Mr. B, 64, has a 10-year history of chronic obstructive pulmonary disease (COPD). He arrives at the pulmonary clinic with a 2-day history of increasing shortness of breath and sputum changing to a green color. He has “usual cough and wheezing,” but no “real increase.” Mr. B denies chest pain, an increase in volume of sputum, sore throat, or nasal discharge; he also has a history of hypertension, which is well controlled.
Mr. B has a 62-pack-year history and continues to smoke 1.5 packs per day; he and his wife are not interested in stopping. He states he has been taking tiotropium dry powder inhaler (DPI, 2 puffs, 1 capsule) once a day, and albuterol (HFA oral inhaler, 2 puffs) about once a week when he anticipates dyspnea due to impending activities. Mr. B works full time as a manager of a house painting company.
Mr. B's vital signs, including oxygen saturation, are all either at or less than 10% above baseline; his body mass index (BMI) is 23.3. He is alert and conversational. Spirometry at his last well visit (6 months earlier) was post bronchodilator: forced expiratory volume (FEV1)/forced vital capacity (FVC), 28%; FEV1, 31%; and FVC, 84%, which is considered grade 3 (severe) according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD).1 His last COPD exacerbation was 18 months earlier and he was treated in the pulmonary clinic with outpatient prednisone and antibiotics. Mr. B has had at least two acute exacerbations of COPD (AECOPD) in the past, which have required ED visits. Mr. B's COPD Assessment Test (CAT) score is 9, and his COPD combined assessment is C, indicating a high risk with fewer symptoms.2 The combined COPD assessment tool (ABCD) from yearly GOLD reports (2011 to 2016) was found to be no better than just using the spirometric grade for mortality predictions or other important health outcomes. Therefore, a refinement of the ABCD assessment tool in GOLD 2017 separates spirometric grades from the ABCD groups. According to the 2017 GOLD revised combined assessment, Mr. B would be labeled GOLD grade 3 (spirometrics) group C (assessment of symptoms and exacerbation history).1
A chest exam reveals a barrel chest; on physical exam he has hyperresonance to percussion, scattered wheezes bilaterally with no bronchial breath sounds, no intercostal retractions, and no egophony or whispered pectoriloquy.
Mr. B exemplifies a typical individual with AECOPD. However, if a patient is unknown to the provider and has no spirometry records, the diagnosis is not as clear. The provider may see a patient who was given a COPD diagnosis based only on a long smoking history and signs and symptoms.
An overview of COPD
It is estimated that 15.7 million adults in the United States have COPD, and more than 38% are current smokers. Over 24% of individuals with COPD report being unable to work compared with those without COPD (5%).3 COPD prevalence was stable from 1998 to 2009 and was significantly higher among women than men.4 COPD is the third leading cause of death in the United States, with related medical costs at $32 billion in 2010.3 Prevalence is greatest in older age groups, with women having higher rates than men throughout the lifespan (except for those age 75 and older).4
COPD is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.1 AECOPD and other coexisting illnesses contribute to the overall severity in patients. Worldwide, cigarette smoking is the major risk factor for developing COPD. Not all individuals with the same smoking history will develop COPD, likely because of differences in genetic predisposition to the disease. Genetic studies have linked genetic loci with COPD; however, it remains uncertain whether these genes are directly causal for COPD. Occupational exposure to dusts and chemical agents, including indoor air pollution from biomass cooking in poorly ventilated homes, is an underrated risk factor for COPD.1,5
Alpha-1 antitrypsin (AAT) deficiency is an autosomal recessive disorder affecting the lungs or liver. Approximately 3% of all individuals diagnosed with COPD may have undetected AAT.5 The mutation on the SERPINA1 gene (located on chromosome 14) is known, and a simple blood test can detect AAT deficiency. This gene provides instructions for the liver to make AAT, which protects the liver and lungs from proteolytic enzymes. Without sufficient AAT, these proteolytic enzymes destroy lung tissue, and COPD develops.5
In a patient workup, if the following three factors are seen, there is a very strong assurance there is airflow obstruction (FEV1 less than 70%): History of more than 55 pack years of smoking, wheezing on auscultation, and patient self-reporting of wheezing.6 In addition, the patient should be at high suspicion of COPD if presenting with dyspnea, chronic cough, or sputum in the presence of exposure to risk factors.
