INTRODUCTION — Most exacerbations of chronic obstructive pulmonary disease (COPD) are due to respiratory tract infection. An important part of the evaluation is determining which patients have a treatable cause of infection and when to pursue microbiologic testing.
The role of infection in exacerbations of COPD will be reviewed here. The management of infection in exacerbations of COPD is presented separately. Precipitants, risk factors, and other interventions (eg, bronchodilators, glucocorticoids, oxygen, and mechanical ventilation) are also discussed separately. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease" and "COPD exacerbations: Management".)
DEFINITION — The Global Initiative for Chronic Obstructive Lung Disease guidelines define an exacerbation of COPD as an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days, which may be accompanied by tachypnea and/or tachycardia, and is often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insult to the airways [1,2].
ETIOLOGY — It is estimated that 70 to 80 percent of exacerbations of COPD are due to respiratory infections. The remaining 20 to 30 percent are due to eosinophilic inflammation [3], environmental pollution, nonadherence to maintenance medication, or have an unknown etiology [4]. Viral and bacterial infections cause most exacerbations, whereas atypical bacteria are a relatively uncommon cause [5,6].
Viruses — Viruses can be detected in one-third to two-thirds of exacerbations using culture, serology, and polymerase chain reaction (PCR)-based methods. The most common viruses associated with exacerbations of COPD are rhinoviruses [7]. Influenza, parainfluenza, coronavirus, and adenovirus are also common during exacerbations [7-15]. Respiratory syncytial virus and human metapneumovirus were more recently associated with exacerbations [16,17].
During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, a substantial reduction in viral respiratory illness and associated hospitalizations for COPD exacerbations was seen, probably due to masking and social distancing [18,19]. Though no systematic studies are available, it is likely that SARS-CoV-2 infection could present as an exacerbation in a patient with COPD, and therefore should be in the differential diagnosis [20]. A pre-existent diagnosis of COPD does increase mortality associated with SARS-CoV-2 infection [20]. (See 'Detection of respiratory viruses' below.)
However, the detection of a virus in the sputum sample of a patient having a COPD exacerbation is relatively common and does not necessarily mean that this is the cause of the exacerbation. In fact, such viruses have been found in up to 15 percent of asymptomatic individuals with stable COPD using sensitive PCR-based assays [7,9,13,14]. Influenza virus is an exception since asymptomatic colonization is unusual.
The mechanisms by which viruses induce exacerbations have been partially elucidated. Viral infection of the airway epithelial cells induces inflammation [21]. This causes airway epithelial damage, muscarinic receptor stimulation, and induction of inflammatory mediators (eg, cytokines, chemokines) [22]. Airway eosinophilia is sometimes associated with viral-mediated exacerbations, which highlights the importance of the host response to infection and its impact on both inflammation and symptoms [14].
Bacteria — Bacterial infections appear to trigger one-third to one-half of COPD exacerbations. Nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae are the bacteria most frequently isolated bronchoscopically from patients having an exacerbation of COPD (table 1) [23-29]. Pseudomonas aeruginosa and Enterobacteriaceae are also commonly isolated, particularly from patients with severe COPD.
Exacerbations of COPD are strongly associated with acquisition of a new strain of H. influenzae, M. catarrhalis, S. pneumoniae, or P. aeruginosa [29-34]. As a result, it has been proposed that acquisition of a new bacterial strain plays a central role in the pathogenesis of an exacerbation. This hypothesis is supported by the following observations:
●Exacerbations with new bacterial strains are more likely to be associated with a humoral immune response – In one study, exacerbations with a new strain of H. influenzae were significantly more likely to be associated with a humoral immune response than exacerbations with pre-existing strains of H. influenzae (61 versus 21 percent) [35]. These new antibodies were strain specific. M. catarrhalis, S. pneumoniae, and P. aeruginosa also induce an antibody response that is measurable following an exacerbation of COPD [33,36-38].
