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Evaluation for infection in exacerbations of chronic obstructive pulmonary disease

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].

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All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2023. This topic last updated: Jan 03, 2023.

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:

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.

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].

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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].

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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 (FEV ), 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

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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]:

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 [FEV ] <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

Increased dyspnea●

Increased sputum volume and/or viscosity●

Increased sputum purulence●

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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 (FEV <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].

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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.

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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.

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The evidence demonstrating the limited utility of routine sputum Gram stain and culture includes the following:

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".)

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.

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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].

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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.

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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.)

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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.)

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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.)

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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.

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.)

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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.)

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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.)

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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.)

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Management – The management of infection in exacerbations of COPD is presented separately. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease".)

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68. Daubin C, Valette X, Thiollière F, et al. Procalcitonin algorithm to guide initial antibiotic therapy in acute exacerbations of COPD admitted to the ICU: a randomized multicenter study. Intensive Care Med 2018; 44:428.

69. Mathioudakis AG, Chatzimavridou-Grigoriadou V, Corlateanu A, Vestbo J. Procalcitonin to guide antibiotic administration in COPD exacerbations: a meta-analysis. Eur Respir Rev 2017; 26.

70. Stolz D, Christ-Crain M, Bingisser R, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest 2007; 131:9.

71. Prins HJ, Duijkers R, van der Valk P, et al. CRP-guided antibiotic treatment in acute exacerbations of COPD in hospital admissions. Eur Respir J 2019; 53.

72. Butler CC, Gillespie D, White P, et al. C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations. N Engl J Med 2019; 381:111.

73. Sherman S, Skoney JA, Ravikrishnan KP. Routine chest radiographs in exacerbations of chronic obstructive pulmonary disease. Diagnostic value. Arch Intern Med 1989; 149:2493.

74. Jain P, Misra A. Routine chest x-ray in chronic obstructive airways disease: a myth. N Z Med J 1990; 103:163.

75. Tsai TW, Gallagher EJ, Lombardi G, et al. Guidelines for the selective ordering of admission chest radiography in adult obstructive airway disease. Ann Emerg Med 1993; 22:1854.

76. Emerman CL, Cydulka RK. Evaluation of high-yield criteria for chest radiography in acute exacerbation of chronic obstructive pulmonary disease. Ann Emerg Med 1993; 22:680.

77. Malagari K, Voloudaki A. Radiology of AECOPD. In: Acute Exacerbations of Chronic Obstructi ve Pulmonary Disease, Siafakis N, Antonisen NR, Georgopoulos D (Eds), CRC Press, Boca Ra ton, FL 2003. p.161.

78. Royal College of Physicians. National COPD Audit 2008 http://www.rcplondon.ac.uk/resourc es/chronic-obstructive-pulmonary-disease-audit (Accessed on January 17, 2014).

Topic 108592 Version 21.0

GRAPHICS

Relative frequency of bacterial pathogens isolated from 14 antibiotic comparison trials in exacerbations of chronic obstructive pulmonary disease*

Pathogen Percentage of bacterial isolates (range)

Haemophilus influenzae 13 to 50

Moraxella catarrhalis 9 to 21

Streptococcus pneumoniae 7 to 26

Pseudomonas aeruginosa 1 to 13

* Enterobacteriaceae have been isolated from the respiratory tract of 3 to 19 percent of patients with chronic obstructive pulmonary disease (COPD) exacerbations and Staphylococcus aureus has been isolated from the respiratory tract of 1 to 20 percent of patients with COPD exacerbations, but their pathogenic significance in this setting has not been defined. Haemophilus parainfluenzae has been isolated from the respiratory tract of 2 to 32 percent of patients with COPD exacerbations, but these organisms are unlikely to cause COPD exacerbations.

Modified with permission from the American Thoracic Society. Copyright © 2004 American Thoracic Society. Sethi S. Bacteria in exacerbations of chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society 2004; 1:109. Official Journal of the American Thoracic Society.

Graphic 70203 Version 9.0

Risk factors for infection with Pseudomonas aeruginosa in patients with acute COPD exacerbations

Chronic colonization or previous isolation of Pseudomonas aeruginosa from sputum (particularly in the past 12 months)

Very severe COPD (FEV <30% predicted)

Bronchiectasis on chest imaging

Broad-spectrum antibiotic use within the past 3 months

Chronic systemic glucocorticoid use

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

References: 1. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation:

a prospective study. Eur Respir J 2009; 34:1072. 2. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012;

7:1129. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary

disease: characterization and risk factors. BMC Pulm Med 2014; 14:103. 4. Boixeda R, Almagro P, Díez-Manglano J, et al. Bacterial flora in the sputum and comorbidity in patients with acute

exacerbations of COPD. Int J Chron Obstruct Pulmon Dis 2015; 10:2581.

Graphic 126162 Version 1.0

1

1

Influenza diagnostic tests for respiratory specimens

Test Time to results

Comments

Recommended tests

Conventional molecular assays, including real-time RT-PCR and multiplex PCR (nucleic acid detection)

1 to 8 hours High sensitivity and very high specificity Can differentiate influenza A and B, as well as influenza A subtypes Multiplex PCR detects other respiratory viruses and bacterial pathogens

Rapid molecular assays (nucleic acid detection)

15 to 30 minutes High sensitivity and specificity Can differentiate influenza A and B, but cannot not differentiate influenza A subtypes

Additional tests

Rapid influenza diagnostic tests (antigen detection)

<15 minutes Low to moderate sensitivity; high specificity

Direct and indirect immunofluorescence (antigen detection)

1 to 4 hours Moderately high sensitivity; high specificity

Viral culture

Shell viral culture 1 to 3 days Moderately high sensitivity; highest specificity Not useful for timely clinical management Used for public health surveillance

Conventional culture 3 to 10 days

Refer to UpToDate content on diagnosis of influenza in adults and children for additional details about the choice and interpretation of influenza tests. Refer to the United States Centers for Disease Control and Prevention information on influenza testing methods for additional details.

RT-PCR: reverse-transcriptase polymerase chain reaction.

References: 1. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America:

2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal

[1,2]

influenza. Clin Infect Dis 2019; 68:895. 2. United States Centers for Disease Control and Prevention. Influenza virus testing methods. Available at:

https://www.cdc.gov/flu/professionals/diagnosis/table-testing-methods.htm (Accessed on August 31, 2021).

Graphic 69655 Version 21.0

Contributor Disclosures

Sanjay Sethi, MD Grant/Research/Clinical Trial Support: Astra Zeneca [COPD]; Regeneron [COPD]; Theravance [COPD]. Consultant/Advisory Boards: Astra Zeneca [COPD]; BI [COPD]; Chiesi [COPD]; GSK [Asthma, COPD]; Nuvaira [COPD]; Pulmonx [COPD]. Speaker's Bureau: AstraZeneca [COPD]; BI [COPD]; GSK [COPD]. All of the relevant financial relationships listed have been mitigated. Timothy F Murphy, MD No relevant financial relationship(s) with ineligible companies to disclose. Julio A Ramirez, MD, FACP Grant/Research/Clinical Trial Support: Eli Lilly [Monoclonal antibodies]; Janssen [Vaccines]; Pfizer [Vaccines]. Consultant/Advisory Boards: Dompe [Infectious diseases]; Nabriva [Respiratory infections]; Paratek [Respiratory infections]; Pfizer [Vaccines]. All of the relevant financial relationships listed have been mitigated. Sheila Bond, MD No relevant financial relationship(s) with ineligible companies to disclose. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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COPD exacerbations: Clinical manifestations and evaluation

INTRODUCTION

The Global Initiative for Chronic Obstructive Lung Disease (GOLD), a report produced by the National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO), defines an exacerbation of chronic obstructive pulmonary disease (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]. This generally includes an acute change in one or more of the following cardinal symptoms:

The clinical manifestations and evaluation of patients with exacerbations of COPD are discussed in detail here. A table to assist with emergency management of severe acute exacerbations of COPD is provided ( table 1). The diagnosis and treatment of stable COPD and the treatment, risk factors, prognosis, and prevention of exacerbations of COPD are discussed separately.

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All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2023. This topic last updated: Sep 25, 2023.

Cough increases in frequency and severity●

Sputum production increases in volume and/or changes character●

Dyspnea increases●

(See "Chronic obstructive pulmonary disease: Diagnosis and staging".)●

(See "Stable COPD: Overview of management".)●

EPIDEMIOLOGY

Among patients with COPD, the frequency of exacerbation varies with the severity of disease, and some patients have more frequent exacerbations than others independent of other measures of disease severity [1,3].

RISK FACTORS AND TRIGGERS

Risk factors — According to observational studies, the risk of developing an exacerbation of COPD correlates with the following features [8-13]:

(See "COPD exacerbations: Management".)●

(See "COPD exacerbations: Prognosis, discharge planning, and prevention".)●

Among almost 100,000 patients with COPD, the number of exacerbations in a baseline year of observation predicted the rate over the subsequent 10 years [4]. Approximately, 25 percent did not have an exacerbation; those with one baseline exacerbation were likely to have another (hazard ratio [HR] 1.71, 95% CI 1.66-1.77); and those with ≥5 events were even more likely to have future events (HR 3.41, 95% CI 3.27-3.56).

●

A study of Medicare beneficiaries found a 64 percent readmission rate after a discharge for a COPD exacerbation [5].

●

In a survey that included over 4000 respondents with COPD, approximately 10 to 25 percent needed an emergency room evaluation for COPD and 5 to 10 percent required hospitalization [6].