Spirometry is required to make a diagnosis of COPD, and the finding of a post bronchodilator FEV1/FVC less than 70% establishes the presence of airflow limitation, confirming the diagnosis.1 The value of the FEV1 establishes the degree of severity of COPD, expressed as a percentage compared with a normal reference, placing the patient in the GOLD 1 to 4 classification of airflow limitation (see Classification of severity of airflow limitation in COPD).1
COPD exacerbations are defined as an acute worsening of respiratory symptoms that result in additional therapy and usually last 7 to 10 days and are classified as mild, moderate, and severe (see Classification of exacerbation severity).1 Cardinal findings of an exacerbation are an increase in dyspnea, sputum volume, and/or sputum purulence.7 Patients may also have increased cough, fever, myalgia, and pharyngitis. However, exacerbations rely on patients reporting symptoms, which often go unreported and untreated.8 Unlike a myocardial infarction with specific biomarkers (such as troponins and ECG confirming the diagnosis), to date, AECOPD has no biomarkers to establish the diagnosis. Therefore, the clinician currently must rely on symptoms and clinical assessment for AECOPD diagnosis.9
Exacerbations have negative effects on a patient's health status, rates of hospitalization and readmission, disease progression, quality of life, exercise capacity, and lung function. Recovery takes several weeks and is associated with high health-related expenditures (over $10 billion annually in the United States); significant mortality occurs in patients needing hospitalization.1,10,11 The frequency of exacerbations increases in patients with increases in airflow obstruction (for example, GOLD grade 3 or 4) with an average of one to three exacerbations annually.
A history of prior exacerbations is a strong indicator of future exacerbations.10 Some patients, unrelated to the GOLD grade or disease severity, are more prone to exacerbations and are called frequent exacerbators, with two or more exacerbations annually. These patients should be identified for maximum therapy because they have a worse quality of life and an increased risk of hospitalization and death.1,12
Etiology of AECOPD
Infection (bacterial or viral) is the most common cause of 70% of AECOPD, with bacterial 40% to 60%, viral 30%, and atypical bacteria 5% to 10%.13 A change in color of the sputum and increase in purulence is a good marker for bacterial cause. Common bacterial organisms responsible for AECOPD are Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. Patients with the most impaired lung function (lowest FEV1) may have other bacteria, such as Pseudomonas aeruginosa or Gram-negative bacteria, requiring antibiotics different from the empirical treatment.13 Environmental factors such as pollution and ambient temperature may also initiate and/or amplify exacerbations.2
Viral etiologies are usually due to rhinovirus.1 Therefore, it is important to assess for previous upper respiratory infection, which may suggest etiology. Previous viral infection may subject the patient to a bacterial infection.13
Patient assessment and diagnostics
Most patients with COPD are treated in primary care, and diagnosis and management place a large burden on these practices.14 The diagnosis of AECOPD relies on a clinical presentation of the patient who has an acute change in his or her usual symptoms different than a usual day-to-day variation. The clinical picture may range from a mild change in symptoms to respiratory failure due to hypoxemia or acute respiratory acidosis.2
Patient history. Look for changes in the normal daily variation of the cardinal signs and symptoms of COPD: an increase in dyspnea, increase in sputum volume, and change in the color of the sputum. Other factors to assess include chronology of symptoms; changes in ability to perform activities of daily living (ADL) due to increased dyspnea; characteristics of sputum; present treatment regimen and adherence; and number, date of previous exacerbations, and how and where the exacerbations were treated.
