a useful tool for patient care (e.g., cardiac rate monitoring by. 24 h holter) or for research (e.g., physical activity monitoring by actimeters) (11). Objective cough ...
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University of Rochester Rochester, New York Fernando Martinez, M.D., M.S. Division of Pulmonary and Critical Care Medicine University of Michigan Health System Ann Arbor, Michigan References 1. Zhang W, Yan SD, Zhu A, Zou YS, Williams M, Godman GC, Thomashow BM, Ginsburg ME, Stern DM, Yan SF. Expression of Egr-1 in late stage emphysema. Am J Pathol 2000;157:1311–1320. 2. Ning W, Li CJ, Kaminski N, Feghali-Bostwick CA, Alber SM, Di YP, Otterbein SL, Song R, Hayashi S, Zhou Z, et al. Comprehensive gene expression profiles reveal pathways related to the pathogenesis of chronic obstructive pulmonary disease. Proc Natl Acad Sci USA 2004; 101:14895–14900. 3. Golpon HA, Coldren CD, Zamora MR, Cosgrove GP, Moore MD, Tuder RM, Geraci MW, Voelkel NF. Emphysema lung tissue gene expression profiling. Am J Respir Cell Mol Biol 2004;31:595–600. 4. Spira A, Beane J, Pinto-Plata V, Kadar A, Liu G, Shah V, Celli B, Brody JS. Gene expression profiling of human lung tissue from smokers with severe emphysema. Am J Respir Cell Mol Biol 2004;31:601–610. 5. Hackett NR, Heguy A, Harvey BG, O’Connor TP, Luettich K, Flieder DB, Kaplan R, Crystal RG. Variability of antioxidant-related gene expression in the airway epithelium of cigarette smokers. Am J Respir Cell Mol Biol 2003;29:331–343. 6. Adair-Kirk TL, Atkinson JJ, Griffin GL, Watson MA, Kelley DG, DeMello D, Senior RM, Betsuyaku T. Distal airways in mice exposed to cigarette smoke: Nrf2-regulated genes are increased in Clara cells. Am J Respir Cell Mol Biol 2008;39:400–411. 7. Rangasamy T, Misra V, Zhen L, Tankersley CG, Tuder RM, Biswal S. Cigarette smoke-induced emphysema in A/J mice is associated with pulmonary oxidative stress, apoptosis of lung cells, and global alterations in gene expression. Am J Physiol Lung Cell Mol Physiol 2009; 296:L888–L900. 8. Cavarra E, Fardin P, Fineschi S, Ricciardi A, De Cunto G, Sallustio F, Zorzetto M, Luisetti M, Pfeffer U, Lungarella G, et al. Early response of gene clusters is associated with mouse lung resistance or sensitivity to cigarette smoke. Am J Physiol Lung Cell Mol Physiol 2009;296: L418–L429. 9. Meng QR, Gideon KM, Harbo SJ, Renne RA, Lee MK, Brys AM, Jones R. Gene expression profiling in lung tissues from mice exposed to cigarette smoke, lipopolysaccharide, or smoke plus lipopolysaccharide by inhalation. Inhal Toxicol 2006;18:555–568. 10. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald-Smith GP, Gao H, Hennessy L, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci USA 2013;110:3507–3512.