●

In a separate survey of more than 1000 patients, 21 percent of those who reported a COPD exacerbation required hospitalization [7].

●

Advanced age●

Productive cough●

Longer duration of COPD●

History of antibiotic therapy●

COPD-related hospitalization within the previous year●

Chronic mucous hypersecretion●

Peripheral blood eosinophil count >0.3 x 10 cells/L (340 cells/microL)● 4 9

Theophylline therapy●

Women are slightly more likely to experience a COPD exacerbation than men [13,14]. In general, worsening airflow limitation (lower forced expiratory volume in one second [FEV ]) is associated with an increasing risk of COPD exacerbation, although airflow limitation alone does not provide a good assessment of exacerbation risk [1].

Other potential contributors to an increased risk of exacerbations include the following:

Presence of one or more comorbidities (eg, ischemic heart disease, heart failure, or diabetes mellitus)  

●

1

Severity of COPD and history of prior exacerbations – The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines suggest using primarily history of exacerbations, history of hospitalization for exacerbation, and symptoms to assess the exacerbation risk [1]. The number of exacerbations in the previous 12 months is stratified: a history of zero or one exacerbation suggests a low future risk of exacerbations, while two or more suggest a high future risk [1]. Symptoms (based on instruments such as the COPD Assessment Test [CAT] and the modified Medical Research Council Dyspnea Scale) further divide patients at low-risk into separate categories for more individualized pharmacologic management ( algorithm 1).

●

In the prospective Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, 2138 patients with moderate to severe airflow limitation (forced expiratory volume in one second [FEV ] <80 percent predicted) were followed for three years [15]. The single best predictor of exacerbations was a history of prior exacerbations, regardless of severity of airway obstruction [4].

1

Worsening airflow obstruction remains associated with an increasing prevalence of exacerbations, hospitalization, and death [16]. It is used as a component of the BODE index, a prognostic tool that can also be used to assess therapeutic response to medications, pulmonary rehabilitation therapy, and other interventions [17].

Different COPD staging systems and severity assessments are discussed in more detail separately. (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Assessment of severity and staging'.)

Gastroesophageal reflux disease – Gastroesophageal reflux disease (GERD) may be an additional risk factor for COPD exacerbations [18,19]. In the ECLIPSE study noted above, the occurrence of two or more exacerbations in a year was associated with a history of GERD or heartburn [15]. A similar observation was made in a case-control study that assessed the presence of GERD symptoms and frequency of COPD exacerbations in 80

●

Triggers — Respiratory infections, most commonly viral (eg, rhinovirus) or bacterial, are estimated to trigger approximately 70 percent of COPD exacerbations ( table 2) [1,26]; atypical bacteria are a relatively uncommon cause [27,28]. The remaining 30 percent are due to environmental pollution, pulmonary embolism, or have an unknown etiology [1,29-31]. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease".)

COPD exacerbations have been associated with exposure to poor outdoor air quality, such as higher levels of ozone, carbon monoxide, particulate matter (up to 10 microns), and nitrogen dioxide [32,33]. Increased ambient levels of fine particulate matter (≤2.5 microns, aka PM ) are associated with an increase in hospitalization and mortality in COPD [34]. In a trial of 116 patients with COPD and exposure to poor air quality at home (PM >10 mcg/m ), use of indoor

patients with COPD. The presence of GERD symptoms was associated with an increased risk of COPD exacerbations (RR 6.55, 95% CI 1.86-23.11) [18]. However, in an observational study of 638 patients with stable COPD, therapy with proton pump inhibitors did not decrease the risk for severe exacerbations [20]. Additional studies are needed to determine whether GERD contributes to the development of COPD exacerbations.

Left ventricular diastolic dysfunction – Left ventricular diastolic dysfunction at baseline is associated with a higher frequency of hospitalization for COPD exacerbation [21]. Diastolic dysfunction is common in patients with COPD, likely due to both comorbid vascular mechanisms (eg, hypertension, coronary artery disease, systemic inflammation) as well as metabolic and structural consequences of COPD (eg, lung hyperinflation, chronic hypoxia, and hypercapnia) [22,23]. Many of these contributing factors worsen during an exacerbation and may lead to diastolic decompensation, followed by pulmonary congestion and bronchial hyper-reactivity [24]. High heart rates, whether due to breathlessness, anxiety, or atrial arrhythmias, further exacerbate this pathophysiology.

●

Pulmonary hypertension – Secondary pulmonary hypertension may be an additional risk factor for COPD exacerbations, possibly as an indicator of disease severity. In a follow-up to the ECLIPSE study, chest computed tomography scans were used to compute the ratio of the diameter of the pulmonary artery to the diameter of the aorta (PA:A ratio) [25]. In the study, a PA:A ratio greater than 1 was an independent risk factor for a future severe exacerbation (OR 3.44, 95% CI 2.78-4.25). Notably, a PA:A ratio >1 suggests the presence of pulmonary hypertension, although it does not clarify the cause of pulmonary hypertension (eg, hypoxemia due to COPD or other lung disease, left heart failure, sleep apnea). The clinical usefulness of this observation in terms of treatment decisions is unclear.

●

2.5

2.5 3

air filters versus sham air filters resulted in a dose-dependent improvement in respiratory symptoms and risk of moderate exacerbations [35].

As dyspnea and cough are nonspecific symptoms, COPD exacerbations of unknown etiology may be triggered or caused by other medical conditions, such as myocardial ischemia, heart failure, aspiration, or pulmonary embolism [1,36].

The relationship between COPD exacerbation and pulmonary embolism is illustrated by a prospective multicenter study of 1580 patients with COPD who were admitted to the hospital with acute worsening of respiratory symptoms [37]. Pulmonary embolism was identified in 266 (17 percent) when all patients were screened with CT of the pulmonary arteries (CTPA); 166 patients (11 percent) had pulmonary embolism involving the main or lobar pulmonary arteries. The presence of new purulent sputum reduced the odds of pulmonary embolism. Although the frequency of pulmonary embolism among patients hospitalized with an exacerbation of COPD varies across studies [38-41], a systematic review prior to this multicenter study showed a similar pooled prevalence of 23 percent when all patients were evaluated by CTPA within 48 hours of hospital admission (seven studies, 999 patients) [42]. An important limitation of these studies is their inability to determine whether the pulmonary embolism is the cause of the COPD exacerbation, a result of the COPD exacerbation, or a mere bystander.

CLINICAL MANIFESTATIONS

The clinical manifestations of exacerbations of COPD range from a mild increase in dyspnea, cough that is productive or nonproductive to respiratory failure with acute respiratory acidosis and/or hypoxemia.

Medical history — By definition, patients present with the acute onset or worsening of respiratory symptoms, such as dyspnea, cough, and/or sputum production, over several hours to days [1,43]. These symptoms should be characterized further in terms of the following features:

Associated features that might suggest an alternate diagnosis or comorbidity include:

Time course of the symptoms●

Comparison to baseline level of symptoms●

Severity of respiratory compromise (eg, dyspnea at rest, dyspnea climbing stairs, dyspnea severity using a visual analog [1-10] scale)

●

Delineation of sputum characteristics (eg, amount, color, purulence, blood)●

Use of home oxygen now or in the past●

Patients should be asked if they currently smoke cigarettes or use vaping products. The past history of exacerbations should be ascertained: number of prior exacerbations, courses of systemic glucocorticoids, antibiotic therapy in the preceding three months, prior exacerbations requiring hospitalization or ventilatory support, and response to therapy of previous exacerbations.

Physical examination — Physical findings associated with an exacerbation of COPD often include wheezing and tachypnea and may include features of respiratory compromise such as difficulty speaking due to respiratory effort, use of accessory respiratory muscles, and paradoxical chest wall/abdominal movements (asynchrony between chest and abdominal motion with respiration). Tachycardia is also frequently present.

If present, decreased mental status could reflect hypercapnia or hypoxemia and asterixis could indicate hypercapnia.

Attention should also be paid to other physical findings, such as fever, hypotension, bibasilar fine crackles and peripheral edema, which might suggest a comorbidity or alternate diagnosis.

EVALUATION AND DIAGNOSIS

The goals of the evaluation of a suspected exacerbation of COPD are to confirm the diagnosis, identify the cause (when possible), assess the severity of respiratory impairment and contribution from comorbidities, and exclude alternate diagnostic possibilities. A rapid overview for the evaluation and management of severe exacerbations of COPD is provided in the table ( table 1).

Initial evaluation — The choice of specific tests is guided by the severity of the exacerbation and the particular associated clinical findings. (See 'Clinical manifestations' above.)

For patients with a mild exacerbation (absence of resting dyspnea or respiratory distress, preserved ability to perform activities of daily living), who do not require emergency

Constitutional symptoms (eg, fever, chills, night sweats)●

Chest pain, chest pressure, peripheral edema, or palpitations●

Risk factors for coronary disease●

Risk factors for thromboembolic disease●

Upper respiratory symptoms that might suggest a viral respiratory infection or exposure to anyone with influenza

●

department treatment, the evaluation may be limited to clinical assessment and possibly pulse oxygen saturation.

For patients who require emergency department care, the evaluation should generally include the following ( table 1):

We do not use procalcitonin or C-reactive protein to determine the need for antibiotics in COPD exacerbations, as study results do not clearly and consistently demonstrate that either assay adds value to clinical judgment alone. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'Procalcitonin and C-reactive protein'.)