The clinician should administer the CAT, which is a validated tool to assess the impact of COPD symptoms on the patient's life, noting an upward shift in a score above 10 (www.catesonline.org).1 Comorbidities or clinical findings should be determined that might suggest an alternate diagnosis, constitutional symptoms, upper respiratory symptoms, chest pain, pressure or pedal edema, and risk factors for cardiac or thromboembolic disease.
Physical exam. Tachypnea and wheezing are often seen during a physical exam in a patient with AECOPD. Physical findings, such as bibasilar crackles, bronchial breath sounds, egophony, fever, hypotension, and peripheral edema, might suggest an alternate diagnosis or comorbidity and will necessitate investigation toward a diagnosis (for example, pneumonia) other than AECOPD. The following diagnostic tests may (or may not) be considered to aid in the diagnosis and determine exacerbation severity:
- Pulse oximetry: An oxygen saturation of 88% or less, taken at rest; breathing room air determines if supplemental oxygen is needed.
- Chest X-ray: May be useful to identify other diagnoses that mimic symptoms of AECOPD, such as pneumonia and chronic heart failure.
- ECG: May be helpful in ruling out cardiac diseases.
- Lab studies: Complete blood cell count may show polycythemia, anemia, or an elevated white blood cell count. Electrolyte disturbances and hyperglycemia can be associated with AECOPD but are usually associated with comorbidities.
- Sputum cultures: Not necessary in the outpatient setting, as the presence of purulent sputum is sufficient to begin empirical antibiotic therapy based on the usual bacteria found in AECOPD. In addition, cultures delay treatment.
- Spirometry: Not recommended during AECOPD, as it is very difficult for patients to complete and measurements are not accurate.2
An increase in dyspnea in patients with COPD may be due to coexisting comorbidities. The differential diagnosis of AECOPD should include diagnoses that can mimic or worsen exacerbations, including pulmonary embolism, escalating chronic heart failure, pneumonia, and acute coronary syndrome.1 Pneumonia may be a top diagnosis to rule out, especially if the patient with COPD has a history of pneumonia.
There is a potential increase for pneumonia with certain inhaled corticosteroid (ICS) combination medications. Studies have demonstrated that combinations containing budesonide have a lower risk of pneumonia when compared with combinations containing fluticasone. Therefore, if the patient is at high risk for pneumonia and on fluticasone, a red flag to rule out pneumonia should be in the workup and a possible switch to budesonide should be considered.8
COPD predisposes patients to community-acquired pneumonia and confounds its treatment and outcomes. The chest X-ray is usually unchanged in AECOPD, whereas in pneumonia, the classic findings of an infiltrate and consolidation will be present.15 Pneumonia has been considered a more serious acute infection, but AECOPD occurs with greater frequency and also has serious consequences.16
The 5-year mortality for patients hospitalized with AECOPD is 50%.1 Factors independently associated with poorer outcomes include: age over 65, lower BMI, comorbidities (cardiac disease or lung cancer), previous admissions for AECOPD, clinical severity of the first exacerbation, and the need for long-term oxygen at discharge.1
More than 80% of AECOPD can be managed on an outpatient basis with standard treatment of bronchodilators, corticosteroids, and antibiotics.1 Studies suggest approximately 25% of outpatients treated for AECOPD either relapse with a need to urgently see their provider or an ED due to worsening dyspnea or have a second exacerbation within 30 days of the initial presentation.8 Although patients may have additional medications for the exacerbation, their usual daily regimen of medications for COPD should be maintained.
