Acute Exacerbation of Respiratory Diseases Steven A Sahn
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Acute Exacerbations of COPDCHAPTER 1

Charlie Strange
 
EPIDEMIOLOGY
Chronic obstructive pulmonary disease (COPD) is a common lung disease, which is defined by fixed obstruction on spirometry.1 Since most of the world does not use spirometry, regularly across the affected population, methods like questionaires, have been used in national health surveys to establish the prevalence of disease. Using questionnaires to ask about the prevalence of chronic bronchitis or emphysema, the National Health Interview Survey found 10 million adults in the United States during 2000 affected with this disease.2 Underdiagnosis is prominent in every recent survey performed. Therefore, when the Third National Health and Nutrition Examination Survey (NHANES III) performed spirometry, it was possible to extrapolate that 23.6 million individuals have COPD in the United States. Importantly, 2.4 million of these had severe or very severe disease with forced expiratory volume in 1 second (FEV1) less than 50% of the predicted, representing 1.4% of the population.3 This severely impaired population is the group which has the majority of diagnosed COPD exacerbations.
COPD is poorly recognized throughout the world. Instead, most of the world recognizes chronic bronchitis more often than COPD.4 In a 2002 health survey, administered by the World Health Organization, only 15% of Americans and fewer individuals from Germany, China and Brazil were able to identify COPD as a disease of the lungs.4 The misdiagnosis is not helped by the International Classification of Disease (ICD 9 and ICD 10) descriptions of COPD that code COPD into a variety of overlapping categories. Chronic bronchitis has been characterized as the most common phenotype of COPD throughout the past 30 years. However, when chronic bronchitis is defined as a chronic productive cough for three months from each of two successive years, there is an increased recognition that some individuals will not have concomitant airflow obstruction. Therefore, current understanding is that airflow obstruction is necessary to define the disease accurately.
An acute exacerbation of COPD is a major cause of morbidity, the need for urgent care, hospitalization, and mortality. However, very few patients know the meaning of the word exacerbation. In an international study, Kessler et al. found that 21.6% of individuals with advanced COPD knew the meaning of the term and instead preferred terms such as crisis (16%) or infection (20%).5 Nevertheless, the definitions and terminology used for an acute exacerbation of COPD have now been sufficiently codified to suggest that a change in terminology is unlikely to occur.
 
CURRENT DEFINITION
An acute exacerbation of COPD was first established by Anthonison as a clinical worsening of at least two of the following three symptoms: worsened dyspnea, 3worsened sputum volume, and change in sputum color.6 Since the majority of the patients met the clinical definition of chronic bronchitis and the Anthonison's study demonstrated some role for antibiotics in treatment, the subsequent literature became adulterated with terminology that used the term “acute exacerbation of chronic bronchitis” (AECB). This term continues to be used by the United States Food and Drug Administration to define antibiotics effective for upper respiratory infections. The association with infection has persisted in most perceptions about the disease. This chapter will suggest that patients with AECB receive spirometry to define and stage COPD, but will hereafter use the terminology acute exacerbation of COPD that has an evidence-based therapy.
The global initiative for chronic obstructive lung disease (GOLD) guidelines currently define an acute exacerbation of COPD as an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough with or without sputum that is beyond normal day-to-day variation, is acute in onset, and may warrant a change in medication in a patient with underlying COPD.1 As a result, much effort has been expended on measuring the diseased state accurately and accounting for the daily variability in symptoms. Therefore, accurate diagnosis of an exacerbation of COPD requires use of spirometry to first diagnose COPD, since treatment of individuals with bronchitic symptoms without obstruction can lead to overdiagnosis.
 
