Although there is no universal agreement on how to define or diagnose AECOPD, they are commonly defined as acute events with worsening respiratory symptoms beyond normal day-to-day variations. They usually require increased rescue β-agonist inhaler use to control symptoms.³⁶ One widely used scale to diagnose the presence and severity of AECOPD requires patients to have at least one of the following clinical presentations: upper respiratory tract infection symptoms within the previous 7 days, increased wheezing, fever without another identified cause, or an increase in heart rate or respiratory rate greater than 20% from baseline. This scale then categorizes patients into three groups based on whether they have worsening dyspnea, increase in sputum purulence, and/or increase in sputum volume. A severe exacerbation has all three criteria, a moderate exacerbation has two, and a mild exacerbation has only one.³⁷ Risk factors associated with COPD exacerbations include having three or more COPD exacerbations in the previous year, reduced FEV₁, smoking, and nonadherence with oxygen therapy.^38,39 The risk for severe exacerbation depends on each patient’s medical history, including baseline FEV₁, number of prior exacerbations, prior need for mechanical ventilation, and comorbidities. Whereas the vast majority of AECOPD can be managed in the outpatient setting, the presence of high severity should prompt consideration of hospital admission.⁴ The clinical signs of risk for respiratory failure are the most important measure of the current exacerbation’s severity. Tachypnea (especially with a respiratory rate above 25 breaths/min), tachycardia, inability to speak full sentences, and fatigue are indications for hospitalization. Oxygen saturation above 90% can be misleading because hypoxemia is frequently a late event in the progression to respiratory failure. In an acutely symptomatic patient, arterial blood gas analysis is more useful than oximetry because it can diagnose hypercapnia as well as hypoxemia. Use of accessory muscles with paradoxical breathing characterized by inward motion of the abdomen during inspiration indicates diaphragmatic fatigue and impending respiratory failure. Abdominal paradoxical breathing, progressive hypercapnia, or deteriorating mental status usually indicates the need for ventilatory support in an intensive care unit with noninvasive or invasive positive-pressure ventilation.⁴

Additional diagnostic tests include chest radiography to identify pulmonary infiltrates and electrocardiography to assess for cardiac ischemia and arrhythmias, particularly paroxysmal atrial tachycardia. The basic metabolic panel is helpful to assess severity for AECOPD. Elevated levels of sodium bicarbonate are a sign of chronic hypercapnia. Increased anion gap is a sign of anaerobic metabolism of the respiratory muscles or sepsis syndrome or both. Hyponatremia sometimes occurs as a result of the syndrome of inappropriate secretion of antidiuretic hormone. Hyperglycemia is a response to stress or systemic corticosteroids, and renal insufficiency is a manifestation of reduced cardiac output in end-stage pulmonary hypertension. The presence of these derangements may warrant hospitalization.⁴

Radiology

Although chest radiography is an insensitive test to diagnose COPD, it is the usual first step in the evaluation of patients with progressive dyspnea and cough. It is useful to assess the symptomatic patient for advanced lung cancer, pulmonary fibrosis, or congestive heart failure. Sometimes COPD is suspected because the chest radiograph shows hyperinflation with flattened diaphragm or increased retrosternal space. If bullae are observed, then COPD is highly likely. CT is the imaging modality of choice for the evaluation of COPD and many other symptomatic pulmonary diseases. Data suggest that quantitative CT allows estimation of the risk for exacerbation frequency and determination of indices of disease impact such as BODE.⁴⁰

COPD patients have a 20-fold increase in alveolar macrophages in alveoli, bronchioles, and small airways.^55,56 Because alveolar macrophages are a major source of inflammatory cytokines and growth factors, recruitment of inflammatory cells into the lung accelerates the vicious inflammatory cycle produced by microaspiration. In spite of increased numbers, alveolar macrophages have impaired phagocytosis, reducing their ability to clear bacteria from the lower airway and thereby causing further inflammation and oxidative stress.^57–60 Neutrophils are also recruited and activated by nonresolving pulmonary inflammation, particularly during exacerbations. Neutrophil elastase and metalloproteinases lead to lung parenchyma destruction. Neutrophil elastase is also a potent mucous secretagogue leading to mucous gland hyperplasia.⁶¹ Because neutrophils have a short tissue life span, the airway neutrophilia observed in COPD requires continuous neutrophil recruitment.⁶² Smoking also impairs neutrophil phagocytic function.⁶³ Collectins, pentraxins, and complement also are deficient,⁶⁴ further impairing mucosal immunity and predisposing to lower respiratory tract infections.

