with ICD-10-CM plus a thorough, effective preparation will lead to reduced costs and a smooth transition. Coding descriptor changes and additional codes occur in ICD-10-CM for chronic bronchitis and emphysema, asthma, and respiratory failure. These changes will affect the coding of these diseases and disorders by physicians. Because the number of codes will increase more than fivefold, the complexity of documentation to support ICD-10-CM will increase substantially. The documentation in the patient’s chart to support the ICD-10-CM codes used will need to be enhanced. The requirement for accurate and comprehensive documentation cannot be emphasized enough. All of the coding and documentation changes will be a challenge to pulmonary, critical care, and sleep physicians. They must be prepared fully when ICD-10-CM coding begins and ICD-9-CM coding stops abruptly on October 1, 2015.


Chest. 2015;148(5):1361. doi:10.1378/chest.15-1200

I am no stranger to the fear of death
   thrust onto fossil reefs off San Andrés
   lost in a forest on Osa
   sucked into waters off Puntarenas
   pierced by a black palm in Belize
   broadsided on Bloomfield Avenue
or to little girls immortalized in grief
   Wordsworth humanized
   Darwin pathologized
      my grandfather spurning God.
I was no stranger to my mother's manic breath
smearing my chest with VapoRub®
beckoning my allergist to a home visit
   Tedral® calming asthmatic symptoms
   a six-year-old's body limp as waning daffodils
      helpless as hares pursued by house cats
      hopeless as fishermen waiting for sturgeon's return
   stethoscope echoing heaves too shallow for life-support
   a non-believer praying for a miracle
      in her child's room
   where chameleons changed color
   where canaries preened
   where curtains were closed to sounds of cars and cardinals.

Chest. 2015;148(5):1362. doi:10.1378/chest.15-1264

Death comes, sometimes,
like a merry-go-round,
turning with just the drum
thrumming one-one-one,
with a single lonely rider
round and round, on the same
hysterical horse winding round,
the same lonely rider staring
at you, only you, with
one finger pressed to his lips.
But more often than not
there’s free admission,
and death is only
that stupid bald guy
with the scales and
a face like a closed fist,
trying like all sweaty hell
to guess your weight
as it goes down and down
like cotton candy.
But always there is the funhouse,
that is never any fun, riddled
with mirrors and minotaurs,
as you watch yourself turning
into stranger after stranger,
head on the ceiling, hands on the floor,
and you cannot make yourself believe
the whispers behind that last mirror
that reflects what it cannot see.


Chest. 2015;148(5):1363. doi:10.1378/chest.15-2128

The authors have reported to CHEST that errors appeared in Table 3 in “Dosing Frequency of Unfractionated Heparin Thromboprophylaxis: A Meta-analysis” (Chest 2011; 140(2):374-381). The original table analyzed the Forette and Wolmark study as UFH tid.

Selected Reports

Chest. 2015;148(5):e136-e138. doi:10.1378/chest.15-0699

Panniculitis associated with α1-antitrypsin deficiency (AATD) is well documented but rare. We report the first case, to our knowledge, of successful induction of clinical remission of AATD-related panniculitis following a single 120-mg/kg dose administration of plasma-purified α1-antitrypsin (AAT). A 23-year-old man with known PiZZ AATD presented to the hospital with a diffusely swollen and tender right upper limb. This was associated with subcutaneous induration, and a discrepancy of 5 cm in upper limb circumference at the mid arm was noted. There was no convincing precipitant for cellulitis or an infectious cause, and inflammatory markers were raised, with a C-reactive protein (CRP) level of 93.9 mg/L and erythrocyte sedimentation rate (ESR) of 71 mm/h. Doppler ultrasonography ruled out DVT. No antimicrobials or antiinflammatory medications were administered during or prior to admission. Biopsy specimens of the right upper limb revealed extensive panniculitis with neutrophils, foamy macrophages, and fat necrosis. A diagnosis of AATD-associated panniculitis was made. Following this, a single IV dose of 120 mg/kg of plasma-purified AAT was administered. By day 7 post AAT infusion, CRP level had normalized to 4.6 mg/L and ESR had dropped to 22 mm/h. Limb circumference discrepancy on day 7 was 1 cm. There was no tenderness to palpation or induration, and a clinical remission of panniculitis was observed. We report the first case, to our knowledge, of clinical remission following a single treatment with IV AAT at a dose of 120 mg/kg. This opens avenues to more timely and effective treatment of the more severe presentations of AAT-associated panniculitis.