Additional testing — Additional tests are largely used to exclude processes in the differential diagnosis and are obtained depending on the degree of diagnostic uncertainty following clinical evaluation and initial testing.

Assessment of pulse oxygen saturation●

A chest radiograph to exclude pneumonia, pneumothorax, pulmonary edema, pleural effusion, followed by a chest CT angiogram to exclude pulmonary embolism in those whose chest radiograph does not reveal an acute process

●

Laboratory studies (eg, complete blood count and differential, serum electrolytes and glucose)

●

Arterial blood gas (ABG) analysis is obtained if acute or acute-on-chronic respiratory acidosis is suspected or if ventilatory support is anticipated. Concern about acute-on- chronic hypercapnia might be prompted by a history of prior elevation in arterial tension of carbon dioxide (PaCO ), an elevated serum bicarbonate (perhaps reflecting compensation for chronic hypercapnia), or the presence of severe airflow obstruction (eg, forced expiratory volume in one second [FEV ] <50 percent of predicted)

●

2

1

Electrocardiogram and blood cardiac troponins are obtained to evaluate tachycardia and/or potential myocardial ischemia. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department".)

●

Plasma brain natriuretic peptide (BNP) or NT-proBNP can help to exclude heart failure, as indicated by features such as crackles on chest auscultation, peripheral edema, suggestive chest radiographic findings (eg, vascular congestion, pleural effusion). If the clinical picture is unclear, an echocardiogram should be obtained. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)

●

Chest CT pulmonary angiogram can help exclude pulmonary embolism as a trigger or alternative diagnosis for respiratory symptoms. The frequency of pulmonary embolism in patients with COPD and acute respiratory symptoms in the hospital setting appears to be between 15 to 25 percent [37,42]. In one multicenter study of nearly 1600 patients hospitalized for COPD exacerbation who were assessed with CT pulmonary angiogram, the rates of pulmonary embolism based on low, moderate, or high probability Wells criteria scores were 7, 38, and 74 percent, respectively [37]. Purulent sputum production decreased the odds of venous thromboembolism by approximately 60 percent. Given this prevalence rate, we suggest obtaining imaging for pulmonary embolism (typically CT pulmonary angiogram) in patients with severe symptoms who do not have evidence of other triggers (eg, infection or heart failure). (See 'Differential diagnosis' below and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".)

●

Sputum Gram stain and culture are not obtained for most exacerbations of COPD. However, sputum Gram stain and culture can be useful in patients at risk for a poor outcome or increased risk of infection with Pseudomonas ( table 3 and table 4). Sputum culture may be helpful in patients who are strongly suspected of having a bacterial infection but fail to respond to initial antibiotic therapy. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'When to obtain sputum studies'.)

●

Influenza testing is appropriate during influenza season or in patients with features of influenza (eg, acute onset of fever, myalgias, coryza during an influenza outbreak). Rapid antigen testing and direct or indirect immunofluorescence antibody staining tests are useful screening tests for influenza infection but have limited sensitivity; polymerase chain reaction (PCR)-based testing is more sensitive and specific. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

●

COVID-19 – Test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the coronavirus disease 2019 (COVID-19) pandemic. (See "COVID-19: Diagnosis".)

●

Respiratory virus panel in selected patients – The majority of COPD exacerbations are caused by viral infections, predominantly adenovirus. While not necessary in most patients, PCR diagnostic panels can detect multiple respiratory viruses simultaneously (eg, influenza, adenovirus, parainfluenza virus, respiratory syncytial virus, human metapneumovirus, coronavirus, and rhinovirus). These studies are more frequently

●

Severity of exacerbation — The classification of exacerbation severity proposed by an international commission and adopted by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) is based on symptoms, vital signs, and arterial blood gas (ABG) and c-reactive protein values (if obtained) ( figure 1) [1,17]:

DIFFERENTIAL DIAGNOSIS

Patients with COPD who present to the hospital with acute worsening of dyspnea should be evaluated for potential alternative diagnoses, such as heart failure, cardiac arrhythmia, pneumonia, pulmonary embolism, and pneumothorax [1,44,45]. A chest radiograph will differentiate among several of these possibilities (eg, heart failure, pneumonia, pneumothorax); a clear chest radiograph may be a clue to pulmonary embolism, especially when dyspnea and hypoxemia are more prominent than cough or sputum production.

The importance of considering these alternate diagnoses was illustrated in an autopsy study of 43 patients with COPD who died within 24 hours of admission for a COPD exacerbation [44]. The primary causes of death were heart failure, pneumonia, pulmonary thromboembolism, and COPD in 37, 28, 21, and 14 percent, respectively.

obtained in patients with community-acquired pneumonia, and the exact indications for their use in COPD exacerbations are not clear.

Mild – Dyspnea <5 on a visual analog (1-10) scale (VAS); respiratory rate <24 breaths per minute; heart rate <95 beats per minute; resting SaO2 ≥92 percent breathing ambient air or the patient's usual oxygen prescription and change in saturation ≤3 percent from baseline (if known); CRP<10 mg/L (if obtained). Treatment with short-acting bronchodilators is often sufficient for mild exacerbations.

●

Moderate – Three out of five of the following: Dyspnea ≥5 on VAS; respiratory rate ≥24 breaths per minute, heart rate ≥95 beats per minute; resting SaO2 <92 percent breathing ambient air or the patient's usual oxygen prescription and/or change in saturation >3 percent from baseline (if known); CRP ≥10 mg/L (if obtained). Treatment of moderate exacerbations generally includes short-acting bronchodilators plus antibiotics and/or oral glucocorticoids.

●

Severe – Meets moderate criteria combined with hypercapnia and acidosis on ABG (PaCO2 >45 mmHg and pH <7.35). Treatment of severe exacerbations includes short-acting bronchodilators, antibiotics, and oral or intravenous glucocorticoids. Severe exacerbations may be associated with respiratory failure and require noninvasive or invasive ventilation.

●

Heart failure – Acute decompensated heart failure (ADHF) is characterized by the development of acute dyspnea associated with elevated intracardiac filling pressures with or without pulmonary edema. HF may be new or an exacerbation of chronic disease. The diagnosis of ADHF is a clinical diagnosis based upon the presence of a constellation of symptoms and signs of HF. While test results (eg, natriuretic peptide level, chest radiograph, echocardiogram) are often supportive, the diagnosis cannot be based on a single test. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)

●

Cardiac arrhythmias – Cardiac arrhythmias, such as atrial fibrillation, are frequent in patients with COPD, and may be a trigger or consequence of COPD exacerbation [1]. A bedside electrocardiogram can be diagnostic. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".)

●

Pneumonia – Pneumonia can present with acute shortness of breath, hypoxemia, and an inconclusive pulmonary examination. Chest radiograph findings may differ, but some cases of bibasilar pneumonia may be similar to HF, although evidence of upper zone redistribution is not present with pneumonia. Fever and leukocytosis may suggest an infectious process. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

●

Pneumothorax – COPD is a risk factor for pneumothorax. Worsening dyspnea can be due to either a COPD exacerbation or pneumothorax, but acute pleuritic chest pain would be more suggestive of pneumothorax while increased volume of sputum and sputum purulence would suggest a COPD exacerbation. A pneumothorax is usually apparent on conventional chest radiograph or thoracic ultrasound, although bullous emphysema can mimic a pneumothorax and necessitate a chest computed tomography (CT) scan for differentiation. (See "Clinical presentation and diagnosis of pneumothorax".)

●

Pulmonary embolism – The sudden onset of symptoms such as dyspnea, pleuritic chest pain, tachypnea, and cough may be caused by a pulmonary embolism. The suspicion for pulmonary embolism rises in the absence of purulent sputum production, history of an upper respiratory infection, or pneumothorax [36-42,46,47]. (See 'Triggers' above and 'Additional testing' above.)

●

Testing may include a blood D-dimer test, lower extremity compression ultrasonography with Doppler, and CT pulmonary angiogram. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute 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 – A COPD exacerbation is an event characterized by dyspnea and/or cough and sputum production that worsens over ≤14 days and is often associated with increased local and systemic inflammation arising from airway infection, pollution, or other insult to the airways. (See "COPD exacerbations: Management", section on 'Introduction'.)

●

Risk factors – Risk factors for exacerbations of COPD include advanced age, productive cough, duration of COPD, history of antibiotic therapy, COPD-related hospitalization within the previous year, chronic mucous hypersecretion, blood eosinophil count >0.34 x 10 cells/L (340 cells/microL), and comorbid disease. The single best predictor of exacerbations is a history of prior exacerbations. (See 'Risk factors and triggers' above and "COPD exacerbations: Prognosis, discharge planning, and prevention", section on 'Prognosis after an exacerbation'.)

●

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Triggers – Respiratory infections are estimated to trigger approximately 70 percent of COPD exacerbations. Viral and bacterial infections are most common; atypical bacterial infection is an uncommon trigger. Other potential triggers include myocardial ischemia, heart failure, aspiration, and pulmonary embolism. (See 'Triggers' above.)

●

Clinical manifestations●

Symptoms – The three cardinal symptoms of COPD exacerbation are dyspnea, cough, and/or sputum production; they can occur alone or in combination. Exacerbations typically develop over several hours to days. Symptoms such as fever, chills, night sweats, chest pain, or peripheral edema suggest an alternate or comorbid diagnosis. (See 'Clinical manifestations' above.)

