COPD patient profiles in primary care. Referral criteria

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"apellidos" => "Figueira-Gonçalves" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "j" "identificador" => "aff0050" ] 1 => array:2 [ "etiqueta" => "k" "identificador" => "aff0055" ] ] ] ] "afiliaciones" => array:11 [ 0 => array:3 [ "entidad" => "Institute for Health Research, Aragón, Centro de Salud Campo de Belchite, Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Neumología, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense de Madrid, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Neumología, Hospital Clínico Universitario de Valencia, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Instituto de Investigación Sanitaria INCLIVA, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "UGC Valle de Lecrín, Granada, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Departamento de Medicina de la Universidad de Oviedo, Centro de Salud de Contrueces-Vega, Gijón, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "EAP Ribes-Olivella (SAP Alt Penedés Garraf), Institut Català de la Salut, Barcelona, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Farmacéutico Comunitario, Mazarrón, Murcia, Spain" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Centro de Salud de Riaza, Segovia, Spain" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Servicio de Respiratorio, Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Instituto Canario de Enfermedades Tropicales y Salud Pública, Universidad de La Laguna, Santa Cruz de Tenerife, Spain" "etiqueta" => "k" "identificador" => "aff0055" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Perfiles de pacientes con EPOC en Atención Primaria. Criterios de derivación" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1400 "Ancho" => 2925 "Tamanyo" => 242561 ] ] "descripcion" => array:1 [ "en" => "COPD exacerbation syndrome (CES) severity criteria. Mild: all green-coloured criteria must be met; moderate: in the presence of any yellow criteria; severe: any red criteria, regardless of baseline risk stratification; very severe: any purple criteria, regardless of baseline risk stratification.<a class="elsevierStyleCrossRef" href="#bib0340">29</a>" ] ] ] "textoCompleto" => "IntroductionChronic obstructive pulmonary disease (COPD) is a common, preventable and treatable condition characterised by persistent respiratory symptoms and chronic airflow limitation. The disease remains a growing cause of morbidity, mortality and disability, affecting 392 million people worldwide.<a class="elsevierStyleCrossRef" href="#bib0200">1</a> COPD is the third leading cause of mortality globally and the fourth in Spain.<a class="elsevierStyleCrossRef" href="#bib0205">2</a> According to data from the EPISCAN II study, the prevalence of COPD in the Spanish population, aged 40 years and older, in 2021 was 11.8%, with a high variability between the different communities.<a class="elsevierStyleCrossRef" href="#bib0210">3</a> In the octogenarian population this prevalence can be as high as 30%.Despite these data, COPD remains as an underdiagnosed disease in Spain. Indeed, the IBERPOC and EPISCAN studies estimated that the rates were 78% in 1997 and 73% in 2007.<a class="elsevierStyleCrossRef" href="#bib0215">4</a> Nowadays, this figure remains high, as reported by EPISCAN II results (74.7%).<a class="elsevierStyleCrossRef" href="#bib0210">3</a>Lack of public awareness of the disease may be another factor delaying diagnosis. For example, chronic cough, which is usually the first symptom to manifest itself, may be the first symptom to be recognised, is frequently discounted by the patient as an expected consequence of smoking and/or environmental exposures.<a class="elsevierStyleCrossRef" href="#bib0220">5</a>The primary care physician is usually the first contact for patients who consult for chronic respiratory symptoms such as cough, dyspnoea or expectoration. If the patient is also a smoker, the possibility of COPD should be assessed. The anamnesis, the physical examination and the exposure to tobacco smoke should lead to suspicion of COPD diagnosis, which will be confirmed by chronic airflow obstruction on forced spirometry.<a class="elsevierStyleCrossRef" href="#bib0225">6</a> This situation of the primary care physician, at the gateway to the health system, gives him/her an important responsibility to reduce the high under-diagnosis of COPD and to improve the quality of life of these patients.<a class="elsevierStyleCrossRef" href="#bib0230">7</a> However, this role requires the physician to be aware of the particularities of the different types of COPD patients. This document will review the diagnostic tests and possible treatments required for different COPD patient profiles, as well as the reasons why they may be referred to higher levels of care.Profiles of COPD patients in primary careThere are several classes of patients in the primary care setting, and they may be classified according to whether or not they have a diagnosis of COPD, disease control or exacerbations.Undiagnosed patient with an exacerbation of the diseaseSuspicion of undiagnosed COPD should be triggered in an adult smoker or ex-smoker of more than 10 pack-years, or chronic exposure to inhaled toxicants, who presents with respiratory symptoms (dyspnoea or chronic cough with or without associated expectoration). Another important factor is age, as symptoms in patients who are smokers or ex-smokers usually appear after the age of 35 years.<a class="elsevierStyleCrossRefs" href="#bib0235">8,9</a>The clinical manifestations of COPD are non-specific and often remain asymptomatic until late in the disease.<a class="elsevierStyleCrossRef" href="#bib0245">10</a>Dyspnoea is the main symptom; it particularly occurs during exertion or physical activity. Moderate-to-severe dyspnoea has been reported by>40% of patients diagnosed with COPD in primary care.<a class="elsevierStyleCrossRef" href="#bib0250">11</a> This clinical manifestation is measured by the 5-level modified Medical Research Council scale (mMRC), which is integrated in the GOLD clinical classification scheme. It consists of five statements about perceived breathlessness: grade 0: “I only get breathless with strenuous exercise”; grade 1: “I get short of breath when hurrying on the level or up a slight hill”; grade 2: “I walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level”; grade 3: “I stop for breath after walking 100 metres or after a few minutes on the level”; grade 4: “I am too breathless to leave the house”.<a class="elsevierStyleCrossRef" href="#bib0255">12</a>Chronic cough is often the first symptom of COPD. Initially, the cough may be intermittent, but subsequently it may be present every day, often throughout the day, and may be unproductive or productive,<a class="elsevierStyleCrossRef" href="#bib0220">5</a> with a sputum production which is usually mucoid. Inspiratory and/or expiratory wheezes and chest tightness are symptoms that may vary between days, and over the course of a single day. Chest tightness often follows exertion, is poorly localised, is muscular in character, and may arise from isometric contraction of the intercostal muscles. An absence of wheezing or chest tightness does not exclude a diagnosis of COPD, nor does the presence of these symptoms confirm a diagnosis of asthma.<a class="elsevierStyleCrossRef" href="#bib0250">11</a> Additionally, fatigue is one of the most common and distressing symptoms experienced by people with COPD.<a class="elsevierStyleCrossRef" href="#bib0260">13</a> Finally, other symptomatology in advanced stages can include weight loss, anorexia, muscle dysfunction, depressive symptoms or anxiety are common.<a class="elsevierStyleCrossRef" href="#bib0225">6</a>Tests to be performed for diagnosisForced spirometry is a noninvasive, reproducible, cheap, and essential test for confirming the diagnosis and assessing the severity of obstruction in COPD. It is a test that measures the volume of air moved by the lungs as a function of time and determines airflow obstruction.<a class="elsevierStyleCrossRef" href="#bib0235">8</a> Good quality spirometric measurement is possible in any healthcare setting and all healthcare workers who care for people with COPD should have access to it.<a class="elsevierStyleCrossRef" href="#bib0250">11</a> To achieve quality spirometry, it is important that the patient comes correctly prepared for the test. To this end, written instructions should be given in advance, explaining exactly what the manoeuvre consists of and the importance of their cooperation.<a class="elsevierStyleCrossRef" href="#bib0265">14</a> In Spain, the Spanish Society of Pneumology and Thoracic Surgery (SEPAR) and other primary care societies have published guidelines with recommendations for the correct execution of a spirometry test.<a class="elsevierStyleCrossRefs" href="#bib0265">14,15</a>Once the correct performance of manoeuvres has been confirmed, their interpretation will be done through three parameters such as FEV1, FVC and FEV1/FVC, and their results are evaluated in relation to the value that a healthy individual of the same sex, height, age and weight should have.<a class="elsevierStyleCrossRef" href="#bib0275">16</a> Forced vital capacity (FVC), which is the largest volume of air expelled in a forced expiratory manoeuvre from a maximal inspiration (considering normal more than 80% of its reference value). Another relevant parameter is the forced expiratory volume in the first second (FEV1), which represents the volume of mobilised air in the first second of forced expiration (being normal more than 80% of its theoretical value). Finally, FEV1/FVC ratio is the percentage of FVC exhaled in the first second (higher than 70% is the normal reference).A minimum of three acceptable manoeuvres to a maximum of eight shall be performed, allowing sufficient time in between for the patient to recover from the effort.<a class="elsevierStyleCrossRef" href="#bib0265">14</a>Then, the bronchodilator test should be performed, which consists of a repeat spirometry test after administration of a short-acting bronchodilator (salbutamol or terbutaline) in a chamber. In patients with heart rhythm disturbances or intolerance to beta-2 agonists, the use of ipratropium bromide is an alternative, although the waiting time will increase. The test is positive (i.e. the obstruction is reversible) when the post-bronchodilation FEV1 improves at least 12% and more than 200ml regarding the pre-bronchodilation value. The diagnosis of COPD will be confirmed if after bronchodilator testing the FEV1/FVC is less than 70%. It is recommended to perform a forced spirometry after 3 months of treatment to confirm the existence of a chronic airflow obstruction.Other diagnostic tests are available to help clarify the diagnosis, such as plain chest radiography, useful to rule out other respiratory, cardiac and musculoskeletal pathologies,<a class="elsevierStyleCrossRefs" href="#bib0235">8,10</a> pulse oximetry, where a COPD patient may present with a value below 92%,<a class="elsevierStyleCrossRef" href="#bib0395">17</a> and physical activity assessment, as sedentary lifestyles in some patients cause dyspnoea to be unclear.<a class="elsevierStyleCrossRef" href="#bib0250">11</a>Once the diagnosis is stablished, the level of risk must be assessed. This classification relies on the likelihood to experience exacerbations, disease progression, future complications, increased consumption of healthcare resources or increased mortality. Spanish COPD Guidelines (GesEPOC) proposes a classification into low and high risk,<a class="elsevierStyleCrossRef" href="#bib0240">9</a> considering the degree of obstruction (measured by post-bronchodilator FEV1(%)), the level of dyspnoea (regarding the modified Medical Research Council (mMRC) scale) and the history of exacerbations during the previous year.Patients with post-bronchodilation FEV1 equal to or greater than 50%, a mMRC 0–1 and, maximum, one exacerbation without hospitalisation in the last year, will be categorised as low risk. All of the above criteria must be met. Therefore, patients who do not meet at least one of the above-mentioned conditions will be considered high-risk patients. That is, post-bronchodilation FEV1 less than 50%, mMRC between 2 and 4 or who have had more than one exacerbation that resolved with outpatient treatment and/or an exacerbation that required hospital admission.<a class="elsevierStyleCrossRef" href="#bib0240">9</a>Phenotype characterisationIn high-risk patients, GesEPOC 2021 recognises three phenotypes in the pharmacological treatment scheme: non-exacerbator, eosinophilic exacerbator and non-eosinophilic exacerbator. This represents an update to the GesEPOC 2017 guideline, based on the new evidence available.<a class="elsevierStyleCrossRef" href="#bib0240">9</a>The non-exacerbator is characterised by a maximum of one exacerbation in the previous year without requiring hospital care.<a class="elsevierStyleCrossRef" href="#bib0240">9</a> Exacerbator phenotype is defined as any patient with COPD who has two or more moderate outpatient exacerbations in the previous year, or at least one severe exacerbation, requiring hospital care.<a class="elsevierStyleCrossRef" href="#bib0285">18</a> Due to the different response to drug treatments, it is important to differentiate those with an eosinophilic or non-eosinophilic phenotype. Patients with >300eosinophils/mm3 in stable phase will be classified as eosinophilic exacerbator.<a class="elsevierStyleCrossRef" href="#bib0240">9</a> Non-eosinophilic exacerbator phenotype are those who meets the criteria for the exacerbating phenotype, but at the same time has <300eosinophils/mm3 in peripheral blood.<a class="elsevierStyleCrossRef" href="#bib0240">9</a>TreatmentThe general objectives of COPD treatment are summarised as: reducing the symptoms of the disease, reducing the frequency and severity of exacerbations, improving quality of life and survival. With regard to the initial pharmacological treatment of a newly diagnosed patient, the GesEPOC guidelines propose a treatment based on risk and phenotype.<a class="elsevierStyleCrossRef" href="#bib0240">9</a>Inhaled treatment of the low-risk patientIn the low-risk patient, no oral or anti-inflammatory treatment is indicated, and pharmacological treatment will consist of prescription of long-acting bronchodilators (LABD). Short-acting bronchodilators (SABD) can be of two types: anticholinergics (SAMAs) such as ipratropium bromide and short-acting beta-2 agonists (SABAs) such as salbutamol or terbutaline. Due to their rapid mechanism of action, these drugs, added to regular treatment, are the drugs of choice for on-demand treatment of symptoms at any level of disease severity.