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11. Spira A, Beane J, Shah V, Liu G, Schembri F, Yang X, Palma J, Brody JS. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci USA 2004;101:10143–10148. 12. Ammous Z, Hackett NR, Butler MW, Raman T, Dolgalev I, O’Connor TP, Harvey BG, Crystal RG. Variability in small airway epithelial gene expression among normal smokers. Chest 2008;133: 1344–1353. 13. Bhattacharya S, Tyagi S, Srisuma S, Demeo DL, Shapiro SD, Bueno R, Silverman EK, Reilly JJ, Mariani TJ, Peripheral blood gene expression profiles in COPD subjects. J Clin Bioinform 2011;1:12. 14. Poliska S, Csanky E, Szanto A, Szatmari I, Mesko B, Szeles L, Dezso B, Scholtz B, Podani J, Kilty I, et al. Chronic obstructive pulmonary disease-specific gene expression signatures of alveolar macrophages as well as peripheral blood monocytes overlap and correlate with lung function. Respiration 2011;81:499–510. 15. Steiling K, van den Berge M, Hijazi K, Florido R, Campbell J, Liu G, Xiao J, Zhang X, Duclos G, Drizik E, et al. A dynamic bronchial airway gene expression signature of chronic obstructive pulmonary disease and lung function impairment. Am J Respir Crit Care Med 2013;187:933–942. 16. He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J. Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein: implication for heme oxygenase-1 gene regulation. J Biol Chem 2001;276:20858–20865. 17. Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, Yates MS, Kombairaju P, Yamamoto M, Liby KT, et al. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci USA 2009;106:250–255. 18. Goven D, Boutten A, Lecon-Malas V, Marchal-Somme J, Amara N, Crestani B, Fournier M, Leseche G, Soler P, Boczkowski J, et al. Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema. Thorax 2008;63:916–924. 19. Suzuki M, Betsuyaku T, Ito Y, Nagai K, Nasuhara Y, Kaga K, Kondo S, Nishimura M. Down-regulated NF-E2-related factor 2 in pulmonary macrophages of aged smokers and patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2008;39:673–682. 20. Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, Macnee W, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010;182:598–604. 21. Agusti A, Sobradillo P, Celli B. Addressing the complexity of chronic obstructive pulmonary disease: from phenotypes and biomarkers to scale-free networks, systems biology, and P4 medicine. Am J Respir Crit Care Med 2011;183:1129–1137. Copyright ª 2013 by the American Thoracic Society DOI: 10.1164/rccm.201302-0340ED
Chronic Cough in Chronic Obstructive Pulmonary Disease: Time for Listening? Cough is a troublesome and disabling symptom that occurs in many acute and chronic respiratory diseases, but little is known on its pathophysiology and efficacious therapeutic approaches are still lacking in most conditions. In patients with chronic obstructive pulmonary disease (COPD), chronic cough and sputum production are reported by a subset of patients (1) and are related to disease progression (2). Cough is one of the important and frequently reported symptoms of COPD exacerbations, but little is known about cough intensity and frequency at exacerbations, and cough has not been consistently used as a major symptom in exacerbation definitions (3). Although several studies have highlighted associations between chronic cough and
sputum production and COPD exacerbations (4–6), this finding was not replicated in another study (7). The prevalence of chronic cough and sputum production in these studies was highly variable, likely reflecting not only different characteristics of patients but also difference in the definition, perception, and/or reporting of these symptoms. Indeed, these studies had to rely on subjective assessment of cough and sputum production (using standardized questions), which may be influenced by reporting bias related to interpretation, cultural factors, or social behavior. In this issue of the Journal, Sumner and coworkers (pp. 943–949) present interesting and original data on objective measurement of
Editorials
cough in patients with COPD (8). The authors used a custom-built device for cough sound monitoring over a 24-hour period in a group of 68 unselected current and ex-smokers with COPD, and compared their findings in these patients to those in a group of smokers without COPD and healthy nonsmokers. Most of the patients completed the 24-hour recording period. The authors reported that current smokers without COPD and ex-smokers with COPD had increased cough frequency compared with nonsmokers; current smokers with COPD, as expected, had the highest cough frequency. When the authors examined possible factors associated with cough frequency in patients with COPD, they found that current smoking, self-reported sputum production, and percentage of sputum neutrophils related to cough, whereas cough reflex sensitivity to capsaicin only weakly correlated with cough frequency and did not significantly predict cough frequency in a multivariate analysis. This study provides interesting suggestions for developing therapeutic strategies aimed at reducing cough in patients with COPD: it proposes that targeting mucus hypersecretion and/or neutrophil recruitment in the airways could represent useful approaches. Interestingly, strong links exist between cigarette smoke, mucous cell hyperplasia in airway epithelium, and neutrophil recruitment (9). Cigarette smoke is a potent inducer of