•

Physical exam findings – Physical findings associated with an exacerbation of COPD often include wheezing and tachypnea and may include features of respiratory compromise. Patients should be examined for physical findings, such as fever,

•

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REFERENCES

1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diag nosis, Management and Prevention of Chronic Obstructive Pulmonary Disease: 2023 Repor t. www.goldcopd.org www.goldcopd.org (Accessed on December 13, 2022).

2. Celli BR, Fabbri LM, Aaron SD, et al. An Updated Definition and Severity Classification of Chronic Obstructive Pulmonary Disease Exacerbations: The Rome Proposal. Am J Respir Crit Care Med 2021; 204:1251.

3. Seemungal TA, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157:1418.

4. Rothnie KJ, Müllerová H, Smeeth L, Quint JK. Natural History of Chronic Obstructive Pulmonary Disease Exacerbations in a General Practice-based Population with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2018; 198:464.

5. Lindenauer PK, Dharmarajan K, Qin L, et al. Risk Trajectories of Readmission and Death in the First Year after Hospitalization for Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2018; 197:1009.

6. Landis SH, Muellerova H, Mannino DM, et al. Continuing to Confront COPD International Patient Survey: methods, COPD prevalence, and disease burden in 2012-2013. Int J Chron Obstruct Pulmon Dis 2014; 9:597.

hypotension, bibasilar fine crackles and peripheral edema, which might suggest a comorbidity or alternate diagnosis. (See 'Physical examination' above.)

Evaluation – For patients who require emergency department care, the evaluation should generally include a pulse oxygen saturation, chest radiograph, complete blood count and differential, and serum electrolytes and glucose ( table 1). Arterial blood gases (ABGs) are obtained when acute or acute-on-chronic hypercapnia is suspected due to prior elevation in arterial tension of carbon dioxide (PaCO ), an elevated serum bicarbonate, or the presence of severe airflow obstruction (eg, FEV <50 percent predicted). (See 'Initial evaluation' above.)

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Differential diagnosis – The most common processes in the differential diagnosis of a COPD exacerbation are heart failure, cardiac arrhythmias, pulmonary embolism, pneumonia, and pneumothorax. (See 'Differential diagnosis' above.)

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7. Miravitlles M, Anzueto A, Legnani D, et al. Patient's perception of exacerbations of COPD– the PERCEIVE study. Respir Med 2007; 101:453.

8. Miravitlles M, Guerrero T, Mayordomo C, et al. Factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory COPD patients: a multiple logistic regression analysis. The EOLO Study Group. Respiration 2000; 67:495.

9. Rascon-Aguilar IE, Pamer M, Wludyka P, et al. Role of gastroesophageal reflux symptoms in exacerbations of COPD. Chest 2006; 130:1096.

10. Niewoehner DE, Lokhnygina Y, Rice K, et al. Risk indexes for exacerbations and hospitalizations due to COPD. Chest 2007; 131:20.

11. Burgel PR, Nesme-Meyer P, Chanez P, et al. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest 2009; 135:975.

12. Vedel-Krogh S, Nielsen SF, Lange P, et al. Blood Eosinophils and Exacerbations in Chronic Obstructive Pulmonary Disease. The Copenhagen General Population Study. Am J Respir Crit Care Med 2016; 193:965.

13. Oshagbemi OA, Keene SJ, Driessen JHM, et al. Trends in moderate and severe exacerbations among COPD patients in the UK from 2005 to 2013. Respir Med 2018; 144:1.

14. Stolz D, Kostikas K, Loefroth E, et al. Differences in COPD Exacerbation Risk Between Women and Men: Analysis From the UK Clinical Practice Research Datalink Data. Chest 2019; 156:674.

15. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010; 363:1128.

16. Soriano JB, Lamprecht B, Ramírez AS, et al. Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2007 and 2011 staging systems: a pooled analysis of individual patient data. Lancet Respir Med 2015; 3:443.

17. Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004; 350:1005.

18. Terada K, Muro S, Sato S, et al. Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation. Thorax 2008; 63:951.

19. Kim J, Lee JH, Kim Y, et al. Association between chronic obstructive pulmonary disease and gastroesophageal reflux disease: a national cross-sectional cohort study. BMC Pulm Med 2013; 13:51.

20. Baumeler L, Papakonstantinou E, Milenkovic B, et al. Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in

COPD. Respirology 2016; 21:883.

21. Bhatt SP, Agusti A, Bafadhel M, et al. Phenotypes, Etiotypes, and Endotypes of Exacerbations of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2023.

22. López-Sánchez M, Muñoz-Esquerre M, Huertas D, et al. High Prevalence of Left Ventricle Diastolic Dysfunction in Severe COPD Associated with A Low Exercise Capacity: A Cross- Sectional Study. PLoS One 2013; 8:e68034.

23. Farouk H, Albasmi M, El Chilali K, et al. Left ventricular diastolic dysfunction in patients with chronic obstructive pulmonary disease: Impact of methods of assessment. Echocardiography 2017; 34:359.

24. Bhatt SP, Dransfield MT. Chronic obstructive pulmonary disease and cardiovascular disease. Transl Res 2013; 162:237.

25. Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med 2012; 367:913.

26. Sapey E, Bafadhel M, Bolton CE, et al. Building toolkits for COPD exacerbations: lessons from the past and present. Thorax 2019; 74:898.

27. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med 2008; 359:2355.

28. Mohan A, Chandra S, Agarwal D, et al. Prevalence of viral infection detected by PCR and RT- PCR in patients with acute exacerbation of COPD: a systematic review. Respirology 2010; 15:536.

29. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med 2000; 343:269.

30. Sapey E, Stockley RA. COPD exacerbations . 2: aetiology. Thorax 2006; 61:250.

31. Gan WQ, FitzGerald JM, Carlsten C, et al. Associations of ambient air pollution with chronic obstructive pulmonary disease hospitalization and mortality. Am J Respir Crit Care Med 2013; 187:721.

32. de Miguel-Díez J, Hernández-Vázquez J, López-de-Andrés A, et al. Analysis of environmental risk factors for chronic obstructive pulmonary disease exacerbation: A case-crossover study (2004-2013). PLoS One 2019; 14:e0217143.

33. Ross BA, Doiron D, Benedetti A, et al. Short-term air pollution exposure and exacerbation events in mild to moderate COPD: a case-crossover study within the CanCOLD cohort. Thorax 2023; 78:974.

34. Li MH, Fan LC, Mao B, et al. Short-term Exposure to Ambient Fine Particulate Matter Increases Hospitalizations and Mortality in COPD: A Systematic Review and Meta-analysis. Chest 2016; 149:447.

35. Hansel NN, Putcha N, Woo H, et al. Randomized Clinical Trial of Air Cleaners to Improve Indoor Air Quality and Chronic Obstructive Pulmonary Disease Health: Results of the CLEAN AIR Study. Am J Respir Crit Care Med 2022; 205:421.

36. Tillie-Leblond I, Marquette CH, Perez T, et al. Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med 2006; 144:390.

37. Liu X, Jiao X, Gong X, et al. Prevalence, Risk Factor and Clinical Characteristics of Venous Thrombus Embolism in Patients with Acute Exacerbation of COPD: A Prospective Multicenter Study. Int J Chron Obstruct Pulmon Dis 2023; 18:907.

38. Pourmand A, Robinson H, Mazer-Amirshahi M, Pines JM. Pulmonary Embolism Among Patients With Acute Exacerbation Of Chronic Obstructive Pulmonary Disease: Implications For Emergency Medicine. J Emerg Med 2018; 55:339.

39. Hassen MF, Tilouche N, Jaoued O, Elatrous S. Incidence and Impact of Pulmonary Embolism During Severe COPD Exacerbation. Respir Care 2019; 64:1531.

40. Couturaud F, Bertoletti L, Pastre J, et al. Prevalence of Pulmonary Embolism Among Patients With COPD Hospitalized With Acutely Worsening Respiratory Symptoms. JAMA 2021; 325:59.

41. Jiménez D, Agustí A, Tabernero E, et al. Effect of a Pulmonary Embolism Diagnostic Strategy on Clinical Outcomes in Patients Hospitalized for COPD Exacerbation: A Randomized Clinical Trial. JAMA 2021; 326:1277.

42. Sato R, Hasegawa D, Nishida K, et al. Prevalence of pulmonary embolism in patients with acute exacerbations of COPD: A systematic review and meta-analysis. Am J Emerg Med 2021; 50:606.

43. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 1987; 106:196.

44. Zvezdin B, Milutinov S, Kojicic M, et al. A postmortem analysis of major causes of early death in patients hospitalized with COPD exacerbation. Chest 2009; 136:376.

45. Myint PK, Lowe D, Stone RA, et al. U.K. National COPD Resources and Outcomes Project 2008: patients with chronic obstructive pulmonary disease exacerbations who present with radiological pneumonia have worse outcome compared to those with non-pneumonic chronic obstructive pulmonary disease exacerbations. Respiration 2011; 82:320.

46. Rizkallah J, Man SFP, Sin DD. Prevalence of pulmonary embolism in acute exacerbations of COPD: a systematic review and metaanalysis. Chest 2009; 135:786.

47. Aleva FE, Voets LWLM, Simons SO, et al. Prevalence and Localization of Pulmonary Embolism in Unexplained Acute Exacerbations of COPD: A Systematic Review and Meta- analysis. Chest 2017; 151:544.

Topic 122144 Version 20.0

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Initial emergency management of severe COPD exacerbations: Rapid overview of emergency management

Clinical features

Features of COPD exacerbation: Diffuse wheezing, distant breath sounds, barrel-shaped chest, tachypnea, tachycardia, smoking >20 pack years.