<a class="elsevierStyleCrossRef" href="#bib0240">9</a>LABD can be beta-2 adrenergic (LABA) or anticholinergic (LAMA). The LABAs available in Spain are salmeterol, formoterol, indacaterol, olodaterol and vilanterol and the LAMAs are tiotropium, aclidinium, glycopyrronium and umeclidinium. LABD should be used as the first step in the treatment of all patients with persistent symptoms who require regular treatment, because they provide better symptom control than SABD and improve lung function, exercise capacity and quality of life.<a class="elsevierStyleCrossRef" href="#bib0290">19</a>Inhaled treatment of the high-risk patientIt shall be chosen according to the phenotype of the patient. The initial treatment in a patient with non-exacerbator high-risk COPD is dual bronchodilation. This recommendation is based on the demonstration of greater bronchodilator efficacy compared to monotherapy, accompanied by a significant improvement in dyspnoea, quality of life and a reduction in the use of rescue medication.<a class="elsevierStyleCrossRef" href="#bib0295">20</a>Frequent exacerbator patients with a high concentration of eosinophils (>300cells/mm3) in the blood experience a greater clinical response to inhaled corticosteroids (ICs) and justify the use of ICs associated with a LABA as a first option to reduce the risk of exacerbations.<a class="elsevierStyleCrossRef" href="#bib0300">21</a>In non-eosinophilic exacerbator phenotype: LABA/LAMA treatment is recommended as first choice in most non-eosinophilic exacerbating patients. Although GesEPOC 2021 recommends initial therapy with LABA/ICS for eosinophilic exacerbator patients,<a class="elsevierStyleCrossRef" href="#bib0240">9</a> the GOLD document, in its 2023 version, advocates the use of triple therapy,<a class="elsevierStyleCrossRef" href="#bib0305">22</a> discarding LABA/ICS as initial treatment. In non-eosinophilic exacerbator patients who continue to present exacerbations despite double bronchodilation, triple therapy could be considered in the case of exacerbations with a good response to systemic corticosteroids and if its eosinophil count is close to 300eosinophils/mm3. IC in the form of triple therapy may be useful if they have eosinophil counts between 100 and 300cells/mm3. The efficacy of ICs in patients with eosinophil counts <100cells/mm3 is very limited and their use is discouraged to avoid adverse effects.<a class="elsevierStyleCrossRef" href="#bib0205">2</a> In this case, or if exacerbations are observed in spite of triple therapy, initiation of roflumilast or prolonged use of azithromycin should be considered, as well as to check the inhalation technique, assess comorbidity and test the possibility of chronic bronchial infection through sputum culture.The “Criteria for referral in COPD. Continuity of care” document supports the use of initial treatment with triple therapy (LAMA–LABA–ICS) in COPD patients with an eosinophils count >100cells/mm3 who develop an exacerbation requiring hospital admission.<a class="elsevierStyleCrossRef" href="#bib0310">23</a>Derivation criteriaAs described in the document “Criteria for referral in COPD. Continuity of care”,<a class="elsevierStyleCrossRef" href="#bib0310">23</a> they should be referred to pneumology those patients who arrive at the primary care clinic without a diagnosis of COPD is related to the impossibility of performing spirometry, either because of a lack of a spirometer or because unavailable qualified personnel. Patients whose diagnosis is in doubt after a valid spirometry test will also be referred.<a class="elsevierStyleCrossRef" href="#bib0310">23</a>Uncontrolled diagnosed patientThe patient classified as uncontrolled has an increased risk of both short-term exacerbation in the next six months and long-term exacerbation and increased risk of deterioration in their health-related quality of life,<a class="elsevierStyleCrossRef" href="#bib0315">24</a> so a detailed analysis of the possible causes of this lack of control is required and an increase in treatment intensity may be necessary.<a class="elsevierStyleCrossRef" href="#bib0240">9</a>Tests to be performed for diagnosis.The objective will be to classify the degree to which COPD patients are controlled and to reassess their risk group, in order to consider whether they need a readjustment of medication or a referral to the next level of care. According to GOLD, to determine the risk group, lung function is not assessed, only the clinical condition is taken into account by means of the degree of dyspnoea mMRC or the COPD Assessment Test (CAT) and the number and type of exacerbations in the previous year.<a class="elsevierStyleCrossRef" href="#bib0225">6</a>CAT consists of eight simple questions that measure aspects of cough, expectoration, chest tightness, dyspnoea, household activities, self-confidence, sleep and energy. Each of these questions can be weighted by a score ranging from 0 (best) to 5 (worst).<a class="elsevierStyleCrossRef" href="#bib0320">25</a> It is very useful in aiding doctor–patient communication, as it helps to identify aspects of the impact of the disease that may go unnoticed in routine questioning. It is important in follow-up to detect clinically important changes.<a class="elsevierStyleCrossRef" href="#bib0235">8</a> CAT scores greater than or equal to 10 indicate a significant impact on disease-related health status, suggesting that a personalised assessment should be performed. An increase in this score of more than two points should alert that there is a decompensation of the process which should be evaluated.Another prognostic tool, supported by the mMRC, are BODE and BODEx indexes. BODE index is a multicomponent index of prognostic severity of COPD that integrates information from BMI (body mass index), FEV1, mMRC and six-minute walk test.<a class="elsevierStyleCrossRef" href="#bib0235">8</a> Although the determination of the four components of BODE is relatively simple, the generalisation of the index has been slower than expected, especially in primary care, probably due to the need to perform the six-minute walk test ≤which, although of low complexity and cost, requires time and adequate space for its performance. For this reason, some authors have proposed replacing this exercise test (E of the BODE index) with the recording of severe exacerbations (Ex of severe exacerbations), in what is called BODEx index, whose score ranges from 0 to 9 and is grouped into four risk groups, expressed in quartiles. Result between 0–2 points would correspond to the first quartile, 3–4 to the second, 5–6 to the third and 7–9 to the fourth one.<a class="elsevierStyleCrossRef" href="#bib0325">26</a> Body mass index is scored as 0 (>21kg/m2) or 1 (21kg/m2); FEV1 (%) as 0 (>65), 1 (50–64), 2 (36–49) or 3 (<35); mMRC as 0 (0–1), 1 (2), 2 (3) or 3 (4); finally, exacerbations (those involving emergency room visits or hospital admissions) as 0 (0), 1 (1–2) or 2 (>2).TreatmentOnce the patient's degree of control has been assessed, treatment can be adjusted. GesEPOC 2021 proposes a treatment guided by the patient's risk level and phenotype.In low-risk patients not controlled with monotherapy, the first step is to check for proper device technique. If this is correct, a change of monotherapy (LABA instead of LAMA, or vice versa) or the introduction of dual bronchodilator therapy (LABA and LAMA) can be considered.<a class="elsevierStyleCrossRef" href="#bib0240">9</a>In non-exacerbator high-risk patients an evaluation of the treatable traits will be required and if the uncontrolled symptom is dyspnoea, theophylline will be added to the double bronchodilator therapy.<a class="elsevierStyleCrossRef" href="#bib0240">9</a> In high-risk exacerbator patients, who continue to have frequent exacerbations despite treatment with LAMA–LABA, escalation to triple therapy will be indicated if they present an eosinophil count above 100cells/mm3.Recent studies of fixed triple therapy have shown greater efficacy in improving lung function, respiratory symptoms and a greater reduction in the risk of exacerbations than the LABA/IC combination.<a class="elsevierStyleCrossRef" href="#bib0300">21</a> Triple therapy has also shown a greater reduction in the risk of exacerbations than the LABA/LAMA combination, especially in patients who had a higher blood eosinophil concentration.<a class="elsevierStyleCrossRef" href="#bib0235">8</a> In patients in whom triple therapy does not work, parallel assessment or treatment of treatable traits such as dyspnoea, chronic bronchial infection, sleep apnea or cardiac disease should be considered.For both types of exacerbator profiles (eosinophilic and non-eosinophilic), it is indicated the use of roflumilast as a second-line therapy or, in case of patients with at least three exacerbations in the previous year, long-term treatment with macrolides.<a class="elsevierStyleCrossRef" href="#bib0240">9</a>Although there is no clear time period to assess the effects of a change in medication, six to twelve weeks may be a reasonable time to estimate changes in the degree of dyspnoea. For the effect on quality of life and exacerbations, longer time periods are required.<a class="elsevierStyleCrossRef" href="#bib0330">27</a>Derivation criteriaIn general, a patient diagnosed with COPD should be referred to Pneumology when, despite appropriate treatment, there is no improvement, worsening, frequent exacerbations or a disproportion between lung function and symptoms, as well as in high-risk patients for complex tests only available at hospital level, when it is considered necessary to indicate continuous home oxygen therapy or to indicate surgical techniques.<a class="elsevierStyleCrossRefs" href="#bib0235">8,26</a>Other reasons for referral are related to the occurrence of symptoms or unexpected clinical manifestations such as haemoptysis, appearance of peripheral oedema or persistent infections, as well as patients in need of non-pharmacological treatment such as non-invasive ventilation or home oxygen therapy (these have oxygen saturations that are consistently below 90%). Finally, a BODEx score above 5 should also be a reason for patient escalation.<a class="elsevierStyleCrossRefs" href="#bib0225">6,28</a>Diagnosed patient presenting with an exacerbation.COPD exacerbation syndrome (CES) is defined as an episode of clinical instability that occurs as a consequence of worsening expiratory airflow limitation or the underlying inflammatory process compared to the individual's baseline condition. From a pathophysiological point of view, CES is a complex and heterogeneous event comprising a set of diverse alterations, which either in isolation or more frequently in combination are expressed clinically in a similar manner in the COPD patient.<a class="elsevierStyleCrossRef" href="#bib0340">29</a>Many CES are observed in clusters, which raises the question of whether they are actually new events or incomplete resolutions of previous episodes. To distinguish these situations, the following definitions are established.<a class="elsevierStyleCrossRef" href="#bib0235">8</a> First, therapeutic failure is defined as a worsening of symptoms that occurs during the CES and requires additional treatment.<a class="elsevierStyleCrossRef" href="#bib0345">30</a> A relapse, it is when a new worsening of symptoms occurs between the end of CES treatment and four weeks thereafter.<a class="elsevierStyleCrossRef" href="#bib0235">8</a> Finally, recurrence, which occurs when symptoms recur less than one year after the previous CES, after a period of relative good health. This is defined as at least four weeks after completion of treatment for the previous CES or six weeks after the onset of symptoms. Recurrences are considered as new episodes of CES.<a class="elsevierStyleCrossRef" href="#bib0345">30</a>The cause of exacerbation of COPD in 50–70% of cases is infectious, of which 30% are viral infections, and in 5–10% the cause is environmental pollution. However, the aetiology is unknown in one third of cases.<a class="elsevierStyleCrossRef" href="#bib0235">8</a>Tests to be performed for diagnosisIn order to establish the diagnosis of COPD exacerbation in primary care, it is very important to carry out a detailed anamnesis and physical examination.Step 1: Diagnosis of exacerbation syndrome of COPDClinical suspicion is established by an acute, sustained and significant worsening of respiratory symptoms (dyspnoea, cough, changes in sputum colour or volume) compared to baseline in a patient with a previous diagnosis of COPD. The cardinal symptom of CES is a significant increase in dyspnoea. GesEPOC recommends the use of the modified Medical Research Council (mMRC) scale to assess this clinical manifestation.<a class="elsevierStyleCrossRef" href="#bib0350">31</a>Increased cough or changes in colour and/or increased volume of sputum are also considered symptoms.Sometimes it is difficult to discriminate whether the origin of the condition is COPD-specific or related to comorbidity. In these cases, it is recommended to diagnose and treat both conditions. However, there is a fine line between COPD exacerbation and pneumonia. The symptomatology is virtually identical and the underlying mechanisms are similar. The pulmonary microbiome between COPD patients with and without pulmonary infiltrate does not differ, the triggering factors are similar and so is the treatment.<a class="elsevierStyleCrossRef" href="#bib0355">32</a> The main difference is that in the presence of pneumonia, inflammation is higher and the prognosis worse, suggesting that we may be dealing with different expressions of the same pathological process. For this reason, pneumonia, classified in previous editions of GesEPOC as a comorbidity, is now considered a type of CES.<a class="elsevierStyleCrossRef" href="#bib0335">28</a>Step 2: Assess the severity of the episodeThis should be done after diagnosis and is important for deciding on appropriate treatment. The classification of severity according to GesEPOC is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.<a class="elsevierStyleCrossRef" href="#bib0340">29</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>TreatmentOutpatient treatment will be initiated in cases of mild or moderate severity, or referral to the hospital emergency department if the exacerbation is severe or very severe.