CLINICAL ATTRIBUTES OF A COPD EXACERBATION
Recent interest in therapies designed to decrease exacerbations has helped to focus the specifics of the definition. Unfortunately, the anatomy of an exacerbation has significant variability in most domains. In part, this variability is dependent on the severity and the phenotype of COPD. Additionally, exacerbations can be defined on the basis of clinical grounds or healthcare utilization, recognizing that more than 30% of exacerbations are not reported to a healthcare professional.7
Individuals with COPD on an average have 1–4 exacerbations yearly; however, the frequency is dependent on past exacerbation frequency and severity of COPD.8 Exacerbations can be measured by number, time to first exacerbation, duration of exacerbation, or intensity of exacerbation. However, the best measure to study for clinical trials is based on the event frequency and the variability in that event measurement.
Most of the individuals with COPD have day-to-day variability in symptoms that is poorly understood. Individuals with chronic bronchitis have more airway hyperresponsiveness and may be more susceptible to an exacerbation than individuals with emphysema. Nevertheless, the burden of a given exacerbation is likely no different between these subgroups of COPD. Instead, COPD exacerbation symptoms and healthcare utilization are closely related to baseline health status.
4
Unfortunately, uniform definitions of an acute exacerbation of COPD have not been prospectively validated. Although symptom-based definitions are popular, it has been recognized that patients under-report exacerbation frequency by approximately 50%.9 Newer attempts to prospectively validate whether symptoms are worse than day-to-day variation have been proposed. The most recent new instruments to define the frequency and severity of COPD exacerbations have been the exacerbations of chronic pulmonary disease tool (EXACT) questionnaire10 and the COPD assessment tool (CAT).11 These new tools are currently in the validation stages.
 
HEALTHCARE UTILIZATION
COPD exacerbations are responsible for physician visits, emergency room visits, hospitalizations, intensive care unit (ICU) admissions, respiratory failure and mechanical ventilation days, and death.
Indirect costs include days unable to perform usual activities and premature disability. In one study, disability between ages of 40 years and 63 years occurred in 22.8% of diagnosed COPD patients as compared to 7.3% of the remainder of the population.12
The sum of these costs varies throughout the world. Annual societal costs in 2002 ranged from US$ 1,361 in the Netherlands to US$ 6,475 in Spain.13 Additionally, the costs associated with the last 6 months of life appear higher for COPD than for lung cancer.14 The majority of these costs are with COPD exacerbation treatment.
 
PATHOPHYSIOLOGY
The inflamed airway of COPD is of multifactorial etiology. Polymorphonuclear (PMN) predominant airways cellularity is induced by cigarette smoking; however, this PMN predominant inflammation persists despite smoking cessation. Mucous gland hypertrophy leading to mucous hypersecretion, airway wall thickening, and transition of the airway to have persistent bacterial colonization, are all part of COPD pathogenesis.
The etiology of a COPD exacerbation remains incompletely understood. However, most evidence suggests that acute airways inflammation occurs on top of the chronic neutrophilic airways inflammation. PMN and eosinophils have been found in bronchial tissue.15, 16 Elevations of IL-6, fibrinogen, C-reactive protein, and procalcitonin have been found in airways and serum, suggesting systemic inflammation.17, 18 In short, most of the efforts have been spent on characterizing the cause of inflammation, recognizing that the two most likely etiologies are microbial and environmental for which there is limited therapy.
Bacterial exacerbations of COPD have traditionally been characterized when sputum purulence is prominent.Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae appear to be the predominant initiating pathogens.19 5However, many different serotypes of each pathogen can incite specific adaptive immune responses that typically peak at 4–8 weeks after the acquisition of a new bacterial strain. Additionally, some strains of acquired bacteria adhere to airway epithelial cells and elicit IL-8 in higher levels than other strains.20 The immune response, which elicits antibodies that bind to the bacterial cell surface, is also highly strain specific.21 Therefore, recurrent exacerbations can occur with small differences in surface antigen presentation with the same bacterial species.
The consequences of airways inflammation are worsened mucosal edema, airway secretions, and bronchospasm. Then ventilation-perfusion mismatch and dyspnea occur followed by cough, dyspnea, sputum production, and these lead to worsened quality of life. Patient perception, access to care, and physician's interpretation of symptoms then become the variables that define subsequent course.
In addition to bacterial infection, environmental factors play a role in some exacerbations. Airway injuries from chemical inhalation, industrial pollutants, and allergens have been identified as causes for some acute exacerbations of COPD. A history of exposure, eosinophilic airways inflammation, and less systemic inflammatory symptoms suggest these causes.1 The hunt for environmental causes of exacerbations is occasionally worthwhile, particularly when IgE-mediated allergens are involved. Thus, study of the impact of oral and inhaled corticosteroid therapy on COPD exacerbations is complicated by the need to systematically account for overlap populations with allergic disease.
Viral infections also play a role in acute exacerbations of COPD. Many prospective studies have been performed that used highly sensitive techniques of polymerase chain reaction (PCR) with or without reverse transcriptase PCR to define viral presence during exacerbations. A recent meta-analysis22 has suggested that 34.1% (95% CI: 23.9–44.4) of acute exacerbations were associated with viral pathogens. The specific viruses implicated included picornavirus 17.3% (95% CI: 7.2–27.3), influenza 7.4% (95% CI: 2.9–12.0), respiratory syncytial virus 5.3% (95% CI: 1.6–9.0), corona viruses 3.1% (95% CI: 0.4–5.8), parainfluenza 2.6% (95% CI: 0.4–4.8), adenovirus 1.1% (95% CI: −1.1–3.3), and human metapneumovirus 0.7% (95% CI: −0.3–1.8). Unfortunately, the systemic response to viral infections is similar to bacterial infections. Biomarker development to discriminate the cause of acute exacerbations has not been optimized. Serum procalcitonin and C-reactive protein (CRP) are not different between viral and nonviral causes of exacerbations.23
Influenza vaccination with the trivalent split virion vaccine has been demonstrated in some studies to lower the healthcare utilization for severe COPD patients through less hospital presentations, episodes of pneumonia, and intensive care unit stays.24 Although the immunological response to vaccination may not be as robust in a COPD population as in others without systemic illness, the benefits are sufficient to make influenza vaccination a standard of care for all COPD patients.
6
 