Features of severe respiratory insufficiency: Use of accessory muscles; brief, fragmented speech; inability to lie supine; profound diaphoresis; agitation; asynchrony between chest and abdominal motion with respiration; failure to improve with initial emergency treatment.

Features of impending respiratory arrest: Inability to maintain respiratory effort, cyanosis, hemodynamic instability, and depressed mental status

Features of cor pulmonale: Jugular venous distension, prominent left parasternal heave, peripheral edema.

COPD exacerbations are most often precipitated by infection (viral or bacterial).

Severe respiratory distress in a patient with known or presumed COPD can be due to an exacerbation of COPD or a comorbid process, such as acute coronary syndrome, decompensated heart failure, pulmonary embolism, pneumonia, pneumothorax, sepsis.

Management

Assess patient's airway, breathing, and circulation; secure as necessary.

Provide supplemental oxygen to target a pulse oxygen saturation of 88 to 92% or PaO of 60 to 70 mmHg (7.98 to 9.31 kPa); Venturi mask can be useful for titrating FiO ; high FiO usually not needed and can contribute to hypercapnia (high FiO requirement should prompt consideration of alternative diagnosis [eg, PE]).

Determine patient preferences regarding intubation based on direct questioning or advance directive whenever possible.

Provide combination of aggressive bronchodilator therapy and ventilatory support (NIV or invasive ventilation).

Noninvasive ventilation (NIV): Appropriate for the majority of patients with severe exacerbations of COPD unless immediate intubation is needed or NIV is otherwise contraindicated

Contraindications to NIV include: Severely impaired consciousness, inability to clear secretions or protect airway, high aspiration risk.

Initial settings for bilevel NIV: 8 cm H O inspiratory pressure (may increase up to 15 cm H O if needed to aid ventilation); 3 cm H O expiratory pressure.

Administer bronchodilators via nebulizer or MDI: Nebulizer usually requires interruption of NIV; MDIs can be delivered in line using adaptor (refer to dosing below).

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Obtain ABG after two hours of NIV and compare with baseline: Worsening or unimproved gas exchange and pH <7.25 are indications for invasive ventilation.

Tracheal intubation and mechanical ventilation: Indicated for patients with acute respiratory failure, hemodynamic instability (eg, heart rate <50/minute, uncontrolled arrhythmia) and those in whom NIV is contraindicated or who fail to improve with NIV and aggressive pharmacotherapy

Rapid sequence induction (eg, etomidate, ketamine, or propofol).

Intubate with #8 endotracheal tube (8 mm internal diameter) or larger, if possible.

Initial ventilator settings aim to maintain adequate oxygenation and ventilation while minimizing elevated airway pressures: SIMV, tidal volume 6 to 8 mL/kg, respiratory rate 10 to 12/minute, inspiratory flow rate 60 to 80 L/min (increase if needed to enable longer expiratory phase), PEEP 5 cm H O. May need to tolerate elevated PaCO to avoid barotrauma (ie, permissive hypercapnia). In patients with chronic hypercapnia, aim for PaCO close to baseline.

Administer inhaled bronchodilator therapy: Usually via MDI with in-line adaptor (refer to dosing below).

Diagnostic testing

Assess oxygen saturation with continuous pulse oximetry.

Obtain ABG in all patients with severe COPD exacerbation.

ETCO monitoring (capnography) has only moderate correlation with arterial PaCO in COPD exacerbations.

Do not assess peak expiratory flow or spirometry in acute severe COPD exacerbations as results are not accurate.

Obtain portable chest radiograph: Look for signs of pneumonia, acute heart failure, pneumothorax.

When evidence of acute infection (eg, purulent phlegm, pneumonia) is absent and chest radiograph is unrevealing, obtain CT pulmonary angiogram for possible pulmonary embolism.

Obtain complete blood count, electrolytes (Na+, K+, Cl–, HCO3–), BUN, and creatinine; also obtain cardiac troponin, BNP, or NT-proBNP, if diagnosis is uncertain.

Test for influenza infection during influenza season.*

Obtain ECG: Look for arrhythmia, ischemia, cor pulmonale.

Pharmacotherapy

Inhaled beta agonist: Albuterol 2.5 mg diluted to 3 mL via nebulizer or 2 to 4 inhalations from MDI every hour for 2 or 3 doses; up to 8 inhalations may be used for intubated patients, if needed.

Short-acting muscarinic antagonist (anticholinergic agent): Ipratropium 500 micrograms (can be combined with albuterol) in 3 mL via nebulizer or 2 to 4 inhalations from MDI every hour for 2 to 3 doses.

Intravenous glucocorticoid (eg, methylprednisolone 60 mg to 125 mg IV, repeat every 6 to 12

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hours).

Antibiotic therapy*: Appropriate for majority of severe COPD exacerbations; select antibiotic based on likelihood of particular pathogens (eg, Pseudomonas risk factors , prior sputum cultures, local patterns of resistance).

No Pseudomonas risk factor(s) : Ceftriaxone 1 to 2 grams IV, or cefotaxime 1 to 2 grams IV, or levofloxacin 500 mg IV or orally, or moxifloxacin 400 mg IV or orally

Pseudomonas risk factor(s) : Piperacillin-tazobactam 4.5 grams IV, or cefepime 2 grams IV, or ceftazidime 2 grams IV

Antiviral therapy (influenza suspected)*: Oseltamivir 75 mg orally every 12 hours or peramivir 600 mg IV once (for patients unable to take oral medication).

Monitoring

Perform continual monitoring of oxygen saturation, blood pressure, heart rate, respiratory rate.

Close monitoring of respiratory status.

Continuous ECG monitoring.

Monitor blood glucose.

Disposition

Criteria for ICU admission include:

Patients with high-risk comorbidities (pneumonia, cardiac arrhythmia, heart failure, diabetes mellitus, renal failure, liver failure)

Continued need for NIV or invasive ventilation

Hemodynamic instability

Need for frequent nebulizer treatments or monitoring

COPD: chronic obstructive pulmonary disease; PaO : arterial tension of oxygen; FiO : fraction of inspired oxygen; PE: pulmonary embolism; NIV: noninvasive ventilation; MDI: metered dose inhaler; ABG: arterial blood gas; SIMV: synchronized intermittent mechanical ventilation; PEEP: positive end- expiratory pressure; PaCO : arterial tension of carbon dioxide; ETCO : end-tidal carbon dioxide; BUN: blood urea nitrogen; BNP: brain natriuretic peptide; NT-ProBNP: N-terminal pro-BNP; ECG: electrocardiogram; IV: intravenous; ICU: intensive care unit.

* When influenza is suspected, therapy should not be delayed while awaiting results of testing. Doses shown are for patients with normal renal function. Some agents require dose adjustment for renal impairment; refer to separate UpToDate algorithms of antibiotic treatment of exacerbations of COPD.

¶ Pseudomonas infection risk factors: Broad spectrum antibiotic use in the past 3 months; chronic colonization or previous isolation of Pseudomonas aeruginosa from sputum (particularly in past 12 months); very severe underlying COPD (FE 1 <30% predicted); chronic systemic glucocorticoid use.

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Graphic 65420 Version 12.0

New diagnosis of COPD

COPD: chronic obstructive pulmonary disease; COVID-19: coronavirus disease 2019; GOLD: Global Initiative f CAT: COPD Assessment Test; SABA: short-acting beta-agonist; SAMA: short-acting muscarinic antagonist; LAM (anticholinergic); LABA: long-acting beta-agonist; mMRC: Modified Medical Research Council; FEV : forced ex forced vital capacity.

* COPD is diagnosed based on the presence of chronic respiratory symptoms (dyspnea, cough, sputum prod limitation. All patients with COPD defined by GOLD have airflow limitation based on a reduced FEV /FVC ratio is determined by the reduction in FEV .

¶ An exacerbation of COPD is characterized by increased dyspnea and/or cough and sputum that worsens in accompanied by tachypnea or tachycardia, and is often caused by infection, environmental irritation, or othe exacerbations" are typically defined as those which require treatment with systemic glucocorticoids. More o been proposed but are difficult to establish via patient history. Please refer to UpToDate content on "COPD e and evaluation" for additional information.

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Δ CAT: http://www.catestonline.org (Accessed on January 12, 2023).

◊ For those prescribed a LABA alone, SAMA-SABA combination therapy is likely to be most potent but will ha LAMA. For those prescribed a LAMA, SAMA should generally not be used concomitantly, so SABA alone is pre

§ Occasional patients with only minimal intermittent symptoms are appropriate for only as-needed rescue th acting bronchodilators.

Graphic 54300 Version 13.0

Relative frequency of bacterial pathogens isolated from 14 antibiotic comparison trials in exacerbations of chronic obstructive pulmonary disease*

Pathogen Percentage of bacterial isolates (range)

Haemophilus influenzae 13 to 50

Moraxella catarrhalis 9 to 21

Streptococcus pneumoniae 7 to 26

Pseudomonas aeruginosa 1 to 13

* Enterobacteriaceae have been isolated from the respiratory tract of 3 to 19 percent of patients with chronic obstructive pulmonary disease (COPD) exacerbations and Staphylococcus aureus has been isolated from the respiratory tract of 1 to 20 percent of patients with COPD exacerbations, but their pathogenic significance in this setting has not been defined. Haemophilus parainfluenzae has been isolated from the respiratory tract of 2 to 32 percent of patients with COPD exacerbations, but these organisms are unlikely to cause COPD exacerbations.