Bronchodilators. Daily, short-acting inhaled beta2-agonists with or without short-acting muscarinic antagonists in increased dose or frequency are the preferred bronchodilators for exacerbation treatment. Muscarinic antagonist drugs block the bronchoconstrictor effects of acetylcholine on M3 muscarinic receptors in airway smooth muscle and are commonly called anticholinergic drugs.1 There are no differences in FEV1 if the mode of delivery is by a metered-dose inhaler (MDI, with or without a spacer) or nebulizer. No clinical studies have compared the use of long-acting bronchodilators (either long-acting beta2-adrenergic agonists [LABA] or long-acting muscarinic antagonists [LAMA]) with or without an ICS during an exacerbation.1
Systemic corticosteroids. Studies indicate that systemic corticosteroids in AECOPD shorten recovery time, improve lung function (FEV1) and arterial hypoxemia, and reduce the risks of early relapse, treatment failure, and length of hospital stay.1 Prednisone (40 mg orally daily for 5 days) is the recommended treatment versus a longer course.1
Some resources limit the use of corticosteroids to moderate or severe exacerbations, and others suggest using corticosteroids for most severe exacerbations.1,8,12,17,18 The provider needs to consider the total lifetime exposure of corticosteroids and use clinical judgment as to administration depending on the patient's exacerbation severity. No taper of corticosteroids is needed in a 5-day course.
Antibiotics. GOLD guidelines recommend that patients with AECOPD should be given antibiotics if they have three cardinal symptoms—an increase in dyspnea, increase in sputum volume, and sputum purulence; have two of the cardinal symptoms if increased purulence of sputum is one of the two symptoms; or if they require mechanical ventilation. Recommended length of treatment with antibiotics is usually 5 to 7 days.1 Other experts vary slightly and recommend antibiotics with a moderate or severe AECOPD, defined as having two of the three cardinal symptoms above or requiring hospitalization. These experts do not initiate antibiotics in a mild exacerbation defined as having one of the cardinal symptoms and not requiring hospitalization.15,18
The optimal antibiotic regimen for AECOPD treatment has not been determined. In patients with moderate or severe exacerbations, screening for risk factors determines whether a patient has uncomplicated COPD or complicated COPD, and this guides antibiotic choice. Risk factors include age over 65, comorbid conditions (especially cardiac disease), FEV1 under 50%, two or more exacerbations per year, and antibiotic therapy within the past 3 months.15,18
The provider should understand the local bacterial resistance pattern, which is the basis for the choice of antibiotic. Initial empirical treatment in patients with no risk factors (uncomplicated COPD) consists of an advanced macrolide (azithromycin or clarithromycin) or cephalosporin (cefuroxime, cefpodoxime, cefdinir), doxycycline, or trimethoprim/sulfamethoxazole. If patients had antibiotic exposure in the last 3 months, an alternative class is chosen.
If patients have one or more risk factors (complicated COPD), amoxicillin-clavulanate should be chosen. Patients with complicated AECOPD will likely benefit from early treatment with the most potent antibiotics, such as amoxicillin/clavulanate, which have a a broad spectrum of activity against the likely pathogens.15,18 This also may prevent relapses of the next exacerbation occurring in a few weeks.19
Respiratory fluoroquinolones (levofloxacin and moxifloxacin) have been widely used for complicated AECOPD. However, in 2016, the FDA updated the black box warning for fluoroquinolones and now includes a warning for tendonitis, tendon rupture, worsening of myasthenia gravis, peripheral neuropathy (may be irreversible), and central nervous system effects. These adverse reactions can occur hours to weeks after exposure to the drugs. The risk of serious adverse reactions generally outweighs the benefit of fluoroquinolones, and the FDA states that in AECOPD, these drugs should be reserved for use in patients who have no alternative treatment options.20,21 If patients have complicated COPD and risk factors for Pseudomonas, they should be referred to a pulmonologist for at least initial management because the options for antibiotics are limited and may include inhaled antibiotics.
Route of delivery is oral or I.V. infusion, depending on the patient's ability to eat and the specifics of the drug's pharmacokinetics. Improvements in dyspnea and sputum purulence suggest a positive response.1 The frequent exacerbator phenotype presents a challenge to the primary care provider, and referral to a pulmonologist would be wise.
