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        "titulo" => "Informe 2017 de la Iniciativa Global para el Diagn&#243;stico&#44; Tratamiento y Prevenci&#243;n de la Enfermedad Pulmonar Obstructiva Cr&#243;nica&#58; Resumen Ejecutivo de GOLD"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">This Executive Summary of the Global Strategy for the Diagnosis&#44; Management&#44; and Prevention of COPD &#40;GOLD&#41; 2017 Report is based on peer-reviewed publications to October 2016&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Levels of evidence are assigned to evidence-based recommendations where appropriate&#46; Categories used to grade the levels of evidence are provided in Table S1 in the Supplementary Appendix&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Definition and Factors That Influence COPD Development and Progression</span><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key Points&#91;TS&#58; Set all &#8220;Key Points&#8221;&#93; boxes as they were in original GOLD &#40;http&#58;&#47;&#47;www&#46;atsjournals&#46;org&#47;doi&#47;pdf&#47;10&#46;1164&#47;rccm&#46;201204-0596PP&#41;&#46;&#93;</span><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">&#8226;</span><p id="par0020" class="elsevierStylePara elsevierViewall">COPD is a common&#44; preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation due to airway and&#47;or alveolar abnormalities usually caused by significant exposure to noxious particles or gases&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">&#8226;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Dyspnea&#44; cough and&#47;or sputum production are the most frequent symptoms&#59; symptoms are commonly under-reported by patients&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">&#8226;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Tobacco smoking is the main risk exposure for COPD&#44; but environmental exposures like biomass fuel exposure and air pollution may contribute&#46; Besides exposures&#44; host factors &#40;genetic abnormalities&#44; abnormal lung development and accelerated aging&#41; predispose individuals to develop COPD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">&#8226;</span><p id="par0035" class="elsevierStylePara elsevierViewall">COPD may be punctuated by acute worsening of respiratory symptoms&#44; called exacerbations&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">&#8226;</span><p id="par0040" class="elsevierStylePara elsevierViewall">In most patients&#44; COPD is associated with significant concomitant chronic diseases&#44; which increase morbidity and mortality&#46;</p></li></ul></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Definition and Pathogenesis</span><p id="par0045" class="elsevierStylePara elsevierViewall">COPD is a common&#44; preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and&#47;or alveolar abnormalities usually caused by significant exposure to noxious particles or gases&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The chronic airflow limitation that characterizes COPD is caused by a mixture of small airways disease &#40;e&#46;g&#46;&#44; obstructive bronchiolitis&#41; and parenchymal destruction &#40;emphysema&#41;&#44; the relative contributions of which vary from person to person&#46; Chronic inflammation causes structural changes&#44; small airways narrowing and destruction of lung parenchyma&#46; A loss of small airways may contribute to airflow limitation and mucociliary dysfunction&#44; a characteristic feature of the disease&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Chronic respiratory symptoms may precede the development of airflow limitation and be associated with acute respiratory events&#46;<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">1</span></a> Chronic respiratory symptoms may exist in individuals with normal spirometry<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">1&#44;2</span></a> and a significant number of smokers without airflow limitation have structural evidence of lung disease manifested by the presence of emphysema&#44; airway wall thickening and gas trapping&#46;<a class="elsevierStyleCrossRefs" href="#bib1000"><span class="elsevierStyleSup">1&#44;2</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Factors That Influence Disease Development and Progression</span><p id="par0060" class="elsevierStylePara elsevierViewall">Although cigarette smoking is the most well studied COPD risk factor&#44; epidemiologic studies demonstrate that non-smokers may also develop chronic airflow limitation&#46;<a class="elsevierStyleCrossRef" href="#bib1010"><span class="elsevierStyleSup">3</span></a> Compared to smokers with COPD&#44; never smokers with chronic airflow limitation have fewer symptoms&#44; milder disease and a lower burden of systemic inflammation&#46;<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">4</span></a> Never smokers with chronic airflow limitation do not have an increased risk of lung cancer&#44; or cardiovascular comorbidities&#59; however&#44; they have an increased risk of pneumonia and mortality from respiratory failure&#46;<a class="elsevierStyleCrossRef" href="#bib1015"><span class="elsevierStyleSup">4</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Processes occurring during gestation&#44; birth&#44; and exposures during childhood and adolescence affect lung growth&#46;<a class="elsevierStyleCrossRefs" href="#bib1020"><span class="elsevierStyleSup">5&#44;6</span></a> Reduced maximal attained lung function &#40;as measured by spirometry&#41; may identify individuals at increased risk for COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib1005"><span class="elsevierStyleSup">2&#44;7</span></a> Factors in early life termed &#8220;childhood disadvantage factors&#8221; are as important as heavy smoking in predicting lung function in adult life&#46;<a class="elsevierStyleCrossRef" href="#bib1035"><span class="elsevierStyleSup">8</span></a> An examination of three different longitudinal cohorts found that approximately 50&#37; of patients developed COPD due to an accelerated decline in FEV<span class="elsevierStyleInf">1</span>&#59; the other 50&#37; developed COPD due to abnormal lung growth and development&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Cigarette smokers have a higher prevalence of respiratory symptoms and lung function abnormalities&#44; a greater annual rate of decline in FEV<span class="elsevierStyleInf">1</span>&#44; and a greater COPD mortality rate than non-smokers&#46;<a class="elsevierStyleCrossRef" href="#bib1040"><span class="elsevierStyleSup">9</span></a> Other types of tobacco &#40;e&#46;g&#46;&#44; pipe&#44; cigar&#44; water pipe&#41;<a class="elsevierStyleCrossRefs" href="#bib1045"><span class="elsevierStyleSup">10&#8211;12</span></a> and marijuana<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">13</span></a> are also risk factors for COPD&#46; Passive exposure to cigarette smoke&#44; also known as environmental tobacco smoke &#40;ETS&#41;&#44; may also contribute to respiratory symptoms and COPD<a class="elsevierStyleCrossRef" href="#bib1065"><span class="elsevierStyleSup">14</span></a> by increasing the lung&#39;s total burden of inhaled particles and gases&#46; Smoking during pregnancy may pose a risk for the fetus&#44; by affecting in utero lung growth and development&#44; and possibly priming the immune system&#46;<a class="elsevierStyleCrossRef" href="#bib1070"><span class="elsevierStyleSup">15</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Occupational exposures&#44; including organic and inorganic dusts&#44; chemical agents and fumes&#44; are under-appreciated risk factors for COPD development&#46;<a class="elsevierStyleCrossRefs" href="#bib1075"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Wood&#44; animal dung&#44; crop residues&#44; and coal&#44; typically burned in open fires or poorly functioning stoves&#44; may lead to indoor air pollution&#46;<a class="elsevierStyleCrossRef" href="#bib1085"><span class="elsevierStyleSup">18</span></a> Indoor pollution from biomass cooking and heating&#44; in poorly ventilated dwellings&#44; is a risk for COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib1090"><span class="elsevierStyleSup">19&#8211;21</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Asthma may be a risk for the development of chronic airflow limitation and COPD&#46;<a class="elsevierStyleCrossRef" href="#bib1105"><span class="elsevierStyleSup">22</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Airway hyper-responsiveness can exist without a clinical diagnosis of asthma and is an independent predictor of COPD and respiratory mortality in population studies<a class="elsevierStyleCrossRefs" href="#bib1110"><span class="elsevierStyleSup">23&#44;24</span></a> and may indicate a risk for excessive lung function decline in mild COPD&#46;<a class="elsevierStyleCrossRef" href="#bib1120"><span class="elsevierStyleSup">25</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">A history of severe childhood respiratory infection is associated with reduced lung function and increased respiratory symptoms in adulthood&#46;<a class="elsevierStyleCrossRef" href="#bib1125"><span class="elsevierStyleSup">26</span></a> HIV infection accelerates the onset of smoking-related emphysema and COPD<a class="elsevierStyleCrossRef" href="#bib1130"><span class="elsevierStyleSup">27</span></a>&#59; tuberculosis has also been identified as a risk for COPD as well as a potential comorbidity&#46;<a class="elsevierStyleCrossRefs" href="#bib1135"><span class="elsevierStyleSup">28&#8211;30</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis and Initial Assessment</span><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key Points</span><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">&#8226;</span><p id="par0105" class="elsevierStylePara elsevierViewall">COPD should be considered in any patient with dyspnea&#44; chronic cough or sputum production&#44; and&#47;or a history of exposure to risk factors&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">&#8226;</span><p id="par0110" class="elsevierStylePara elsevierViewall">Spirometry is required to make the diagnosis&#59; a post-bronchodilator FEV<span class="elsevierStyleInf">1</span>&#47;FVC<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;70 confirms the presence of persistent airflow limitation&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">&#8226;</span><p id="par0115" class="elsevierStylePara elsevierViewall">The goals of COPD assessment are to determine the level of airflow limitation&#44; the impact of disease on the patient&#39;s health status&#44; and the risk of future events &#40;such as exacerbations&#44; hospital admissions&#44; or death&#41; to guide therapy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">&#8226;</span><p id="par0120" class="elsevierStylePara elsevierViewall">Concomitant chronic diseases occur frequently in COPD patients and should be treated because they can independently affect mortality and hospitalizations&#46;</p></li></ul></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Diagnosis</span><p id="par0125" class="elsevierStylePara elsevierViewall">COPD should be considered in any patient with dyspnea&#44; chronic cough or sputum production&#44; and&#47;or a history of exposure to risk factors for the disease &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> and <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Spirometry is required to make the diagnosis in this clinical context<a class="elsevierStyleCrossRef" href="#bib1150"><span class="elsevierStyleSup">31</span></a>&#59; a post-bronchodilator FEV<span class="elsevierStyleInf">1</span>&#47;FVC<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;70 confirms the presence of persistent airflow limitation and identifies the presence of COPD in patients with appropriate symptoms and predisposing risks&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Symptoms</span><p id="par0130" class="elsevierStylePara elsevierViewall">Chronic and progressive dyspnea is the most characteristic symptom of COPD&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Dyspnea</span>&#46; Dyspnea is a major cause of the disability and anxiety in COPD&#46;<a class="elsevierStyleCrossRef" href="#bib1155"><span class="elsevierStyleSup">32</span></a> The terms used to describe dyspnea vary individually and culturally&#46;<a class="elsevierStyleCrossRef" href="#bib1160"><span class="elsevierStyleSup">33</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Cough</span>&#46; Chronic cough is often the first symptom of COPD and frequently discounted by the patient as a consequence of smoking and&#47;or environmental exposures&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Sputum production</span>&#46; Regular sputum production<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleUnderline">&#62;</span><span class="elsevierStyleHsp" style=""></span>3 months in 2 consecutive years is the classical definition of chronic bronchitis<a class="elsevierStyleCrossRef" href="#bib1165"><span class="elsevierStyleSup">34</span></a>&#59; an arbitrary definition that does not reflect the range of sputum production reported in COPD&#46; Patients producing large volumes of sputum may have underlying bronchiectasis&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Wheezing and chest tightness</span>&#46; Wheezing and chest tightness may vary between days&#44; and throughout a single day&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Additional features in severe disease</span>&#46; Fatigue&#44; weight loss and anorexia are common in patients with more severe forms of COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib1170"><span class="elsevierStyleSup">35&#44;36</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Medical History</span><p id="par0160" class="elsevierStylePara elsevierViewall">A detailed medical history of any patient who is known&#44; or suspected&#44; to have COPD should include&#58;<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">&#8226;</span><p id="par0165" class="elsevierStylePara elsevierViewall">Exposure to risk factors&#44; such as smoking and occupational or environmental exposures&#46;</p></li><li class="elsevierStyleListItem" id="lsti0055"><span class="elsevierStyleLabel">&#8226;</span><p id="par0170" class="elsevierStylePara elsevierViewall">Past medical history&#44; including asthma&#44; allergy&#44; sinusitis&#44; or nasal polyps&#59; respiratory infections in childhood&#59; other chronic respiratory and non-respiratory diseases&#46;</p></li><li class="elsevierStyleListItem" id="lsti0060"><span class="elsevierStyleLabel">&#8226;</span><p id="par0175" class="elsevierStylePara elsevierViewall">Family history of COPD or other chronic respiratory diseases&#46;</p></li><li class="elsevierStyleListItem" id="lsti0065"><span class="elsevierStyleLabel">&#8226;</span><p id="par0180" class="elsevierStylePara elsevierViewall">Pattern of symptom development&#58; age of onset&#44; type of symptom&#44; more frequent or prolonged &#8220;winter colds&#44;&#8221; and social restriction&#46;</p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">&#8226;</span><p id="par0185" class="elsevierStylePara elsevierViewall">History of exacerbations or previous hospitalizations for a respiratory disorder&#46;</p></li><li class="elsevierStyleListItem" id="lsti0075"><span class="elsevierStyleLabel">&#8226;</span><p id="par0190" class="elsevierStylePara elsevierViewall">Presence of comorbidities&#44; such as heart disease&#44; osteoporosis&#44; musculoskeletal disorders&#44; and malignancies&#46;</p></li><li class="elsevierStyleListItem" id="lsti0080"><span class="elsevierStyleLabel">&#8226;</span><p id="par0195" class="elsevierStylePara elsevierViewall">Impact of disease on patient&#39;s life&#44; including