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Concept: Pulmonology

237

Background Bronchoscopy is frequently nondiagnostic in patients with pulmonary lesions suspected to be lung cancer. This often results in additional invasive testing, although many lesions are benign. We sought to validate a bronchial-airway gene-expression classifier that could improve the diagnostic performance of bronchoscopy. Methods Current or former smokers undergoing bronchoscopy for suspected lung cancer were enrolled at 28 centers in two multicenter prospective studies (AEGIS-1 and AEGIS-2). A gene-expression classifier was measured in epithelial cells collected from the normal-appearing mainstem bronchus to assess the probability of lung cancer. Results A total of 639 patients in AEGIS-1 (298 patients) and AEGIS-2 (341 patients) met the criteria for inclusion. A total of 43% of bronchoscopic examinations were nondiagnostic for lung cancer, and invasive procedures were performed after bronchoscopy in 35% of patients with benign lesions. In AEGIS-1, the classifier had an area under the receiver-operating-characteristic curve (AUC) of 0.78 (95% confidence interval [CI], 0.73 to 0.83), a sensitivity of 88% (95% CI, 83 to 92), and a specificity of 47% (95% CI, 37 to 58). In AEGIS-2, the classifier had an AUC of 0.74 (95% CI, 0.68 to 0.80), a sensitivity of 89% (95% CI, 84 to 92), and a specificity of 47% (95% CI, 36 to 59). The combination of the classifier plus bronchoscopy had a sensitivity of 96% (95% CI, 93 to 98) in AEGIS-1 and 98% (95% CI, 96 to 99) in AEGIS-2, independent of lesion size and location. In 101 patients with an intermediate pretest probability of cancer, the negative predictive value of the classifier was 91% (95% CI, 75 to 98) among patients with a nondiagnostic bronchoscopic examination. Conclusions The gene-expression classifier improved the diagnostic performance of bronchoscopy for the detection of lung cancer. In intermediate-risk patients with a nondiagnostic bronchoscopic examination, a negative classifier score provides support for a more conservative diagnostic approach. (Funded by Allegro Diagnostics and others; AEGIS-1 and AEGIS-2 ClinicalTrials.gov numbers, NCT01309087 and NCT00746759 .).

Concepts: Pulmonology, Lung, Lung cancer, Positive predictive value, Negative predictive value, Sensitivity and specificity, Carcinoma, Lesion

213

Background Previous trials suggesting that high-frequency oscillatory ventilation (HFOV) reduced mortality among adults with the acute respiratory distress syndrome (ARDS) were limited by the use of outdated comparator ventilation strategies and small sample sizes. Methods In a multicenter, randomized, controlled trial conducted at 39 intensive care units in five countries, we randomly assigned adults with new-onset, moderate-to-severe ARDS to HFOV targeting lung recruitment or to a control ventilation strategy targeting lung recruitment with the use of low tidal volumes and high positive end-expiratory pressure. The primary outcome was the rate of in-hospital death from any cause. Results On the recommendation of the data monitoring committee, we stopped the trial after 548 of a planned 1200 patients had undergone randomization. The two study groups were well matched at baseline. The HFOV group underwent HFOV for a median of 3 days (interquartile range, 2 to 8); in addition, 34 of 273 patients (12%) in the control group received HFOV for refractory hypoxemia. In-hospital mortality was 47% in the HFOV group, as compared with 35% in the control group (relative risk of death with HFOV, 1.33; 95% confidence interval, 1.09 to 1.64; P=0.005). This finding was independent of baseline abnormalities in oxygenation or respiratory compliance. Patients in the HFOV group received higher doses of midazolam than did patients in the control group (199 mg per day [interquartile range, 100 to 382] vs. 141 mg per day [interquartile range, 68 to 240], P<0.001), and more patients in the HFOV group than in the control group received neuromuscular blockers (83% vs. 68%, P<0.001). In addition, more patients in the HFOV group received vasoactive drugs (91% vs. 84%, P=0.01) and received them for a longer period than did patients in the control group (5 days vs. 3 days, P=0.01). Conclusions In adults with moderate-to-severe ARDS, early application of HFOV, as compared with a ventilation strategy of low tidal volume and high positive end-expiratory pressure, does not reduce, and may increase, in-hospital mortality. (Funded by the Canadian Institutes of Health Research; Current Controlled Trials numbers, ISRCTN42992782 and ISRCTN87124254 , and ClinicalTrials.gov numbers, NCT00474656 and NCT01506401 .).