Ultrasound Corner

Chest. 2015;148(5):e139-e141. doi:10.1378/chest.14-3152

A 69-year-old man with COPD and ischemic heart disease was admitted with dyspnea to the ED. Nine hours prior to the admission, the patient had been seen in an outpatient clinic where a CT scan-guided biopsy of an opacity in the right lung had been performed. After the biopsy, the patient did not have any complaints. A control CT scan of the chest following the biopsy as well as a control chest radiograph 4 h after the biopsy had been performed did not have signs of pneumothorax or other complications. The patient was allowed to go home without any further observation.

Chest Imaging and Pathology for Clinicians

Chest. 2015;148(5):e142-e147. doi:10.1378/chest.15-0498

A 66-year-old male nonsmoker from Arizona was referred to our practice for evaluation of chronic cough. He had a history of biopsy-proven relapsing polychondritis manifesting as right auricular and nasal pain and swelling 9 months prior to presentation. The onset of his cough coincided with the diagnosis of relapsing polychondritis, and he was prescribed prednisone 90 mg/d, which promptly relieved his rheumatologic and respiratory symptoms. A chest radiograph, obtained prior to the initiation of therapy, was normal. Any attempts at decreasing the dose of the glucocorticoid to < 30 mg/d resulted in recurrence of the cough but not of the auricular or nasal symptoms. A second chest radiograph done 6 months before presentation, while the patient was receiving prednisone 20 mg/d, was normal as well. In anticipation of our evaluation, he stopped all glucocorticoids for 7 days. He was not receiving any other medications, and he had no history of an atopic diathesis.

Pulmonary, Critical Care, and Sleep Pearls

Chest. 2015;148(5):e148-e151. doi:10.1378/chest.15-0813

A 34-year-old woman presented with her third episode of acute-onset right-sided chest pain and dyspnea. She had two prior similar occurrences of right-sided sharp, pleuritic chest pain with radiation to the back and dyspnea. Chest radiographs during these presentations revealed a small apical right-sided pneumothorax that was managed conservatively with high-flow oxygen. All three presentations were associated with vigorous exercise and the first day of her menses. She denied cough, hemoptysis, fever, smoking history, airplane travel, scuba diving, or trauma during these presentations. The patient has been trying to conceive for the past year but has been unsuccessful because of uterine fibroids but no history of endometriosis.

Chest. 2015;148(5):e152-e155. doi:10.1378/chest.15-0861

A 23-year-old white man was admitted to the hospital for evaluation of recurrent hemoptysis. He denied any other associated symptoms, including dyspnea, chest pain, productive cough, wheezing, fever, or weight loss. He had no significant past medical history and was not taking any medication. He had no significant family history for cardiopulmonary diseases.

Topics: hemoptysis
Chest. 2015;148(5):e156-e160. doi:10.1378/chest.15-1124

A 21-year-old woman with cystic fibrosis (CF) was seen in the pulmonary clinic complaining of abdominal pain. Her past medical history included bilateral lung transplantation for CF pulmonary disease 26 months previously, as well as gastroesophageal reflux disease and pancreatic insufficiency. Her baseline weight was 49.1 kg (BMI, 19.4 kg/m2).


Chest. 2015;148(5):e161. doi:10.1378/chest.15-1555
Chest. 2015;148(5):e161-e162. doi:10.1378/chest.15-1578
Chest. 2015;148(5):e163-e164. doi:10.1378/chest.15-1579
Chest. 2015;148(5):e165. doi:10.1378/chest.15-1632
Chest. 2015;148(5):e165. doi:10.1378/chest.15-2047
Chest. 2015;148(5):e166. doi:10.1378/chest.15-1296
Chest. 2015;148(5):e166-e167. doi:10.1378/chest.15-1952

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