<a class="elsevierStyleCrossRef" href="#bib0245">10</a> More than 80% of exacerbations are managed in primary care and the objective here is to resolve the current process by minimising its negative effects and preventing new exacerbations.<a class="elsevierStyleCrossRef" href="#bib0245">10</a>Pharmacological treatmentThe first action is to optimise bronchodilation by increasing the dose and/or frequency of short-acting bronchodilators. These are the drugs of choice due to their rapid onset of action and efficacy in bronchodilation. SABAs (salbutamol or terbutaline) should be used first and if necessary, a SAMA (ipratropium)<a class="elsevierStyleCrossRef" href="#bib0235">8</a> could be added. If the patient was using a long-acting bronchodilator, it should not be discontinued during exacerbation.<a class="elsevierStyleCrossRefs" href="#bib0235">8,33</a>Systemic glucocorticoidsThey can improve lung function, oxygenation and decrease recovery time.<a class="elsevierStyleCrossRefs" href="#bib0235">8,10</a> Currently, short courses of 5–7 days of 0.5mg/kg/day of prednisone (or equivalent) up to a maximum of 40mg/day are recommended.<a class="elsevierStyleCrossRef" href="#bib0225">6</a>AntibioticsIts use reduces the risk of treatment failure and increases the time to the next exacerbation, without affecting health-related quality of life (HRQoL), recurrences or mortality.<a class="elsevierStyleCrossRef" href="#bib0365">34</a> Antibiotic administration is especially indicated when there is a change in sputum colour (from mucous to dark)<a class="elsevierStyleCrossRef" href="#bib0365">34</a>; when the patient requires both invasive and non-invasive ventilatory support<a class="elsevierStyleCrossRefs" href="#bib0365">34,35</a> and in cases with elevated C-reactive protein (≥20mg/dL), even if the sputum appearance is inconclusive.<a class="elsevierStyleCrossRef" href="#bib0375">36</a> Antibiotics are also recommended in all patients with CES presenting with pneumonia, in accordance with the recommendations of the clinical practice guidelines on pneumonia.<a class="elsevierStyleCrossRef" href="#bib0380">37</a>The recommended antibiotics are prescribed according to the severity of the exacerbation. In case of mild exacerbation, amoxicillin–clavulanic acid 875/125mg/8h for 7 days. Moderate to very severe exacerbation without risk of Pseudomonas infection, amoxicillin–clavulanic acid, ceftriaxone or cefotaxime would be the antibiotics of choice. The alternative, moxifloxacin 400mg/24h for 5 days or levofloxacin 500mg/24h for 7 days. When severe to very severe exacerbation with risk of Pseudomonas infection is handled the treatment will be a β-lactam with anti-pseudomonal activity, such as ceftazidime or piperacillin–tazobactam. As second line, ciprofloxacin 500–750mg/12h for 10 days or levofloxacin 500mg/12h for 7 days would be considered.<a class="elsevierStyleCrossRefs" href="#bib0235">8,38</a>Venous thromboembolic disease prophylaxisThe use of low-molecular-weight heparins is recommended in severe/very severe or moderate exacerbations where the patient is to remain in bed or inactive.<a class="elsevierStyleCrossRef" href="#bib0340">29</a>Non-pharmacological treatmentOxygen therapy is considered one of the key elements in the management of severe CES with respiratory failure. Its goal is to achieve a SaO2 between 88 and 92%. However, oxygen administration must be controlled, as in some patients the main stimulus to the respiratory centre depends on the degree of hypoxaemia rather than the usual hypercapnic stimulus.<a class="elsevierStyleCrossRef" href="#bib0340">29</a> Moreover, pulmonary rehabilitation after hospital discharge has been shown to improve patients’ quality of life and reduce readmissions.<a class="elsevierStyleCrossRef" href="#bib0225">6</a>Derivation criteriaThe reasons for referral from primary care are diverse. All cases of CES classified as severe or very severe, patients who cannot comply with treatment at home or those who cannot be properly diagnosed due to the impossibility of performing the relevant tests should be referred to a specialist. Likewise, patients with severe comorbidities or unexpected complications, such as heart disease, arrhythmias, or renal or hepatic failure, should also be referred.<a class="elsevierStyleCrossRef" href="#bib0225">6</a>After diagnosis, and once treatment has been prescribed, the correct follow-up of the patient who has presented a CES is a key point that can be carried out in primary care, with the aim of preventing new exacerbations. Whenever possible, after the diagnosis of CES or hospital discharge, the patient should be evaluated by the primary care physician within the following 3–5 days. Those who required hospital admission should also be referred to the specialist within a maximum of 2–4 weeks.<a class="elsevierStyleCrossRef" href="#bib0390">39</a>ConclusionsCOPD is a disease with a high under-diagnosis rate. The role of primary care, as one of the entry points for COPD patients into the healthcare system, is essential to prevent this. The active suspicion of the disease in patients with risk factors, the correct management of those already diagnosed or those suffering exacerbations, as well as the provision of diagnostic equipment such as spirometers, will be key to providing the primary care physician with the necessary tools to improve the quality of life of the COPD patient. In carrying out these tasks, the necessary tests should be in place to assess the patient's profile and, based on this, to prescribe appropriate treatment. When the diagnosis is not clear, when the necessary means for such diagnosis are not available, or when the treatment does not achieve an adequate level of control over the symptoms, coordination with higher levels of care should be established to refer patients who cannot be managed by primary care.Authors’ contributionsAll authors have contributed in the conceptualization, methodology, software, validation, formal analysis, investigation, resources, data curation, writing – original draft preparation, writing – review and editing, visualisation, supervision and project administration. All authors have read and agreed to the published version of the manuscript.FundingThis research has not received specific support from public sector agencies, the commercial sector or non-profit organisations.Conflicts of interestEva Trillo-Calvo has received honoraria for speaking engagements and funding for conference attendance from Laboratories Menarini, GlaxoSmithKline, AstraZeneca, Lundbeck, Esteve, FAES, Boehringer Ingelheim, and Servier.Javier de Miguel Díez has received honoraria and funding from Laboratories AstraZeneca, Bial, Boehringer, Chiesi, Esteve, FAES, Ferrer, Gebro Pharma, GlaxoSmithKline, Janssen, Menarini, MundiPharma, Novartis, Roche, Rovi, Teva y Pfizer.Cruz González Villaescusa has received honoraria and funding from Laboratories AstraZeneca, Bial, Boehringer, Chiesi, FAES, Ferrer, Gebro Pharma, GlaxoSmithKline, Menarini y Teva.Pablo Panero Hidalgo has received honoraria for speaking engagements and funding for conference attendance from Laboratories GSK, Menarini, Lilly, AstraZeneca, Lundbeck, Esteve, FAES, Boehringer Ingelheim, Almirall, Chiesi and Novartis.Juan Enrique Cimas has received honoraria in the last three years for spirometry and COPD courses from semfyc and SESPA.Marta Villanueva Pérez has received honoraria for speaking engagements and funding from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, and Teva.Francisco Javier Plaza Zamora has received honoraria for speaking engagements and funding from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mundipharma, and Teva.María Sanz Almazán has received honoraria for speaking engagements and funding for conference attendance from Laboratories Menarini, GlaxoSmithKline, Vifor Pharma, AstraZeneca, Novo Nordisk, and Bial.Juan Marco Figueira-Gonçalves has received honoraria for speaking engagements and funding for conference attendance from Laboratories Esteve, MundiPharma, AstraZeneca, Boehringer Ingelheim, Ferrer, Menarini, Rovi, GlaxoSmithKline, Chiesi, Novartis, and Gebro Pharma." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres2174579" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1842913" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1842914" "titulo" => "Abbreviations" ] 3 => array:3 [ "identificador" => "xres2174578" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1842915" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Profiles of COPD patients in primary care" "secciones" => array:12 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Undiagnosed patient with an exacerbation of the disease" ] 1 => array:3 [ "identificador" => "sec0020" "titulo" => "Tests to be performed for diagnosis" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Phenotype characterisation" ] ] ] 2 => array:3 [ "identificador" => "sec0030" "titulo" => "Treatment" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Inhaled treatment of the low-risk patient" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Inhaled treatment of the high-risk patient" ] ] ] 3 => array:2 [ "identificador" => "sec0045" "titulo" => "Derivation criteria" ] 4 => array:2 [ "identificador" => "sec0050" "titulo" => "Uncontrolled diagnosed patient" ] 5 => array:2 [ "identificador" => "sec0055" "titulo" => "Tests to be performed for diagnosis." ] 6 => array:2 [ "identificador" => "sec0060" "titulo" => "Treatment" ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Derivation criteria" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Diagnosed patient presenting with an exacerbation." ] 9 => array:3 [ "identificador" => "sec0075" "titulo" => "Tests to be performed for diagnosis" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0080" "titulo" => "Step 1: Diagnosis of exacerbation syndrome of COPD" ] 1 => array:2 [ "identificador" => "sec0085" "titulo" => "Step 2: Assess the severity of the episode" ] ] ] 10 => array:3 [ "identificador" => "sec0090" "titulo" => "Treatment" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "Pharmacological treatment" ] 1 => array:2 [ "identificador" => "sec0100" "titulo" => "Systemic glucocorticoids" ] 2 => array:2 [ "identificador" => "sec0105" "titulo" => "Antibiotics" ] 3 => array:2 [ "identificador" => "sec0110" "titulo" => "Venous thromboembolic disease prophylaxis" ] 4 => array:2 [ "identificador" => "sec0115" "titulo" => "Non-pharmacological treatment" ] ] ] 11 => array:2 [ "identificador" => "sec0120" "titulo" => "Derivation criteria" ] ] ] 7 => array:2 [ "identificador" => "sec0125" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0130" "titulo" => "Authors’ contributions" ] 9 => array:2 [ "identificador" => "sec0135" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0140" "titulo" => "Conflicts of interest" ] 11 => array:2 [ "identificador" => "xack754346" "titulo" => "Acknowledgments" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-11-24" "fechaAceptado" => "2024-01-06" "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1842913" "palabras" => array:3 [ 0 => "Chronic obstructive pulmonary disease" 1 => "Continuity of patient care" 2 => "Referral and consultation" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1842914" "palabras" => array:11 [ 0 => "COPD" 1 => "mMRC" 2 => "GOLD" 3 => "FVC" 4 => "FEV1" 5 => "LABD" 6 => "SABD" 7 => "SAMA" 8 => "LAMA" 9 => "ICs" 10 => "CES" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1842915" "palabras" => array:3 [ 0 => "Enfermedad pulmonar obstructiva crónica" 1 => "Continuidad de la atención al paciente" 2 => "Derivación y consulta" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "COPD is a disease with a high prevalence that diminishes the quality of life of many patients. Despite this, there are still high rates of under-diagnosis in Spain, partly due to a lack of recognition of the pathology by patients. In this context, the role played by primary care teams becomes fundamental, as they are one of the first lines of entry into the health system. In this paper we explain the different COPD profiles that may be present, and update the tools for diagnosis and treatment, which, together with an attitude of active suspicion of the disease, can help in the correct management of patients, whether they are undiagnosed or have subsequent complications." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La EPOC es una enfermedad con una elevada prevalencia que disminuye la calidad de vida de muchos pacientes. A pesar de esto, en España siguen existiendo altas tasas de infradiagnóstico, en parte, debido a la falta de reconocimiento de la patología por parte de los pacientes. En este contexto, el papel que desempeñan los equipos de atención primaria es fundamental, ya que son una de las primeras líneas de entrada al sistema sanitario. En este trabajo se revisan los diferentes perfiles de EPOC que pueden presentarse, y se actualizan las herramientas de diagnóstico y tratamiento, las cuales, unidas a una actitud de sospecha activa de la enfermedad, pueden ayudar en el correcto manejo de los pacientes, tanto si no cuentan con un diagnóstico como si se presentan complicaciones posteriores." ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1400 "Ancho" => 2925 "Tamanyo" => 242561 ] ] "descripcion" => array:1 [ "en" => "COPD exacerbation syndrome (CES) severity criteria. Mild: all green-coloured criteria must be met; moderate: in the presence of any yellow criteria; severe: any red criteria, regardless of baseline risk stratification; very severe: any purple criteria, regardless of baseline risk stratification.<a class="elsevierStyleCrossRef" href="#bib0340">29</a>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:39 [ 0 => array:3 [ "identificador" => "bib0200" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "GOLD REPORT 2022 V1.1 22NOV2021_WMV" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "Global Initiative for Chronic Obstructive Lung Disease" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:1 [ "fecha" => "2022" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0205" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cardiopulmonary axis and cardiovascular mortality in patients with COPD" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. 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COPD patient profiles in primary care. Referral criteria