limitation of activity&#44; missed work and economic impact&#44; and feelings of depression or anxiety&#46;</p></li><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">&#8226;</span><p id="par0200" class="elsevierStylePara elsevierViewall">Social and family support available to the patient&#46;</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">&#8226;</span><p id="par0205" class="elsevierStylePara elsevierViewall">Possibilities for reducing risk factors&#44; especially smoking cessation&#46;</p></li></ul></p><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Physical examination</span><p id="par0210" class="elsevierStylePara elsevierViewall">Although important for general health&#44; a physical examination is rarely diagnostic in COPD&#46; Physical signs of airflow limitation&#47;hyperinflation are usually not identifiable until significantly impaired lung function is present&#46;<a class="elsevierStyleCrossRefs" href="#bib1180"><span class="elsevierStyleSup">37&#44;38</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Spirometry</span><p id="par0215" class="elsevierStylePara elsevierViewall">Spirometry is the most reproducible and objective measurement of airflow limitation&#46; It is a noninvasive and readily available test&#46; Good quality spirometry is possible in any healthcare setting&#59; all healthcare workers who care for COPD patients should have access to spirometry&#46;</p><p id="par0220" class="elsevierStylePara elsevierViewall">A post-bronchodilator fixed ratio of FEV<span class="elsevierStyleInf">1</span>&#47;FVC<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;70 is the spirometric criterion for airflow limitation&#46; This criterion is simple and independent of reference values and has been used in numerous clinical trials&#46; However&#44; it may result in more frequent diagnosis of COPD in the elderly&#44;<a class="elsevierStyleCrossRefs" href="#bib1190"><span class="elsevierStyleSup">39&#44;40</span></a> and less frequent diagnosis in adults<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>45 years&#44;<a class="elsevierStyleCrossRef" href="#bib1195"><span class="elsevierStyleSup">40</span></a> especially in mild disease&#44; compared to a cut-off based on the lower limit of normal &#40;LLN&#41; values for FEV<span class="elsevierStyleInf">1</span>&#47;FVC&#46; Several limitations occur with using LLN as the diagnostic criterion for spirometric obstruction&#58; 1&#41; LLN values are dependent on the choice of reference equations that use post-bronchodilator FEV<span class="elsevierStyleInf">1</span>&#44; 2&#41; there are no longitudinal studies that validate using the LLN&#44; and 3&#41; studies using LLN in populations where smoking is not the major cause of COPD are lacking&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Normal spirometry may be defined by a new approach from the Global Lung Initiative &#40;GLI&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib1200"><span class="elsevierStyleSup">41&#44;42</span></a> Using GLI equations&#44; <span class="elsevierStyleItalic">z</span> scores were calculated for FEV<span class="elsevierStyleInf">1</span>&#44; FVC&#44; and FEV<span class="elsevierStyleInf">1</span>&#47;FVC and compared to fixed ratio data&#46; The findings suggest that among adults with GLI-defined normal spirometry&#44; the use of a fixed ratio may misclassify individuals as having respiratory impairment&#46; These findings await additional study in other cohorts&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">The risk of misdiagnosis and over-treatment using the fixed ratio as a diagnostic criterion is limited since spirometry is only one parameter used to establish the clinical diagnosis of COPD&#46; GOLD favors using the fixed ratio over LLN since diagnostic simplicity and consistency are crucial for the busy clinician&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Assessing the degree of reversibility of airflow limitation &#40;e&#46;g&#46;&#44; measuring FEV<span class="elsevierStyleInf">1</span> before and after bronchodilator or corticosteroids&#41; to make therapeutic decisions is not recommended<a class="elsevierStyleCrossRef" href="#bib1210"><span class="elsevierStyleSup">43</span></a> since it does not aid the diagnosis of COPD&#44; differentiate COPD from asthma&#44; or predict the long-term response to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib1215"><span class="elsevierStyleSup">44</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">In asymptomatic individuals without exposures to tobacco or other noxious stimuli&#44; screening spirometry is not indicated&#46; However&#44; in those with symptoms and&#47;or risk factors &#40;e&#46;g&#46;&#44;<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>20 pack-years of smoking or recurrent chest infections&#41;&#44; the diagnostic yield for COPD is relatively high and spirometry should be considered&#46;<a class="elsevierStyleCrossRefs" href="#bib1220"><span class="elsevierStyleSup">45&#44;46</span></a> GOLD advocates active case finding<a class="elsevierStyleCrossRefs" href="#bib1220"><span class="elsevierStyleSup">45&#44;47</span></a> i&#46;e&#46;&#44; performing spirometry in patients with symptoms and&#47;or risk factors&#44; but not routine screening spirometry in asymptomatic individuals without COPD risk factors&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Assessment</span><p id="par0245" class="elsevierStylePara elsevierViewall">The goals of COPD assessment to guide therapy are 1&#41; to determine the level of airflow limitation&#59; 2&#41; to define its impact on the patient&#39;s health status and&#59; 3&#41; identify the risk of future events &#40;such as exacerbations&#44; hospital admissions or death&#41;&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">To achieve these goals&#44; COPD assessment must consider separately the following aspects of the disease&#58;<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">&#8226;</span><p id="par0255" class="elsevierStylePara elsevierViewall">Presence and severity of the spirometric abnormality</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">&#8226;</span><p id="par0260" class="elsevierStylePara elsevierViewall">Current nature and magnitude of symptoms</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">&#8226;</span><p id="par0265" class="elsevierStylePara elsevierViewall">History&#47;future risk of exacerbations</p></li><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">&#8226;</span><p id="par0270" class="elsevierStylePara elsevierViewall">Presence of comorbidities</p></li></ul></p><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Classification of severity of airflow limitation</span><p id="par0275" class="elsevierStylePara elsevierViewall">Spirometry should be performed after administration of an adequate dose of at least one short-acting inhaled bronchodilator in order to minimize variability&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">The role of spirometry for the diagnosis&#44; assessment and follow-up of COPD is summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Assessment of symptoms</span><p id="par0285" class="elsevierStylePara elsevierViewall">COPD was previously viewed as a disease largely characterized by breathlessness&#46; A simple measure of breathlessness such as the Modified British Medical Research Council &#40;mMRC&#41; Questionnaire<a class="elsevierStyleCrossRef" href="#bib1235"><span class="elsevierStyleSup">48</span></a> was considered adequate for assessment of symptoms<a class="elsevierStyleCrossRefs" href="#bib1240"><span class="elsevierStyleSup">49&#8211;51</span></a> However&#44; COPD impacts patients well beyond dyspnea&#46;<a class="elsevierStyleCrossRef" href="#bib1255"><span class="elsevierStyleSup">52</span></a> For this reason&#44; a comprehensive assessment of symptoms is recommended&#46; The most comprehensive disease-specific health status questionnaires include the Chronic Respiratory Questionnaire &#40;CRQ&#41;<a class="elsevierStyleCrossRef" href="#bib1260"><span class="elsevierStyleSup">53</span></a> and St&#46; George&#39;s Respiratory Questionnaire &#40;SGRQ&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1265"><span class="elsevierStyleSup">54</span></a> These are too complex to use in clinical practice&#44; but shorter measures e&#46;g&#46;&#44; the COPD Assessment Test &#40;CAT<span class="elsevierStyleSup">TM</span>&#41; are suitable&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Choice of thresholds</span><p id="par0290" class="elsevierStylePara elsevierViewall">SGRQ scores<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>25 are uncommon in COPD patients<a class="elsevierStyleCrossRef" href="#bib1270"><span class="elsevierStyleSup">55</span></a> and scores &#8805; 25 are very uncommon in healthy persons&#46;<a class="elsevierStyleCrossRefs" href="#bib1275"><span class="elsevierStyleSup">56&#44;57</span></a> The equivalent cut-point for the CAT<span class="elsevierStyleSup">TM</span> is 10&#46;<a class="elsevierStyleCrossRef" href="#bib1285"><span class="elsevierStyleSup">58</span></a> A mMRC threshold of &#8805; 2 is used to separate &#8220;less breathlessness&#8221; from &#8220;more breathlessness&#8221;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Assessment of exacerbation risk</span><p id="par0295" class="elsevierStylePara elsevierViewall">The best predictor of frequent exacerbations &#40;defined as &#8805; 2 exacerbations per year&#41; is a history of earlier treated events&#46;<a class="elsevierStyleCrossRef" href="#bib1290"><span class="elsevierStyleSup">59</span></a> Hospitalization for a COPD exacerbation has a poor prognosis and an increased risk of death&#46;<a class="elsevierStyleCrossRef" href="#bib1295"><span class="elsevierStyleSup">60</span></a></p><p id="par0300" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Blood eosinophil count</span>&#46; Post-hoc analysis of two clinical trials in COPD patients with an exacerbation history showed that higher blood eosinophil counts may predict increased exacerbation rates in patients treated with long acting beta agonists &#40;LABA&#41; &#40;without inhaled corticosteroid&#44; ICS&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib1300"><span class="elsevierStyleSup">61&#44;62</span></a> The treatment effect of ICS&#47;LABA versus LABA on exacerbations was greater in patients with higher blood eosinophil counts&#46; These findings suggest that blood eosinophil counts are 1&#41; a biomarker of exacerbation risk in patients with a history of exacerbations and 2&#41; can predict the effects of ICS on exacerbation prevention&#46; Prospective trials are required to validate the use of blood eosinophil counts to predict ICS effects&#44; to determine a cut-off threshold for blood eosinophils that predicts exacerbation risk&#44; and to clarify blood eosinophil cut-off values that could be used in clinical practice&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Assessment of concomitant chronic diseases &#40;comorbidities&#41;</span><p id="par0305" class="elsevierStylePara elsevierViewall">Patients with COPD often have important concomitant chronic illnesses as COPD represents an important component of multimorbidity particularly in the elderly&#46;<a class="elsevierStyleCrossRefs" href="#bib1295"><span class="elsevierStyleSup">60&#44;63&#8211;65</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Revised combined COPD assessment</span><p id="par0310" class="elsevierStylePara elsevierViewall">The &#8220;ABCD&#8221; assessment tool of the 2011 GOLD Report was a major step forward from the simple spirometric grading system of earlier GOLD Reports because it incorporated patient-reported outcomes and highlighted the importance of exacerbation prevention in COPD management&#46; However&#44; there were important limitations&#46; ABCD assessment performed no better than spirometric grades for mortality prediction&#44; or other important health outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib1325"><span class="elsevierStyleSup">66&#8211;68</span></a> Moreover&#44; group &#8220;D&#8221; outcomes were modified by two parameters&#58; lung function and&#47;or exacerbation history&#44; which caused confusion&#46;<a class="elsevierStyleCrossRef" href="#bib1340"><span class="elsevierStyleSup">69</span></a> To address these concerns&#44; the 2017 GOLD Report provides a refinement of the ABCD assessment that separates spirometric grades from &#8220;ABCD&#8221; groupings&#46; For some therapy recommendations&#44; especially pharmacologic treatments&#44; ABCD groups are derived exclusively from patient symptoms and their exacerbation history&#46; However&#44; spirometry&#44; in conjunction with patient symptoms and exacerbation history&#44; remains vital for the diagnosis&#44; prognostication and consideration of other important therapeutic approaches&#44; especially non-pharmacological therapies&#46; This new approach to assessment is illustrated in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0315" class="elsevierStylePara elsevierViewall">In the refined assessment scheme&#44; patients should undergo spirometry to determine the severity of airflow limitation &#40;i&#46;e&#46;&#44; spirometric grade&#41;&#46; They should also undergo assessment of either dyspnea using mMRC or symptoms using CAT<span class="elsevierStyleSup">TM</span>&#46; Finally&#44; their history of exacerbations &#40;including prior hospitalizations&#41; should be recorded&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">The number provides information regarding severity of airflow limitation &#40;spirometric grades 1 to 4&#41; while the letter &#40;groups A to D&#41; provides information regarding symptom burden and risk of exacerbation&#46; FEV<span class="elsevierStyleInf">1</span> is a very important parameter at the population-level in the prediction of important clinical outcomes such as mortality and hospitalizations or prompting consideration for non-pharmacologic therapies such as lung reduction or lung transplantation&#46; However&#44; at the individual patient level&#44; FEV<span class="elsevierStyleInf">1</span> loses precision and thus cannot be used alone to determine all therapeutic options&#46; Furthermore&#44; in some circumstances&#44; such as during hospitalization or urgent presentation to the clinic or emergency room&#44; the ability to assess patients based on symptoms and exacerbation history&#44; independent of the spirometric value&#44; allows clinicians to initiate a treatment plan based on the revised ABCD scheme&#46; This approach acknowledges the limitations of FEV<span class="elsevierStyleInf">1</span> in making treatment decisions for individualized patient care and highlights the importance of patient symptoms and exacerbation risks in guiding therapies in COPD&#46; The separation of airflow limitation from clinical parameters makes it clearer what is being evaluated and ranked&#46; This should facilitate more precise treatment recommendations based on parameters that are driving the patient&#39;s symptoms at any given time&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Example</span>&#46; Consider two patients - both patients with FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30&#37; of predicted&#44; CAT scores of 18 and one with no exacerbations in the past year&#44; and the other with three exacerbations in the past year&#46; Both would have been labelled GOLD D in the prior classification scheme&#46; However&#44; with the new proposed scheme&#44; the subject with 3 exacerbations in the past year would be labelled GOLD grade 4&#44; group D&#46; Individual decisions on pharmacotherapeutic approaches would use the recommendations based on the ABCD assessment to treat the patient&#39;s major problem at this time&#44; i&#46;e&#46;&#44; persistent