Self-management. The role of self-management delivered immediately post-AECOPD (during hospitalization or within 1 month after exacerbation) is unclear. Self-management interventions include action plans; education; skills such as self-efficacy, problem solving, and management of emotions; and roles/goal setting. A systematic review of self-management interventions delivered in the hospital or patients' homes by nurses found health outcomes to vary widely with difficulty determining effectiveness of interventions, as the studies were so heterogeneous.22
Self-management delivered immediately appears to have limited effectiveness, especially related to readmissions and improving health-related quality of life. Some trials demonstrating success included structured, 12-month face-to-face follow-up, which was individualized and focused on reinforcing self-management skills.22 Overall, implementing self-management is likely more effective once the patient is not acutely breathless and his or her ability to focus on information is improved.
Current guidelines support the initiation of a pulmonary rehabilitation program early (within 3 weeks) after hospital discharge for AECOPD because it is feasible, safe, effective, and leads to gains in exercise tolerance, symptoms, and quality of life.23
Exercise-based pulmonary rehabilitation, especially resistance training of the leg muscles during exacerbations, is well tolerated, safe, and may result in gains in exercise tolerance.23 In addition, integrating the transtheoretical model, stages of change in the process helps the provider determine if the patient is ready to change behavior, and thus, when to proceed.24
Indications for ED/hospital assessment
Several factors warrant referral to the local ED and/or hospital admission: severe symptoms, acute respiratory failure, onset of new physical signs, failure of exacerbation to respond to initial medical management, presence of serious comorbidities, and inadequate home support.1
Severe respiratory compromise may manifest with use of accessory muscles, paradoxical chest wall/abdominal movements (chest and abdominal motion are asynchronous with respiration), worsening or new onset of central cyanosis, development of peripheral edema, and hemodynamic instability. If present, a deteriorating mental state could reflect hypercapnia or hypoxemia, and asterixis could indicate increased hypercapnia. With these severe respiratory findings, transferring to the closest ED is necessary for more intense management than the primary care setting can provide.2 The clinical findings of AECOPD are heterogenous, and with hospitalized patients, the exacerbation severity is based on clinical signs and classified as no respiratory failure, acute respiratory failure (nonlife-threatening) or acute respiratory failure (life-threatening).1
In the outpatient management of AECOPD, the familiarity of the patient to the practice and the severity of the AECOPD often dictate follow-up time. Follow-up within 1 month of hospital discharge has been related to less exacerbation-related readmissions. If the patient has been hospitalized for an exacerbation, two follow-up times (1 to 4 weeks and 12 to 16 weeks) after discharge are suggested. Items to be assessed at each of the two visits include inhaler technique, understanding of the treatment plan, reassessment of the need for long-term oxygen, documented symptoms via a validated questionnaire, the ability to perform physical activity and ADL, status of comorbidities, and the ability to cope in the patient's usual environment. In addition, at the 12 to 16 weeks follow-up, the FEV1 via spirometry should be measured.1
If the patient has more than two exacerbations a year, referral to a pulmonary clinic is appropriate. Any therapy preventing AECOPD will improve health, prevent decline in FEV1, and reduce hospitalizations for AECOPD as exacerbations are related to increased mortality and morbidity.12,25,26 (See Key recommendations for AECOPD prevention.)
Back to the case patient
Mr. B was deemed to have moderate exacerbation because he exhibited two of the three cardinal symptoms of AECOPD (increasing dyspnea and purulent sputum). The exacerbation is complicated due to his risk factor of FEV1 less than 50%. The CAT was administered, and as expected in an exacerbation, the score was elevated to 13. Other than oxygen saturation (90%), there were no diagnostic or lab tests needed. His physical exam and presentation did not point to pneumonia. Managment consisted of a bronchodilator (maintenance albuterol increased to 2 puffs four times a day for at least 3 days); a corticosteroid (prednisone 40 mg orally daily for 5 days); and antibiotics (because Mr. B had increased purulence of sputum and increased dyspnea, antibiotics were warranted). As he was considered to have a complicated moderate exacerbation and given the expanded black box warnings for fluoroquinolones, amoxicillin/clavulanate, orally every 12 hours for 7 days, was ordered rather than the levofloxacin he received in the past.