●Exacerbations with new bacterial strains are associated with a more robust inflammatory response – Exacerbations of COPD with a new strain of bacteria have been associated with more intense neutrophilic airway inflammation and systemic inflammation than exacerbations not associated with a change in pre-existing bacterial strains or recovery of pathogenic bacteria [39]. Resolution of the airway inflammation is related to eradication of pathogenic bacteria from sputum and resolution of clinical symptoms. In an animal model, new strains of H. influenzae that were known to be associated with COPD exacerbation caused significantly more airway neutrophil recruitment than colonizing strains of H. influenzae [40].
Most of the human studies were performed in patients with COPD who had chronic bronchitis because expectorated sputum could be obtained easily. Thus, the degree to which the data can be generalized to exacerbations in patients with COPD who do not have chronic bronchitis is unknown. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Definitions'.)
The idea that exacerbations of COPD are due to acquisition of a new strain of bacteria has largely replaced the older hypothesis that increases in the concentration of colonizing bacteria are the primary cause of exacerbations. The older theory was largely disproven by a comprehensive analysis of the relationship among sputum bacterial concentrations, exacerbation occurrence, and new pathogen acquisition [41]. The analysis demonstrated that an increase in bacterial load is not a cause of exacerbation.
Molecular diagnostics, specifically 16S ribosomal ribonucleic acid (rRNA) sequencing, have been extensively employed in the study of the airway microbiome at exacerbations and in stable COPD [15,42-45]. A reduction in diversity and an increase in Proteobacteria with increasing severity of COPD and at exacerbation have been consistently described. Another intriguing observation suggests that even exacerbations with a dominant pathogen could be polymicrobial. When known pathogens such as H. influenzae increased during acute exacerbations of COPD, closely related bacterial taxa in the phylogenetic tree were also enriched, while there was a decline in those taxa that were phylogenetically distant [43]. Though much is being learned about acute exacerbations of COPD with these new techniques, their clinical significance is not yet known.
Atypical bacteria — There are conflicting data regarding the incidence of atypical bacterial infection in patients having an exacerbation of COPD. This is related, in large part, to the varying criteria used to diagnose exacerbation and infection. The incidence of Chlamydia pneumoniae in exacerbations of COPD was 3 to 5 percent in studies using rigorous methodology that excluded pneumonia and defined infection as a strict fourfold increase in titer or a positive culture [10,46,47]. However, based on more recent studies of patients with community-acquired pneumonia that used molecular techniques, the incidence is likely even lower (<1 percent) except in the setting of epidemics (see "Pneumonia caused by Chlamydia pneumoniae in adults", section on 'Epidemiology'). Mycoplasma pneumoniae and Legionella spp are also rare causes of COPD exacerbations.
Coinfection — Coinfection with multiple pathogens is increasingly being considered in studies looking at the pathogenesis of COPD exacerbation. Such studies categorize exacerbations of COPD due to respiratory infection as being caused by viral infection alone, bacterial infection alone, or both [14,48,49]. In one study, exacerbations were equally distributed across the three categories [14].
Coinfection appears to increase the severity of COPD exacerbations. In a study of inpatients, coinfection was associated with a greater decrement of lung function and longer hospitalization [14]. In a similar study of outpatients, coinfection was associated with more symptoms, a larger fall in the forced expiratory volume in one second (FEV1), higher bacterial loads, and systemic inflammation [48].
In a human experimental model of rhinovirus-induced exacerbations, 15 days after inoculation with rhinovirus, a majority of individuals with COPD developed secondary bacterial infection, highlighting the importance of coinfection or sequential infection in exacerbations of COPD [44]. A study employing microbiome analyses to longitudinally collected sputum samples before, at, and after exacerbations demonstrated little change in microbial community structure but increased abundance of Proteobacteria at the time of exacerbations [43].