exacerbations&#46; The other patient&#44; who has had no exacerbations&#44; would be classified as GOLD grade 4&#44; group B&#46; In such patients &#8212;besides pharmacotherapy and rehabilitation &#8212;lung reduction&#44; lung transplantation or bullectomy may be important therapeutic considerations given their symptom burden and level of spirometric limitation&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Alpha-1 antitrypsin deficiency</span><p id="par0330" class="elsevierStylePara elsevierViewall">The World Health Organization recommends that all patients with a diagnosis of COPD be screened once for alpha-1 antitrypsin deficiency&#46;<a class="elsevierStyleCrossRef" href="#bib1345"><span class="elsevierStyleSup">70</span></a> A low concentration &#40;&#60; 20&#37; normal&#41; is suggestive of homozygous deficiency&#46; Family members should be screened and together with the patient referred to specialist centres for advice and management&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Additional investigations</span><p id="par0335" class="elsevierStylePara elsevierViewall">In order to rule out other concomitant disease contributing to respiratory symptoms&#44; or in cases where patients do not respond to the treatment plan as expected&#44; additional testing may be required&#46; Thoracic imaging &#40;chest x-ray&#44; chest CT&#41;&#59; assessment of lung volumes and&#47;or diffusion capacity&#44; oximetry and arterial blood gas measurement and exercise testing and assessment of physical activity should be considered&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Composite scores&#46;</span> The BODE &#40;Body mass index&#44; Obstruction&#44; Dyspnea&#44; and Exercise&#41; method gives a composite score that is a better predictor of subsequent survival than any single component&#46;<a class="elsevierStyleCrossRef" href="#bib1350"><span class="elsevierStyleSup">71</span></a> Simpler alternatives that do not include exercise testing need validation to confirm suitability for routine clinical use&#46;<a class="elsevierStyleCrossRefs" href="#bib1355"><span class="elsevierStyleSup">72&#44;73</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Differential diagnoses&#46;</span> In some patients&#44; features of asthma and COPD may coexist&#46; The terms Asthma-COPD Overlap Syndrome &#40;ACOS&#41; or Asthma-COPD Overlap &#40;ACO&#41; acknowledge the overlap of these two common disorders causing chronic airflow limitation rather than a distinct syndrome&#46; Most other potential differential diagnoses are easier to distinguish from COPD&#46;</p><p id="par0350" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Other considerations&#46;</span> Some patients without evidence of airflow limitation have evidence of structural lung disease on chest imaging &#40;emphysema&#44; gas trapping&#44; airway wall thickening&#41;&#46; Such patients may report exacerbations of respiratory symptoms or even require treatment with respiratory medications on a chronic basis&#46; Whether these patients have acute or chronic bronchitis&#44; a persistent form of asthma or an earlier presentation of what will become COPD as it is currently defined&#44; is unclear and requires further study&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Prevention and Maintenance Therapy</span><p id="par0355" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key Points</span><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">&#8226;</span><p id="par0360" class="elsevierStylePara elsevierViewall">Smoking cessation is key&#46; Pharmacotherapy and nicotine replacement increase long-term smoking abstinence rates&#46;</p></li><li class="elsevierStyleListItem" id="lsti0120"><span class="elsevierStyleLabel">&#8226;</span><p id="par0365" class="elsevierStylePara elsevierViewall">The effectiveness and safety of e-cigarettes as a smoking cessation aid is uncertain&#46;</p></li><li class="elsevierStyleListItem" id="lsti0125"><span class="elsevierStyleLabel">&#8226;</span><p id="par0370" class="elsevierStylePara elsevierViewall">Pharmacologic therapy can reduce COPD symptoms&#44; reduce the frequency and severity of exacerbations&#44; and improve health status and exercise tolerance&#46;</p></li><li class="elsevierStyleListItem" id="lsti0130"><span class="elsevierStyleLabel">&#8226;</span><p id="par0375" class="elsevierStylePara elsevierViewall">Each pharmacologic treatment regimen should be individualized and guided by the severity of symptoms&#44; risk of exacerbations&#44; side-effects&#44; comorbidities&#44; drug availability and cost&#44; and the patient&#39;s response&#44; preference and ability to use various drug delivery devices&#46;</p></li><li class="elsevierStyleListItem" id="lsti0135"><span class="elsevierStyleLabel">&#8226;</span><p id="par0380" class="elsevierStylePara elsevierViewall">Inhaler technique needs to be assessed regularly&#46;</p></li><li class="elsevierStyleListItem" id="lsti0140"><span class="elsevierStyleLabel">&#8226;</span><p id="par0385" class="elsevierStylePara elsevierViewall">Influenza and pneumococcal vaccinations decrease the incidence of lower respiratory tract infections&#46;</p></li><li class="elsevierStyleListItem" id="lsti0145"><span class="elsevierStyleLabel">&#8226;</span><p id="par0390" class="elsevierStylePara elsevierViewall">Pulmonary rehabilitation improves symptoms&#44; quality of life&#44; and physical and emotional participation in everyday activities&#46;</p></li><li class="elsevierStyleListItem" id="lsti0150"><span class="elsevierStyleLabel">&#8226;</span><p id="par0395" class="elsevierStylePara elsevierViewall">In patients with severe resting chronic hypoxemia&#44; long-term oxygen therapy improves survival&#46;</p></li><li class="elsevierStyleListItem" id="lsti0155"><span class="elsevierStyleLabel">&#8226;</span><p id="par0400" class="elsevierStylePara elsevierViewall">In patients with stable COPD and resting or exercise-induced moderate desaturation&#44; long-term oxygen treatment should not be prescribed routinely&#44; however&#44; individual patient factors should be considered&#46;</p></li><li class="elsevierStyleListItem" id="lsti0160"><span class="elsevierStyleLabel">&#8226;</span><p id="par0405" class="elsevierStylePara elsevierViewall">In patients with severe chronic hypercapnia and a history of hospitalization for acute respiratory failure&#44; long-term non-invasive ventilation may decrease mortality and prevent re-hospitalization&#46;</p></li><li class="elsevierStyleListItem" id="lsti0165"><span class="elsevierStyleLabel">&#8226;</span><p id="par0410" class="elsevierStylePara elsevierViewall">In select patients with advanced emphysema refractory to optimized medical care&#44; surgical or bronchoscopic interventional treatments may be beneficial&#46;</p></li><li class="elsevierStyleListItem" id="lsti0170"><span class="elsevierStyleLabel">&#8226;</span><p id="par0415" class="elsevierStylePara elsevierViewall">Palliative approaches are effective in controlling symptoms in advanced COPD&#46;</p></li></ul></p></span></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Smoking Cessation</span><p id="par0420" class="elsevierStylePara elsevierViewall">Smoking cessation influences the natural history of COPD&#46; If effective resources and time are dedicated to smoking cessation&#44; long-term quit success rates of up to 25&#37; can be achieved&#46;<a class="elsevierStyleCrossRef" href="#bib1365"><span class="elsevierStyleSup">74</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Nicotine replacement products</span>&#46; Nicotine replacement therapy increases long-term smoking abstinence rates<a class="elsevierStyleCrossRefs" href="#bib1370"><span class="elsevierStyleSup">75&#8211;77</span></a> and is more effective than placebo&#46; E-cigarettes are increasingly used as a form of nicotine replacement therapy&#44; although their efficacy remains controversial&#46;<a class="elsevierStyleCrossRefs" href="#bib1385"><span class="elsevierStyleSup">78&#8211;82</span></a></p><p id="par0430" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Pharmacologic products</span>&#46; Varenicline&#44;<a class="elsevierStyleCrossRef" href="#bib1410"><span class="elsevierStyleSup">83</span></a> bupropion&#44;<a class="elsevierStyleCrossRef" href="#bib1415"><span class="elsevierStyleSup">84</span></a> and nortriptyline<a class="elsevierStyleCrossRef" href="#bib1420"><span class="elsevierStyleSup">85</span></a> increase long-term quit rates&#44;<a class="elsevierStyleCrossRef" href="#bib1420"><span class="elsevierStyleSup">85</span></a> but should be used as part of an interventional program rather than as a sole intervention&#46;</p><p id="par0435" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Smoking cessation programs&#46;</span> A five-step program for intervention<a class="elsevierStyleCrossRefs" href="#bib1425"><span class="elsevierStyleSup">86&#44;87</span></a> provides a framework to guide healthcare providers to help patients stop smoking&#46;<a class="elsevierStyleCrossRefs" href="#bib1380"><span class="elsevierStyleSup">77&#44;86&#44;88</span></a> Counseling delivered by health professionals significantly increases quit rates over self-initiated strategies&#46;<a class="elsevierStyleCrossRef" href="#bib1440"><span class="elsevierStyleSup">89</span></a> The combination of pharmacotherapy and behavioral support increases smoking cessation rates&#46;<a class="elsevierStyleCrossRef" href="#bib1445"><span class="elsevierStyleSup">90</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Vaccinations</span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Influenza vaccine and Pneumococcal vaccines</span><p id="par0440" class="elsevierStylePara elsevierViewall">Influenza vaccination reduces serious illness&#44;<a class="elsevierStyleCrossRef" href="#bib1450"><span class="elsevierStyleSup">91</span></a> death&#44;<a class="elsevierStyleCrossRefs" href="#bib1455"><span class="elsevierStyleSup">92&#8211;95</span></a> the risk of ischemic heart disease<a class="elsevierStyleCrossRef" href="#bib1475"><span class="elsevierStyleSup">96</span></a> and the total number of exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib1455"><span class="elsevierStyleSup">92</span></a> Vaccines containing either killed or live inactivated viruses are recommended<a class="elsevierStyleCrossRef" href="#bib1480"><span class="elsevierStyleSup">97</span></a> as they are more effective in elderly patients with COPD&#46;<a class="elsevierStyleCrossRef" href="#bib1485"><span class="elsevierStyleSup">98</span></a></p><p id="par0445" class="elsevierStylePara elsevierViewall">Pneumococcal vaccinations&#44; PCV13 and PPSV23&#44; are recommended for all patients &#8805; 65 years of age &#40;see Table S2 in the Supplementary Appendix&#41;&#46;</p></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Pharmacologic Therapy for Stable COPD</span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Overview of medications</span><p id="par0450" class="elsevierStylePara elsevierViewall">Pharmacologic therapy for COPD reduces symptoms&#44; the frequency and severity of exacerbations&#44; and improves exercise tolerance and health status&#46; No existing medication modifies the long-term decline in lung function&#46;<a class="elsevierStyleCrossRefs" href="#bib1490"><span class="elsevierStyleSup">99&#8211;103</span></a> The classes of medications used to treat COPD are shown in Table S3 of the Supplementary Appendix&#46; The choice within each class depends on the availability and cost of medication and favorable clinical response balanced against side effects&#46; Each treatment regimen needs to be individualized as the relationship between severity of symptoms&#44; airflow limitation&#44; and severity of exacerbations varies between patients&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Bronchodilators</span><p id="par0455" class="elsevierStylePara elsevierViewall">Bronchodilators increase FEV<span class="elsevierStyleInf">1</span>&#44; reduce dynamic hyperinflation&#44; at rest and during exercise&#44;<a class="elsevierStyleCrossRefs" href="#bib1515"><span class="elsevierStyleSup">104&#44;105</span></a> and improve exercise performance&#46; Bronchodilator medications are usually given on a regular basis to prevent or reduce symptoms&#46; Toxicity is dose-related&#46;</p><p id="par0460" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Beta</span><span class="elsevierStyleInf"><span class="elsevierStyleBold">2</span></span><span class="elsevierStyleBold">-agonists</span>&#46; Beta<span class="elsevierStyleInf">2</span>-agonists&#44; including short-acting &#40;SABA&#41; and long-acting &#40;LABA&#41; agents&#44; relax airway smooth muscle&#46; Stimulation of beta<span class="elsevierStyleInf">2</span>-adrenergic receptors can produce resting sinus tachycardia and precipitate cardiac rhythm disturbances in susceptible patients&#46; Exaggerated somatic tremor occurs in some patients treated with higher doses of beta<span class="elsevierStyleInf">2</span>-agonists&#46;</p><p id="par0465" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Antimuscarinic drugs&#46;</span> Ipratropium&#44; a short acting muscarinic antagonist&#44; provides small benefits over short-acting beta<span class="elsevierStyleInf">2</span>-agonist in terms of lung function&#44; health status and requirement for oral steroids&#46;<a class="elsevierStyleCrossRef" href="#bib1525"><span class="elsevierStyleSup">106</span></a> Long acting muscarinic antagonist &#40;LAMA&#41; treatment improves symptoms and health status&#44;<a class="elsevierStyleCrossRefs" href="#bib1530"><span class="elsevierStyleSup">107&#44;108</span></a> improves the effectiveness of pulmonary rehabilitation<a class="elsevierStyleCrossRefs" href="#bib1540"><span class="elsevierStyleSup">109&#44;110</span></a> and reduces exacerbations and related hospitalizations&#46;<a class="elsevierStyleCrossRef" href="#bib1530"><span class="elsevierStyleSup">107</span></a> Clinical trials have shown a greater effect on exacerbation rates for LAMA treatment &#40;tiotropium&#41; versus LABA treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib1550"><span class="elsevierStyleSup">111&#44;112</span></a> An unexpected small increase in cardiovascular events was reported in COPD patients regularly treated with ipratropium bromide&#46;<a class="elsevierStyleCrossRefs" href="#bib1560"><span class="elsevierStyleSup">113&#44;114</span></a> A large trial reported no difference in mortality&#44; cardiovascular morbidity or exacerbation rates when using tiotropium as a dry-powder inhaler compared to a mist delivered by the Respimat<span class="elsevierStyleSup">&#174;</span> inhaler&#46;<a class="elsevierStyleCrossRef" href="#bib1570"><span class="elsevierStyleSup">115</span></a></p><p id="par0470" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Methylxanthines&#46;</span> Theophylline exerts a modest bronchodilator effect in stable COPD&#44;<a class="elsevierStyleCrossRef" href="#bib1575"><span class="elsevierStyleSup">116</span></a> and improves FEV<span class="elsevierStyleInf">1</span> and breathlessness when added to salmeterol&#46;<a class="elsevierStyleCrossRefs" href="#bib1580"><span class="elsevierStyleSup">117&#44;118</span></a> There is limited and contradictory evidence regarding the effect of low-dose theophylline on exacerbation rates&#46;<a class="elsevierStyleCrossRefs" href="#bib1590"><span class="elsevierStyleSup">119&#44;120</span></a> Toxicity is dose-related&#44; which is a problem as most of the benefit occurs when near-toxic doses are given&#46;<a class="elsevierStyleCrossRefs" href="#bib1575"><span class="elsevierStyleSup">116&#44;121</span></a></p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Combination bronchodilator therapy</span><p id="par0475" class="elsevierStylePara elsevierViewall">Combining bronchodilators with different