Self-management and prevention of AECOPD was also addressed. Mr. B was not interested in smoking cessation despite knowing the risks, benefits, and the help he could receive. Mr. B was up-to-date with an influenza vaccine and had already received a pneumococcal vaccine. He was given a pneumococcal 13-valent conjugate vaccine at this visit. Mr. B was interested in a formal pulmonary rehabilitation program, and plans were made to find out specifics and funding to discuss at the next visit.
Mr. B had been resistant to an action plan but now believed it would be beneficial, as he did not want to miss work due to an exacerbation. This would also be addressed at the next visit. Mr. B's inhaler technique was assessed. When he removed his MDI from his pocket, it was obvious he had not cleaned it in some time, so a discussion ensued along with a return demonstration.
Inhaler medications are expensive, and generics are used when available. Mr. B would be Medicare eligible on his next birthday, and his interest/need for a nebulizer and medications would be explored at that time. He was already on maintenance LAMA (tiotropium), which is indicated for AECOPD prevention. Adding a LABA via a combination LABA/LAMA or ICS/LABA to further protect against COPD exacerbations should be considered. The decision was made to continue Mr. B's LAMA during his AECOPD and to not step up his therapy. Phone follow-up occurred in 2 days, and Mr. B was progressing positively and would return to the clinic in 3 months.
The future of COPD
COPD is a complex disease with a variety of presentations or phenotypes, such as those with small airway disease and those with terminal bronchiolar disease or those with frequent or those with rare exacerbations).27 A large 3-year multicenter international study (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) identified a variety of cellular, genetic, serum, and other type biomarkers in COPD. However, these biomarkers require validation in clinical trials and drug development before they can be used in clinical practice.28
In July 2015, the FDA approved the first COPD biomarker for use in interventional clinical trials (plasma fibrinogen, which is elevated in inflammation).29 Future research hopes to expand the number of biomarkers for more accurate diagnosis of COPD and AECOPD and potential novel bronchodilators and anti-inflammatory drugs that will expand the usual treatments in patients with an exacerbation of COPD.8
Key recommendations for AECOPD prevention1,8,12,25,26
- Pulmonary rehabilitation: For patients with moderate to very severe COPD stages who had exacerbation ≤4 weeks post hospitalization.
- Education with an action plan and case management, which includes direct access to healthcare specialist with monthly follow-up. The MDI and DPI are complex with varied instructions. Older patients may have age-related changes that hinder their ability to use MDI or DPI and may prefer nebulizers. The choice of delivery of medication should be individualized. Reassess the technique of the patient's use and cleaning of the device at each visit.
- Vaccines: An annual influenza vaccine should be given yearly to all patients with COPD. The pneumococcal vaccine should be given to all patients over age 65 and younger patients with significant comorbid conditions, including chronic heart or lung disease.
- Smoking cessation counseling and treatment: Smoking cessation slows lung function decline and lessens symptoms, but evidence for cessation in preventing AECOPD is low. However, smoking cessation is beneficial in regards to other health-related issues.
- Pulmonary rehabilitation: Rehabilitation improves quality of life, exercise tolerance, and dyspnea. For prevention of rehospitalization, the effect on preventing AECOPD largely occurs with rehabilitation ≤4 weeks post hospitalization.
- Pharmacologic inhaled therapies for AECOPD prevention: Various classes of medications used for maintenance reduce the frequency of COPD exacerbations:
- – Bronchodilators: LABA or LAMA or LABA + LAMA.
- – Corticosteroid combination medications: LABA + ICS or LABA + LAMA + ICS.
