MKSAP primer: COPD

MKSAP primer: Chronic obstructive pulmonary disease.


Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder that includes emphysema, chronic bronchitis, obliterative bronchiolitis and asthmatic bronchitis. Emphysema is defined pathologically as the presence of abnormal permanent enlargement of the airspaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. Chronic bronchitis is defined clinically as chronic productive cough on most days for three months in each of two consecutive years in a patient in whom other causes of chronic sputum production have been excluded. In patients with COPD, either or both of these conditions may be present.

Chronic inflammation underlies both asthma and COPD, but the nature of the inflammation differs, as does the response to different classes of medications. A 20-year longitudinal study found that physician-diagnosed asthma was associated with an increased risk of chronic bronchitis, emphysema and COPD. Reversibility of airflow obstruction was once thought to be the major distinction between the two disorders, with reversibility being the hallmark of asthma and irreversible obstruction the hallmark of COPD. Partial reversibility is the norm for most patients with COPD, whereas asthmatics have greater reversibility.

Risk factors

Risk factors for COPD include both host factors and environmental exposures. The genetic host factor that has been best documented is the hereditary deficiency of a1-antitrypsin (AAT). Other candidate genes identified in the pathogenesis of COPD include those involved in detoxification of cigarette smoke products such as microsomal epoxide hydrolase and glutathione s-transferase.

Predisposing environmental exposures include tobacco smoke, heavy exposure to occupational dust and chemicals (such as vapors, irritants and fumes), and indoor and outdoor air pollution.

Cigarette smoking is the most important etiologic factor, having a highly significant effect on age of onset, dose, and duration of smoking. Smoking leads to an inflammatory response, oxidative stress, lung destruction and interference with lung repair. Smoking cessation slows the accelerated decline in COPD-related FEV1 and reduces all-cause mortality rates by 27%, primarily because of a significant reduction in concurrent cardiovascular mortality. Low-grade systemic inflammation is present (higher C-reactive protein, fibrinogen level) in persons with moderate to severe airflow obstruction.

The mortality rate in women has doubled over the past 20 years. Earlier studies showed men at greater risk than women, but more recent studies from developed countries show that the prevalence is equal, and some studies have suggested that women are more susceptible to the effects of tobacco smoke than men. In 2000, for the first time, more women died of COPD than men.

Airway hyperresponsiveness to environmental or pharmacologic agents such as methacholine affects 60% to 80% of patients with COPD. Such hyperresponsiveness may develop after exposure to tobacco smoke or other environmental insults. Asthma is also characterized by increased airway hyperresponsiveness. However, in asthma it correlates better with inflammation whereas in COPD airway hyperresponsiveness correlates with airway narrowing.

Such developmental risk factors as perinatal events and childhood illness also have a profound effect on lung growth. Other influences include processes occurring during gestation, low birth weight, and exposures during the first year of life. Viral infections may alter lung growth, and there is some evidence that viral genomes from adenoviruses can be incorporated and expressed in airway cells, predisposing to inflammation and injury later in life.

High levels of urban air pollution are harmful to patients with existing lung disease. The causative role of air pollution in COPD is unclear, but it is not as important as cigarette smoke. Exacerbations of COPD may be increased during ozone alerts and increased air levels of particulates and irritants. Indoor air pollution from biomass fuel burned for cooking and heating is also a risk factor. The role of recurrent infection in adults is controversial. Many patients do not completely recover lung function and health status after a serious infection. There is also evidence that the risk of developing COPD is inversely related to socioeconomic status. Malnutrition can worsen COPD.

Natural history

The natural history of COPD is variable. However, the often-quoted statistic that 15% to 20% of smokers develop clinically significant COPD underestimates the toll of the disease. COPD may have its roots decades before the onset of symptoms. Impaired growth of lung function during childhood and adolescence caused by recurrent infections or tobacco smoking leads to lower maximally attained lung function in early adulthood. An accelerated decline in lung function is the single most important feature of COPD. If the patient continues to smoke, the loss of lung function progresses. In the NIH Lung Health Study, men who quit smoking during the first year had an FEV1 decline of 30 mL per year, whereas men who continued to smoke throughout the 14.5 years of the study had an FEV1 decline of 66 mL per year. There was a survival advantage in quitting.

Classification of severity

The diagnosis of COPD is confirmed by spirometry. The presence of a post-bronchodilator FEV1 less than 80% of the predicted normal value in combination with an FEV1–FVC ratio of less than 0.7 confirms the presence of airflow limitation. A single measurement of FEV1 incompletely represents the complex clinical consequences of COPD because 1) FEV1 does not always correlate with symptoms; 2) persistent cough and sputum production often precede the development of airflow limitation; and 3) in the course of the disease, systemic consequences (such as weight loss and peripheral muscle wasting and dysfunction) may develop, and hyperinflation or abnormalities of gas exchange out of proportion to FEV1 abnormalities may contribute to substantial morbidity.