mucous cell hyperplasia and neutrophil recruitment, and stimulates mucous hypersecretion at least in part mediated by local release of neutrophil serine proteases (e.g., elastase) (10). Neutrophils also promote mucous cell hyperplasia via secretion of serine proteases and reactive oxygen species (9). Both mucous cell metaplasia and airway neutrophilia have been shown to persist after smoking cessation in subjects with COPD, providing a potential explanation for the reduced but still persistent cough in ex-smokers with COPD. Objective monitoring of symptoms has been proposed as a useful tool for patient care (e.g., cardiac rate monitoring by 24 h holter) or for research (e.g., physical activity monitoring by actimeters) (11). Objective cough frequency monitoring could represent an interesting novel approach for complementing current methods of cough measurement that include subjective assessment of cough via questionnaires, symptoms diaries, visual analog scale, and self-counting of cough via the pushbutton method. However, there are a number of technical aspects that need to be still addressed before this technique can be widely accepted. First, objective cough frequency monitoring is based on cough sound recording and counting. Cough sound is a complex noise made of three phases (including explosive phase, intermediate phase, and voiced phase) and coughing usually occurs in clusters, making it more difficult to assess with precision (12). Second, the present study was performed in a relatively small number of subjects over a relatively short (24 h) period of time. Although some aspects of cough frequency counting can be semi-automated via the development of dedicated software, the technique still appears time consuming and will require improvement before it can be used practically in clinical trials for monitoring cough over a longer period of time in a larger number of patients. In this regard, the ability to develop an integrated smart phone–based device for recording and analyzing cough frequency would be a major advantage for the dissemination of this technique. An important aspect of cough-recording monitoring is its ability to examine cough variability under various clinical situations. When Sumner and colleagues analyzed the nycthemeral variations of cough in their study, they found that cough was almost absent during night time and was maximal during the hour after waking, confirming cough recording data obtained by questionnaires (8, 13). The use of objective cough monitoring may provide
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interesting insight into cough frequency and any variability during the course of COPD exacerbations and their recovery. There is increasing interest in gastro-esophageal reflux disease (GERD) in COPD—a condition associated with chronic cough and with frequent COPD exacerbations—and there is a need to understand the contribution of cough to this syndrome (7). Finally, objective cough recording is feasible and may provide a useful endpoint for assessing the effect of current therapeutic interventions in COPD (e.g., smoking cessation, bronchodilators, and antiinflammatory agents) and for developing new therapies that target potential mechanisms of cough in patients with COPD. It may soon become time for listening to cough via objective cough recording! Author disclosures are available with the text of this article at www.atsjournals.org.
Pierre-Régis Burgel, M.D., Ph.D. Department of Respiratory Medicine Hôpital Cochin, AP-HP Paris, France and Université Paris Descartes Sorbonne Paris Cité Paris, France Jadwiga A. Wedzicha, M.D. Centre for Respiratory Medicine University College London London, United Kingdom
References 1. Burgel PR. Chronic cough and suptum production: a clinical COPD phenotype? Eur Respir J 2012;40:4–6. 2. Vestbo J, Prescott E, Lange P. Association of chronic mucus hypersecretion with FEV1 decline and chronic obstructive pulmonary disease morbidity: Copenhagen city heart study group. Am J Respir Crit Care Med 1996;153:1530–1535. 3. Anthonisen NR, Manfreda J, Warren CPW, Herhfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987;106:196–204. 4. Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418–1422. 5. Burgel PR, Nesme-Meyer P, Chanez P, Caillaud D, Carre P, Perez T, Roche N. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest 2009;135: 975–982. 6. Kim V, Han MK, Vance GB, Make BJ, Newell JD, Hokanson JE, Hersh CP, Stinson D, Silverman EK, Criner GJ; COPDGene Investigators. The chronic bronchitic phenotype of COPD: an analysis of the COPDgene study. Chest 2011;140:626–633. 7. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, et al. Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010;363:1128–1138. 8. Sumner H, Woodcock A, Kolsum U, Dockry R, Lazaar AL, Singh D, Vestbo J, Smith JA. Predictors of objective cough frequency in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013;187:943–949. 9. Burgel PR, Nadel JA. Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur Respir J 2008;32:1068–1081. 10. Nadel JA. Role of neutrophil elastase in hypersecretion during copd exacerbations, and proposed therapies. Chest 2000;117:386S–389S. 11. Watz H, Waschki B, Boehme C, Claussen M, Meyer T, Magnussen H. Extrapulmonary effects of chronic obstructive pulmonary disease on physical activity: a cross-sectional study. Am J Respir Crit Care Med 2008;177:743–751.