Perfiles de pacientes con EPOC en Atención Primaria. Criterios de derivación

E. Trillo-Calvoa, J. de Miguel Díezb,

Corresponding author

jdemigueldiez@telefonica.net

Corresponding author.

, C. González Villaescusac,d, P. Panero Hidalgoe, J.E. Cimas Hernandof, M. Villanueva Pérezg, F.J. Plaza Zamorah, M. Sanz Almazáni, J.M. Figueira-Gonçalvesj,k

a Institute for Health Research, Aragón, Centro de Salud Campo de Belchite, Zaragoza, Spain

b Servicio de Neumología, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense de Madrid, Madrid, Spain

c Servicio de Neumología, Hospital Clínico Universitario de Valencia, Spain

d Instituto de Investigación Sanitaria INCLIVA, Spain

e UGC Valle de Lecrín, Granada, Spain

f Departamento de Medicina de la Universidad de Oviedo, Centro de Salud de Contrueces-Vega, Gijón, Spain

g EAP Ribes-Olivella (SAP Alt Penedés Garraf), Institut Català de la Salut, Barcelona, Spain

h Farmacéutico Comunitario, Mazarrón, Murcia, Spain

i Centro de Salud de Riaza, Segovia, Spain

j Servicio de Respiratorio, Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain

k Instituto Canario de Enfermedades Tropicales y Salud Pública, Universidad de La Laguna, Santa Cruz de Tenerife, Spain