mechanisms and durations of action may increase the degree of bronchodilation with a lower risk of side-effects compared to increasing the dose of a single bronchodilator &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1605"><span class="elsevierStyleSup">122</span></a> There are numerous combinations of a LABA and LAMA in a <span class="elsevierStyleItalic">single inhaler</span> available &#40;Table S3&#41;&#46; These combinations improve lung function compared to placebo<a class="elsevierStyleCrossRef" href="#bib1605"><span class="elsevierStyleSup">122</span></a> and have a greater impact on patient reported outcomes compared to monotherapies&#46;<a class="elsevierStyleCrossRefs" href="#bib1610"><span class="elsevierStyleSup">123&#8211;126</span></a> LABA&#47;LAMA improves symptoms and health status in COPD patients&#44;<a class="elsevierStyleCrossRef" href="#bib1630"><span class="elsevierStyleSup">127</span></a> is more effective than long-acting bronchodilator monotherapy for preventing exacerbations&#44;<a class="elsevierStyleCrossRef" href="#bib1635"><span class="elsevierStyleSup">128</span></a> and decreases exacerbations to a greater extent than ICS&#47;LABA combination&#46;<a class="elsevierStyleCrossRef" href="#bib1640"><span class="elsevierStyleSup">129</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Anti-inflammatory agents</span><p id="par0480" class="elsevierStylePara elsevierViewall">Exacerbations represent the main clinically relevant end-point used for the efficacy assessment of anti-inflammatory drugs &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Inhaled corticosteroids</span><p id="par0485" class="elsevierStylePara elsevierViewall">In patients with moderate to very severe COPD and exacerbations&#44; an inhaled corticosteroid &#40;ICS&#41; combined with a LABA is more effective than either component alone in improving lung function&#44; health status and reducing exacerbations&#46;<a class="elsevierStyleCrossRefs" href="#bib1645"><span class="elsevierStyleSup">130&#44;131</span></a> However&#44; survival is not affected by combination therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib1655"><span class="elsevierStyleSup">132&#44;133</span></a></p><p id="par0490" class="elsevierStylePara elsevierViewall">ICS use has a higher prevalence of oral candidiasis&#44; hoarse voice&#44; skin bruising and pneumonia&#46;<a class="elsevierStyleCrossRef" href="#bib1665"><span class="elsevierStyleSup">134</span></a> Patients at higher risk of pneumonia include those who currently smoke&#44; are aged<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleUnderline">&#62;</span><span class="elsevierStyleHsp" style=""></span>55 years&#44; have a history of prior exacerbations or pneumonia&#44; a body mass index &#40;BMI&#41;<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>25<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#44; a poor MRC dyspnea grade and&#47;or severe airflow limitation&#46;<a class="elsevierStyleCrossRef" href="#bib1670"><span class="elsevierStyleSup">135</span></a></p><p id="par0495" class="elsevierStylePara elsevierViewall">Results from RCTs have yielded variable results regarding the risk of decreased bone density and fractures with ICS treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib1500"><span class="elsevierStyleSup">101&#44;136&#8211;139</span></a> Observational studies suggest that ICS treatment could be associated with increased risks of diabetes&#47;poor control of diabetes&#44;<a class="elsevierStyleCrossRef" href="#bib1695"><span class="elsevierStyleSup">140</span></a> cataracts&#44;<a class="elsevierStyleCrossRef" href="#bib1700"><span class="elsevierStyleSup">141</span></a> and mycobacterial infection<a class="elsevierStyleCrossRef" href="#bib1705"><span class="elsevierStyleSup">142</span></a> including tuberculosis&#46;<a class="elsevierStyleCrossRefs" href="#bib1710"><span class="elsevierStyleSup">143&#44;144</span></a></p><p id="par0500" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ICS withdrawal</span>&#46; Withdrawal studies provide equivocal results regarding the consequences of withdrawal on lung function&#44; symptoms and exacerbations&#46;<a class="elsevierStyleCrossRefs" href="#bib1720"><span class="elsevierStyleSup">145&#8211;149</span></a></p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Triple inhaled therapy</span><p id="par0505" class="elsevierStylePara elsevierViewall">Combination of LABA plus LAMA plus ICS &#40;triple therapy&#41; may improve lung function and patient reported outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib1745"><span class="elsevierStyleSup">150&#8211;153</span></a> and reduce exacerbation risk&#46;<a class="elsevierStyleCrossRefs" href="#bib1750"><span class="elsevierStyleSup">151&#44;154&#8211;156</span></a> However&#44; one RCT failed to demonstrate any benefit of adding an ICS to LABA plus LAMA on exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib1780"><span class="elsevierStyleSup">157</span></a> More evidence is needed to compare the benefits of triple therapy &#40;LABA&#47;LAMA&#47;ICS&#41; to LABA&#47;LAMA&#46;</p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Oral glucocorticoids</span><p id="par0510" class="elsevierStylePara elsevierViewall">Oral glucocorticoids have no role in the chronic daily treatment in COPD because of a lack of benefit balanced against a high rate of systemic complications&#46;</p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Phosphodiesterase-4 inhibitors</span><p id="par0515" class="elsevierStylePara elsevierViewall">Roflumilast reduces moderate and severe exacerbations treated with systemic corticosteroids in patients with chronic bronchitis&#44; severe to very severe COPD&#44; and a history of exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib1785"><span class="elsevierStyleSup">158</span></a> Phosphodiesterase-4 &#40;PDE4&#41; inhibitors have more adverse effects than inhaled medications for COPD&#46;<a class="elsevierStyleCrossRef" href="#bib1790"><span class="elsevierStyleSup">159</span></a> The most frequent are diarrhea&#44; nausea&#44; reduced appetite&#44; weight loss&#44; abdominal pain&#44; sleep disturbance&#44; and headache&#46; Roflumilast should be avoided in underweight patients and used with caution in patients with depression&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Antibiotics</span><p id="par0520" class="elsevierStylePara elsevierViewall">Azithromycin &#40;250<span class="elsevierStyleHsp" style=""></span>mg&#47;day or 500<span class="elsevierStyleHsp" style=""></span>mg three times per week&#41; or erythromycin &#40;500<span class="elsevierStyleHsp" style=""></span>mg two times per day&#41; for one year reduces the risk of exacerbations in patients prone to exacerbations&#46;<a class="elsevierStyleCrossRefs" href="#bib1795"><span class="elsevierStyleSup">160&#8211;162</span></a> Azithromycin use showed a reduced exacerbation rate in former smokers only and was associated with an increased incidence of bacterial resistance and impaired hearing tests&#46;<a class="elsevierStyleCrossRef" href="#bib1805"><span class="elsevierStyleSup">162</span></a> Pulse moxifloxacin therapy in patients with chronic bronchitis and frequent exacerbations does not reduce exacerbation rate&#46;<a class="elsevierStyleCrossRef" href="#bib1810"><span class="elsevierStyleSup">163</span></a></p></span><span id="sec0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0190">Mucolytic &#40;mucokinetics&#44; mucoregulators&#41; and antioxidant agents &#40;N-acetylcysteine&#44; carbocysteine&#41;</span><p id="par0525" class="elsevierStylePara elsevierViewall">Regular treatment with mucolytics such as carbocysteine and N-acetylcysteine may reduce exacerbations and modestly improve health status in patients not receiving ICS&#46;<a class="elsevierStyleCrossRefs" href="#bib1815"><span class="elsevierStyleSup">164&#44;165</span></a></p></span><span id="sec0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0195">Other drugs with anti-inflammatory potential</span><p id="par0530" class="elsevierStylePara elsevierViewall">Although RCTs suggest that immunoregulators decrease the severity and frequency of exacerbations&#44;<a class="elsevierStyleCrossRefs" href="#bib1825"><span class="elsevierStyleSup">166&#44;167</span></a> the long-term effects of this therapy are unknown&#46; Nedocromil and leukotriene modifiers have not been adequately tested in COPD&#46;<a class="elsevierStyleCrossRef" href="#bib1835"><span class="elsevierStyleSup">168</span></a> There was no evidence of benefit&#44; and some evidence of harm&#44; following treatment with an anti-TNF-alpha antibody &#40;infliximab&#41; in moderate to severe COPD&#46;<a class="elsevierStyleCrossRef" href="#bib1840"><span class="elsevierStyleSup">169</span></a> Simvastatin did not prevent exacerbations in patients with COPD who had no metabolic or cardiovascular indication for statin treatment&#46;<a class="elsevierStyleCrossRef" href="#bib1845"><span class="elsevierStyleSup">170</span></a> An association between statin use and improved outcomes has been reported in observational studies of patients with COPD who received them for cardiovascular and metabolic indications&#46;<a class="elsevierStyleCrossRef" href="#bib1850"><span class="elsevierStyleSup">171</span></a> There is no evidence that vitamin D supplementation reduces exacerbations in unselected patients&#46;<a class="elsevierStyleCrossRef" href="#bib1855"><span class="elsevierStyleSup">172</span></a></p></span><span id="sec0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0200">Issues related to inhaled delivery</span><p id="par0535" class="elsevierStylePara elsevierViewall">Observational studies have identified a significant relationship between poor inhaler use and symptom control in COPD&#46;<a class="elsevierStyleCrossRef" href="#bib1860"><span class="elsevierStyleSup">173</span></a> Determinants of poor inhaler technique include older age&#44; use of multiple devices&#44; and lack of previous education on inhaler technique&#46;<a class="elsevierStyleCrossRef" href="#bib1865"><span class="elsevierStyleSup">174</span></a> Education improves inhalation technique in some but not all patients&#44;<a class="elsevierStyleCrossRef" href="#bib1865"><span class="elsevierStyleSup">174</span></a> especially when the &#8220;teach-back&#8221; approach is implemented&#46;<a class="elsevierStyleCrossRef" href="#bib1870"><span class="elsevierStyleSup">175</span></a></p><p id="par0540" class="elsevierStylePara elsevierViewall">Other pharmacologic treatments for COPD are summarized in Table S4 in the Supplementary Appendix&#46;</p><p id="par0545" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Alpha-1 antitrypsin augmentation therapy</span>&#46; Observational studies suggest a reduction in spirometric progression in alpha-1 antitrypsin deficiency patients treated with augmentation therapy versus non-treated patients&#46;<a class="elsevierStyleCrossRef" href="#bib1875"><span class="elsevierStyleSup">176</span></a> Studies using sensitive parameters of emphysema progression determined by CT scans provide evidence for an effect on preserving lung tissue compared to placebo&#46;<a class="elsevierStyleCrossRefs" href="#bib1880"><span class="elsevierStyleSup">177&#8211;179</span></a></p><p id="par0550" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Antitussives</span>&#46; The role of antitussives in patients with COPD is inconclusive&#46;<a class="elsevierStyleCrossRef" href="#bib1895"><span class="elsevierStyleSup">180</span></a></p><p id="par0555" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Vasodilators</span>&#46; Available studies report worsening gas exchange<a class="elsevierStyleCrossRef" href="#bib1900"><span class="elsevierStyleSup">181</span></a> with little improvement in exercise capacity or health status in COPD patients&#46;<a class="elsevierStyleCrossRefs" href="#bib1905"><span class="elsevierStyleSup">182&#44;183</span></a></p></span></span><span id="sec0185" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0205">Rehabilitation&#44; Education&#44; and Self-Management</span><span id="sec0190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0210">Pulmonary Rehabilitation</span><p id="par0560" class="elsevierStylePara elsevierViewall">Pulmonary rehabilitation is a comprehensive intervention based on thorough patient assessment followed by patient-tailored therapies &#40;e&#46;g&#46;&#44; exercise training&#44; education&#44; self-management interventions aimed at behavior changes to improve physical and psychological condition and promote adherence to health-enhancing behaviors in patients with COPD&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1915"><span class="elsevierStyleSup">184</span></a> The benefits of pulmonary rehabilitation are considerable &#40;Table S5 in the Supplementary Appendix&#41;&#46; Pulmonary rehabilitation can reduce readmissions and mortality in patients following a recent exacerbation &#40;&#8804; 4 weeks from prior hospitalization&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib1920"><span class="elsevierStyleSup">185</span></a> Initiating pulmonary rehabilitation before hospital discharge&#44; however&#44; may compromise survival&#46;<a class="elsevierStyleCrossRef" href="#bib1925"><span class="elsevierStyleSup">186</span></a></p><p id="par0565" class="elsevierStylePara elsevierViewall">Pulmonary rehabilitation represents integrated patient management that includes a range of healthcare professionals<a class="elsevierStyleCrossRef" href="#bib1930"><span class="elsevierStyleSup">187</span></a> and sites&#44; including hospital inpatient and outpatient settings and&#47;or the patient&#39;s home&#46;<a class="elsevierStyleCrossRef" href="#bib1915"><span class="elsevierStyleSup">184</span></a></p></span><span id="sec0195" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0215">Education&#44; Self-Management&#44; and Integrative Care</span><p id="par0570" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Education</span>&#46; Smoking cessation&#44; correct use of inhaler devices&#44; early recognition of exacerbation&#44; decision making&#44; when to seek help&#44; surgical interventions&#44; and the consideration of advance directives&#44; are examples of educational topics&#46;</p><p id="par0575" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Self-management</span>&#46; Self-management interventions that use written negotiated action plans for worsening symptoms may lead to less respiratory-related hospitalization and all cause hospitalizations and improved health status&#46;<a class="elsevierStyleCrossRef" href="#bib1935"><span class="elsevierStyleSup">188</span></a> The health benefits of COPD self-management programs may be negated by increased mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib1940"><span class="elsevierStyleSup">189&#44;190</span></a> Generalization to real life remains difficult&#46;</p><p id="par0580" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Integrated care programs</span>&#46; Integrated care programs improve several clinical outcomes&#44; although not mortality&#46;<a class="elsevierStyleCrossRef" href="#bib1950"><span class="elsevierStyleSup">191</span></a> However&#44; a large multi-center study within an existing well-organized system of care did not confirm this&#46;<a class="elsevierStyleCrossRef" href="#bib1955"><span class="elsevierStyleSup">192</span></a> Delivering integrated interventions by telemedicine provided no significant benefit&#46;<a class="elsevierStyleCrossRef" href="#bib1960"><span class="elsevierStyleSup">193</span></a></p></span></span><span id="sec0200" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0220">Supportive&#44; Palliative&#44; End-of-Life&#44; and Hospice Care</span><span id="sec0205" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0225">Symptom