CLINICAL IMPACT
 
Symptoms
Cough, sputum production, and dyspnea are the core symptoms of a COPD acute exacerbation. Cough frequency, cough severity, and sputum volume remain quite difficult outcomes to systematically capture. Dyspnea has well-validated tools for clinical assessment for both baseline and transitional dyspnea indices; however, dyspnea occurs more commonly in patients with advanced COPD and does not occur in milder disease. Recently, the breathlessness, cough, and sputum severity (BCSS) instrument has been used to measure chronic COPD symptoms.25 This instrument is not designed to measure the severity or define the frequency of acute exacerbations.
 
Emergency Room Care and Hospitalization
Both emergency room (ER) utilization and hospitalization for acute exacerbation are significant events in the life of a COPD patient. Exacerbation rates are not linear over time in all patients with COPD. The first ER visit or hospitalization increases the risk of a second event and is a marker of significant one year mortality. The number and frequency of exacerbations have been the subjects of many studies since those outcomes correlate to mortality and quality of life.
The annual rate of COPD exacerbations, requiring ER or hospital care, is related to the GOLD stage of COPD. Recently, the addition of other clinical parameters in addition to FEV1 has allowed better estimates of exacerbation risk. In a recent study of the BODE score, Marin et al.26 showed that the annual rate of COPD exacerbations was 1.95 (95% CI: 0.90–2.1) in this COPD population. However, the mean time to a first exacerbation was inversely proportional to the worsening of the BODE quartiles (7.9 years, 5.7 years, 3.4 years, and 1.3 years for BODE scores of 0–2, 3–4, 5–6, and 7–10, respectively). Similarly, the mean time to a first COPD emergency room visit was 6.7 years, 3.6 years, 2.0 years, and 0.8 years for BODE quartiles.
8
Hospital outcomes of patients admitted for an acute exacerbation of COPD are also heterogeneous. In one recent series of 282 patients, 28 patients (9.9%) died during hospitalization, 241 patients (85.5%) were discharged to home, and 13 patients (4.6%) needed long-term care. Survival for two years was over 50%, although quality of life was poor.27 Living alone may be an independent predictor of hospitalization.
 
Quality of Life
Quality of life in COPD has most often been measured by the disease-specific St George's respiratory questionnaire (SGRQ). The SGRQ was devised for patients with stable chronic bronchitis and was designed with a recall period of 1–12 months. Other disease specific questionnaires include the chronic respiratory disease questionnaire (CRQ), and the baseline and transitional dyspnea index (BDI, TDI). CRQ and the SGRQ appear to be acceptable to patients during acute exacerbation. However, the recall period of the SGRQ symptom component should be shortened if used during acute exacerbation.28
Quality of life is often poor after a COPD exacerbation. The study to understand prognoses and preferences for outcomes and risk of treatments (SUPPORT) prospectively evaluated 1,016 individuals with COPD admitted to the hospital with a pCO2 > 50 mmHg. At six months, only 26% of the cohort were able to rate a good, very good, or excellent quality of life.29
 