1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2017. http://www.goldcopd.org.
2. Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2016. http://www.goldcopd.org.
3. Wheaton AG, Cunningham TJ, Ford ES, Croft JB. Employment and activity limitations among adults with chronic obstructive pulmonary disease—United States, 2013. MMWR Morb Mortal Wkly Rep
4. Akinbami LJ, Xiang L. Chronic obstructive pulmonary disease among adults aged 18 and over in the United States, 1998-2009. CDC: NCHS Data Brief
. 2011. http://www.cdc.gov
5. Kaufman JS. Nursing management obstructive pulmonary diseases. In: Lewis SL, Dirksen SR, Heitkemper MM, Bucher L, eds. Medical-Surgical Nursing: Assessment and Management of Clinical Problems
. 9th ed. St. Louis, MO: Elsevier; 2014.
6. Qaseem A, Wilt TJ, Weinberger SE, et al Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med
7. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med
8. Aaron SD. Management and prevention of exacerbations of COPD. BMJ
9. Mohan A, Sethi S. The reliability and validity of patient-reported chronic obstructive pulmonary disease exacerbations. Curr Opin Pulm Med
10. Reilly JJ, Silverman EK, Shapiro SD. Chronic obstructive pulmonary disease. In: Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine
. 19th ed. New York, NY: McGraw Hill; 2015.
11. Suh ES, Mandal S, Hart N. Admission prevention in COPD: non-pharmacological management. BMC Med
12. Wedzicha JA, Singh R, Mackay AJ. Acute COPD exacerbations. Clin Chest Med
13. Miravitlles M, Anzueto A. Role of infection in exacerbations of chronic obstructive pulmonary disease. Curr Opin Pulm Med
14. Sethi S, Mahler DA, Marcus P, Owen CA, Yawn B, Rennard S. Inflammation in COPD: implications for management. Am J Med
15. Bartlett JG, Sethi S. Management of infection in exacerbations of chronic obstructive pulmonary disease. UpToDate. 2016. http://www.uptodate.com.
16. Rangelov K, Sethi S. Role of infections. Clin Chest Med
17. Walters JA, Tan DJ, White CJ, Wood-Baker R. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev
18. Stoller JK. Management of exacerbations of chronic obstructive pulmonary disease. UpToDate. 2016. http://www.uptodate.com.
19. Wilson R, Sethi S, Anzueto A, Miravitlles M. Antibiotics for treatment and prevention of exacerbations of chronic obstructive pulmonary disease. J Infect
20. U.S. Food and Drug Administration. FDA updates warnings for fluoroquinolone antibiotics. 2016. http://www.fda.gov
21. Infectious Diseases Society of America. Fluoroquinolone antibacterial drugs for systemic use: drug safety communication-warnings updated due to disabling side effects. 2016. http://www.idsociety.org
22. Harrison SL, Janaudis-Ferreira T, Brooks D, Desveaux L, Goldstein RS. Self-management following an acute exacerbation of COPD: a systematic review. Chest
23. Spruit MA, Singh SJ, Garvey C, et al An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation. Am J Respir Crit Care Med
24. Prochaska JO, DiClemente CC, Norcross JC. In search of how people change. Applications to addictive behaviors. Am Psychol
25. Criner GJ, Bourbeau J, Diekemper RL, et al Executive summary: prevention of acute exacerbation of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest
26. Taffet GE, Donohue JF, Altman PR. Considerations for managing chronic obstructive pulmonary disease in the elderly. Clin Interv Aging
27. Rosenberg SR, Kalhan R. Biomarkers in chronic obstructive pulmonary disease. Transl Res
28. Faner R, Tal-Singer R, Riley JH, et al Lessons from ECLIPSE: a review of COPD biomarkers. Thorax
29. FDA approves first COPD biomarker: paving way for new, improved treatments and cures. COPD Foundation. 2015. http://www.copdfoundation.org