Control and Palliative Care</span><p id="par0585" class="elsevierStylePara elsevierViewall">The goal of palliative care is to prevent and relieve suffering&#44; and to improve quality of life for patients and their families&#44; regardless of the stage of disease or the need for other therapies&#46;<a class="elsevierStyleCrossRef" href="#bib1965"><span class="elsevierStyleSup">194</span></a> Palliation efforts should be focused on the relief of dyspnea&#44; pain&#44; anxiety&#44; depression&#44; fatigue&#44; and poor nutrition&#46;</p></span><span id="sec0210" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0230">End-of-Life and Hospice Care</span><p id="par0590" class="elsevierStylePara elsevierViewall">End of life care discussions should include patients and their families&#46;<a class="elsevierStyleCrossRef" href="#bib1970"><span class="elsevierStyleSup">195</span></a> Advance care planning can reduce anxiety for patients and their families&#44; ensure that care is consistent with their wishes and avoid unnecessary&#44; unwanted and costly invasive therapies<a class="elsevierStyleCrossRefs" href="#bib1975"><span class="elsevierStyleSup">196&#44;197</span></a> Table S6 in the Supplementary Appendix summarizes the approach to palliation&#44; end-of-life and hospice care</p></span></span><span id="sec0215" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0235">Other Treatments</span><span id="sec0220" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0240">Oxygen Therapy and Ventilatory Support</span><p id="par0595" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Oxygen therapy</span>&#46; The long-term administration of oxygen &#40;&#62; 15<span class="elsevierStyleHsp" style=""></span>hours per day&#41; to patients with chronic respiratory failure increases survival in patients with severe resting hypoxemia&#46;<a class="elsevierStyleCrossRef" href="#bib1985"><span class="elsevierStyleSup">198</span></a> Long term oxygen therapy does not lengthen time to death or first hospitalization or provide sustained benefit for any of the measured outcomes in patients with stable COPD and resting or exercise-induced moderate arterial oxygen desaturation&#46;<a class="elsevierStyleCrossRef" href="#bib1990"><span class="elsevierStyleSup">199</span></a></p><p id="par0600" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Ventilatory support&#46;</span> Whether to use NPPV chronically at home to treat patients with acute on chronic respiratory failure following hospitalization remains undetermined&#46; Retrospective studies have provided inconclusive data&#46;<a class="elsevierStyleCrossRefs" href="#bib1995"><span class="elsevierStyleSup">200&#44;201</span></a> RCTs have yielded conflicting data on the use of home NPPV on survival and re-hospitalization in chronic hypercapnic COPD&#46;<a class="elsevierStyleCrossRefs" href="#bib2005"><span class="elsevierStyleSup">202&#8211;205</span></a> In patients with both COPD and obstructive sleep apnea continuous positive airway pressure improves survival and avoids hospitalization &#40;Table S7 in the Supplementary Appendix&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib2025"><span class="elsevierStyleSup">206</span></a></p></span></span><span id="sec0225" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0245">Interventional Therapy</span><span id="sec0230" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0250">Surgical Interventions</span><p id="par0605" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Lung volume reduction surgery</span>&#46; A RCT confirmed that COPD patients with upper-lobe emphysema and low post-rehabilitation exercise capacity experienced improved survival when treated with lung volume reduction surgery &#40;LVRS&#41; compared to medical treatment&#46;<a class="elsevierStyleCrossRef" href="#bib2030"><span class="elsevierStyleSup">207</span></a> In patients with high post-pulmonary rehabilitation exercise capacity&#44; no difference in survival was noted after LVRS&#44; although health status and exercise capacity improved&#46; LVRS has been demonstrated to result in higher mortality than medical management in severe emphysema patients with an FEV<span class="elsevierStyleInf">1</span> &#8804; 20&#37; predicted and either homogeneous emphysema in high resolution computed tomography or a DLCO of &#8804; 20&#37; of predicted&#46;<a class="elsevierStyleCrossRef" href="#bib2035"><span class="elsevierStyleSup">208</span></a></p><p id="par0610" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Bullectomy</span>&#46; In selected patients with relatively preserved underlying lung&#44; bullectomy is associated with decreased dyspnea&#44; improved lung function and exercise tolerance&#46;<a class="elsevierStyleCrossRef" href="#bib2040"><span class="elsevierStyleSup">209</span></a></p><p id="par0615" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Lung transplantation</span>&#46; In selected patients lung transplantation has been shown to improve health status and functional capacity but not to prolong survival&#46;<a class="elsevierStyleCrossRefs" href="#bib2040"><span class="elsevierStyleSup">209&#8211;211</span></a> Bilateral lung transplantation has been reported to have longer survival than single lung transplantation in COPD patients&#44; especially those<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>60 years of age&#46;<a class="elsevierStyleCrossRef" href="#bib2055"><span class="elsevierStyleSup">212</span></a></p></span><span id="sec0235" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0255">Bronchoscopic Interventions to Reduce Hyperinflation in Severe Emphysema</span><p id="par0620" class="elsevierStylePara elsevierViewall">Less invasive bronchoscopic approaches to lung reduction have been developed&#46;<a class="elsevierStyleCrossRef" href="#bib2060"><span class="elsevierStyleSup">213</span></a> Prospective studies have shown that the use of bronchial stents is not effective<a class="elsevierStyleCrossRef" href="#bib2065"><span class="elsevierStyleSup">214</span></a> while use of lung sealant caused significant morbidity and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib2070"><span class="elsevierStyleSup">215</span></a> A RCT of endobronchial valve placement showed statistically significant improvements in FEV<span class="elsevierStyleInf">1</span> and 6-minute walk distance compared to control therapy at 6 months post intervention<a class="elsevierStyleCrossRef" href="#bib2075"><span class="elsevierStyleSup">216</span></a> but the magnitude of the observed improvements was not clinically meaningful&#46; Subsequently&#44; efficacy of the same endobronchial valve has been studied in patients with heterogeneous&#44;<a class="elsevierStyleCrossRef" href="#bib2080"><span class="elsevierStyleSup">217</span></a> or heterogeneous and homogenous emphysema<a class="elsevierStyleCrossRef" href="#bib2085"><span class="elsevierStyleSup">218</span></a> with mixed outcomes&#46;</p><p id="par0625" class="elsevierStylePara elsevierViewall">Two multicenter trials have examined nitinol coils implanted into the lung compared to usual care reported increases in 6<span class="elsevierStyleHsp" style=""></span>minute walk distance with coil treatment compared to control and smaller improvements in FEV<span class="elsevierStyleInf">1</span> and quality of life measured by St George&#39;s Respiratory Questionnaire&#46;<a class="elsevierStyleCrossRefs" href="#bib2090"><span class="elsevierStyleSup">219&#44;220</span></a></p><p id="par0630" class="elsevierStylePara elsevierViewall">Additional data are needed to define the optimal patient population to receive a specific bronchoscopic lung volume technique and to compare the long-term durability of improvements in functional or physiological performance to LVRS relative to side effects&#46;<a class="elsevierStyleCrossRef" href="#bib2095"><span class="elsevierStyleSup">220</span></a></p><p id="par0635" class="elsevierStylePara elsevierViewall">Key points for interventional therapy in stable COPD are summarized in Table S8 in the Supplementary Appendix&#46;</p></span></span><span id="sec0240" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0260">Management of Stable COPD</span><p id="par0640" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key Points</span><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0175"><span class="elsevierStyleLabel">&#8226;</span><p id="par0645" class="elsevierStylePara elsevierViewall">The management strategy for stable COPD should be based on individualized symptom assessment and future risk of exacerbations&#46;</p></li><li class="elsevierStyleListItem" id="lsti0180"><span class="elsevierStyleLabel">&#8226;</span><p id="par0650" class="elsevierStylePara elsevierViewall">All individuals who smoke should be supported to quit&#46;</p></li><li class="elsevierStyleListItem" id="lsti0185"><span class="elsevierStyleLabel">&#8226;</span><p id="par0655" class="elsevierStylePara elsevierViewall">The main treatment goals are reduction of symptoms and future risk of exacerbations&#46;</p></li><li class="elsevierStyleListItem" id="lsti0190"><span class="elsevierStyleLabel">&#8226;</span><p id="par0660" class="elsevierStylePara elsevierViewall">Management strategies are not limited to pharmacologic treatments&#44; and should be complemented by appropriate non-pharmacologic interventions&#46;</p></li></ul></p><p id="par0665" class="elsevierStylePara elsevierViewall">Effective COPD management should be based on an individualized assessment to reduce both current symptoms and future risks of exacerbations &#40;Figure S1 in the Supplementary Appendix&#41;&#46;</p><p id="par0670" class="elsevierStylePara elsevierViewall">We propose personalization of initiating and escalating&#47;de-escalating treatments based on the level of symptoms and an individual&#39;s risk of exacerbations&#46; The basis for these recommendations is partially based on evidence generated in RCTs&#46; These recommendations are intended to support clinician decision-making&#46;</p></span><span id="sec0245" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0265">Identify and Reduce Exposure to Risk Factors</span><p id="par0675" class="elsevierStylePara elsevierViewall">Cigarette smoking is the most commonly encountered and easily identifiable risk factor for COPD&#59; smoking cessation should be continually encouraged for current smokers&#46; Reduction of total personal exposure to occupational dusts&#44; fumes&#44; and gases&#44; and to indoor and outdoor air pollutants&#44; should be addressed&#46;</p></span><span id="sec0250" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0270">Treatment of Stable COPD</span><span id="sec0255" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0275">Pharmacologic Treatment</span><p id="par0680" class="elsevierStylePara elsevierViewall">Pharmacologic therapies can reduce symptoms&#44; the risk and severity of exacerbations&#44; and improve health status and exercise tolerance&#46; The choice within each class depends on the availability of medication and the patient&#39;s response and preference &#40;<a class="elsevierStyleCrossRefs" href="#tbl0025">Tables 5&#8211;7</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="tbl0035"></elsevierMultimedia></span><span id="sec0260" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0280">Pharmacologic treatment algorithms</span><p id="par0685" class="elsevierStylePara elsevierViewall">A proposed model for the initiation&#44; and then subsequent escalation and&#47;or de-escalation of pharmacologic management according to the individualized assessment of symptoms and exacerbation risk is shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46; In past GOLD Reports&#44; recommendations were only given for initial therapy&#46; However&#44; many COPD patients are already on treatment and return with persistent symptoms after initial therapy&#44; or less commonly with resolution of some symptoms that may subsequently require less therapy&#46; Therefore&#44; we now suggest escalation and de-escalation strategies&#46; The recommendations are based on available efficacy and safety data&#46; We acknowledge that treatment escalation has not been systematically tested&#59; trials of de-escalation are also limited and only include ICS&#46; There is a lack of direct evidence supporting the therapeutic recommendations for patients in groups C and D&#46; These recommendations will be re-evaluated as additional data become available&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><span id="sec0265" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0285">Group A</span><p id="par0690" class="elsevierStylePara elsevierViewall">All Group A patients should be offered a bronchodilator to reduce breathlessness&#46; This can be either a short or a long-acting bronchodilator based on the individual patient&#39;s preference&#46; The bronchodilator should be continued if symptomatic benefit is noted&#46;</p></span><span id="sec0270" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0290">Group B</span><p id="par0695" class="elsevierStylePara elsevierViewall">Initial therapy should be a long acting bronchodilator&#46; Long-acting bronchodilators are superior to short-acting bronchodilators taken intermittently&#46;<a class="elsevierStyleCrossRefs" href="#bib1525"><span class="elsevierStyleSup">106&#44;221</span></a> There is no evidence to recommend one class of long-acting bronchodilators over another for symptom relief&#44; the choice should depend on individual patient response&#46;</p><p id="par0700" class="elsevierStylePara elsevierViewall">For patients with persistent breathlessness on monotherapy<a class="elsevierStyleCrossRef" href="#bib2105"><span class="elsevierStyleSup">222</span></a> the use of two bronchodilators is recommended&#46; For patients with severe breathlessness&#44; initial therapy with two bronchodilators may be considered&#46;</p></span><span id="sec0275" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0295">Group C</span><p id="par0705" class="elsevierStylePara elsevierViewall">Initial therapy should be a single long acting bronchodilator&#46; In two head-to head comparisons<a class="elsevierStyleCrossRefs" href="#bib1555"><span class="elsevierStyleSup">112&#44;223</span></a> the LAMA tested superior to the LABA regarding exacerbation prevention&#44; therefore we recommend initiating a LAMA in this group&#46;</p><p id="par0710" class="elsevierStylePara elsevierViewall">Patients with persistent exacerbations may benefit from adding a second long acting bronchodilator &#40;LABA&#47;LAMA&#41;&#44; or using a combination of a long acting beta<span class="elsevierStyleInf">2</span>-agonist and an inhaled corticosteroid &#40;LABA&#47;ICS&#41;&#46; As ICS increases the risk for developing pneumonia&#44; our primary choice is LABA&#47;LAMA&#46;</p></span><span id="sec0280" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0300">Group D</span><p id="par0715" class="elsevierStylePara elsevierViewall">We recommend initiating a LABA&#47;LAMA combination because&#58;<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0195"><span class="elsevierStyleLabel">&#8226;</span><p id="par0720" class="elsevierStylePara elsevierViewall">In studies with patient reported outcomes as the primary endpoint&#44; LABA&#47;LAMA combinations showed superior results compared to a single bronchodilator&#46;</p></li><li class="elsevierStyleListItem" id="lsti0200"><span class="elsevierStyleLabel">&#8226;</span><p id="par0725" class="elsevierStylePara elsevierViewall">LABA&#47;LAMA combination was superior to LABA&#47;ICS combination in preventing exacerbations and improving other patient reported outcomes in Group D patients&#46;</p></li><li class="elsevierStyleListItem" id="lsti0205"><span class="elsevierStyleLabel">&#8226;</span><p id="par0730" class="elsevierStylePara