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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">COPD exacerbation syndrome &#40;CES&#41; severity criteria&#46; Mild&#58; all green-coloured criteria must be met&#59; moderate&#58; in the presence of any yellow criteria&#59; severe&#58; any red criteria&#44; regardless of baseline risk stratification&#59; very severe&#58; any purple criteria&#44; regardless of baseline risk stratification&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a></p>"
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with a high variability between the different communities&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">3</span></a> In the octogenarian population this prevalence can be as high as 30&#37;&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Despite these data&#44; COPD remains as an underdiagnosed disease in Spain&#46; Indeed&#44; the IBERPOC and EPISCAN studies estimated that the rates were 78&#37; in 1997 and 73&#37; in 2007&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">4</span></a> Nowadays&#44; this figure remains high&#44; as reported by EPISCAN II results &#40;74&#46;7&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">3</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Lack of public awareness of the disease may be another factor delaying diagnosis&#46; For example&#44; chronic cough&#44; which is usually the first symptom to manifest itself&#44; may be the first symptom to be recognised&#44; is frequently discounted by the patient as an expected consequence of smoking and&#47;or environmental exposures&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The primary care physician is usually the first contact for patients who consult for chronic respiratory symptoms such as cough&#44; dyspnoea or expectoration&#46; If the patient is also a smoker&#44; the possibility of COPD should be assessed&#46; The anamnesis&#44; the physical examination and the exposure to tobacco smoke should lead to suspicion of COPD diagnosis&#44; which will be confirmed by chronic airflow obstruction on forced spirometry&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a> This situation of the primary care physician&#44; at the gateway to the health system&#44; gives him&#47;her an important responsibility to reduce the high under-diagnosis of COPD and to improve the quality of life of these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">7</span></a> However&#44; this role requires the physician to be aware of the particularities of the different types of COPD patients&#46; This document will review the diagnostic tests and possible treatments required for different COPD patient profiles&#44; as well as the reasons why they may be referred to higher levels of care&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Profiles of COPD patients in primary care</span><p id="par0025" class="elsevierStylePara elsevierViewall">There are several classes of patients in the primary care setting&#44; and they may be classified according to whether or not they have a diagnosis of COPD&#44; disease control or exacerbations&#46;</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Undiagnosed patient with an exacerbation of the disease</span><p id="par0030" class="elsevierStylePara elsevierViewall">Suspicion of undiagnosed COPD should be triggered in an adult smoker or ex-smoker of more than 10 pack-years&#44; or chronic exposure to inhaled toxicants&#44; who presents with respiratory symptoms &#40;dyspnoea or chronic cough with or without associated expectoration&#41;&#46; Another important factor is age&#44; as symptoms in patients who are smokers or ex-smokers usually appear after the age of 35 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The clinical manifestations of COPD are non-specific and often remain asymptomatic until late in the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Dyspnoea is the main symptom&#59; it particularly occurs during exertion or physical activity&#46; Moderate-to-severe dyspnoea has been reported by&#62;40&#37; of patients diagnosed with COPD in primary care&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a> This clinical manifestation is measured by the 5-level modified Medical Research Council scale &#40;mMRC&#41;&#44; which is integrated in the GOLD clinical classification scheme&#46; It consists of five statements about perceived breathlessness&#58; grade 0&#58; &#8220;I only get breathless with strenuous exercise&#8221;&#59; grade 1&#58; &#8220;I get short of breath when hurrying on the level or up a slight hill&#8221;&#59; grade 2&#58; &#8220;I walk slower than people of the same age on the level because of breathlessness or have to stop for breath when walking at my own pace on the level&#8221;&#59; grade 3&#58; &#8220;I stop for breath after walking 100 metres or after a few minutes on the level&#8221;&#59; grade 4&#58; &#8220;I am too breathless to leave the house&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">12</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Chronic cough is often the first symptom of COPD&#46; Initially&#44; the cough may be intermittent&#44; but subsequently it may be present every day&#44; often throughout the day&#44; and may be unproductive or productive&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">5</span></a> with a sputum production which is usually mucoid&#46; Inspiratory and&#47;or expiratory wheezes and chest tightness are symptoms that may vary between days&#44; and over the course of a single day&#46; Chest tightness often follows exertion&#44; is poorly localised&#44; is muscular in character&#44; and may arise from isometric contraction of the intercostal muscles&#46; An absence of wheezing or chest tightness does not exclude a diagnosis of COPD&#44; nor does the presence of these symptoms confirm a diagnosis of asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a> Additionally&#44; fatigue is one of the most common and distressing symptoms experienced by people with COPD&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">13</span></a> Finally&#44; other symptomatology in advanced stages can include weight loss&#44; anorexia&#44; muscle dysfunction&#44; depressive symptoms or anxiety are common&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Tests to be performed for diagnosis</span><p id="par0050" class="elsevierStylePara elsevierViewall">Forced spirometry is a noninvasive&#44; reproducible&#44; cheap&#44; and essential test for confirming the diagnosis and assessing the severity of obstruction in COPD&#46; It is a test that measures the volume of air moved by the lungs as a function of time and determines airflow obstruction&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> Good quality spirometric measurement is possible in any healthcare setting and all healthcare workers who care for people with COPD should have access to it&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a> To achieve quality spirometry&#44; it is important that the patient comes correctly prepared for the test&#46; To this end&#44; written instructions should be given in advance&#44; explaining exactly what the manoeuvre consists of and the importance of their cooperation&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">14</span></a> In Spain&#44; the Spanish Society of Pneumology and Thoracic Surgery &#40;SEPAR&#41; and other primary care societies have published guidelines with recommendations for the correct execution of a spirometry test&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">14&#44;15</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Once the correct performance of manoeuvres has been confirmed&#44; their interpretation will be done through three parameters such as FEV<span class="elsevierStyleInf">1</span>&#44; FVC and FEV<span class="elsevierStyleInf">1</span>&#47;FVC&#44; and their results are evaluated in relation to the value that a healthy individual of the same sex&#44; height&#44; age and weight should have&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">16</span></a> Forced vital capacity &#40;FVC&#41;&#44; which is the largest volume of air expelled in a forced expiratory manoeuvre from a maximal inspiration &#40;considering normal more than 80&#37; of its reference value&#41;&#46; Another relevant parameter is the forced expiratory volume in the first second &#40;FEV<span class="elsevierStyleInf">1</span>&#41;&#44; which represents the volume of mobilised air in the first second of forced expiration &#40;being normal more than 80&#37; of its theoretical value&#41;&#46; Finally&#44; FEV<span class="elsevierStyleInf">1</span>&#47;FVC ratio is the percentage of FVC exhaled in the first second &#40;higher than 70&#37; is the normal reference&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">A minimum of three acceptable manoeuvres to a maximum of eight shall be performed&#44; allowing sufficient time in between for the patient to recover from the effort&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">14</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Then&#44; the bronchodilator test should be performed&#44; which consists of a repeat spirometry test after administration of a short-acting bronchodilator &#40;salbutamol or terbutaline&#41; in a chamber&#46; In patients with heart rhythm disturbances or intolerance to beta-2 agonists&#44; the use of ipratropium bromide is an alternative&#44; although the waiting time will increase&#46; The test is positive &#40;i&#46;e&#46; the obstruction is reversible&#41; when the post-bronchodilation FEV<span class="elsevierStyleInf">1</span> improves at least 12&#37; and more than 200<span class="elsevierStyleHsp" style=""></span>ml regarding the pre-bronchodilation value&#46; The diagnosis of COPD will be confirmed if after bronchodilator testing the FEV<span class="elsevierStyleInf">1</span>&#47;FVC is less than 70&#37;&#46; It is recommended to perform a forced spirometry after 3 months of treatment to confirm the existence of a chronic airflow obstruction&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Other diagnostic tests are available to help clarify the diagnosis&#44; such as plain chest radiography&#44; useful to rule out other respiratory&#44; cardiac and musculoskeletal pathologies&#44;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;10</span></a> pulse oximetry&#44; where a COPD patient may present with a value below 92&#37;&#44;<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">17</span></a> and physical activity assessment&#44; as sedentary lifestyles in some patients cause dyspnoea to be unclear&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">11</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Once the diagnosis is stablished&#44; the level of risk must be assessed&#46; This classification relies on the likelihood to experience exacerbations&#44; disease progression&#44; future complications&#44; increased consumption of healthcare resources or increased mortality&#46; Spanish COPD Guidelines &#40;GesEPOC&#41; proposes a classification into low and high risk&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> considering the degree of obstruction &#40;measured by post-bronchodilator FEV<span class="elsevierStyleInf">1</span>&#40;&#37;&#41;&#41;&#44; the level of dyspnoea &#40;regarding the modified Medical Research Council &#40;mMRC&#41; scale&#41; and the history of exacerbations during the previous year&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Patients with post-bronchodilation FEV<span class="elsevierStyleInf">1</span> equal to or greater than 50&#37;&#44; a mMRC 0&#8211;1 and&#44; maximum&#44; one exacerbation without hospitalisation in the last year&#44; will be categorised as low risk&#46; All of the above criteria must be met&#46; Therefore&#44; patients who do not meet at least one of the above-mentioned conditions will be considered high-risk patients&#46; That is&#44; post-bronchodilation FEV<span class="elsevierStyleInf">1</span> less than 50&#37;&#44; mMRC between 2 and 4 or who have had more than one exacerbation that resolved with outpatient treatment and&#47;or an exacerbation that required hospital admission&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a></p><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Phenotype characterisation</span><p id="par0085" class="elsevierStylePara elsevierViewall">In high-risk patients&#44; GesEPOC 2021 recognises three phenotypes in the pharmacological treatment scheme&#58; non-exacerbator&#44; eosinophilic exacerbator and non-eosinophilic exacerbator&#46; This represents an update to the GesEPOC 2017 guideline&#44; based on the new evidence available&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The non-exacerbator is characterised by a maximum of one exacerbation in the previous year without requiring hospital care&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> Exacerbator phenotype is defined as any patient with COPD who has two or more moderate outpatient exacerbations in the previous year&#44; or at least one severe exacerbation&#44; requiring hospital care&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">18</span></a> Due to the different response to drug treatments&#44; it is important to differentiate those with an eosinophilic or non-eosinophilic phenotype&#46; Patients with &#62;300<span class="elsevierStyleHsp" style=""></span>eosinophils&#47;mm<span class="elsevierStyleSup">3</span> in stable phase will be classified as eosinophilic exacerbator&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> Non-eosinophilic exacerbator phenotype are those who meets the criteria for the exacerbating phenotype&#44; but at the same time has &#60;300<span class="elsevierStyleHsp" style=""></span>eosinophils&#47;mm<span class="elsevierStyleSup">3</span> in peripheral blood&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Treatment</span><p id="par0095" class="elsevierStylePara elsevierViewall">The general objectives of COPD treatment are summarised as&#58; reducing the symptoms of the disease&#44; reducing the frequency and severity of exacerbations&#44; improving quality of life and survival&#46; With