Concepts: Clinical trial, Pulmonology, Sample size, Medical statistics, Intensive care medicine, Acute respiratory distress syndrome, Mechanical ventilation, Pulmonary contusion

196

Exposure to secondhand smoke from burning tobacco products causes premature death and disease, including coronary heart disease, stroke, and lung cancer among nonsmoking adults and sudden infant death syndrome, acute respiratory infections, middle ear disease, exacerbated asthma, respiratory symptoms, and decreased lung function in children (1,2). The U.S. Surgeon General has concluded that there is no risk-free level of exposure to secondhand smoke (1). Previous CDC reports on airport smoke-free policies found that most large-hub airports in the United States prohibit smoking (3); however, the extent of smoke-free policies at airports globally has not been assessed. CDC assessed smoke-free policies at the world’s 50 busiest airports (airports with the highest number of passengers traveling through an airport in a year) as of August 2017; approximately 2.7 billion travelers pass through these 50 airports each year (4). Among these airports, 23 (46%) completely prohibit smoking indoors, including five of the 10 busiest airports. The remaining 27 airports continue to allow smoking in designated smoking areas. Designated or ventilated smoking areas can cause involuntary secondhand smoke exposure among nonsmoking travelers and airport employees. Smoke-free policies at the national, city, or airport authority levels can protect employees and travelers from secondhand smoke inside airports.

Concepts: Cancer, Pulmonology, Asthma, Heart, Tobacco, Tobacco smoking, Passive smoking, Sudden infant death syndrome

196

Characterizing respiratory rate variability (RRV) in humans during sleep is challenging, since it requires the analysis of respiratory signals over a period of several hours. These signals are easily distorted by movement and volitional inputs. We applied the method of spectral analysis to the nasal pressure transducer signal in 38 adults with no obstructive sleep apnea, defined by an apnea-hypopnea index <5, who underwent all-night polysomnography (PSG). Our aim was to detect and quantitate RRV during the various sleep stages, including wakefulness. The nasal pressure transducer signal was acquired at 100 Hz and consecutive frequency spectra were generated for the length of the PSG with the Fast Fourier Transform. For each spectrum, we computed the amplitude ratio of the first harmonic peak to the zero frequency peak (H1/DC), and defined as RRV as (100 - H1/DC) %. RRV was greater during wakefulness compared to any sleep stage, including rapid-eye-movement. Furthermore, RRV correlated with the depth of sleep, being lowest during N3. Patients spent most their sleep time supine, but we found no correlation between RRV and body position. There was a correlation between respiratory rate and sleep stage, being greater in wakefulness than in any sleep stage. We conclude that RRV varies according to sleep stage. Moreover, spectral analysis of nasal pressure signal appears to provide a valid measure of RRV during sleep. It remains to be seen if the method can differentiate normal from pathological sleep patterns.

Concepts: Pulmonology, Sleep, Sleep disorder, Discrete Fourier transform, Sleep apnea, Polysomnography, Obstructive sleep apnea, Sleep medicine