Modified with permission from the American Thoracic Society. Copyright © 2004 American Thoracic Society. Sethi S. Bacteria in exacerbations of chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society 2004; 1:109. Official Journal of the American Thoracic Society.

Graphic 70203 Version 9.0

Risk factors for poor outcomes in patients with acute COPD exacerbations

Comorbid conditions (especially heart failure or ischemic heart disease)

Severe underlying COPD (eg, FEV <50%)

Frequent exacerbations of COPD (ie, ≥2 exacerbations per year)

Hospitalization for an exacerbation within the past 3 months

Receipt of continuous supplemental oxygen

Age ≥65 years*

Patients with greater underlying COPD severity are at higher risk for poor outcomes if initial antibiotic therapy is inadequate. We thus use a broader empiric regimen for such patients.

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

* Older age (eg, age ≥65 years) is also associated with poorer outcomes and/or risk of infection with drug-resistant pathogens. While not a strict indication for broadening antibiotic therapy, we consider older age as additive to the risk factors listed above.

References: 1. Balter MS, La Forge J, Low DE, et al. Canadian guidelines for the management of acute exacerbations of chronic

bronchitis. Can Respir J 2003; 10 Suppl B:3B. 2. Miravitlles M, Murio C, Guerrero T. Factors associated with relapse after ambulatory treatment of acute exacerbations

of chronic bronchitis. DAFNE Study Group. Eur Respir J 2001; 17:928. 3. Wilson R, Jones P, Schaberg T, et al. Antibiotic treatment and factors influencing short and long term outcomes of

acute exacerbations of chronic bronchitis. Thorax 2006; 61:337. 4. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation:

a prospective study. Eur Respir J 2009; 34:1072. 5. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012;

7:1129.

Graphic 126161 Version 1.0

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1

Risk factors for infection with Pseudomonas aeruginosa in patients with acute COPD exacerbations

Chronic colonization or previous isolation of Pseudomonas aeruginosa from sputum (particularly in the past 12 months)

Very severe COPD (FEV <30% predicted)

Bronchiectasis on chest imaging

Broad-spectrum antibiotic use within the past 3 months

Chronic systemic glucocorticoid use

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

References: 1. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation:

a prospective study. Eur Respir J 2009; 34:1072. 2. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012;

7:1129. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary

disease: characterization and risk factors. BMC Pulm Med 2014; 14:103. 4. Boixeda R, Almagro P, Díez-Manglano J, et al. Bacterial flora in the sputum and comorbidity in patients with acute

exacerbations of COPD. Int J Chron Obstruct Pulmon Dis 2015; 10:2581.

Graphic 126162 Version 1.0

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Initial assessment of suspected COPD exacerbation severity and etiology

Diagnostic flowchart for assessment of suspected COPD exacerbation severity and etiology.

ECOPD: exacerbation of chronic obstructive pulmonary disease; ABG: arterial blood gas; CRP: C-reactive protein; HR: heart rate; PaO : arterial partial pressure of oxygen; PaCO : arterial partial pressure of carbon dioxide; pH: arterial acid-base status; RR: respiratory rate; SaO : peripheral arterial oxygen saturation, as determined by pulse oximetry; VAS: visual analog scale.

* Dyspnea (as determined by VAS), RR, HR, oxygen saturation (absolute and/or change), and CRP.

Reprinted with permission of the American Thoracic Society. Copyright © 2023 American Thoracic Society. All rights reserved. Celli BR, Fabbri LM, Aaron SD, et al. An updated definition and severity classification of chronic obstructive pulmonary disease exacerbations: The Rome

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proposal. Am J Respir Crit Care Med 2021; 204:1251. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Contributor Disclosures

James K Stoller, MD, MS Grant/Research/Clinical Trial Support: Alpha-1 Foundation [Alpha-1 antitrypsin detection]. Consultant/Advisory Boards: 23andMe [Alpha-1 antitrypsin deficiency]; 4DMT [Alpha-1 antitrypsin deficiency]; Alpha-1 Foundation [Member, Board of Directors]; Bridgebio [Alpha-1 antitrypsin deficiency]; CSL Behring [Alpha-1 antitrypsin detection]; Dicerna [Alpha-1 antitrypsin deficiency]; Grifols [Alpha-1 antitrypsin detection]; InhibRx [Alpha-1 antitrypsin deficiency]; Insmed [Alpha-1 antitrypsin deficiency]; Korro [Alpha-1 antitrypsin deficiency]; Takeda [Alpha-1 antitrypsin detection]; Vertex [Alpha-1 antitrypsin deficiency]. All of the relevant financial relationships listed have been mitigated. Peter J Barnes, DM, DSc, FRCP, FRS Grant/Research/Clinical Trial Support: AstraZeneca [Asthma, COPD]; Boehringer [COPD]; Novartis [COPD]. Consultant/Advisory Boards: AstraZeneca [Asthma, COPD]; Boehringer [COPD]; Epi-Endo [Asthma, COPD]; Novartis [COPD]; Teva [COPD]. Speaker's Bureau: AstraZeneca [Asthma]; Boehringer [COPD]; Novartis [COPD]; Teva [Asthma]. All of the relevant financial relationships listed have been mitigated. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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Management of infection in exacerbations of chronic obstructive pulmonary disease

INTRODUCTION

Most exacerbations of chronic obstructive pulmonary disease (COPD) are caused by respiratory tract infections. Empiric antibiotic therapy is indicated for patients who are most likely to have a bacterial infection causing the exacerbation and for those who are most ill.

The role of antibiotic therapy in exacerbations of COPD will be reviewed here. The evaluation for infection in exacerbations of COPD and other aspects of management (eg, bronchodilators, glucocorticoids, oxygen, and mechanical ventilation) are discussed separately. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease" and "COPD exacerbations: Management".)

DEFINITIONS

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].

The three cardinal symptoms that characterize an exacerbation of COPD are [1,3]:

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All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2023. This topic last updated: Mar 03, 2023.

Other findings that may accompany the cardinal symptoms of an exacerbation of COPD (eg, tachypnea, chest discomfort, fatigue, sleep disturbance, decline in pulmonary function) are discussed separately. (See "COPD exacerbations: Management".)

INDICATIONS FOR ANTIBACTERIAL THERAPY

Our approach — Empiric antibiotic therapy is indicated for patients who are most likely to have a bacterial infection causing the exacerbation and for those who are most ill [1,4]. In general, we determine the need for antibiotics based on the number of cardinal symptoms present, and the need for hospitalization and/or ventilatory support [1,5-7].

Antibiotics are also indicated for patients with concurrent pneumonia (ie, those with fever, signs of consolidation on chest examination and/or chest imaging). Selection of an antibiotic regimen for patients with pneumonia differs from COPD exacerbations and is discussed separately. (See "Overview of community-acquired pneumonia in adults" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults".)

Rationale — Our approach is based upon randomized trials and large cohort studies demonstrating that prompt, appropriate antibiotic use improves clinical outcomes for selected patients with COPD exacerbations [3,9-16]. The benefit is greatest in severely ill patients and those with a greater number of symptoms but appears to diminish as the severity of illness declines. In a meta-analysis of five randomized trials evaluating 803 patients hospitalized with an acute COPD exacerbation, antibiotic use was associated with reduced treatment failure when compared with placebo (risk ratio [RR] 0.76, 95% CI 0.58-1.0) [9]. The benefits of antibiotic treatment were most prominent in a single trial evaluating 93 intensive care unit (ICU) patients,

Increased dyspnea●

Increased sputum volume and/or viscosity●

Increased sputum purulence●

We suggest empiric antibiotic treatment in patients with a COPD exacerbation and ≥2 of 3 cardinal symptoms: increased dyspnea, increased sputum volume/viscosity, or increased sputum purulence or a COPD exacerbation requiring hospitalization and/or ventilatory support (either invasive or noninvasive).

●

We do not initiate antibiotic therapy in patients with a COPD exacerbation and only 1 of 3 cardinal symptoms who do not require hospitalization or ventilatory support. New onset of increased wheezing may serve as an additional negative predictor for bacterial infection; therefore, if it is a prominent finding, it steers us away from antibiotic use [8].

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which showed a reduction in all-cause mortality (4 versus 22 percent with placebo) in addition to reductions in treatment failure, duration of mechanical ventilation, length of ICU stay, and need for additional courses of antibiotics [10]. In a cohort study evaluating >84,000 hospitalized patients with COPD exacerbations, the risk of treatment failure was lower when antibiotics were given in the first two hospital days compared with later treatment or no treatment (odds ratio [OR] 0.87, 95% CI 0.82-0.92) [12]. Multivariate analysis of this cohort demonstrated that antibiotic treatment was associated with decreased risk of in-hospital mortality (OR 0.60, 95% CI 0.50-0.73) and a substantial reduction in the risk of 30-day readmission for COPD (OR 0.87, 95% CI 0.79-0.96) [14].

Although meta-analyses of randomized trials and large cohort studies have also found reduced treatment failure rates with antibiotic use in outpatients [9,11], the benefit appears to be greatest in those with a higher number of cardinal symptoms. This finding is best supported by the Anthonisen trial, one of the largest and more rigorous randomized trials evaluating the efficacy for antibiotics for COPD exacerbations to date [3]. The trial evaluated 173 patients and a total of 362 COPD exacerbations over a three and a half year period. Antibiotic therapy was associated with increased clinical improvement (defined as resolution of symptoms without additional intervention) compared with placebo (68 versus 55 percent). The greatest effect was observed in patients who presented with increased dyspnea, sputum production, and sputum purulence when compared with placebo (63 versus 43 percent); benefit was least evident in patients with only one of these three symptoms (75 versus 70 percent). This observation serves as the foundation for the antibiotic treatment indications outlined above.