regard to the initial pharmacological treatment of a newly diagnosed patient&#44; the GesEPOC guidelines propose a treatment based on risk and phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a></p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Inhaled treatment of the low-risk patient</span><p id="par0100" class="elsevierStylePara elsevierViewall">In the low-risk patient&#44; no oral or anti-inflammatory treatment is indicated&#44; and pharmacological treatment will consist of prescription of long-acting bronchodilators &#40;LABD&#41;&#46; Short-acting bronchodilators &#40;SABD&#41; can be of two types&#58; anticholinergics &#40;SAMAs&#41; such as ipratropium bromide and short-acting beta-2 agonists &#40;SABAs&#41; such as salbutamol or terbutaline&#46; Due to their rapid mechanism of action&#44; these drugs&#44; added to regular treatment&#44; are the drugs of choice for on-demand treatment of symptoms at any level of disease severity&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">LABD can be beta-2 adrenergic &#40;LABA&#41; or anticholinergic &#40;LAMA&#41;&#46; The LABAs available in Spain are salmeterol&#44; formoterol&#44; indacaterol&#44; olodaterol and vilanterol and the LAMAs are tiotropium&#44; aclidinium&#44; glycopyrronium and umeclidinium&#46; LABD should be used as the first step in the treatment of all patients with persistent symptoms who require regular treatment&#44; because they provide better symptom control than SABD and improve lung function&#44; exercise capacity and quality of life&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Inhaled treatment of the high-risk patient</span><p id="par0110" class="elsevierStylePara elsevierViewall">It shall be chosen according to the phenotype of the patient&#46; The initial treatment in a patient with non-exacerbator high-risk COPD is dual bronchodilation&#46; This recommendation is based on the demonstration of greater bronchodilator efficacy compared to monotherapy&#44; accompanied by a significant improvement in dyspnoea&#44; quality of life and a reduction in the use of rescue medication&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">20</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Frequent exacerbator patients with a high concentration of eosinophils &#40;&#62;300<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span>&#41; in the blood experience a greater clinical response to inhaled corticosteroids &#40;ICs&#41; and justify the use of ICs associated with a LABA as a first option to reduce the risk of exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">21</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">In non-eosinophilic exacerbator phenotype&#58; LABA&#47;LAMA treatment is recommended as first choice in most non-eosinophilic exacerbating patients&#46; Although GesEPOC 2021 recommends initial therapy with LABA&#47;ICS for eosinophilic exacerbator patients&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> the GOLD document&#44; in its 2023 version&#44; advocates the use of triple therapy&#44;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">22</span></a> discarding LABA&#47;ICS as initial treatment&#46; In non-eosinophilic exacerbator patients who continue to present exacerbations despite double bronchodilation&#44; triple therapy could be considered in the case of exacerbations with a good response to systemic corticosteroids and if its eosinophil count is close to 300<span class="elsevierStyleHsp" style=""></span>eosinophils&#47;mm<span class="elsevierStyleSup">3</span>&#46; IC in the form of triple therapy may be useful if they have eosinophil counts between 100 and 300<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span>&#46; The efficacy of ICs in patients with eosinophil counts &#60;100<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span> is very limited and their use is discouraged to avoid adverse effects&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">2</span></a> In this case&#44; or if exacerbations are observed in spite of triple therapy&#44; initiation of roflumilast or prolonged use of azithromycin should be considered&#44; as well as to check the inhalation technique&#44; assess comorbidity and test the possibility of chronic bronchial infection through sputum culture&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">The &#8220;Criteria for referral in COPD&#46; Continuity of care&#8221; document supports the use of initial treatment with triple therapy &#40;LAMA&#8211;LABA&#8211;ICS&#41; in COPD patients with an eosinophils count &#62;100<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span> who develop an exacerbation requiring hospital admission&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">23</span></a></p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Derivation criteria</span><p id="par0130" class="elsevierStylePara elsevierViewall">As described in the document &#8220;Criteria for referral in COPD&#46; Continuity of care&#8221;&#44;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">23</span></a> they should be referred to pneumology those patients who arrive at the primary care clinic without a diagnosis of COPD is related to the impossibility of performing spirometry&#44; either because of a lack of a spirometer or because unavailable qualified personnel&#46; Patients whose diagnosis is in doubt after a valid spirometry test will also be referred&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Uncontrolled diagnosed patient</span><p id="par0135" class="elsevierStylePara elsevierViewall">The patient classified as uncontrolled has an increased risk of both short-term exacerbation in the next six months and long-term exacerbation and increased risk of deterioration in their health-related quality of life&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">24</span></a> so a detailed analysis of the possible causes of this lack of control is required and an increase in treatment intensity may be necessary&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Tests to be performed for diagnosis&#46;</span><p id="par0140" class="elsevierStylePara elsevierViewall">The objective will be to classify the degree to which COPD patients are controlled and to reassess their risk group&#44; in order to consider whether they need a readjustment of medication or a referral to the next level of care&#46; According to GOLD&#44; to determine the risk group&#44; lung function is not assessed&#44; only the clinical condition is taken into account by means of the degree of dyspnoea mMRC or the COPD Assessment Test &#40;CAT&#41; and the number and type of exacerbations in the previous year&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">CAT consists of eight simple questions that measure aspects of cough&#44; expectoration&#44; chest tightness&#44; dyspnoea&#44; household activities&#44; self-confidence&#44; sleep and energy&#46; Each of these questions can be weighted by a score ranging from 0 &#40;best&#41; to 5 &#40;worst&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">25</span></a> It is very useful in aiding doctor&#8211;patient communication&#44; as it helps to identify aspects of the impact of the disease that may go unnoticed in routine questioning&#46; It is important in follow-up to detect clinically important changes&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> CAT scores greater than or equal to 10 indicate a significant impact on disease-related health status&#44; suggesting that a personalised assessment should be performed&#46; An increase in this score of more than two points should alert that there is a decompensation of the process which should be evaluated&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Another prognostic tool&#44; supported by the mMRC&#44; are BODE and BODEx indexes&#46; BODE index is a multicomponent index of prognostic severity of COPD that integrates information from BMI &#40;body mass index&#41;&#44; FEV<span class="elsevierStyleInf">1</span>&#44; mMRC and six-minute walk test&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> Although the determination of the four components of BODE is relatively simple&#44; the generalisation of the index has been slower than expected&#44; especially in primary care&#44; probably due to the need to perform the six-minute walk test &#8804;which&#44; although of low complexity and cost&#44; requires time and adequate space for its performance&#46; For this reason&#44; some authors have proposed replacing this exercise test &#40;E of the BODE index&#41; with the recording of severe exacerbations &#40;Ex of severe exacerbations&#41;&#44; in what is called BODEx index&#44; whose score ranges from 0 to 9 and is grouped into four risk groups&#44; expressed in quartiles&#46; Result between 0&#8211;2 points would correspond to the first quartile&#44; 3&#8211;4 to the second&#44; 5&#8211;6 to the third and 7&#8211;9 to the fourth one&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">26</span></a> Body mass index is scored as 0 &#40;&#62;21<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41; or 1 &#40;21<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span>&#41;&#59; FEV<span class="elsevierStyleInf">1</span> &#40;&#37;&#41; as 0 &#40;&#62;65&#41;&#44; 1 &#40;50&#8211;64&#41;&#44; 2 &#40;36&#8211;49&#41; or 3 &#40;&#60;35&#41;&#59; mMRC as 0 &#40;0&#8211;1&#41;&#44; 1 &#40;2&#41;&#44; 2 &#40;3&#41; or 3 &#40;4&#41;&#59; finally&#44; exacerbations &#40;those involving emergency room visits or hospital admissions&#41; as 0 &#40;0&#41;&#44; 1 &#40;1&#8211;2&#41; or 2 &#40;&#62;2&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatment</span><p id="par0155" class="elsevierStylePara elsevierViewall">Once the patient&#39;s degree of control has been assessed&#44; treatment can be adjusted&#46; GesEPOC 2021 proposes a treatment guided by the patient&#39;s risk level and phenotype&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">In low-risk patients not controlled with monotherapy&#44; the first step is to check for proper device technique&#46; If this is correct&#44; a change of monotherapy &#40;LABA instead of LAMA&#44; or vice versa&#41; or the introduction of dual bronchodilator therapy &#40;LABA and LAMA&#41; can be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">In non-exacerbator high-risk patients an evaluation of the treatable traits will be required and if the uncontrolled symptom is dyspnoea&#44; theophylline will be added to the double bronchodilator therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a> In high-risk exacerbator patients&#44; who continue to have frequent exacerbations despite treatment with LAMA&#8211;LABA&#44; escalation to triple therapy will be indicated if they present an eosinophil count above 100<span class="elsevierStyleHsp" style=""></span>cells&#47;mm<span class="elsevierStyleSup">3</span>&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Recent studies of fixed triple therapy have shown greater efficacy in improving lung function&#44; respiratory symptoms and a greater reduction in the risk of exacerbations than the LABA&#47;IC combination&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">21</span></a> Triple therapy has also shown a greater reduction in the risk of exacerbations than the LABA&#47;LAMA combination&#44; especially in patients who had a higher blood eosinophil concentration&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> In patients in whom triple therapy does not work&#44; parallel assessment or treatment of treatable traits such as dyspnoea&#44; chronic bronchial infection&#44; sleep apnea or cardiac disease should be considered&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">For both types of exacerbator profiles &#40;eosinophilic and non-eosinophilic&#41;&#44; it is indicated the use of roflumilast as a second-line therapy or&#44; in case of patients with at least three exacerbations in the previous year&#44; long-term treatment with macrolides&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">9</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Although there is no clear time period to assess the effects of a change in medication&#44; six to twelve weeks may be a reasonable time to estimate changes in the degree of dyspnoea&#46; For the effect on quality of life and exacerbations&#44; longer time periods are required&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">27</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Derivation criteria</span><p id="par0185" class="elsevierStylePara elsevierViewall">In general&#44; a patient diagnosed with COPD should be referred to Pneumology when&#44; despite appropriate treatment&#44; there is no improvement&#44; worsening&#44; frequent exacerbations or a disproportion between lung function and symptoms&#44; as well as in high-risk patients for complex tests only available at hospital level&#44; when it is considered necessary to indicate continuous home oxygen therapy or to indicate surgical techniques&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;26</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Other reasons for referral are related to the occurrence of symptoms or unexpected clinical manifestations such as haemoptysis&#44; appearance of peripheral oedema or persistent infections&#44; as well as patients in need of non-pharmacological treatment such as non-invasive ventilation or home oxygen therapy &#40;these have oxygen saturations that are consistently below 90&#37;&#41;&#46; Finally&#44; a BODEx score above 5 should also be a reason for patient escalation&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">6&#44;28</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Diagnosed patient presenting with an exacerbation&#46;</span><p id="par0195" class="elsevierStylePara elsevierViewall">COPD exacerbation syndrome &#40;CES&#41; is defined as an episode of clinical instability that occurs as a consequence of worsening expiratory airflow limitation or the underlying inflammatory process compared to the individual&#39;s baseline condition&#46; From a pathophysiological point of view&#44; CES is a complex and heterogeneous event comprising a set of diverse