Pulmonary inflammation continues after smoking cessation, in part owing to permanent structural damage and in part owing to recovery of the proinflammatory capacity of epithelial cells.⁶⁵ Bacterial colonization in the lower airways is also an important determinant of the degree of airway and systemic inflammation in stable COPD.⁶⁶ Inflammatory mediators “spill over,” producing systemic inflammation with elevated levels of C-reactive protein (CRP), fibrinogen, or leukocyte count. An elevated CRP level is most strongly associated with ischemic heart disease in smokers. Systemic comorbidities such as vascular disease are major risk factors for mortality during COPD exacerbations.^67,68 Systemic inflammation caused by COPD is also hypothesized to be associated with anemia, osteoporosis, depression, and the metabolic syndrome.^69–71

Microbes in Stable COPD

Increased bacterial colonization of the lower airways in COPD occurs owing to chronic microaspiration, impaired clearance of bacteria, and frequent COPD exacerbations.^72,73 COPD patients frequently have microaspiration owing to gastroesophageal reflux due to incoordination between breathing and swallowing.^74–76 Impaired mucociliary clearance in smokers reduces the ability to clear oral microbes from the lower airways, exacerbating inflammation. This leads to chronic cough with progressive incoordination of breathing with swallowing. Inhaled medications may also carry oral bacteria into the lower airway. This vicious cycle could explain the association of poor oral health and increased airway bacterial load, COPD exacerbations, and reduced lung function.^77–81

Viruses and bacteria in the lower airway perpetuate the inflammation in COPD, causing damage by a number of mechanisms.^11,82,83 They may be ciliotoxic, invade epithelial cells causing apoptosis, increase mucin production, or degrade humoral immunity via secretion of IgA proteases.^84,85 Bacterial molecules such as endotoxins, membrane lipoproteins, peptidoglycan fragments, and lipoteichoic acid activate the innate immune response, exacerbating inflammation.⁸⁶ COPD patients whose airways are heavily colonized with bacteria have higher concentrations of inflammatory cytokines and neutrophils in respiratory secretions.⁸³ High bacterial burden in the lower airway is associated with accelerated FEV₁ decline, more comorbidity, more exacerbations, and worse symptoms during exacerbations.^{15,87,88–90}

In stable COPD, the rates of positive routine bacterial cultures of sputum vary between 22% and 83%.^91–93 However, interpreting sputum culture is difficult owing to upper airway contamination, which reduces specificity, and failure to grow fastidious bacteria from the complex lower airway microbiome, which reduces sensitivity. In stable COPD, nonpotential pathogenic microorganisms are isolated much more frequently than potential pathogenic microorganisms.⁹¹ Nonpotential pathogenic microorganisms are usually oropharyngeal microbes such as Corynebacterium spp., Neisseria spp., Enterococcus spp., coagulase-negative staphylococci, Streptococcus viridans, and fungi such as Candida spp.⁹¹ The most commonly isolated potential pathogenic microorganisms are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.^52,91,94 Culture-independent technologies that assay microbial nucleic acids and antigens often have found potential pathogens in culture-negative respiratory specimens.^95,96 For example, one third of stable COPD patients have Haemophilus influenzae within airway epithelial cells and alveolar macrophages.⁹⁷ High-throughput sequencing of microbial 16S rRNA genes yields relatively unbiased estimates of the relative abundance of uncultivable and cultivable bacteria.^98,99 The lower airways of normal individuals harbor low levels of oral bacteria such as Prevotella spp. and Veillonella spp.^100,101 Culture-independent techniques have challenged the dogma that the lower airway is normally sterile and provide evidence that there are residential organisms, especially in individuals with already damaged lungs. Oral anaerobes likely modulate the pulmonary immune response in health and disease. This possibility is supported by a growing body of data linking periodontitis, COPD exacerbations, and reduced lung function.¹⁰² However, the technical challenges produced by contamination of lower airway samples with upper airway secretions needs to be resolved to better understand the role of airway microbiome in COPD pathogenesis.