Based upon these studies, most clinical practice guidelines recommend antibiotic treatment of moderate to severe exacerbations for outpatients and patients who require hospitalization but not routinely for those with mild exacerbations in the outpatient setting [1]. Our approach is similar to but varies slightly from the strategy outlined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), which recommends antibiotic therapy for patients who have the following features: a severe exacerbation requiring mechanical ventilation (noninvasive or invasive), an exacerbation with all three cardinal symptoms, or an exacerbation with two of these three symptoms if sputum purulence is one of the symptoms [1,3,17]. While some studies suggest that sputum purulence is associated with an increased likelihood of infection [18,19], this finding is not consistent across studies [20,21], and we do not consider this finding alone to be clearly predictive of need for antibiotic treatment [22,23].

CRP and procalcitonin — Multiple studies have addressed use of serum biomarkers, such as C- reactive protein (CRP) and procalcitonin, to help determine the need for antibiotic treatment in patients with COPD exacerbations [24-29]. However, study results do not clearly and

consistently demonstrate that use of either assay adds value to clinical judgment alone; we generally do not use them to guide treatment decisions. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'Procalcitonin and C- reactive protein' and "Procalcitonin use in lower respiratory tract infections", section on 'Acute exacerbations of chronic obstructive pulmonary disease'.)

EMPIRIC ANTIBACTERIAL TREATMENT

Risk stratification — We use a "risk stratification" approach when selecting initial empiric antibiotic therapy for the treatment of acute exacerbations of COPD [30,31]. We categorize patients based on treatment setting (eg, outpatient versus inpatient), risk for poor clinical outcomes, and risk for infection with Pseudomonas ( algorithm 1A-B).

This approach to risk stratification promotes judicious antibiotic use by reserving broader spectrum empiric regimens for patients with greater underlying COPD severity [32,39,40].

Risk for poor outcomes – Patients with greater underlying COPD severity are at higher risk for poor outcomes if initial antibiotic therapy is inadequate. We thus use a broader empiric regimen for such patients. Risk factors for poor outcomes include [32-34]:

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Comorbid conditions (especially heart failure or ischemic heart disease)• Severe underlying COPD (forced expiratory volume in one second [FEV ] <50 percent)• 1

Frequent exacerbations of COPD (ie, ≥2 exacerbations per year)• Hospitalization for an exacerbation within the past three months• Receipt of continuous supplemental oxygen•

Older age (eg, age ≥65 years) is also associated with poorer outcomes and/or risk of infection with drug-resistant pathogens. While not a strict indication for broadening antibiotic therapy, we consider older age as additive to the risk factors listed above.

Risk for pseudomonal infection – Patients with greater underlying COPD severity are also at risk for infection with Pseudomonas. Specific factors associated with an increased risk of Pseudomonas infection include [35-38]:

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Chronic colonization or previous isolation of Pseudomonas aeruginosa from sputum• Very severe COPD (FEV <30 percent predicted)• 1

Bronchiectasis on chest imaging (eg, chest radiograph, computed tomography)• Broad-spectrum antibiotic use within the past three months• Chronic systemic glucocorticoid use•

Although it has not been validated in clinical trials, similar approaches are used for the treatment of other infectious diseases (eg, community-acquired pneumonia, acute rhinosinusitis) [41,42].

Antibiotic selection — Empiric antibiotic regimens are designed to target the most likely infecting pathogens ( table 1). Specific antibiotic selection and need for sputum Gram stain and culture vary based on risk for poor clinical outcomes, risk for infection with Pseudomonas, and treatment setting ( algorithm 1A-B) [1,34,37]. Determining need for hospitalization in patients with COPD exacerbations is discussed elsewhere. (See "COPD exacerbations: Management", section on 'Triage to home or hospital'.) (Related Pathway(s): Chronic obstructive pulmonary disease: Identifying patients with an acute exacerbation who warrant hospitalization.)

Outpatients — Antibiotic therapy is indicated for outpatients with COPD exacerbations and an increase in ≥2 of 3 cardinal symptoms: dyspnea, sputum volume/viscosity, or sputum purulence ( algorithm 1A) [34,37]. Patients with only one cardinal symptom generally do not require antibiotic therapy. (See 'Indications for antibacterial therapy' above.) (Related Pathway(s): Chronic obstructive pulmonary disease: Empiric antimicrobial therapy for outpatients with acute exacerbations.)

For outpatients who do not have risk factors for poor outcomes or Pseudomonas infection, we target Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis and select among the following options: a macrolide (ie, azithromycin, clarithromycin) or a second- or third-generation cephalosporin (eg, cefuroxime, cefpodoxime, cefdinir). Trimethoprim-sulfamethoxazole is a reasonable alternative to these agents but not first line because trial data suggest it may be less effective [43]. We no longer use doxycycline based on a randomized trial showing minimal benefit [44].

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For outpatients who have risk factors for poor outcomes (but no increased risk for Pseudomonas infection) ( table 2), we broaden the initial regimen to include treatment for macrolide-resistant S. pneumoniae and to enhance eradication of H. influenzae. For these patients, we select either amoxicillin-clavulanate or a respiratory fluoroquinolone (ie, levofloxacin or moxifloxacin).

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For outpatients who have risk factors for poor outcomes and a risk for Pseudomonas infection ( table 3), we generally treat with ciprofloxacin. Because fluoroquinolone resistance is prevalent among P. aeruginosa strains, we also obtain a sputum Gram stain and culture with susceptibility testing for these patients to help guide subsequent

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In most cases, several treatment options are available. We select among antibiotic options based on the patient's previous response to that agent, patient allergies and intolerances, the drug's adverse event profile, drug interactions, susceptibility pattern of organisms isolated in recent sputum cultures (if available), and local antimicrobial resistance patterns. In some instances, local antibiotic resistance rates can be determined by obtaining an antibiogram from a local hospital. However, this information is not always available or readily accessible.

In general, we also avoid using the same antibiotic class more than once within a three-month period. Antibiotic exposure in the previous three months is one of the best predictors of pathogens resistant to that drug class in an individual patient. For example, if a patient has responded well and tolerated a certain antibiotic and that antibiotic was not used within the past three months, then that agent (or one in the same class) is a good choice. However, if that agent was used within the past three months, then an agent of a different class should be selected.

The antibiotic selection outlined above is based on the susceptibility profiles and evolving resistance patterns of the most common pathogens. For example, amoxicillin, which was favored in the past, is no longer a recommended agent because it is inactivated by many nontypeable H. influenzae and most strains of M. catarrhalis. Doxycycline resistance among S. pneumoniae is prevalent in some regions, and it does not appear to improve clinical outcomes when compared with systemic glucocorticoids alone [44,45]; thus, it is also no longer first line. This approach is further supported by a meta-analysis of 12 randomized trials evaluating >2100 patients, which showed that amoxicillin-clavulanic acid, macrolides, second- or third-generation cephalosporins, and fluoroquinolones were more effective than amoxicillin, ampicillin, pivampicillin, trimethoprim-sulfamethoxazole, and doxycycline for the treatment of COPD

management decisions (eg, change in therapy based on susceptibility testing for those who do not respond to empiric treatment). (See 'Follow-up' below.)

Some experts add amoxicillin or another agent with better activity against S. pneumoniae to ciprofloxacin for broader empiric treatment.

Levofloxacin is a reasonable alternative for patients who have risk factors for Pseudomonas infection but no prior history of positive cultures for Pseudomonas. Although levofloxacin is less potent than ciprofloxacin for the treatment of Pseudomonas, it has comparatively greater activity against other common pathogens (S. pneumoniae and M. catarrhalis). Moxifloxacin is not recommended for patients with risk factors for Pseudomonas, as it has little activity against this pathogen.

exacerbations (odds ratio [OR] 0.51, 95% CI 0.34-0.75) [46]. Treatment success was defined as resolution or improvement of symptoms.

Several studies have compared the efficacy of macrolides, fluoroquinolones, and amoxicillin- clavulanate with one another [43,47,48]. One meta-analysis of 19 trials, evaluating >7400 patients with COPD exacerbations, compared the effectiveness of macrolides (ie, azithromycin, clarithromycin), fluoroquinolones (ie, levofloxacin, moxifloxacin, ciprofloxacin), and amoxicillin- clavulanate [43]. Antibiotic selection did not affect short-term treatment success, defined as resolution or improvement of symptoms. However, among patients who had a pathogen isolated from sputum at presentation, treatment success was lower for macrolides when compared with fluoroquinolones (OR 0.47, 95% CI 0.31-0.69). Recurrence, in the 26 weeks following therapy, was also less frequent in patients who were treated with fluoroquinolones compared with macrolides. The reduction in treatment success observed with macrolides may be related to their limited ability to eradicate H. influenzae. Amoxicillin-clavulanate had similar efficacy when compared with other agents but was associated with more adverse effects (mostly diarrhea) than the other drugs. In a subsequent randomized trial evaluating >500 patients with exacerbations of COPD, moxifloxacin and amoxicillin-clavulanate appeared to have similar overall efficacy [47]. However, clinical failure rates were lower with moxifloxacin when the analysis was limited to patients with a pathogen isolated from sputum (19 versus 25 percent). Adverse effects associated with fluoroquinolone use are discussed separately. (See "Fluoroquinolones" and "Fluoroquinolones", section on 'Adverse effects'.)