Mortality
The mortality following a COPD exacerbation requiring hospitalization is unexpectedly high. Risk factors for high mortality include age, severity of COPD, extent of comorbidities, and intensive care unit admission. In one large study, the one year mortality of COPD exacerbations admitted to the ICU in individuals over the age of 65 years was 59%.30 Most studies have shown that need for mechanical ventilation is not a strong predictor of subsequent survival, although repeated need for mechanical ventilation is a more ominous event. Although exacerbations of COPD currently rank as the fourth most common cause of death in the United States, few studies have been performed with all cause mortality as the endpoint.
 
TREATMENT
Outcomes of acute exacerbations are related to the treatment received. Early treatment is associated with faster recovery time. Failure to report an exacerbation to a physician is associated with more hospitalization. Quality of life also appears better when exacerbations are treated as compared to a population with more untreated events.7 A number of large studies have been performed and analyzed in an attempt to both prevent exacerbations from occurring and optimize treatment of the exacerbation. Statements from the 2009 GOLD guidelines concerning COPD exacerbations are given in table 1-1.1
9
Table 1-1   GOLD Guideline Statements Concerning COPD Exacerbation1
Recommendation
Specific statement
Grade
Monitoring
Frequency, severity, likely causes of exacerbations, and psychological wellbeing should be monitored.
*
Prevention
An inhaled glucocorticosteroid combined with an inhaled beta-2 agonist is more effective than the individual components in reducing exacerbations
A
Treatment
Inhaled bronchodilators (particularly inhaled beta-2 agonists with or without anticholinergics) and oral glucocorticosteroids are effective treatments for exacerbations of COPD.
A
Antibiotics
Patients experiencing COPD exacerbations with clinical signs of airway infection (e.g., increased sputum purulence) may benefit from antibiotic treatment.
B
Ventilation
Noninvasive mechanical ventilation in exacerbations improves respiratory acidosis, increases pH, decreases the need for endotracheal intubation, and reduces PaCO2, respiratory rate, severity of breathlessness, the length of hospital stay, and mortality.
A
*Not graded.
 
Bronchodilators
In COPD exacerbations, bronchodilators improve lung function, reduce symptoms, and when administered chronically, decrease the rate of subsequent exacerbations. These benefits appear to be present with both beta-agonist and anticholinergic bronchodilators, and occur when bronchodilators are administered on top of inhaled corticosteroid therapy.31 A large study of adding salmeterol to tiotropium found no additional benefit in the reduction of exacerbation frequency, although lung function was marginally better and fewer hospitalizations were recorded compared to tiotropium alone.32 Few studies have been performed on the optimal dose or dosing frequency of bronchodilators during COPD exacerbations with robust study endpoints. COPD exacerbation outcome is not different between albuterol 2.5 mg and 5.0 mg by nebulizer every 4 hours.33 However, nebulized bronchodilators using significantly higher doses than bronchodilators administered by metered dose inhalers have been shown to have a marginal benefit during periods of clinical worsening.34
 
Corticosteroids
A few randomized controlled trials of oral or parenteral corticosteroids for COPD exacerbations, which adequately control for other variables, have been performed. 10A 2001 Cochrane review of seven such studies suggested that lung function was improved for 72 hours after the initiation of corticosteroids35 with some studies suggesting that the rate of treatment failure is less. A Veterans Administration cooperative study randomized a hospitalized COPD exacerbation cohort to placebo, short-term corticosteroids (2 weeks), or long-term corticosteroids (8 weeks). The rate of treatment failure was worse for the placebo arm and not different for the two corticosteroid arms.36
The dose and mode of corticosteroid delivery remains controversial. Recognizing that oral corticosteroids are 95% bioavailable within a short timeframe, oral dosing of corticosteroids for COPD exacerbations has achieved some favor. Recent propensity adjusted database studies suggest no difference in outcome between orally administered and intravenously administered corticosteroid dosing;37 however, more studies are clearly needed.
Studies using inhaled corticosteroids have also been performed. Inhaled corticosteroids reduce the rate of exacerbations compared to placebo, predominantly in patients with FEV1 percent predicted values < 50%.38 Combination of corticosteroid and beta-agonist inhalers shows reduced frequency of moderate and severe exacerbations than long-acting beta agonist inhalers alone39, 40 or inhaled corticosteroids alone.40 However, corticosteroid treatment of an existing exacerbation should usually be treated with oral or parenteral corticosteroids since the dose-response curve of inhaled corticosteroids is relatively flat.
 