alterations&#44; which either in isolation or more frequently in combination are expressed clinically in a similar manner in the COPD patient&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Many CES are observed in clusters&#44; which raises the question of whether they are actually new events or incomplete resolutions of previous episodes&#46; To distinguish these situations&#44; the following definitions are established&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> First&#44; therapeutic failure is defined as a worsening of symptoms that occurs during the CES and requires additional treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">30</span></a> A relapse&#44; it is when a new worsening of symptoms occurs between the end of CES treatment and four weeks thereafter&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> Finally&#44; recurrence&#44; which occurs when symptoms recur less than one year after the previous CES&#44; after a period of relative good health&#46; This is defined as at least four weeks after completion of treatment for the previous CES or six weeks after the onset of symptoms&#46; Recurrences are considered as new episodes of CES&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">30</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">The cause of exacerbation of COPD in 50&#8211;70&#37; of cases is infectious&#44; of which 30&#37; are viral infections&#44; and in 5&#8211;10&#37; the cause is environmental pollution&#46; However&#44; the aetiology is unknown in one third of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Tests to be performed for diagnosis</span><p id="par0210" class="elsevierStylePara elsevierViewall">In order to establish the diagnosis of COPD exacerbation in primary care&#44; it is very important to carry out a detailed anamnesis and physical examination&#46;</p><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Step 1&#58; Diagnosis of exacerbation syndrome of COPD</span><p id="par0215" class="elsevierStylePara elsevierViewall">Clinical suspicion is established by an acute&#44; sustained and significant worsening of respiratory symptoms &#40;dyspnoea&#44; cough&#44; changes in sputum colour or volume&#41; compared to baseline in a patient with a previous diagnosis of COPD&#46; The cardinal symptom of CES is a significant increase in dyspnoea&#46; GesEPOC recommends the use of the modified Medical Research Council &#40;mMRC&#41; scale to assess this clinical manifestation&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">31</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Increased cough or changes in colour and&#47;or increased volume of sputum are also considered symptoms&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Sometimes it is difficult to discriminate whether the origin of the condition is COPD-specific or related to comorbidity&#46; In these cases&#44; it is recommended to diagnose and treat both conditions&#46; However&#44; there is a fine line between COPD exacerbation and pneumonia&#46; The symptomatology is virtually identical and the underlying mechanisms are similar&#46; The pulmonary microbiome between COPD patients with and without pulmonary infiltrate does not differ&#44; the triggering factors are similar and so is the treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">32</span></a> The main difference is that in the presence of pneumonia&#44; inflammation is higher and the prognosis worse&#44; suggesting that we may be dealing with different expressions of the same pathological process&#46; For this reason&#44; pneumonia&#44; classified in previous editions of GesEPOC as a comorbidity&#44; is now considered a type of CES&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Step 2&#58; Assess the severity of the episode</span><p id="par0230" class="elsevierStylePara elsevierViewall">This should be done after diagnosis and is important for deciding on appropriate treatment&#46; The classification of severity according to GesEPOC is shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Treatment</span><p id="par0235" class="elsevierStylePara elsevierViewall">Outpatient treatment will be initiated in cases of mild or moderate severity&#44; or referral to the hospital emergency department if the exacerbation is severe or very severe&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">10</span></a> More than 80&#37; of exacerbations are managed in primary care and the objective here is to resolve the current process by minimising its negative effects and preventing new exacerbations&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">10</span></a></p><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Pharmacological treatment</span><p id="par0240" class="elsevierStylePara elsevierViewall">The first action is to optimise bronchodilation by increasing the dose and&#47;or frequency of short-acting bronchodilators&#46; These are the drugs of choice due to their rapid onset of action and efficacy in bronchodilation&#46; SABAs &#40;salbutamol or terbutaline&#41; should be used first and if necessary&#44; a SAMA &#40;ipratropium&#41;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">8</span></a> could be added&#46; If the patient was using a long-acting bronchodilator&#44; it should not be discontinued during exacerbation&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;33</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Systemic glucocorticoids</span><p id="par0245" class="elsevierStylePara elsevierViewall">They can improve lung function&#44; oxygenation and decrease recovery time&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;10</span></a> Currently&#44; short courses of 5&#8211;7 days of 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day of prednisone &#40;or equivalent&#41; up to a maximum of 40<span class="elsevierStyleHsp" style=""></span>mg&#47;day are recommended&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Antibiotics</span><p id="par0250" class="elsevierStylePara elsevierViewall">Its use reduces the risk of treatment failure and increases the time to the next exacerbation&#44; without affecting health-related quality of life &#40;HRQoL&#41;&#44; recurrences or mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">34</span></a> Antibiotic administration is especially indicated when there is a change in sputum colour &#40;from mucous to dark&#41;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">34</span></a>&#59; when the patient requires both invasive and non-invasive ventilatory support<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">34&#44;35</span></a> and in cases with elevated C-reactive protein &#40;&#8805;20<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#44; even if the sputum appearance is inconclusive&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">36</span></a> Antibiotics are also recommended in all patients with CES presenting with pneumonia&#44; in accordance with the recommendations of the clinical practice guidelines on pneumonia&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">37</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">The recommended antibiotics are prescribed according to the severity of the exacerbation&#46; In case of mild exacerbation&#44; amoxicillin&#8211;clavulanic acid 875&#47;125<span class="elsevierStyleHsp" style=""></span>mg&#47;8<span class="elsevierStyleHsp" style=""></span>h for 7 days&#46; Moderate to very severe exacerbation without risk of <span class="elsevierStyleItalic">Pseudomonas</span> infection&#44; amoxicillin&#8211;clavulanic acid&#44; ceftriaxone or cefotaxime would be the antibiotics of choice&#46; The alternative&#44; moxifloxacin 400<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h for 5 days or levofloxacin 500<span class="elsevierStyleHsp" style=""></span>mg&#47;24<span class="elsevierStyleHsp" style=""></span>h for 7 days&#46; When severe to very severe exacerbation with risk of <span class="elsevierStyleItalic">Pseudomonas</span> infection is handled the treatment will be a &#946;-lactam with anti-pseudomonal activity&#44; such as ceftazidime or piperacillin&#8211;tazobactam&#46; As second line&#44; ciprofloxacin 500&#8211;750<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h for 10 days or levofloxacin 500<span class="elsevierStyleHsp" style=""></span>mg&#47;12<span class="elsevierStyleHsp" style=""></span>h for 7 days would be considered&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">8&#44;38</span></a></p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Venous thromboembolic disease prophylaxis</span><p id="par0260" class="elsevierStylePara elsevierViewall">The use of low-molecular-weight heparins is recommended in severe&#47;very severe or moderate exacerbations where the patient is to remain in bed or inactive&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Non-pharmacological treatment</span><p id="par0265" class="elsevierStylePara elsevierViewall">Oxygen therapy is considered one of the key elements in the management of severe CES with respiratory failure&#46; Its goal is to achieve a SaO<span class="elsevierStyleInf">2</span> between 88 and 92&#37;&#46; However&#44; oxygen administration must be controlled&#44; as in some patients the main stimulus to the respiratory centre depends on the degree of hypoxaemia rather than the usual hypercapnic stimulus&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a> Moreover&#44; pulmonary rehabilitation after hospital discharge has been shown to improve patients&#8217; quality of life and reduce readmissions&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a></p></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Derivation criteria</span><p id="par0270" class="elsevierStylePara elsevierViewall">The reasons for referral from primary care are diverse&#46; All cases of CES classified as severe or very severe&#44; patients who cannot comply with treatment at home or those who cannot be properly diagnosed due to the impossibility of performing the relevant tests should be referred to a specialist&#46; Likewise&#44; patients with severe comorbidities or unexpected complications&#44; such as heart disease&#44; arrhythmias&#44; or renal or hepatic failure&#44; should also be referred&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">6</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">After diagnosis&#44; and once treatment has been prescribed&#44; the correct follow-up of the patient who has presented a CES is a key point that can be carried out in primary care&#44; with the aim of preventing new exacerbations&#46; Whenever possible&#44; after the diagnosis of CES or hospital discharge&#44; the patient should be evaluated by the primary care physician within the following 3&#8211;5 days&#46; Those who required hospital admission should also be referred to the specialist within a maximum of 2&#8211;4 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">39</span></a></p></span></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conclusions</span><p id="par0280" class="elsevierStylePara elsevierViewall">COPD is a disease with a high under-diagnosis rate&#46; The role of primary care&#44; as one of the entry points for COPD patients into the healthcare system&#44; is essential to prevent this&#46; The active suspicion of the disease in patients with risk factors&#44; the correct management of those already diagnosed or those suffering exacerbations&#44; as well as the provision of diagnostic equipment such as spirometers&#44; will be key to providing the primary care physician with the necessary tools to improve the quality of life of the COPD patient&#46; In carrying out these tasks&#44; the necessary tests should be in place to assess the patient&#39;s profile and&#44; based on this&#44; to prescribe appropriate treatment&#46; When the diagnosis is not clear&#44; when the necessary means for such diagnosis are not available&#44; or when the treatment does not achieve an adequate level of control over the symptoms&#44; coordination with higher levels of care should be established to refer patients who cannot be managed by primary care&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Authors&#8217; contributions</span><p id="par0285" class="elsevierStylePara elsevierViewall">All authors have contributed in the conceptualization&#44; methodology&#44; software&#44; validation&#44; formal analysis&#44; investigation&#44; resources&#44; data curation&#44; writing &#8211; original draft preparation&#44; writing &#8211; review and editing&#44; visualisation&#44; supervision and project administration&#46; All authors have read and agreed to the published version of the manuscript&#46;</p></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Funding</span><p id="par0290" class="elsevierStylePara elsevierViewall">This research has not received specific support from public sector agencies&#44; the commercial sector or non-profit organisations&#46;</p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conflicts of interest</span><p id="par0295" class="elsevierStylePara elsevierViewall">Eva Trillo-Calvo has received honoraria for speaking engagements and funding for conference attendance from Laboratories Menarini&#44; GlaxoSmithKline&#44; AstraZeneca&#44; Lundbeck&#44; Esteve&#44; FAES&#44; Boehringer Ingelheim&#44; and Servier&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">Javier de Miguel D&#237;ez has received honoraria and funding from Laboratories AstraZeneca&#44; Bial&#44; Boehringer&#44; Chiesi&#44; Esteve&#44; FAES&#44; Ferrer&#44; Gebro Pharma&#44; GlaxoSmithKline&#44; Janssen&#44; Menarini&#44; MundiPharma&#44; Novartis&#44; Roche&#44; Rovi&#44; Teva y Pfizer&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Cruz Gonz&#225;lez Villaescusa has received honoraria and funding from Laboratories AstraZeneca&#44; Bial&#44; Boehringer&#44; Chiesi&#44; FAES&#44; Ferrer&#44; Gebro Pharma&#44; GlaxoSmithKline&#44; Menarini y Teva&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Pablo Panero Hidalgo has received honoraria for speaking engagements and funding for conference attendance from Laboratories GSK&#44; Menarini&#44; Lilly&#44; AstraZeneca&#44; Lundbeck&#44; Esteve&#44; FAES&#44; Boehringer Ingelheim&#44; Almirall&#44; Chiesi and Novartis&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">Juan Enrique Cimas has received honoraria in the last three years for spirometry and COPD courses from semfyc and SESPA&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">Marta Villanueva P&#233;rez has received honoraria for speaking engagements and funding from AstraZeneca&#44; Boehringer Ingelheim&#44; Chiesi&#44; GlaxoSmithKline&#44; and Teva&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">Francisco Javier Plaza Zamora has received honoraria for speaking engagements and funding from AstraZeneca&#44; Boehringer Ingelheim&#44; Chiesi&#44; GlaxoSmithKline&#44; Mundipharma&#44; and Teva&#46;</p><p id="par0330" class="elsevierStylePara elsevierViewall">Mar&#237;a Sanz Almaz&#225;n has received honoraria for speaking engagements and funding for conference attendance from Laboratories Menarini&#44; GlaxoSmithKline&#44; Vifor Pharma&#44; AstraZeneca&#44; Novo Nordisk&#44; and Bial&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">Juan Marco Figueira-Gon&#231;alves has received honoraria for speaking engagements and funding for conference attendance from Laboratories Esteve&#44; MundiPharma&#44; AstraZeneca&#44; Boehringer Ingelheim&#44; Ferrer&#44; Menarini&#44; Rovi&#44; GlaxoSmithKline&#44; Chiesi&#44; Novartis&#44; and Gebro Pharma&#46;</p></span></span>"