CLINICAL FEATURES
General characteristics — The three cardinal symptoms that characterize an exacerbation of COPD are [1,50]:
●Increased dyspnea
●Increased sputum volume and/or viscosity
●Increased sputum purulence
Qualitative research has highlighted the prevalence of additional symptoms of chest tightness and discomfort, sleep disturbance, anxiety, and fatigue during exacerbations [51].
Constitutional symptoms, a decrease in pulmonary function, and tachypnea are variably present during an exacerbation, but the chest radiograph is usually unchanged [1,52,53]. In the presence of severe underlying airflow obstruction, an exacerbation can cause respiratory failure and death. (See "COPD exacerbations: Clinical manifestations and evaluation".)
Features that suggest bacterial infection — Clinical indicators of potential bacterial infection include more severe COPD (eg, forced expiratory volume in one second [FEV1] <50 percent of predicted) and sputum purulence as part of the exacerbation. In one study of 40 patients with COPD exacerbations in whom bronchoscopy was performed, more patients with purulent sputum had bronchial infection than patients with mucoid sputum (77 versus 6 percent) [54]. In a separate study, sputum purulence correlated with increased airway bacteria concentrations and sputum neutrophilia [55]. Based on these observations, we believe that sputum purulence is an important, but not absolute, indicator of bacterial infection in patients with an exacerbation of COPD.
Another reliable clinical predictor of bacterial exacerbation is the Anthonisen criteria (cardinal symptoms of increased dyspnea, sputum volume, and sputum purulence) where the probability of bacterial exacerbation in type 1 and 2 exacerbations (three or two cardinal symptoms present, respectively) is 80 and 35 percent, respectively, whereas it is only 6 percent in type 3 exacerbations (one cardinal symptom present) [54].
EVALUATION FOR INFECTION — While bacterial and viral infections are common causes of COPD exacerbations, determining which patients have a treatable infectious cause of their exacerbation can be difficult. Precise knowledge of the presence and type of infecting organism, when available, enables antibiotic therapy to be targeted to those who are most likely to benefit.
When to obtain sputum studies — For most patients, obtaining sputum Gram stain and culture for microbiologic diagnosis is not necessary and not recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. The diagnostic accuracy of sputum cultures is not high, and the turnaround time is often too long to inform clinical decision-making [1,56].
However, for some patients, pursuing a microbiologic diagnosis is appropriate and we generally obtain sputum Gram stain and culture in the following patients:
●Patients with risk factors for Pseudomonas infection – Risk factors for Pseudomonas infection include recent hospitalization (≥2 days' duration during the past 90 days), frequent administration of antibiotics (≥4 courses within the past year), advanced COPD (FEV1 <30 percent of predicted), isolation of P. aeruginosa during a previous exacerbation, Pseudomonas colonization during a stable period, and systemic glucocorticoid use (table 2) [1,57,58].
In contrast with H. influenzae, M. catarrhalis, and S. pneumoniae, which are difficult to isolate from sputum cultures, Pseudomonas spp can be easily recovered from expectorated sputum obtained before initiating therapy. In addition, the susceptibility pattern of Pseudomonas is unpredictable, making the susceptibility results important for guiding the choice of antibiotic.
●Patients with failure to improve on initial empiric antibiotics – The GOLD guidelines suggest that sputum Gram stain and culture may be helpful in patients who are strongly suspected of having a bacterial infection but fail to respond to initial antibiotic therapy [1]. However, even these cultures should be interpreted with caution because of their unreliability.
●Hospitalized patients, particularly those with impending or actual acute respiratory failure due to an exacerbation of COPD – We obtain a Gram stain and sputum culture in these patients even in the absence of clear risk factors for Pseudomonas infection. Gram stain and culture showing a likely pathogen in large concentrations generally reflects the etiologic agent.