elsevierViewall">Group D patients are at higher risk for pneumonia when receiving ICS treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib1550"><span class="elsevierStyleSup">111&#44;135</span></a></p></li></ul></p><p id="par0735" class="elsevierStylePara elsevierViewall">If a single bronchodilator is initially chosen&#44; a LAMA is preferred for exacerbation prevention based on comparison to LABAs&#46;</p><p id="par0740" class="elsevierStylePara elsevierViewall">LABA&#47;ICS may be the first choice for initial therapy in some patients&#46; These patients may have a history and&#47;or findings suggestive of asthma-COPD overlap and&#47;or high blood eosinophil counts&#46;</p><p id="par0745" class="elsevierStylePara elsevierViewall">In patients who develop additional exacerbations on LABA&#47;LAMA therapy we suggest two alternative pathways&#58;<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0210"><span class="elsevierStyleLabel">&#8728;</span><p id="par0750" class="elsevierStylePara elsevierViewall">Escalation to LABA&#47;LAMA&#47;ICS&#46;</p></li><li class="elsevierStyleListItem" id="lsti0215"><span class="elsevierStyleLabel">&#8728;</span><p id="par0755" class="elsevierStylePara elsevierViewall">Switch to LABA&#47;ICS&#46; If LABA&#47;ICS therapy does not positively impact exacerbations&#47;symptoms&#44; a LAMA can be added&#46;</p></li></ul></p><p id="par0760" class="elsevierStylePara elsevierViewall">If patients treated with LABA&#47;LAMA&#47;ICS still have exacerbations the following options may be considered&#58;<ul class="elsevierStyleList" id="lis0045"><li class="elsevierStyleListItem" id="lsti0220"><span class="elsevierStyleLabel">&#8728;</span><p id="par0765" class="elsevierStylePara elsevierViewall">Add roflumilast&#46; This may be considered in patients with an FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>50&#37; predicted and chronic bronchitis&#44;<a class="elsevierStyleCrossRef" href="#bib2115"><span class="elsevierStyleSup">224</span></a> particularly if they experienced at least one hospitalization for an exacerbation in the previous year&#46;<a class="elsevierStyleCrossRef" href="#bib2120"><span class="elsevierStyleSup">225</span></a></p></li><li class="elsevierStyleListItem" id="lsti0225"><span class="elsevierStyleLabel">&#8728;</span><p id="par0770" class="elsevierStylePara elsevierViewall">Add a macrolide in former smokers&#46; The possibility of developing resistant organisms should be factored into the decision making&#46;</p></li><li class="elsevierStyleListItem" id="lsti0230"><span class="elsevierStyleLabel">&#8728;</span><p id="par0775" class="elsevierStylePara elsevierViewall">Stopping ICS&#46; This recommendation is supported by data that shows an elevated risk of adverse effects &#40;including pneumonia&#41; and no significant harm from ICS withdrawal&#46;</p></li></ul></p></span></span><span id="sec0285" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0305">Nonpharmacologic Treatment</span><span id="sec0290" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0310">Education and self-management</span><p id="par0780" class="elsevierStylePara elsevierViewall">An individual patient&#39;s evaluation and risk assessment &#40;e&#46;g&#46;&#44; exacerbations&#44; patient&#39;s needs&#44; preferences&#44; and personal goals&#41; should aid the design of personalized self-management&#46;</p></span><span id="sec0295" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0315">Pulmonary rehabilitation programs</span><p id="par0785" class="elsevierStylePara elsevierViewall">Patients with high symptom burden and risk of exacerbations &#40;Groups B&#44; C and D&#41;&#44; should take part in a full rehabilitation program that considers the individual&#39;s characteristics and comorbidities&#46;<a class="elsevierStyleCrossRefs" href="#bib1915"><span class="elsevierStyleSup">184&#44;226&#44;227</span></a></p></span><span id="sec0300" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0320">Exercise training</span><p id="par0790" class="elsevierStylePara elsevierViewall">A combination of constant load or interval training with strength training provides better outcomes than either method alone&#46;<a class="elsevierStyleCrossRef" href="#bib2135"><span class="elsevierStyleSup">228</span></a> Adding strength training to aerobic training is effective in improving strength&#44; but does not improve health status or exercise tolerance&#46;<a class="elsevierStyleCrossRef" href="#bib2140"><span class="elsevierStyleSup">229</span></a> Upper extremity exercise training improves arm strength and endurance and improves capacity for upper extremity activities&#46;<a class="elsevierStyleCrossRef" href="#bib2145"><span class="elsevierStyleSup">230</span></a></p></span><span id="sec0305" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0325">Self-management education</span><p id="par0795" class="elsevierStylePara elsevierViewall">An educational program should include smoking cessation&#59; basic information about COPD&#59; aspects of medical treatment &#40;respiratory medications and inhalation devices&#41;&#59; strategies to minimize dyspnea&#59; advice about when to seek help&#59; and possibly a discussion of advance directives and end-of-life issues&#46;</p></span><span id="sec0310" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0330">End-of-life and palliative care</span><p id="par0800" class="elsevierStylePara elsevierViewall">Patients should be informed that should they become critically ill&#44; they or their family members may need to decide whether a course of intensive care is likely to achieve their personal goals of care&#46; Simple&#44; structured conversations about these possible scenarios should be discussed while patients are in their stable state&#46;<a class="elsevierStyleCrossRef" href="#bib2150"><span class="elsevierStyleSup">231</span></a></p></span></span><span id="sec0315" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0335">Nutritional support</span><p id="par0805" class="elsevierStylePara elsevierViewall">For malnourished patients with COPD nutritional supplementation is recommended&#46;</p></span><span id="sec0320" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0340">Vaccination</span><p id="par0810" class="elsevierStylePara elsevierViewall">Influenza vaccination is recommended for all patients with COPD<span class="elsevierStyleBold">&#46;</span> Pneumococcal vaccinations&#44; PCV13 and PPSV23&#44; are recommended for all patients<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>65 years of age&#46; The PPSV23 is also recommended for younger COPD patients with significant comorbid conditions including chronic heart or lung disease&#46;<a class="elsevierStyleCrossRef" href="#bib2155"><span class="elsevierStyleSup">232</span></a></p></span><span id="sec0325" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0345">Oxygen therapy</span><p id="par0815" class="elsevierStylePara elsevierViewall">Long-term oxygen therapy is indicated for stable patients who have&#58;<ul class="elsevierStyleList" id="lis0050"><li class="elsevierStyleListItem" id="lsti0235"><span class="elsevierStyleLabel">&#8226;</span><p id="par0820" class="elsevierStylePara elsevierViewall">PaO<span class="elsevierStyleInf">2</span> at or below 7&#46;3<span class="elsevierStyleHsp" style=""></span>kPa &#40;55<span class="elsevierStyleHsp" style=""></span>mmHg&#41; or SaO<span class="elsevierStyleInf">2</span> at or below 88&#37;&#44; with or without hypercapnia confirmed twice over a three-week period&#59; or</p></li><li class="elsevierStyleListItem" id="lsti0240"><span class="elsevierStyleLabel">&#8226;</span><p id="par0825" class="elsevierStylePara elsevierViewall">PaO<span class="elsevierStyleInf">2</span> between 7&#46;3<span class="elsevierStyleHsp" style=""></span>kPa &#40;55<span class="elsevierStyleHsp" style=""></span>mmHg&#41; and 8&#46;0<span class="elsevierStyleHsp" style=""></span>kPa &#40;60<span class="elsevierStyleHsp" style=""></span>mmHg&#41;&#44; or SaO<span class="elsevierStyleInf">2</span> of 88&#37;&#44; if there is evidence of pulmonary hypertension&#44; peripheral edema suggesting congestive cardiac failure&#44; or polycythemia &#40;hematocrit<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>55&#37;&#41;&#46;</p></li></ul></p></span><span id="sec0330" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0350">Ventilatory support</span><p id="par0830" class="elsevierStylePara elsevierViewall">NIV is occasionally used in patients with stable very severe COPD&#46; NIV may be considered in a selected group of patients&#44; particularly those with pronounced daytime hypercapnia and recent hospitalization&#44; although contradictory evidence exists regarding its effectiveness&#46;<a class="elsevierStyleCrossRef" href="#bib2160"><span class="elsevierStyleSup">233</span></a> In patients with both COPD and obstructive sleep apnea continuous positive airway pressure is indicated&#46;<a class="elsevierStyleCrossRef" href="#bib2025"><span class="elsevierStyleSup">206</span></a></p></span><span id="sec0335" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0355">Interventional bronchoscopy and surgery</span><p id="par0835" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0055"><li class="elsevierStyleListItem" id="lsti0245"><span class="elsevierStyleLabel">&#8226;</span><p id="par0840" class="elsevierStylePara elsevierViewall">In selected patients with heterogeneous or homogenous emphysema and significant hyperinflation refractory to optimized medical care&#44; surgical or bronchoscopic modes of lung volume reduction &#40;e&#46;g&#46;&#44; endobronchial one-way valves or lung coils&#41; may be considered&#46;<a class="elsevierStyleCrossRef" href="#bib2165"><span class="elsevierStyleSup">234</span></a></p></li><li class="elsevierStyleListItem" id="lsti0250"><span class="elsevierStyleLabel">&#8226;</span><p id="par0845" class="elsevierStylePara elsevierViewall">In selected patients with a large bulla&#44; surgical bullectomy may be considered&#46;</p></li><li class="elsevierStyleListItem" id="lsti0255"><span class="elsevierStyleLabel">&#8226;</span><p id="par0850" class="elsevierStylePara elsevierViewall">In selected patients with very severe COPD and without relevant contraindications&#44; lung transplantation may be considered&#46;</p></li></ul></p><p id="par0855" class="elsevierStylePara elsevierViewall">Choosing bronchoscopic lung reduction or LVRS to treat hyperinflation in an emphysematous patient depends on a number of factors that include&#58; the extent and pattern of emphysema identified on HRCT&#59; the presence of interlobar collateral ventilation measured by fissure integrity on HRCT or physiological assessment &#40;endoscopic balloon occlusion and flow assessment&#41;&#59; local proficiency in the performance of the procedures&#59; and patient and provider preferences&#46; An algorithm depicting the various interventions based on radiological and physiological features is shown in <a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0860" class="elsevierStylePara elsevierViewall">Criteria for referral for lung transplantation include COPD with progressive disease&#44; not a candidate for endoscopic or surgical lung volume reduction&#44; BODE index of 5 to 6&#44; Pco<span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>50<span class="elsevierStyleHsp" style=""></span>mmHg or 6&#46;6<span class="elsevierStyleHsp" style=""></span>kPa and&#47;or Pa<span class="elsevierStyleSmallCaps">o</span><span class="elsevierStyleInf">2</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>mmHg or 8<span class="elsevierStyleHsp" style=""></span>kPa&#44; and FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>25&#37; predicted&#46;<a class="elsevierStyleCrossRef" href="#bib2170"><span class="elsevierStyleSup">235</span></a> Recommended criteria for listing include one of the following&#58; BODE index<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>7&#44; FEV<span class="elsevierStyleInf">1</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>15-20&#37; predicted&#44; three or more severe exacerbations during the preceding year&#44; one severe exacerbation with acute hypercapnic respiratory failure&#44; or moderate to severe pulmonary hypertension&#46;<a class="elsevierStyleCrossRefs" href="#bib2170"><span class="elsevierStyleSup">235&#44;236</span></a></p><p id="par0865" class="elsevierStylePara elsevierViewall">Key points for the use of non-pharmacologic treatments are summarized in Table S9 in the Supplementary Appendix&#46;</p></span></span><span id="sec0340" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0360">Monitoring and Follow-Up</span><p id="par0870" class="elsevierStylePara elsevierViewall">Routine follow-up of COPD patients is essential&#46; Symptoms&#44; exacerbations and objective measures of airflow limitation should be monitored to determine when to modify management and to identify any complications and&#47;or comorbidities that may develop&#46; In order to adjust therapy appropriately as the disease progresses&#44; each follow-up visit should include a discussion of the current therapeutic regimen&#46; Symptoms that indicate worsening or development of another comorbid condition should be evaluated and treated&#46;</p><span id="sec0345" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0365">Management of Exacerbations</span><p id="par0875" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key Points</span><ul class="elsevierStyleList" id="lis0060"><li class="elsevierStyleListItem" id="lsti0260"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0880" class="elsevierStylePara elsevierViewall">An exacerbation of COPD is an acute worsening of respiratory symptoms that results in additional therapy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0265"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0885" class="elsevierStylePara elsevierViewall">Exacerbations can be precipitated by several factors&#46; The most common causes are respiratory tract infections&#46;</p></li><li class="elsevierStyleListItem" id="lsti0270"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0890" class="elsevierStylePara elsevierViewall">The goal for treatment of exacerbations is to minimize the negative impact of the current exacerbation and to prevent subsequent events&#46;</p></li><li class="elsevierStyleListItem" id="lsti0275"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0895" class="elsevierStylePara elsevierViewall">Short-acting inhaled beta<span class="elsevierStyleInf">2</span>-agonists&#44; with or without short-acting anticholinergics&#44; are recommended as the initial bronchodilators to treat an acute exacerbation&#46;</p></li><li class="elsevierStyleListItem" id="lsti0280"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0900" class="elsevierStylePara elsevierViewall">Maintenance therapy with long-acting bronchodilators should be initiated as soon as possible before hospital discharge&#46;</p></li><li class="elsevierStyleListItem" id="lsti0285"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0905" class="elsevierStylePara elsevierViewall">Systemic corticosteroids improve lung function &#40;FEV<span class="elsevierStyleInf">1</span>&#41;&#44; oxygenation and shorten recovery time and hospitalization duration&#46;</p></li><li class="elsevierStyleListItem" id="lsti0290"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0910" class="elsevierStylePara elsevierViewall">Antibiotics&#44; when indicated&#44; shorten recovery time&#44; reduce the risk of early relapse&#44; treatment failure&#44; and hospitalization duration&#46;</p></li><li class="elsevierStyleListItem" id="lsti0295"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0915" class="elsevierStylePara elsevierViewall">Methylxanthines are not recommended due to side effects&#46;</p></li><li