The American Thoracic Society/European Respiratory Society spirometric classification based on FEV1 includes five classes: at risk, mild, moderate, severe and very severe. Patients in the “at risk” class are usually those who smoke or have exposure to pollutants; have cough, sputum production or dyspnea; or have a family history of respiratory disease. The GOLD guidelines have a similar classification (see Table).

Another index for grading severity of COPD is the BODE index, consisting of the body mass index (BMI), airflow obstruction, dyspnea and the 6-minute walk distance. Unlike spirometry, BODE seems to correlate well with survival. The FEV1 is included along with the distance walked in 6 minutes. Dyspnea is measured on the Modified Medical Research Council scale, and the BMI is stratified to at least or less than 21 kg/m2.

Differential diagnosis

The differential diagnosis of COPD is extensive. The major disease to differentiate is asthma, which differs by its onset early in life and its more variable symptoms, which are more prominent at night and early morning. Patients with asthma may have concurrent allergic rhinitis and/or eczema, a strong family history of asthma and reversible airflow limitation.

Obliterative bronchiolitis occurs in younger patients and affects nonsmokers who often have a history of rheumatoid arthritis or exposure to toxic fumes. CT scan done on expiration shows hypodense areas. Diffuse panbronchiolitis primarily occurs in men, typically of Asian descent, who are nonsmokers and have chronic sinusitis. Chest radiograph and high-resolution CT scan show diffuse small centrilobular nodular opacities and hyperinflation. This condition may respond to long-term macrolide therapy.

Managing exacerbations

An acute exacerbation of COPD is defined as a subjective increase from baseline in some combination of dyspnea, sputum production and sputum volume over a two-day period.

Exacerbations are often the defining clinical events in the life of a patient with COPD. There are multiple causes of exacerbation, including infection, air pollution, exposure to allergens and ozone. The most common symptoms are increased breathlessness accompanied by wheezing, chest tightness, increased cough and sputum, change in the color and/or the tenacity of sputum and fever. There may also be nonspecific systemic complaints, such as malaise, insomnia, fatigue, depression and confusion. The outcome of an exacerbation is influenced by the disease's severity and the patient's previous exposure to antibiotics or recent use of oral corticosteroids. Arterial blood gas measurements and oxygen saturation are useful in assessing the severity of an exacerbation. Simple lung function studies are useful but are often very hard to perform. In the hospital setting, arterial blood gases are useful to guide oxygen therapy and prevent sedation in a patient with impending respiratory failure. The differential diagnosis for an acute exacerbation includes congestive heart failure, pneumothorax, pleural effusion, pulmonary embolism and arrhythmias, which can be excluded by clinical assessment, chest radiography, electrocardiography, spiral CT scan and other diagnostic procedures.

The presence of increased cough or purulent sputum is sufficient evidence to warrant antibiotic therapy. The most common pathogens are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. More severely affected patients may have gram-negative rods such as Klebsiella or Pseudomonas, which typically cause more severe infection. Rarely, atypical bacteria such as mycoplasma and Chlamydia pneumoniae or Legionella species can be involved. Many exacerbations are due to viruses, but the findings cannot be distinguished from bacterial infection. Similarly, air pollution due to ozone or particulates can cause exacerbations that are indistinguishable from those with bacteria.

Home management

Most exacerbations of COPD are treated at home. The dose or frequency of β-agonists can be increased if no contraindication exists. If not already being used, an anticholinergic agent can be added. If the patient is using only metered-dose inhalers, high-dose nebulized therapy can be considered. Antibiotics and oral corticosteroids are also used.

Systemic corticosteroids

Patients with acute exacerbations of COPD benefit from systemic corticosteroid therapy, with alleviation of symptoms and improved lung function. For patients with moderate COPD, most controlled clinical trials have shown that short-term systemic corticosteroid therapy in combination with other effective therapies leads to small but clinically significant improvement and fewer treatment failures. The usual starting dose is approximately 30 to 40 mg of prednisone for 5 to 10 days with or without a taper. Most benefit occurs during the first one to two weeks of treatment.

Antibiotics

Sputum cultures are not usually necessary. The choice of antibiotics is based on the community patterns of bacterial resistance plus factors such as the patient's stage of disease and recent exposure to antibiotics and systemic corticosteroids. Antibiotics directed at the common pathogens are used. Second- and third-generation cephalosporins, newer macrolides, amoxicillin/clavulanate or fluoroquinolones may be necessary for patients who do not respond to simple oral antibiotics or for patients with β-lactamase–producing organism in the sputum.

Hospital treatment

The indications for hospital assessment or admission for exacerbations of COPD include insufficient home support, older age, diagnostic uncertainty, new occurring arrhythmias, significant comorbidities, failure of an exacerbation to respond to initial medical management, onset of new physical signs such as peripheral edema or cyanosis, severe background COPD (GOLD stage 3 or 4) and marked increase in the intensity of symptoms.

The first treatment a patient receives in the hospital is controlled oxygen if necessary, with adequate levels of oxygenation as defined by a PaO2 of 60 mm Hg and a saturation above 90%. Arterial blood gases should be measured 30 minutes after oxygen is started to ensure that oxygenation is adequate and that there is no carbon dioxide retention or acidosis.