The evidence demonstrating the limited utility of routine sputum Gram stain and culture includes the following:
●Gram stain and culture of expectorated sputum yield similar results during exacerbations and stable disease [8]. In other words, they do not distinguish between true pathogens and colonizing flora. The molecular testing studies cited in the preceding section showed that newly acquired bacterial strains are often associated with exacerbations, but identification of these strains requires sequential cultures and specialized tests that are not available for routine clinical use [41] (see 'Bacteria' above). Additional supporting evidence is the presence of a likely pathogen seen on Gram stain and recovered from culture with heavy growth. Also, the failure to grow an easily cultured pathogen such as gram-negative bacilli or S. aureus from a purulent pretreatment specimen is evidence against their role in the exacerbation.
●The most common bacterial pathogens (H. influenzae, M. catarrhalis, S. pneumoniae) are frequently difficult to isolate in sputum, which increases the likelihood of a false-negative result. In one study that collected sequential sputum cultures from patients with stable COPD, molecular typing revealed that apparently identical bacterial strains of H. influenzae were intermittently recovered, suggesting that false-negative culture results were common [59]. Support for this hypothesis was provided by the observation that strain-specific H. influenzae deoxyribonucleic acid (DNA) was detected in some culture-negative sputum samples. H. influenzae is particularly problematic because Haemophilus haemolyticus, which is not a pathogen, is frequently misidentified as H. influenzae [31].
●Studies comparing culture to quantitative polymerase chain reaction (PCR) for the three most common bacterial pathogens (H. influenzae, M. catarrhalis, S. pneumoniae) also demonstrated a doubling of pathogen detection with the latter technique, confirming the low sensitivity of sputum culture [60,61]. However, the detection of these organisms by PCR can be misleading given its high sensitivity and the fact that these organisms can be part of the colonizing oropharyngeal flora.
Detection of respiratory viruses — A key step in evaluating for viral infection is to detect influenza, as it is amenable to antiviral treatment. We therefore test for influenza in all patients with COPD exacerbations when influenza is suspected (eg, during influenza season). Test selection (eg, rapid diagnostic test, PCR) depends on the treatment setting and available resources (table 3) (see "Seasonal influenza in adults: Clinical manifestations and diagnosis").
During the pandemic, we test all patients with new or worsening respiratory symptoms, regardless of vaccination status. (See "COVID-19: Diagnosis".)
The role of testing for other respiratory viruses in patients with a COPD exacerbation is less clear, as these are not amenable to specific antiviral treatment. PCR-based diagnostic panels that can detect multiple respiratory viruses simultaneously and can be performed in two to three hours in hospital laboratories have been developed [62-66]. Viruses detected by such panels include influenza, adenovirus, parainfluenza virus, respiratory syncytial virus, human metapneumovirus, coronavirus, and rhinovirus [66]. The impact of detection of these viruses (other than influenza) on clinical decision making is minimal, as they can be detected in a stable state, concomitant bacterial infection is not excluded and specific antiviral treatment is not available. We do not routinely use these panels in immunocompetent COPD patients presenting with an exacerbation. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Respiratory virus treatment' and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Other respiratory viruses'.)
Procalcitonin and C-reactive protein — Numerous studies have investigated the utility of procalcitonin and C-reactive protein (CRP) to help determine the need for antibiotic therapy in patients with acute exacerbations of COPD [67-72]. However, study results do not clearly and consistently demonstrate that use of either assay adds value to clinical judgment alone.
In one randomized trial evaluating >650 patients with acute exacerbations of COPD, CRP-guided antibiotic use was associated with a 20 percent decrease in antibiotic use (57 versus 77 percent) when compared with usual care and was not associated with an increase in adverse events [72]. The reduction in antibiotic use was greatest in patients with ≥2 Anthonisen criteria (ie, increased dyspnea, sputum production, and/or sputum purulence). While these findings are compelling, narrow-spectrum antibiotics (ie, amoxicillin or doxycycline) were used to treat >75 percent of patients in the study, suggesting that treatment in the usual care arm may have been suboptimal. Standard endpoints, such as treatment failure or relapse within four to eight weeks, were not included in this study. More studies with appropriate endpoints and outcomes are required before we incorporate CRP testing into routine clinical practice.