Antibiotics
Antibiotics improve the time until COPD exacerbation recovery in most antibiotic studies performed. A recent study has shown that the addition of doxycycline to systemic corticosteroids improved the rate of clinical cure by day 10. Microbiological clearance and symptom scores were better; use of open label antibiotics was less. However, like most of the studies, eventual recovery of the patient at 30 days was not different.41
With data suggesting that new strains of bacterial organisms are associated with COPD exacerbations, there is interest in defining if antibiotics and microbial cure suppress subsequent acute exacerbations. One recent large study with 842 patients found a longer time between exacerbations when antibiotics were used for the index exacerbation with the beneficial effects seen mostly in the first 3 months following treatment (hazard ratio 0.72, 95% confidence interval 0.62–0.83). In addition, adding antibiotics to oral corticosteroids reduced the risk of all-cause mortality.42
Antibiotics should be targeted to the new bacterial species responsible for the exacerbation, if known. Unfortunately, respiratory tract cultures are difficult 11to perform since many of the bacterial organisms can also colonize the mouth. Antibiotic use is also complicated by the frequency of Pseudomonas species in the flora of some advanced COPD patients.43
 
Mucolytics and Expectorants
Mucolytics and expectorants have been used for many years to treat symptoms of excess mucus. Guaifenesin has been labeled as possibly effective by the US Food and Drug Administration; however, few trials have been done to define if therapy improves any aspect of a COPD exacerbation. Mucus viscosity is less, but possibly at the cost of excess production of mucus. Therefore, guaifenesin preparations have most commonly been used for short-term.
N-acetylcysteine (NAC) has been studied more robustly because of its efficacy as an antioxidant. Most studies have been done with oral formulations used to prevent exacerbations. A recent meta-analysis that incorporated more than 2,000 patients reported that NAC reduced the odds of COPD patients experiencing one or more exacerbations over the treatment period [odds ratio = 0.49, 95% confidence interval (0.32–0.74), p = 0.001]. Treatment effect was preserved in the presence of active smoking and lessened when used with concomitant inhaled corticosteroids.44 In fact, mucolytics are quite commonly prescribed during a COPD exacerbation in some parts of the world.45
 
Noninvasive Ventilation
A comprehensive discussion of noninvasive ventilation as a treatment strategy for COPD exacerbations is beyond the scope of this chapter. However, this is one of the category A recommendations of the GOLD guidelines at the time of hospitalization when significant hypercapnia is present. Home outpatient use of bilevel positive airway pressure (BIPAP) remains more controversial and is reserved for severely compromized COPD patients.
 
Self-management
Self-management involves a systematic approach to disease-specific education for COPD patients. Typical programs are focused on early treatment of exacerbations and often are added to exercise-based pulmonary rehabilitation. A recent review of this literature suggests that self-management reduces hospital admissions and marginally improves quality of life; primarily through the reduction in dyspnea.46 Further work is required to refine self-management programs so that optimal information can be standardized to get these health improvements.
12
13
 
FUTURE RESEARCH
More precise definition of a COPD exacerbation is one of the goals of the COPD community. Early in this decade it became clear that a paper-based diary was insufficient to adequately characterize exacerbation frequency or severity.47 Therefore, a large effort is being expended to use electronic capture of home events since early treatment of exacerbations has been shown to improve outcome of COPD exacerbations. The EXACT questionnaire is being distributed by a consortium of software vendors to allow home electronic data capture in a very short period of time, daily. Electronic capture has an advantage over diary cards since each entry is timed. When coupled with medication delivery timing devices, a better understanding of the anatomy of a COPD exacerbation will be possible.
Other areas of active research include efforts to better understand the anatomy of large and small airways on CT, oscillometry and optical coherence tomography (OCT).48 A large effort is attempting to better understand the biological events that lead to persistence of neutrophilic inflammation in the airway after the removal of airway injury such as tobacco smoke. Given the enormity of healthcare utilization for COPD exacerbations, much more research effort and more biologic treatment options are needed to understand this frequent clinical condition.
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