class="elsevierStyleListItem" id="lsti0300"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0920" class="elsevierStylePara elsevierViewall">Non-invasive mechanical ventilation should be the first mode of ventilation used to treat acute respiratory failure&#46;</p></li><li class="elsevierStyleListItem" id="lsti0305"><span class="elsevierStyleLabel"><span class="elsevierStyleBold">&#8226;</span></span><p id="par0925" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Following an exacerbation&#44; appropriate measures for exacerbation prevention should be initiated&#46;</span></p></li></ul></p><p id="par0930" class="elsevierStylePara elsevierViewall">Exacerbations are important events in the management of COPD because they negatively impact health status&#44; rates of hospitalization and readmission&#44; and disease progression&#46;<a class="elsevierStyleCrossRefs" href="#bib2180"><span class="elsevierStyleSup">237&#44;238</span></a> COPD exacerbations are complex events usually associated with increased airway inflammation&#44; increased mucus production and marked gas trapping&#46; Increased dyspnea is the key symptom of an exacerbation&#46; Other symptoms include increased sputum purulence and volume&#44; together with increased cough and wheeze&#46;<a class="elsevierStyleCrossRef" href="#bib2190"><span class="elsevierStyleSup">239</span></a> As comorbidities are common in COPD patients&#44; exacerbations must be differentiated from acute coronary syndrome&#44; worsening congestive heart failure&#44; pulmonary embolism and pneumonia&#46;</p><p id="par0935" class="elsevierStylePara elsevierViewall">COPD exacerbations are classified as&#58;<ul class="elsevierStyleList" id="lis0065"><li class="elsevierStyleListItem" id="lsti0310"><span class="elsevierStyleLabel">&#8226;</span><p id="par0940" class="elsevierStylePara elsevierViewall">Mild &#40;treated with short acting bronchodilators only&#44; SABDs&#41;</p></li><li class="elsevierStyleListItem" id="lsti0315"><span class="elsevierStyleLabel">&#8226;</span><p id="par0945" class="elsevierStylePara elsevierViewall">Moderate &#40;treated with SABDs plus antibiotics and&#47;or oral corticosteroids&#41; or</p></li><li class="elsevierStyleListItem" id="lsti0320"><span class="elsevierStyleLabel">&#8226;</span><p id="par0950" class="elsevierStylePara elsevierViewall">Severe &#40;patient requires hospitalization or visits the emergency room&#41;&#46; Severe exacerbations may be associated with acute respiratory failure&#46;</p></li></ul></p><p id="par0955" class="elsevierStylePara elsevierViewall">Exacerbations are mainly triggered by respiratory viral infections although bacterial infections and environmental factors may also initiate and&#47;or amplify these events&#46;<a class="elsevierStyleCrossRef" href="#bib2195"><span class="elsevierStyleSup">240</span></a></p><p id="par0960" class="elsevierStylePara elsevierViewall">Exacerbations can be associated with increased sputum production and&#44; if purulent&#44; increased bacteria may be found in the sputum<a class="elsevierStyleCrossRefs" href="#bib2190"><span class="elsevierStyleSup">239&#44;241&#44;242</span></a> Some evidence supports the concept that eosinophils are increased in the airways&#44; lung&#44; and blood in a significant proportion of patients with COPD&#46; Exacerbations associated with an increase in sputum or blood eosinophils may be more responsive to systemic steroids<a class="elsevierStyleCrossRef" href="#bib2210"><span class="elsevierStyleSup">243</span></a> although more prospective data are needed&#46;<a class="elsevierStyleCrossRef" href="#bib2210"><span class="elsevierStyleSup">243</span></a></p><p id="par0965" class="elsevierStylePara elsevierViewall">Symptoms usually last between 7 to 10 days during an exacerbation&#44; but some events may last longer&#46; At 8 weeks&#44; 20&#37; of patients have not recovered to their pre-exacerbation state&#46;<a class="elsevierStyleCrossRef" href="#bib2215"><span class="elsevierStyleSup">244</span></a> COPD exacerbations increase susceptibility to additional events&#46;<a class="elsevierStyleCrossRefs" href="#bib1290"><span class="elsevierStyleSup">59&#44;245</span></a></p><p id="par0970" class="elsevierStylePara elsevierViewall">COPD patients susceptible to frequent exacerbations &#40;defined as &#8805; 2 exacerbations per year&#41; have worse health status and morbidity than patients with less frequent exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib2185"><span class="elsevierStyleSup">238</span></a> Other factors associated with an increased risk of acute exacerbations and&#47;or severity of exacerbations include an increase in the ratio of the pulmonary artery to aorta cross sectional dimension &#40;i&#46;e&#46;&#44; ratio<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>1&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib2225"><span class="elsevierStyleSup">246</span></a> a greater percentage of emphysema or airway wall thickness<a class="elsevierStyleCrossRef" href="#bib2230"><span class="elsevierStyleSup">247</span></a> measured by chest CT imaging and the presence of chronic bronchitis&#46;<a class="elsevierStyleCrossRefs" href="#bib2235"><span class="elsevierStyleSup">248&#44;249</span></a></p></span></span><span id="sec0350" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0370">Treatment Options</span><span id="sec0355" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0375">Treatment Setting</span><p id="par0975" class="elsevierStylePara elsevierViewall">The goals of exacerbation treatment are to minimize the negative impact of the current exacerbation&#44; and to prevent the development of subsequent events&#46;<a class="elsevierStyleCrossRef" href="#bib2245"><span class="elsevierStyleSup">250</span></a> Depending on the severity of an exacerbation and&#47;or the severity of the underlying disease&#44; an exacerbation can be managed in either the outpatient or inpatient setting&#46; More than 80&#37; of exacerbations are managed on an outpatient basis with bronchodilators&#44; corticosteroids&#44; and antibiotics&#46;<a class="elsevierStyleCrossRefs" href="#bib2250"><span class="elsevierStyleSup">251&#8211;253</span></a></p><p id="par0980" class="elsevierStylePara elsevierViewall">The indications for hospitalization during a COPD exacerbation are shown in Table S10 in the Supplementary Appendix&#46; When patients with a COPD exacerbation come to the emergency department&#44; they should be given supplemental oxygen and assessed to determine whether the exacerbation is life-threatening and requires consideration for non-invasive ventilation and ICU or respiratory unit hospitalization&#46;</p><p id="par0985" class="elsevierStylePara elsevierViewall">Long-term prognosis following hospitalization for COPD exacerbation is poor&#59; five-year mortality rate is about 50&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib2265"><span class="elsevierStyleSup">254</span></a> Factors associated with poor outcome include older age&#44; lower body mass index&#44; comorbidities &#40;e&#46;g&#46;&#44; cardiovascular disease or lung cancer&#41;&#44; previous hospitalizations for COPD exacerbations&#44; clinical severity of the index exacerbation&#44; and need for long-term oxygen therapy at discharge&#46;<a class="elsevierStyleCrossRefs" href="#bib2270"><span class="elsevierStyleSup">255&#44;256</span></a> Patients with a higher prevalence and severity of respiratory symptoms&#44; poorer quality of life&#44; worse lung function&#44; lower exercise capacity&#44; lower lung density and thickened bronchial walls on CT-scan are at increased mortality risk following an acute exacerbation&#46;<a class="elsevierStyleCrossRef" href="#bib2280"><span class="elsevierStyleSup">257</span></a></p><p id="par0990" class="elsevierStylePara elsevierViewall">Key points for the management of all exacerbations are given in <a class="elsevierStyleCrossRef" href="#tbl0040">Table 8</a>&#46;</p><elsevierMultimedia ident="tbl0040"></elsevierMultimedia></span><span id="sec0360" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0380">Pharmacologic Treatment</span><p id="par0995" class="elsevierStylePara elsevierViewall">The most commonly used classes of medications for COPD exacerbations are bronchodilators&#44; corticosteroids&#44; and antibiotics&#46;</p><p id="par1000" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Bronchodilators</span>&#46; Short-acting inhaled beta<span class="elsevierStyleInf">2</span>-agonists&#44; with or without short-acting anticholinergics&#44; are the initial bronchodilators recommended for acute treatment of exacerbations&#46;<a class="elsevierStyleCrossRefs" href="#bib2285"><span class="elsevierStyleSup">258&#44;259</span></a> There are no significant differences in FEV<span class="elsevierStyleInf">1</span> when using metered dose inhalers &#40;MDI&#41; &#40;with or without a spacer device&#41; or nebulizers to deliver the agent&#44;<a class="elsevierStyleCrossRef" href="#bib2295"><span class="elsevierStyleSup">260</span></a> although the latter may be an easier delivery method for sicker patients&#46; Intravenous methylxanthines are not recommended due to side effects&#46;<a class="elsevierStyleCrossRefs" href="#bib2300"><span class="elsevierStyleSup">261&#44;262</span></a></p><p id="par1005" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Glucocorticoids</span>&#46; Systemic glucocorticoids in COPD exacerbations shorten recovery time and improve FEV<span class="elsevierStyleInf">1</span>&#46; They also improve oxygenation&#44;<a class="elsevierStyleCrossRefs" href="#bib2310"><span class="elsevierStyleSup">263&#8211;266</span></a> the risk of early relapse&#44; treatment failure&#44;<a class="elsevierStyleCrossRef" href="#bib2330"><span class="elsevierStyleSup">267</span></a> and the length of hospitalization&#46;<a class="elsevierStyleCrossRefs" href="#bib2310"><span class="elsevierStyleSup">263&#44;265&#44;268</span></a> A dose of 40<span class="elsevierStyleHsp" style=""></span>mg prednisone per day for 5 days is recommended&#46;<a class="elsevierStyleCrossRef" href="#bib2340"><span class="elsevierStyleSup">269</span></a> Therapy with oral prednisolone is equally effective to intravenous administration&#46;<a class="elsevierStyleCrossRef" href="#bib2345"><span class="elsevierStyleSup">270</span></a> Glucocorticoids may be less efficacious to treat exacerbations in patients with lower blood eosinophil levels&#46;<a class="elsevierStyleCrossRefs" href="#bib1290"><span class="elsevierStyleSup">59&#44;243&#44;271</span></a></p><p id="par1010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Antibiotics</span>&#46; The use of antibiotics in exacerbations remains controversial&#46;<a class="elsevierStyleCrossRefs" href="#bib2355"><span class="elsevierStyleSup">272&#8211;274</span></a> Evidence supports the use of antibiotics in patients with exacerbations and increased sputum purulence&#46;<a class="elsevierStyleCrossRefs" href="#bib2360"><span class="elsevierStyleSup">273&#44;274</span></a> One review reported that antibiotics reduce the risk of short-term mortality by 77&#37;&#44; treatment failure by 53&#37; and sputum purulence by 44&#37;<a class="elsevierStyleCrossRef" href="#bib2370"><span class="elsevierStyleSup">275</span></a> Procalcitonin-guided antibiotic treatment may reduce antibiotic exposure and side effects with the same clinical efficacy&#46;<a class="elsevierStyleCrossRefs" href="#bib2375"><span class="elsevierStyleSup">276&#44;277</span></a> A study in patients with exacerbations requiring mechanical ventilation &#40;invasive or noninvasive&#41; reported increased mortality and a higher incidence of secondary nosocomial pneumonia when antibitoics were not given&#46;<a class="elsevierStyleCrossRef" href="#bib2385"><span class="elsevierStyleSup">278</span></a> Antibiotics should be given to patients with acute exacerbations who have three cardinal symptoms&#58; increase in dyspnea&#44; sputum volume&#44; and sputum purulence&#59; have two of the cardinal symptoms&#44; if increased purulence of sputum is one of the two symptoms&#59; or require mechanical ventilation &#40;invasive or noninvasive&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib2190"><span class="elsevierStyleSup">239&#44;240</span></a> The recommended length of antibiotic therapy is 5-7 days&#46;<a class="elsevierStyleCrossRef" href="#bib2390"><span class="elsevierStyleSup">279</span></a></p><p id="par1015" class="elsevierStylePara elsevierViewall">Antibiotic choice should be based on the local bacterial resistance pattern&#46; Usual initial empirical treatment is an aminopenicillin with clavulanic acid&#44; a macrolide&#44; or a tetracycline&#46; In patients with frequent exacerbations&#44; severe airflow limitation&#44;<a class="elsevierStyleCrossRefs" href="#bib2395"><span class="elsevierStyleSup">280&#44;281</span></a> and&#47;or exacerbations requiring mechanical ventilation&#44;<a class="elsevierStyleCrossRef" href="#bib2405"><span class="elsevierStyleSup">282</span></a> cultures from sputum or other materials from the lung should be performed to identify the presence of resistant pathogens&#46; Administration route depends on the patient&#39;s ability to eat and the pharmacokinetics of the antibiotic&#46;</p></span><span id="sec0365" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0385">Respiratory Support</span><p id="par1020" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Oxygen therapy</span>&#46; Supplemental oxygen should be titrated to improve hypoxemia with a target saturation of 88-92&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib2410"><span class="elsevierStyleSup">283</span></a> Once oxygen is started&#44; blood gases should be checked to ensure satisfactory oxygenation without carbon dioxide retention and&#47;or worsening acidosis&#46;</p><p id="par1025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Ventilatory support</span>&#46; Some patients require admission to the intensive care unit&#46; Admission of patients with severe exacerbations to intermediate or special respiratory care units may be appropriate if adequate personnel skills and equipment exist to manage acute respiratory failure&#46;</p><p id="par1030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Noninvasive mechanical ventilation</span>&#46; NIV is preferred over invasive ventilation as the initial mode of ventilation to treat acute respiratory failure in patients hospitalized for acute exacerbations of COPD&#46; NIV has been studied in RCTs showing a success rate of 80-85&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib2415"><span class="elsevierStyleSup">284&#8211;288</span></a> Mortality and intubation rates are reduced by NIV&#46;<a class="elsevierStyleCrossRefs" href="#bib2415"><span class="elsevierStyleSup">284&#44;289&#8211;291</span></a></p><p id="par1035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Invasive mechanical ventilation</span>&#46; The indication for initiating invasive mechanical ventilation during an exacerbation includes failure of an initial trial of NIV&#46;<a class="elsevierStyleCrossRef" href="#bib2455"><span class="elsevierStyleSup">292</span></a> In patients who fail non-invasive ventilation as initial therapy and receive invasive ventilation as subsequent rescue therapy&#44; morbidity&#44; hospital length of stay and mortality are greater&#46;<a class="elsevierStyleCrossRef" href="#bib2430"><span class="elsevierStyleSup">287</span></a></p></span><span id="sec0370" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0390">Hospital Discharge and Follow-Up</span><p id="par1040" class="elsevierStylePara elsevierViewall">Lack of spirometric assessment and arterial blood gas analysis have been associated with re-hospitalization and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib2460"><span class="elsevierStyleSup">293</span></a> Mortality relates to patient