Bronchodilator therapy

Short-acting inhaled β-agonists and anticholinergics given by nebulizer are the preferred bronchodilators for the in-hospital treatment of exacerbations of COPD. A systematic review of bronchodilators showed no difference in FEV1 90 minutes after administration of either β-agonists or anticholinergics. Adding an anticholinergic agent to a short-acting β-agonist confers little advantage over a β-agonist alone. The role of theophylline in COPD exacerbations is controversial. The conclusion from four trials with 169 patients was that methylxanthine therapy did not affect FEV1 at two hours, but slightly improved FEV1 at three days. Nonsignificant reductions in hospitalizations and length of stay with theophylline were offset by increased rates of relapse and occurrence of tremor, palpitations and arrhythmias.

Corticosteroids

Oral or intravenous corticosteroids are recommended as an addition to bronchodilator therapy, although the specific dose is not defined. One dosing regimen consists of intravenous methylprednisolone, 125 mg every six hours for three days, followed by oral prednisone tapered over two weeks (60 mg on days 4 to 7, 40 mg on days 8 to 11, and 20 mg on days 12 to 15). Corticosteroids lead to a greater improvement in lung function, reduced hospital stay and lower rates of relapse and treatment failure.

Antibiotics

Antibiotics are almost always used in in-hospital treatment of exacerbations of COPD. The typical regimen consists of broad-spectrum antibiotics directed at the common bacteria plus coverage for gram-negative organisms. Whether oral or intravenous therapy is given depends on the patient's status and the likelihood of infection with Pseudomonas, which would require therapy with two agents.

Ventilatory support

Noninvasive intermittent positive-pressure ventilation (NPPV) has been shown to be beneficial in acute respiratory failure due to COPD. The addition of NPPV to standard care in patients with acute exacerbation of COPD decreased the rate of endotracheal intubation (RR 28%), length of hospital stay (4.57 days), and in-hospital mortality rate (10%).

The criteria for starting noninvasive ventilation include moderate to severe dyspnea with the use of accessory muscles and paradoxical abdominal motion, moderate to severe acidosis with a pH less than 7.35 and hypercapnia with a PaCO2 greater than 45 mm Hg and a respiration rate greater than 25 breaths per minute. Exclusion criteria include respiratory arrest, cardiovascular instability, somnolence, impaired mental status, lack of cooperation, high risk of aspiration, recent facial or gastrointestinal surgery, craniofacial trauma or extreme obesity. Patients given NPPV must be monitored closely to evaluate their response to treatment and to facilitate intubation if NPPV fails. NPPV failure is indicated by failure to stabilize after two to three hours of NPPV.

Mechanical ventilation is indicated for patients with severe dyspnea, hemodynamic instability, impending respiratory arrest (respiration rate >35 breaths/minute), life-threatening hypoxemia (PaO2 <40 mm Hg), severe acidosis (pH <7.25) and hypercapnia (PaCO2 ≤60 mm Hg), actual respiratory arrest, somnolence, impaired mental status, cardiovascular complications, and such other complications as sepsis, pneumonia, pulmonary embolism, and NPPV failure. Many patients with end-stage COPD require long-term intensive care unit monitoring, and weaning from mechanical ventilation and discontinuing ventilation can be difficult and hazardous in patients with COPD. Therefore, a patient's preference for intervention and intense care should be determined before an acute event occurs.

Hospital discharge and follow-up

Patients discharged from the emergency department or the inpatient service after an exacerbation of COPD should be prescribed oral corticosteroids. In a prospective study of 147 patients seen in the emergency department with an exacerbation of COPD, the relapse rate at 30 days was 43% on placebo versus 27% for patients given prednisone, 40 mg/d for 10 days. Additional benefits were alleviation of dyspnea and modest improvement in FEV1 and health status. The risk of relapse is increased in patients who had an exacerbation requiring emergency department treatment in the previous year and is also increased by acute factors such as respiration rate at presentation to the emergency department and self-reported limitation of activity within the previous 24 hours.

Discharge criteria after an acute exacerbation of COPD include:

  1. 1. the use of inhaled β-agonist no more than every four hours;
  2. 2. the ability to walk across the room;
  3. 3. the ability to eat and to sleep without frequent awakening by dyspnea;
  4. 4. stable clinical status (including arterial blood gases) for 24 hours;
  5. 5. understanding by the patient and home caregivers of the correct use of inhalers;
  6. 6. the completion of follow-up and home-care arrangements; and
  7. 7. confidence on the part of the patient and the physician that the patient can manage successfully.

The evidence is accumulating that both bronchodilators and inhaled corticosteroids reduce exacerbation rates. The role of inhaled corticosteroids combined with long-acting bronchodilators after an acute exacerbation is being prospectively studied. Some observational retrospective studies suggest improved survival and reduced relapse rate when these agents are used over the year after hospitalization. Careful follow-up is imperative either by a telephone call in the week following discharge or by scheduling an evaluation within 30 days.