194

In April 2016, a Virginia dentist who had recently received a diagnosis of idiopathic pulmonary fibrosis (IPF) and was undergoing treatment at a specialty clinic at a Virginia tertiary care center contacted CDC to report concerns that IPF had been diagnosed in multiple Virginia dentists who had sought treatment at the same specialty clinic. IPF is a chronic, progressive lung disease of unknown cause and associated with a poor prognosis (1). Although IPF has been associated with certain occupations (2), no published data exist regarding IPF in dentists. The medical records for all 894 patients treated for IPF at the Virginia tertiary care center during September 1996-June 2017 were reviewed for evidence that the patient had worked as a dentist, dental hygienist, or dental technician; among these patients, eight (0.9%) were identified as dentists and one (0.1%) as a dental technician, and each had sought treatment during 2000-2015. Seven of these nine patients had died. A questionnaire was administered to one of the living patients, who reported polishing dental appliances and preparing amalgams and impressions without respiratory protection. Substances used during these tasks contained silica, polyvinyl siloxane, alginate, and other compounds with known or potential respiratory toxicity. Although no clear etiologies for this cluster exist, occupational exposures possibly contributed. This cluster of IPF cases reinforces the need to understand further the unique occupational exposures of dental personnel and the association between these exposures and the risk for developing IPF so that appropriate strategies can be developed for the prevention of potentially harmful exposures.

Concepts: Medicine, Pulmonology, Physician, Idiopathic pulmonary fibrosis, Dentistry, Dental technician, Dental assistant, Dental therapist

188

Coal workers' pneumoconiosis, also known as “black lung disease,” is an occupational lung disease caused by overexposure to respirable coal mine dust. Inhaled dust leads to inflammation and fibrosis in the lungs, and coal workers' pneumoconiosis can be a debilitating disease. The Federal Coal Mine Health and Safety Act of 1969 (Coal Act),* amended in 1977, established dust limits for U.S. coal mines and created the National Institute for Occupational Safety and Health (NIOSH)-administered Coal Workers' Health Surveillance Program with the goal of reducing the incidence of coal workers' pneumoconiosis and eliminating its most severe form, progressive massive fibrosis (PMF),(†) which can be lethal. The prevalence of PMF fell sharply after implementation of the Coal Act and reached historic lows in the 1990s, with 31 unique cases identified by the Coal Workers' Health Surveillance Program during 1990-1999. Since then, a resurgence of the disease has occurred, notably in central Appalachia (Figure 1) (1,2). This report describes a cluster of 60 cases of PMF identified in current and former coal miners at a single eastern Kentucky radiology practice during January 2015-August 2016. This cluster was not discovered through the national surveillance program. This ongoing outbreak highlights an urgent need for effective dust control in coal mines to prevent coal workers' pneumoconiosis, and for improved surveillance to promptly identify the early stages of the disease and stop its progression to PMF.

Concepts: Epidemiology, Pulmonology, Asthma, Coal, Occupational safety and health, Kentucky, Coal mining, Anthracite

180

Chronic Obstructive Pulmonary Disease (COPD) is characterized by high morbidity and mortality. It remains unknown which aspect of lung function carries the most prognostic information and if simple spirometry is sufficient.Survival was assessed in COPD outpatients whose data had been added prospectively to a clinical audit database from the point of first full lung function testing including spirometry, lung volumes, carbon monoxide diffusion capacity and arterial blood gases. Variables univariately associated with survival were entered into a multivariate Cox proportional hazard model.604 patients were included (mean age 61.9±9.7 years, forced expiratory volume in 1 second 37±18.1%predicted, 62.9% males); 229(37.9%) died during a median follow-up of 83 months. Median survival was 91.9(80.8-103) months with survival rates at 3 and 5 years 0.83 and 0.66, respectively. Carbon monoxide diffusion capacity %predicted quartiles [(best quartile (>51%): HR=: 0.33; 95% CI: 0.96-0. and second quartile (51-37.3%): HR=0.52, versus lowest quartile (<27.9%))], age (HR=:1.04; 95% CI:1.02-1.06) and arterial oxygen partial pressure (HR=: 0.85;95% CI:0.77-0.94) were the only parameters independently associated with mortality.Measurement of diffusion capacity provides additional prognostic information compared to spirometry in patients under hospital follow-up and could be considered routinely.