age&#44; the presence of acidotic respiratory failure&#44; the need for ventilatory support and comorbidities including anxiety and depression&#46;<a class="elsevierStyleCrossRef" href="#bib2465"><span class="elsevierStyleSup">294</span></a></p><p id="par1045" class="elsevierStylePara elsevierViewall">The introduction of care bundles at hospital discharge to include education&#44; optimization of medication&#44; supervision and correction of inhaler technique&#44; assessment and optimal management of comorbidities&#44; early rehabilitation&#44; telemonitoring and continued patient contact have been investigated&#46;<a class="elsevierStyleCrossRef" href="#bib2470"><span class="elsevierStyleSup">295</span></a> There is insufficient data that they influence readmission rates&#44; short-term mortality<a class="elsevierStyleCrossRefs" href="#bib2460"><span class="elsevierStyleSup">293&#44;294&#44;296&#44;297</span></a> or cost-effectiveness&#46;<a class="elsevierStyleCrossRef" href="#bib2465"><span class="elsevierStyleSup">294</span></a></p><p id="par1050" class="elsevierStylePara elsevierViewall">Early follow-up &#40;&#60; 30 days&#41; following discharge should be undertaken when possible and has been related to less exacerbation-related readmissions&#46;<a class="elsevierStyleCrossRefs" href="#bib1925"><span class="elsevierStyleSup">186&#44;298</span></a> Early follow-up permits a careful review of discharge therapy and an opportunity to make changes in therapy&#46; Patients not attending early follow-up have increased 90-day mortality&#46;</p><p id="par1055" class="elsevierStylePara elsevierViewall">Additional follow-up at three months is recommended to ensure return to a stable state and review of patient&#39;s symptoms&#44; lung function &#40;by spirometry&#41;&#44; and when possible the assessment of prognosis using multiple scoring systems such as BODE&#46;<a class="elsevierStyleCrossRefs" href="#bib2485"><span class="elsevierStyleSup">298&#44;299</span></a> An assessment of the presence and management of comorbidities should also be undertaken &#40;Table S11 in the Supplementary Appendix&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib2495"><span class="elsevierStyleSup">300</span></a></p></span><span id="sec0375" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0395">Prevention of Exacerbations</span><p id="par1060" class="elsevierStylePara elsevierViewall">After an acute exacerbation&#44; measures for prevention of further exacerbations should be initiated &#40;Table S12 in the Supplementary Appendix&#41;&#46;</p></span><span id="sec0380" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0400">COPD and Comorbidities</span><p id="par1065" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Key Points</span><ul class="elsevierStyleList" id="lis0070"><li class="elsevierStyleListItem" id="lsti0325"><span class="elsevierStyleLabel">&#8226;</span><p id="par1070" class="elsevierStylePara elsevierViewall">COPD often coexists with other diseases &#40;comorbidities&#41; that may significantly impact patient outcome&#46;</p></li><li class="elsevierStyleListItem" id="lsti0330"><span class="elsevierStyleLabel">&#8226;</span><p id="par1075" class="elsevierStylePara elsevierViewall">The presence of comorbidities should not alter COPD treatment and comorbidities should be treated per usual standards regardless of the presence of COPD&#46;</p></li><li class="elsevierStyleListItem" id="lsti0335"><span class="elsevierStyleLabel">&#8226;</span><p id="par1080" class="elsevierStylePara elsevierViewall">When COPD is part of a multi-morbidity care plan&#44; attention should be directed to ensure simplicity of treatment and minimize polypharmacy&#46;</p></li></ul></p><p id="par1085" class="elsevierStylePara elsevierViewall">COPD often coexists with other diseases &#40;comorbidities&#41; that may have a significant impact on prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib1310"><span class="elsevierStyleSup">63&#44;301&#8211;307</span></a> Some of these arise independently of COPD whereas others may be causally related&#44; either with shared risk factors&#44; or by one disease increasing the risk or compounding the severity of the other&#46;<a class="elsevierStyleCrossRef" href="#bib2535"><span class="elsevierStyleSup">308</span></a> Management of the COPD patient must include identification and treatment of its comorbidities&#59; the most common in COPD are outlined below&#46;</p></span><span id="sec0385" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0405">Cardiovascular disease</span><span id="sec0390" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0410">Heart failure</span><p id="par1090" class="elsevierStylePara elsevierViewall">The prevalence of systolic or diastolic heart failure in COPD patients ranges from 20 to 70&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib2540"><span class="elsevierStyleSup">309</span></a> Unrecognized heart failure may mimic or accompany acute exacerbations of COPD&#59; 40&#37; of COPD patients that are mechanically ventilated because of hypercapnic respiratory failure have evidence of left ventricular dysfunction&#46;<a class="elsevierStyleCrossRefs" href="#bib2545"><span class="elsevierStyleSup">310&#44;311</span></a> Treatment with &#223;<span class="elsevierStyleInf">1</span>-blockers improves survival in chronic heart failure and is recommended&#46; Selective &#223;<span class="elsevierStyleInf">1</span>-blockers should be used&#46;<a class="elsevierStyleCrossRef" href="#bib2555"><span class="elsevierStyleSup">312</span></a></p></span></span><span id="sec0395" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0415">Ischemic heart disease</span><p id="par1095" class="elsevierStylePara elsevierViewall">There is an increased risk of myocardial damage in patients with concomitant ischemic heart disease who have an acute exacerbation of COPD&#46; Patients who demonstrate abnormal cardiac troponins are at an increased risk of adverse outcomes including short-term &#40;30 day&#41; and long-term mortality&#46;<a class="elsevierStyleCrossRef" href="#bib2560"><span class="elsevierStyleSup">313</span></a></p></span><span id="sec0400" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0420">Arrhythmias</span><p id="par1100" class="elsevierStylePara elsevierViewall">Cardiac arrhythmias are common in COPD and vice versa&#46; Atrial fibrillation is frequent and directly associated with FEV<span class="elsevierStyleInf">1</span>&#46; Bronchodilators have been previously described as potentially pro-arrhythmic agents<a class="elsevierStyleCrossRefs" href="#bib2565"><span class="elsevierStyleSup">314&#44;315</span></a>&#59; however&#44; evidence suggests an overall acceptable safety profile for long-acting beta<span class="elsevierStyleInf">2</span>-agonists&#44;<a class="elsevierStyleCrossRef" href="#bib2575"><span class="elsevierStyleSup">316</span></a> anticholinergic drugs &#40;and inhaled corticosteroids&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib1510"><span class="elsevierStyleSup">103&#44;115&#44;253&#44;317&#8211;322</span></a></p></span><span id="sec0405" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0425">Peripheral vascular disease</span><p id="par1105" class="elsevierStylePara elsevierViewall">In a large cohort of patients with COPD of all degrees of severity&#44; 8&#46;8&#37; were diagnosed with peripheral artery disease &#40;PAD&#41; that was higher than the prevalence in non-COPD controls &#40;1&#46;8&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib2610"><span class="elsevierStyleSup">323</span></a> COPD patients with PAD reported a worse functional capacity and worse health status compared to those without PAD&#46;</p></span><span id="sec0410" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0430">Hypertension</span><p id="par1110" class="elsevierStylePara elsevierViewall">Hypertension is likely to be the most frequently occurring comorbidity in COPD and may have implications for prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib2535"><span class="elsevierStyleSup">308&#44;324</span></a></p></span><span id="sec0415" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0435">Osteoporosis</span><p id="par1115" class="elsevierStylePara elsevierViewall">Osteoporosis is often associated with emphysema&#44;<a class="elsevierStyleCrossRefs" href="#bib2620"><span class="elsevierStyleSup">325&#44;326</span></a> decreased body mass index<a class="elsevierStyleCrossRef" href="#bib2630"><span class="elsevierStyleSup">327</span></a> and low fat-free mass&#46;<a class="elsevierStyleCrossRef" href="#bib2635"><span class="elsevierStyleSup">328</span></a> Low bone mineral density and fractures are common in COPD patients even after adjustment for steroid use&#44; age&#44; pack-years of smoking&#44; current smoking&#44; and exacerbations&#46;<a class="elsevierStyleCrossRefs" href="#bib2640"><span class="elsevierStyleSup">329&#44;330</span></a> An association between inhaled corticosteroids and fractures has been found in pharmaco-epidemiological studies&#46; Systemic corticosteroids significantly increase the risk of osteoporosis&#46;</p></span><span id="sec0420" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0440">Anxiety and Depression</span><p id="par1120" class="elsevierStylePara elsevierViewall">Anxiety and depression are both associated with a poor prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib2650"><span class="elsevierStyleSup">331&#44;332</span></a></p></span><span id="sec0425" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0445">COPD and Lung Cancer</span><p id="par1125" class="elsevierStylePara elsevierViewall">The association between emphysema and lung cancer is stronger than between airflow limitation and lung cancer&#46;<a class="elsevierStyleCrossRefs" href="#bib2660"><span class="elsevierStyleSup">333&#8211;335</span></a> Increased age and greater smoking history further increases risk&#46;<a class="elsevierStyleCrossRef" href="#bib2675"><span class="elsevierStyleSup">336</span></a> Two studies of low-dose chest computed tomography &#40;LDCT&#41; screening report improved survival in subjects aged 55-74 years&#44; current smokers or those who quit within the previous 15 years&#44; with a smoking history of at least 30 pack-years&#46;<a class="elsevierStyleCrossRefs" href="#bib2680"><span class="elsevierStyleSup">337&#44;338</span></a> LDCT is now recommended in the U&#46;S&#46; for patients meeting these demographics&#59; however&#44; this is not a worldwide practice&#46;</p></span><span id="sec0430" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0450">Metabolic Syndrome and Diabetes</span><p id="par1130" class="elsevierStylePara elsevierViewall">Metabolic syndrome and diabetes are more frequent in COPD and the latter is likely to affect prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib2505"><span class="elsevierStyleSup">302</span></a> The prevalence of metabolic syndrome has been estimated to be more than 30&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib2690"><span class="elsevierStyleSup">339</span></a></p></span><span id="sec0435" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0455">Gastroesophageal Reflux</span><p id="par1135" class="elsevierStylePara elsevierViewall">Gastroesophageal reflux is an independent risk factor for exacerbations and is associated with worse health status&#46;<a class="elsevierStyleCrossRefs" href="#bib2250"><span class="elsevierStyleSup">251&#44;340&#44;341</span></a></p></span><span id="sec0440" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0460">Bronchiectasis</span><p id="par1140" class="elsevierStylePara elsevierViewall">Bronchiectasis is associated with longer exacerbations<a class="elsevierStyleCrossRef" href="#bib2705"><span class="elsevierStyleSup">342</span></a> and increased mortality&#46;<a class="elsevierStyleCrossRef" href="#bib2495"><span class="elsevierStyleSup">300</span></a></p></span><span id="sec0445" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0465">Obstructive Sleep Apnea</span><p id="par1145" class="elsevierStylePara elsevierViewall">Patients with &#8220;overlap syndrome&#8221; &#40;COPD and OSA&#41; have a worse prognosis compared with COPD or OSA&#46; Apneic events in patients with OSA and COPD have more profound hypoxemia and more cardiac arrhythmias<a class="elsevierStyleCrossRef" href="#bib2710"><span class="elsevierStyleSup">343</span></a> and are more likely to develop daytime pulmonary hypertension<a class="elsevierStyleCrossRefs" href="#bib2715"><span class="elsevierStyleSup">344&#44;345</span></a> than patients with just OSA or COPD alone&#46;</p></span></span><span id="sec0460" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0470">Conflict of Interests</span><p id="par1160" class="elsevierStylePara elsevierViewall">The conflict of interest statement of the authors &#40;GOLD-Disclosures-Authors&#41; is available in the additional material of this article in its electronic version&#44; at <a href="doi:10.1016/j.arbres.2017.02.001">doi&#58;10&#46;1016&#47;j&#46;arbres&#46;2017&#46;02&#46;001</a>&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Definition and Factors That Influence COPD Development and Progression"
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    "fechaRecibido" => "2017-01-26"
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            1 => "COPD diagnosis"
            2 => "COPD management"
            3 => "COPD prevention"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">This Executive Summary of the Global Strategy for the Diagnosis&#44; Management&#44; and Prevention of COPD &#40;GOLD&#41; 2017 Report focuses primarily on the revised and novel parts of the document&#46; The most significant changes include&#58; 1&#41; the assessment of COPD has been refined to separate the spirometric assessment from symptom evaluation&#46; ABCD groups are now proposed to be derived exclusively from patient symptoms and their history of exacerbations&#59; 2&#41; for each of the groups A to D&#44; escalation strategies for pharmacological treatments are proposed&#59; 3&#41; the concept of de-escalation of therapy is introduced in the treatment assessment scheme&#59; 4&#41; nonpharmacologic therapies are comprehensively presented and&#59; 5&#41; the importance of comorbid conditions in managing COPD is reviewed&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Este resumen ejecutivo del Informe de 2017 de la <span class="elsevierStyleItalic">Global Strategy for the Diagnosis&#44; Management&#44; and Prevention of COPD</span> &#40;GOLD&#41; se basa primordialmente en las modificaciones y novedades del informe anterior&#46; Los cambios m&#225;s destacados incluyen&#58; a&#41; se diferencia la exploraci&#243;n espirom&#233;trica de la de los s&#237;ntomas para la evaluaci&#243;n de la enfermedad pulmonar obstructiva cr&#243;nica &#40;EPOC&#41;&#59; de este modo&#44; los grupos ABCD se refieren exclusivamente a s&#237;ntomas y antecedentes de exacerbaciones de los pacientes&#59; b&#41; se optimiza la estrategia terap&#233;utica farmacol&#243;gica en cada uno de los cuatro grupos&#59; c&#41; se propone una reducci&#243;n escalonada de la medicaci&#243;n en el apartado terap&#233;utico&#59; d&#41; se detalla m&#225;s extensamente el tratamiento no farmacol&#243;gico&#59; y&#44; f&#41; se repasa la importancia de las diferentes co-morbilidades en lo que respecta al tratamiento de la EPOC&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Vogelmeier CF&#44; Criner GJ&#44; Martinez FJ&#44; Anzueto A&#44; Barnes PJ&#44; Bourbeau J&#44; et al&#46; Documento sobre la estrategia global para el diagn&#243;stico&#44; el manejo&#44; y la prevenci&#243;n de la Enfermedad Pulmonar Obstructiva Cr&#243;nica&#58; Sumario ejecutivo de la GOLD&#46; Arch Bronconeumol&#46; 2017&#59;53&#58;128&#8211;149&#46;</p>"
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