Respiratory viruses are also frequently found in patients with stable COPD. Using culture or polymerase chain reaction (PCR) techniques to assess sputum, the most common respiratory virus is respiratory syncytial virus (RSV), which is found in up to 23.5% of COPD patients, followed by non-RSV viruses, such as rhinovirus, coronavirus, and parainfluenza virus, in 16.2% of samples.¹⁰³ Increased inflammation has also been reported with adenovirus.¹⁰⁴ High-throughput complementary DNA sequencing can identify viral transcripts in an unbiased approach. A fuller understanding of the role of the virome in stable COPD and in AECOPD awaits resolution of the technical challenges of high-coverage RNA sequencing in lower respiratory tract samples.

Microbes in Acute Exacerbations of COPD

Two thirds of patients with a COPD exacerbation have bacteria or viruses or both cultured from lower airway secretions. Aerobic bacteria are isolated in half of patients, respiratory viruses are isolated in one third, and bacterial/viral coinfection is present in a fourth of patients with acute exacerbations.^52,105 The increased incidence of AECOPD during the winter may reflect the significant role that viruses play in the pathogenesis of AECOPD.

H. influenzae, S. pneumoniae, and M. catarrhalis are the bacterial pathogens most commonly isolated during COPD exacerbations. The same three also colonize stable COPD patients, and higher bacterial loads have been associated with AECOPD.^{52,94,95,106–109} In a series of studies using molecular biologic techniques, Sethi and associates have observed that acquisition of a new bacterial strain precedes AECOPD.^{83,96,106,109,110} The increase in total bacterial load during a COPD exacerbation is relatively small compared with the total bacterial load.¹⁰⁹ In their model, the humoral and cellular immune responses to the new bacterial or viral strain likely drive the increased inflammation that causes the COPD exacerbation.

Individuals with greater degrees of functional impairment, recent antibiotic use, or systemic corticosteroid therapy have higher rates of isolation of gram-negative bacteria, such as Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and members of the Enterobacteriaceae, from sputum.^111,112 Patients with an FEV₁ greater than 35% of predicted value and no systemic corticosteroid or antibiotics within the preceding 3 months have a low probability of Enterobacteriaceae or P. aeruginosa in sputum culture.¹¹² H. influenzae and P. aeruginosa are more common in patients with poorer lung function.¹⁰⁸ Polymicrobial exacerbations occur with advanced pulmonary dysfunction and severe exacerbations.^105,113

The role of “atypical” bacterial pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila in exacerbation is poorly defined, but they are rarely found in AECOPD.^50,103,114 Variations in reported rates of atypical pathogens could be related to the technical or geographic differences between reports.^89,115 When serology or M. pneumoniae antigen detection has been used to indicate the presence of M. pneumoniae as a pathogen, PCR assay and culture frequently do not confirm its presence.^103,116,117 Alternately, two reports from Italy and Greece demonstrate M. pneumoniae among between 7% and 9% of patients with AECOPD using serologic and PCR techniques.^118,119 Controversy also exists regarding the role of C. pneumoniae in COPD exacerbations. Several well-conducted studies detected no C. pneumoniae or L. pneumophila,^103,117 whereas others detected C. pneumoniae in 6% to 9% of those with AECOPD.^89,118 Chronic colonization with C. pneumoniae occurred in one third of patients and was associated with worse pulmonary function in one study.⁸⁹

Unlike stable COPD, rhinovirus is the virus most frequently associated with AECOPD.^103,105,120 Coronavirus, parainfluenza, adenovirus, influenza virus, and human metapneumovirus also occur but are less prevalent.^113,120 Coinfection with viruses and bacteria produce higher bacterial burden, more sputum eosinophils, greater lung function impairment, and longer hospitalization.^105,113 It is likely that viruses and bacteria induce independent inflammatory pathways, accounting for more severe presentations and poorer outcome of patients with coinfection.