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12. Houghton LA, Smith JA. Breaking the sound barrier? Pitfalls and benefits of acoustic cough monitoring. Am J Gastroenterol 2012;107: 1833–1836. 13. Kessler R, Partridge MR, Miravitlles M, Cazzola M, Vogelmeier C, Leynaud D, Ostinelli J. Symptom variability in patients with severe
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COPD: a pan-European cross-sectional study. Eur Respir J 2011;37: 264–272. Copyright ª 2013 by the American Thoracic Society DOI: 10.1164/rccm.201302-0332ED
N95 Respirators or Surgical Masks to Protect Healthcare Workers against Respiratory Infections: Are We There Yet? Prior to 1990, respirators were infrequently used in healthcare delivery. If exposure to an infection was anticipated, the exposed healthcare worker would occasionally don a surgical mask, although this practice was infrequent as well. U.S. practices began to change when the incidence of tuberculosis surged in the 1980s, during the early years of the AIDS epidemic, substantially increasing the number of hospitalized cases. Changes in practice were further provoked between 1988 and 1993, when collective attention turned to several healthcare workers who died from workplace exposure to tuberculosis. In 1994, the Centers for Disease Control and Prevention (CDC) weighed in, recommending that healthcare workers routinely wear respirators whenever potential exposure to airborne infections may occur. Subsequently, the Occupational Safety and Health Administration ushered in a new U.S. practice standard, including a newly categorized respirator called an N95 that fit tightly to the wearer’s face and was capable of preventing inhalation of micron-sized infectious particles. Although they are still worn by healthcare workers today, N95 respirators grew out of the industrial sector in the 1950s, most notably coal mining, as a means to protect against black lung disease. Since then, respirators used by healthcare workers have generally become lighter and disposable with tight-fitting filter material stretched over a polymer frame to approximate the shape of the wearer’s face. But healthcare workers have complained bitterly about the nuisance and discomfort posed by respirators. Recent studies have shown that only a small fraction of healthcare workers routinely wear respirators in a fashion that meets public health guidance. Remaining is a dilemma about the best way to protect healthcare workers against respiratory infections. On one hand, use of an N95 or similar respirator in the healthcare setting makes sense; they were developed to diminish exposure to the type of fine airborne particles believed to cause pulmonary tuberculosis. On the other hand, so many healthcare workers disregard proper respiratordonning practices (1, 2) that surgical masks may make more sense, even when they are known to achieve lower filtration. Ultimately, in the setting of healthcare, insisting on a high degree of theoretical performance may lead to lower overall clinical effectiveness. In the case of healthcare worker protection, Voltaire’s admonition that “the perfect is the enemy of good” may be fitting. Well-designed and reproducible studies supporting or refuting the clinical effectiveness of respirators are lacking (3, 4). Despite a lack of empiric data, medical/surgical masks are commonly but inconsistently used as a means to protect healthcare workers who may be exposed to infectious patients. During the 2009 H1N1 influenza pandemic, uncertainty over the role of aerosol transmission of influenza led the Institute of Medicine and the CDC to recommend routine use of N95 respirators, instead of medical/surgical masks, when healthcare workers were exposed to patients with suspected or confirmed H1N1 influenza (5). In 2010, following the pandemic, CDC rescinded the guidance favoring N95 respirators, and once again endorsed
medical/surgical masks for routine care of patients with respiratory infections. One exception to this recommendation was made for medical procedures that generate aerosols. Perceived higher risks to healthcare workers led CDC to recommend the use of N95 respirators for aerosol-generating procedures. Against this backdrop of uncertainty, the cluster-randomized comparative trial of respiratory/facial protective equipment strategies by MacIntyre and colleagues reported in this issue of the Journal (pp. 960–966) is a welcome addition to the small body of evidence available to date (6). In this study, 1,604 healthcare workers in emergency departments and respiratory wards were randomly assigned by nursing units to one of three strategies: medical/surgical masks, N95 respirators worn while caring for patients with respiratory tract infection, or N95 masks worn throughout the work shift. The results showed no differences between study arms in the outcome measures of greatest clinical relevance, that is, influenza-like illness (ILI), influenza infection documented by nucleic acid test, or respiratory viral infection. Indeed, very few healthcare workers had laboratory-confirmed influenza (6 cases observed in all three arms) or even ILI (12 observed) over the course of the study. These low numbers provide inadequate evidence to draw any conclusions about the clinical effectiveness of the different protective equipment and routines for these important outcomes. Statistical significance was achieved when considering the separate endpoints of (1) clinical respiratory illness (CRI) and (2) identification of bacteria from respiratory samples using a proprietary polymerase chain reaction assay (Seegene, Inc., Seoul, Korea). For these endpoints, N95 respirators were significantly more protective than medical masks. For every 100 healthcare workers observed in each arm of the study, MacIntyre and colleagues observed roughly 10 fewer CRI outcomes in the continuous-use N95 arm when compared with the medical mask arm (17.1% vs. 7.2%). This effect remained significant after the authors adjusted for possible confounding variables using a multivariable Cox proportional hazards model. This study demonstrates the challenges of these complex trials. There were significant imbalances between the three arms of the study in rates of influenza vaccination and proportion of workers who were physicians. Such imbalances may affect the outcome because of differences in exposures or risks and may be difficult to avoid in cluster-randomized trials, especially if clusters are not matched or stratified prior to randomization. The authors adjusted for these potential confounders with a multivariable Cox proportional hazards model. The decrease in bacterial colonization of the respiratory tract in the N95 arm raises interesting questions about the mechanism of protection. Air pollution is a risk factor for lower respiratory tract infection, particularly in Asia, where pollution levels are high (7). Streptococcus pneumoniae infection is highly associated with environmental pollution by secondhand cigarette smoke (8). Other types of air pollution have not been studied