Trials evaluating the use of procalcitonin to guide antibiotic use in acute exacerbations of COPD are discussed separately. (See "Procalcitonin use in lower respiratory tract infections", section on 'Acute exacerbations of chronic obstructive pulmonary disease'.)
Chest imaging — We generally obtain chest imaging (eg, chest radiograph, computed tomography) for patients with possible acute exacerbation of COPD presenting to the emergency department or in hospital settings to help identify concurrent treatable conditions (eg, pneumonia, heart failure, pneumothorax). Observational studies suggest that findings on chest imaging change management in approximately 11 to 33 percent of patients in this setting [73-78].
The value of chest imaging in the outpatient setting is less clear. Systematic studies in office-based settings on the utility of chest radiology are not available and are likely to have a low yield. We therefore use clinical judgement to determine the need for chest radiology for outpatients. Clinical suspicion for pneumonia (eg, high fever, toxic appearance, signs of consolidation or pleural effusion) or for heart failure (eg, increased jugular venous pressure, bibasilar crackles, peripheral edema, abnormal heart sounds) are reasonable indications for chest imaging. Dyspnea and chest discomfort, particularly if sudden onset, should raise suspicion and prompt evaluation for pneumothorax or pulmonary embolism.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)
SUMMARY AND RECOMMENDATIONS
●Definition of an acute COPD exacerbation – An exacerbation of chronic obstructive pulmonary disease (COPD) is defined as an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days, which may be accompanied by tachypnea and/or tachycardia, and is often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insult to the airways. (See 'Definition' above.)
●Causes – Most exacerbations of COPD are due to respiratory infection. The remaining cases are due to eosinophilic inflammation, environmental pollution, or unknown causes. Respiratory infections that can cause exacerbations include viral, bacterial, and mixed infections. (See 'Etiology' above.)
●Clinical features – The three cardinal symptoms that characterize an exacerbation of COPD are increased dyspnea, increased sputum volume and/or viscosity, increased sputum purulence. Other common findings include tachypnea, chest discomfort, fatigue, sleep disturbance, and a decline in pulmonary function. (See 'Clinical features' above.)
In general, patients with more advanced COPD and those with a higher number of cardinal symptoms (particularly sputum purulence) are more likely to have bacterial infections. (See 'Features that suggest bacterial infection' above.)
●Evaluation – Determining which patients have a treatable infection and need microbiologic testing is a key part of the evaluation. (See 'Evaluation for infection' above.)
•When to obtain sputum studies – For most patients, obtaining sputum Gram stain and culture for microbiologic diagnosis is not necessary. We reserve testing for patients with COPD exacerbations with risk factors for Pseudomonas infection (table 2), failure to improve on initial empiric antibiotics, and in hospitalized patients (particularly those with impending or actual acute respiratory failure due to an exacerbation of COPD). (See 'When to obtain sputum studies' above.)
•Testing for respiratory viruses – We test for influenza in all patients with COPD exacerbations when influenza is suspected (eg, the patient presents during influenza season and has a clinical picture suggestive of influenza). (See 'Detection of respiratory viruses' above.)
During the pandemic, we test all patients with new or worsening respiratory symptoms, regardless of vaccination status. (See "COVID-19: Diagnosis".)
•When to obtain chest imaging – We generally obtain chest imaging (eg, chest radiograph, computed tomography) for patients with possible acute exacerbation of COPD presenting to the emergency department or in hospital settings to help identify concurrent treatable conditions (eg, pneumonia, heart failure, pneumothorax). The value of chest imaging in the outpatient setting is less clear. (See 'Chest imaging' above.)
●Management – The management of infection in exacerbations of COPD is presented separately. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease".)
ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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