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            2 => "GOLD"
            3 => "FVC"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">COPD is a disease with a high prevalence that diminishes the quality of life of many patients&#46; Despite this&#44; there are still high rates of under-diagnosis in Spain&#44; partly due to a lack of recognition of the pathology by patients&#46; In this context&#44; the role played by primary care teams becomes fundamental&#44; as they are one of the first lines of entry into the health system&#46; In this paper we explain the different COPD profiles that may be present&#44; and update the tools for diagnosis and treatment&#44; which&#44; together with an attitude of active suspicion of the disease&#44; can help in the correct management of patients&#44; whether they are undiagnosed or have subsequent complications&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La EPOC es una enfermedad con una elevada prevalencia que disminuye la calidad de vida de muchos pacientes&#46; A pesar de esto&#44; en Espa&#241;a siguen existiendo altas tasas de infradiagn&#243;stico&#44; en parte&#44; debido a la falta de reconocimiento de la patolog&#237;a por parte de los pacientes&#46; En este contexto&#44; el papel que desempe&#241;an los equipos de atenci&#243;n primaria es fundamental&#44; ya que son una de las primeras l&#237;neas de entrada al sistema sanitario&#46; En este trabajo se revisan los diferentes perfiles de EPOC que pueden presentarse&#44; y se actualizan las herramientas de diagn&#243;stico y tratamiento&#44; las cuales&#44; unidas a una actitud de sospecha activa de la enfermedad&#44; pueden ayudar en el correcto manejo de los pacientes&#44; tanto si no cuentan con un diagn&#243;stico como si se presentan complicaciones posteriores&#46;</p></span>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">COPD exacerbation syndrome &#40;CES&#41; severity criteria&#46; Mild&#58; all green-coloured criteria must be met&#59; moderate&#58; in the presence of any yellow criteria&#59; severe&#58; any red criteria&#44; regardless of baseline risk stratification&#59; very severe&#58; any purple criteria&#44; regardless of baseline risk stratification&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">29</span></a></p>"
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      "titulo" => "References"
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                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "Global Initiative for Chronic Obstructive Lung Disease"
                          "etal" => false
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                    0 => array:2 [
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                        0 => array:2 [
                          "etal" => false
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                            0 => "A&#46; Calder&#243;n Montero"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.semerg.2023.101928"
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                        "paginaInicial" => "101928"
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                  "contribucion" => array:1 [
                    0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;B&#46; Soriano"
                            1 => "I&#46; Alfageme"
                            2 => "M&#46; Miravitlles"
                            3 => "P&#46; de Lucas"
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                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arbres.2020.07.024"
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                        "paginaInicial" => "61"
                        "paginaFinal" => "69"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32950310"
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                ]
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              "identificador" => "bib0215"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Datos epidemiol&#243;gicos de EPOC en Espa&#241;a"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46;B&#46; Soriano"
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                        ]
                      ]
                    ]
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                    0 => array:1 [
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                0 => array:1 [
                  "referenciaCompleta" => "Cho SH&#44; Lin HC&#44; Ghoshal AG&#44; Bin Abdul Muttalif AR&#44; Thanaviratananich S&#44; Bagga S&#44; et al&#46; Respiratory disease in the Asia-Pacific region&#58; cough as a key symptom&#46; Allergy Asthma Proc&#46; 2016&#59;37&#58;131-40&#46;"
                ]
              ]
            ]
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              "etiqueta" => "6"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Documento SEMG&#46; Manejo y derivaci&#243;n&#58; Enfermedad Pulmonar Obstructiva Cr&#243;nica &#40;EPOC&#41; en AP&#46; Madrid"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "V&#46;F&#46; Romero Sanz"
                            1 => "M&#46; Sanz Almaz&#225;n"
                            2 => "M&#46; B&#225;rcena Cama&#241;o"
                          ]
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                    0 => array:1 [
                      "Libro" => array:1 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Atenci&#243;n a la EPOC en el abordaje al paciente cr&#243;nico en Atenci&#243;n Primaria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46;A&#46; Llauger"
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                            3 => "M&#46; Freixas"
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                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1016/j.arbres.2011.10.001"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:1 [
                      "titulo" => "Gu&#237;a Espa&#241;ola de la EPOC &#40;GesEPOC&#41;&#46; Versi&#243;n 2017"
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2017"
                        "volumen" => "53"
                        "numero" => "Suppl&#46; 1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Actualizaci&#243;n 2021 de la Gu&#237;a Espa&#241;ola de la EPOC &#40;GesEPOC&#41;&#46; Tratamiento farmacol&#243;gico de la EPOC estable"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Miratvilles"
                            1 => "M&#46; Calle"
                            2 => "J&#46; Molina"
                            3 => "P&#46; Almagro"
                            4 => "J&#46;T&#46; G&#243;mez"
                            5 => "A&#46; Trigueros"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arbres.2022.02.006"
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                        "tituloSerie" => "Arch Bronconeumol"
                        "fecha" => "2022"
                        "volumen" => "58"
                        "paginaInicial" => "69"
                        "paginaFinal" => "81"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35431085"
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                  ]
                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Global strategy for the diagnosis&#44; management&#44; and prevention of chronic obstructive pulmonary disease&#46; Report"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;F&#46; Vogelmeier"
                            1 => "A&#46; Agusti"
                            2 => "A&#46; Anzueto"
                            3 => "P&#46;J&#46; Barnes"
                            4 => "J&#46; Bourbeau"
                            5 => "G&#46; Criner"
                          ]
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                    ]
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                    0 => array:1 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "GOLD REPORT 2023"
                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "Global Initiative for Chronic Obstructive Lung Disease"
                          "etal" => false
                        ]
                      ]
                    ]
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                            0 => "J&#46;C&#46; Bestall"
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                            4 => "P&#46;W&#46; Jones"
                            5 => "J&#46;A&#46; Wedzicha"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/thx.54.7.581"
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                        "fecha" => "1999"
                        "volumen" => "54"
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                      ]
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                  ]
                ]
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46;M&#46;J&#46; Go&#235;rtz"
                            1 => "M&#46; Looijmans"
                            2 => "J&#46;B&#46; Prins"
                            3 => "D&#46;J&#46;A&#46; Janssen"
                            4 => "M&#46;S&#46;Y&#46; Thong"
                            5 => "J&#46;B&#46; Peters"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1136/bmjopen-2018-021745"
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                        "tituloSerie" => "BMJ Open"
                        "fecha" => "2018"
                        "volumen" => "8"
                        "paginaInicial" => "e021745"
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46; Garc&#237;a R&#237;o"
                            1 => "M&#46; Calle"
                            2 => "F&#46; Burgos"
                            3 => "P&#46; Casan"
                            4 => "F&#46; Del Campo"
                            5 => "J&#46;B&#46; Galdiz"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.arbres.2013.04.001"
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                        "fecha" => "2013"
                        "volumen" => "49"
                        "paginaInicial" => "388"
                        "paginaFinal" => "401"
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                      ]
                    ]
                  ]
                ]
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                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "semFYC"
                          "etal" => false
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                  ]
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                            0 => "J&#46;L&#46; Viejo Ba&#241;uelos"
                            1 => "J&#46; Hern&#225;nez Hern&#225;ndez"
                            2 => "J&#46; Herrero Roa"
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                        ]
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                      "autores" => array:1 [
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                          "etal" => true
                          "autores" => array:6 [
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                            1 => "S&#46; Th&#233;riault"
                            2 => "B&#46; St-Pierre"
                            3 => "S&#46; Bernard"
                            4 => "F&#46; S&#233;ri&#232;s"
                            5 => "H&#46;J&#46; Bernatchez"
                          ]
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                      ]
                    ]
                  ]
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                      "doi" => "10.1183/23120541.00272-2021"
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                        "tituloSerie" => "ERJ Open Res&#46;"
                        "fecha" => "2021"
                        "volumen" => "7"
                        "paginaInicial" => "00272"
                        "paginaFinal" => "2021"
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                        0 => array:2 [
                          "etal" => false
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                            0 => "J&#46;J&#46; Soler Catalu&#241;a"
                            1 => "M&#46;A&#46; Mart&#237;nez Garc&#237;a"
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                        ]
                      ]
                    ]
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                    0 => array:1 [
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                0 => array:1 [
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                        0 => array:2 [
                          "etal" => false
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