Concepts: Oxygen, Pulmonology, Asthma, Lung, Respiratory physiology, Chronic obstructive pulmonary disease, Spirometry, Respiratory therapy

178

End-stage lung disease is the third leading cause of death worldwide, accounting for 400,000 deaths per year in the United States alone. To reduce the morbidity and mortality associated with lung disease, new therapeutic strategies aimed at promoting lung repair and increasing the number of donor lungs available for transplantation are being explored. Because of the extreme complexity of this organ, previous attempts at bioengineering functional lungs from fully decellularized or synthetic scaffolds lacking functional vasculature have been largely unsuccessful. An intact vascular network is critical not only for maintaining the blood-gas barrier and allowing for proper graft function but also for supporting the regenerative cells. We therefore developed an airway-specific approach to removing the pulmonary epithelium, while maintaining the viability and function of the vascular endothelium, using a rat model. The resulting vascularized lung grafts supported the attachment and growth of human adult pulmonary cells and stem cell-derived lung-specified epithelial cells. We propose that de-epithelialization of the lung with preservation of intact vasculature could facilitate cell therapy of pulmonary epithelium and enable bioengineering of functional lungs for transplantation.

Concepts: Death, Pulmonology, Lung, Mortality rate, Heart, Epithelium, Endothelium, Cornea

173

The presence of acute or chronic respiratory failure is often seen as a terminal phase of chronic obstructive pulmonary disease. A great variability in end-of-life practice is observed in these patients mainly because physicians are not always able to correctly predict survival. There is a need for a clear discussion about decision making earlier than when acute respiratory failure ensues. Indeed, a perceived poor quality of life does not necessarily correlate with a clear willingness to refuse invasive or noninvasive mechanical ventilation. It has been suggested to start palliative care earlier, together with curative and restorative care, when there is an increased intensity of symptoms. The patients eligible for palliative care are those complaining of breathlessness, pain, fatigue and depression, which in some studies accounted for a prevalence much higher than 50%. Among comfort measures for palliation, oxygen is frequently prescribed even when the criteria for long-term home oxygen therapy are not met; however, when compared with air, no benefits on dyspnoea have been found. The only drug with a proven effect on dyspnoea is morphine, but not when it is delivered with a nebuliser. Finally, noninvasive ventilation may be used only as a comfort measure for palliation to maximise comfort by minimising adverse effects.

Concepts: Pulmonology, Pneumonia, Mechanical ventilation, Palliative care, Chronic obstructive pulmonary disease, Palliative medicine, End-of-life care, Terminal sedation

172

Pre-clinical data demonstrate a pivotal role for interleukin (IL)-13 in the development and maintenance of asthma. This study assessed the effects of tralokinumab, an investigational human IL-13-neutralising immunoglobulin G4 monoclonal antibody, in adults with moderate-to-severe uncontrolled asthma despite controller therapies. 194 subjects were randomised to receive tralokinumab (150, 300 or 600 mg) or placebo subcutaneously every 2 weeks. Primary end-point was change from baseline in mean Asthma Control Questionnaire score (ACQ-6; ACQ mean of six individual item scores) at week 13 comparing placebo and combined tralokinumab dose groups. Secondary end-points included pre-bronchodilator lung function, rescue β(2)-agonist use and safety. Numerical end-points are reported as mean±sd. At week 13, change from baseline in ACQ-6 was -0.76±1.04 for tralokinumab versus -0.61±0.90 for placebo (p=0.375). Increases from baseline in forced expiratory volume in 1 s (FEV(1)) were 0.21±0.38 L versus 0.06±0.48 L (p=0.072), with a dose-response observed across the tralokinumab doses tested. β(2)-agonist use (puffs per day) was decreased for tralokinumab -0.68±1.45 versus placebo -0.10±1.49 (p=0.020). The increase in FEV(1) following tralokinumab treatment remained evident 12 weeks after the final dose. Safety profile was acceptable with no serious adverse events related to tralokinumab. No improvement in ACQ-6 was observed, although tralokinumab treatment was associated with improved lung function.

Concepts: Immune system, Pulmonology, Asthma, Lung, Respiratory physiology, Chronic obstructive pulmonary disease, Spirometry, Peak flow meter