Hospitalized patients — For patients hospitalized for treatment of a COPD exacerbation (who lack clinical and radiographic suspicion for pneumonia), we primarily base empiric antibiotic selection on the risk for Pseudomonas ( algorithm 1B). We select among appropriate options based on the patient's previous response to that agent, patient allergies and intolerances, the drug's adverse event profile, drug interactions, local antimicrobial resistance patterns, and the susceptibility pattern of organisms isolated in recent sputum cultures (if available).

For most inpatients without risk factors for Pseudomonas infection, we select either a respiratory fluoroquinolone (ie, levofloxacin 500 mg orally or intravenously [IV] once daily or moxifloxacin 400 mg orally or IV once daily) or a third-generation cephalosporin (eg, ceftriaxone or cefotaxime).

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For most inpatients with risk factors for Pseudomonas infection, we select one of the following: cefepime, ceftazidime, or piperacillin-tazobactam (4.5 g IV every six hours). For those who cannot tolerate these agents, alternatives include ciprofloxacin, aztreonam, certain carbapenems (eg, meropenem, imipenem), and aminoglycosides. Each comes with relative disadvantages when compared with the antipseudomonal beta-lactams

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For all hospitalized patients who are able to produce a good-quality sputum sample, we obtain a Gram stain and culture to help guide management. For most others, we do not obtain microbiologic testing on sputum because it has limited diagnostic accuracy and results are unlikely to change management. (See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'When to obtain sputum studies'.)

Patients with clinical concern for concurrent pneumonia should be treated with empiric antibiotic regimens based on the suspected pathogens, severity of illness, and type of pneumonia. (See "Treatment of community-acquired pneumonia in adults who require hospitalization" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults".)

Additional detail on the antibiotic selection for patients with known or suspected pseudomonal infections are provided separately. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

Duration — The duration of therapy for patients who are clinically improving is generally five days for outpatients and five to seven days for hospitalized patients. However, azithromycin can be given for as few as three days when administered at a dose of 500 mg orally daily because of its long half-life. Patients who are initially started on parenteral antibiotics should be switched to an oral regimen when able to take medications orally.

A meta-analysis that compared five days with seven or more days of antimicrobial therapy (fluoroquinolones, cefixime, or clarithromycin) for exacerbations of COPD found no difference in outcome between the two groups, although there were fewer adverse events among patients who received a five-day course [49].

Some experts use procalcitonin, a biomarker that rises in response to bacterial infections, to guide antibiotic duration. However, clinical utility and safety of using procalcitonin to guide therapy in patients with COPD exacerbations is not firmly established and its use is controversial. (See "Procalcitonin use in lower respiratory tract infections", section on 'Acute exacerbations of chronic obstructive pulmonary disease'.)

RESPIRATORY VIRUS TREATMENT

( table 4). We generally select among them based on local epidemiology, prior susceptibility testing results, drug interactions, and patient comorbidities or intolerances. Two agents are often needed for empiric treatment. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".)

Influenza — Antiviral therapy is usually indicated for patients whose acute exacerbations of COPD have been triggered by influenza virus. However, the benefits of antiviral therapy diminish with time; thus, for patients presenting ≥72 hours after illness onset, we take the patient's clinical trajectory (eg, worsening/improving) into account when deciding to prescribe. For patients with influenza who also meet criteria for antibacterial treatment (ie, ≥2 cardinal symptoms, need for hospitalization and/or ventilatory support), we treat with both antiviral and antibacterial therapy.

Inhaled zanamivir is contraindicated in this patient population due to the risk of airway reactivity. Other agents, such as oral oseltamivir, oral baloxavir, or, in certain situations, intravenous peramivir or zanamivir (not available in the United States) can be used. (See "Seasonal influenza in nonpregnant adults: Treatment".)

Coronavirus disease 2019 — COPD increases the morbidity and mortality associated with coronavirus disease 2019 (COVID-19; caused by severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) and we test all COPD patients with symptoms of an exacerbation for COVID-19.

Standard treatment of the exacerbation with bronchodilators, systemic corticosteroids, and antibiotics should not be altered in patients with both COPD and COVID-19 [50]. However, these patients need to be observed closely for deterioration. Given their age and comorbidity, patients with COPD and COVID-19 are likely to be candidates for COVID-19 specific therapy. (See "COVID-19: Management of adults with acute illness in the outpatient setting" and "COVID-19: Management in hospitalized adults".)

FOLLOW-UP

Most patients should demonstrate some improvement in 48 to 72 hours of starting antibiotic therapy. For those who fail to improve, we generally obtain a sputum culture (if not already obtained) to help guide any subsequent changes in antibiotic treatment, reevaluate our approach to other aspects of care (eg, bronchodilators, need for mechanical ventilation), consider potential contributing comorbidities, and broaden our differential diagnosis to include other cardiopulmonary disorders (eg, pneumonia, heart failure, lung cancer). (See "COPD exacerbations: Management", section on 'Adjusting therapy for poor response' and "Approach to the patient with dyspnea".)

PREVENTION

Vaccination — Patients with COPD should be vaccinated against seasonal influenza virus (annually), SARS CoV-2, and pneumococcus ( table 5).  

The evidence supporting vaccination of patients with COPD includes the following:

Patients with COPD should also receive other vaccines according to the schedule summarized in the following figure ( figure 1); in particular, vaccine uptake for pertussis is low and incidence is rising. (See "Pertussis infection in adolescents and adults: Treatment and prevention", section on 'Vaccination'.)

All patients who lack contraindications should be vaccinated against SARS-CoV-2. (See "COVID- 19: Vaccines".)

Prophylactic macrolides — We do not routinely use prophylactic macrolides or other antibiotics for the long-term care of patients with COPD. For most patients, the benefits of long- term antibiotic use do not outweigh the risks. However, for selected patients with severe COPD with frequent exacerbations (≥2 per year) despite optimal medical management (long-acting bronchodilators, inhaled glucocorticoids, pulmonary rehabilitation, smoking cessation), macrolide prophylaxis may be advantageous. The risks associated with the development of antibiotic resistance should be taken into account when deciding to use long-term prophylaxis. When considering prescription, we carefully weigh the potential benefit against the risk of long- term macrolide use (eg, QT prolongation, other cardiovascular events, Clostridioides difficile infection). (See "Azithromycin and clarithromycin", section on 'Adverse reactions'.)

When prescribing a macrolide for long-term prophylaxis, we typically use azithromycin, which can be given as 250 mg daily [53] or at a lower dose of 250 to 500 mg three times per week [54-

The utility of influenza vaccination is well established for reducing both the rate and severity of symptoms due to influenza, including respiratory symptoms. A meta-analysis of 11 trials, including 6 specifically performed in patients with COPD, found a significant reduction in the number of exacerbations per patient compared with placebo [51]. (See "Seasonal influenza vaccination in adults".)

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For pneumococcal vaccination, a meta-analysis of 12 randomized trials evaluated the efficacy of PPSV23 on 2171 patients with COPD [52]. Analysis of five trials showed a reduction in the rates of community-acquired pneumonia with vaccination (odds ratio [OR] 0.61, 95% CI 0.42-0.89), and four trials showed a reduction in rates of COPD exacerbation (OR 0.60, 95% CI 0.39-0.93). There were no significant differences in all-cause or cardiorespiratory mortality, although event rates were low. (See "Pneumococcal vaccination in adults".)

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57]. We often use 250 mg three times per week to reduce adverse effects, although this dose is less well studied. Erythromycin (500 mg two times per day) is an alternative [1]. While the optimal duration of therapy is not known, a 12-month course is commonly used [1]. If there is suspicion for Mycobacterium avium complex (MAC) infection based on symptoms or radiological signs (bronchiectasis, tree in bud, chronic opacities on chest radiograph or computed tomography), sputum or bronchoscopic cultures for MAC should be obtained prior to initiation of macrolides; their use is not recommended if the cultures are positive. (See "Overview of nontuberculous mycobacterial infections", section on 'Clinical manifestations'.)

The benefit of macrolides is attributed to their immunomodulatory effects in addition to their potential to prevent infection [58,59]. In a systematic review of 14 randomized trials evaluating 3932 patients with moderate-to-severe COPD, the proportion of patients experiencing ≥1 exacerbation was reduced when comparing prophylactic antibiotic use (primarily macrolides) with placebo (OR 0.57, 95% CI 0.42-0.78) [58]. A marginal improvement in quality-of-life measures was detected; trends toward improvement in the number of hospital admissions, change in forced expiratory volume in one second (FEV ), serious adverse events, and all-cause mortality were observed but were not statistically significant.

The benefits and risks of long-term macrolide use are well illustrated in one of the randomized trials included in the meta-analysis [53,58]. In this trial, 1142 patients with COPD were randomly assigned to receive azithromycin 250 mg orally daily or placebo for one year in addition to their usual COPD regimen [53]. The following findings were observed:

1

The median time to first COPD exacerbation was significantly longer among the patients who received azithromycin compared with those who received placebo (266 versus 174 days).

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Patients who received azithromycin had a significant (but modest) reduction in the frequency of COPD exacerbations compared with those who received placebo (1.48 versus 1.83 exacerbations per patient-year; hazard ratio 0.73, 95% CI 0.63-0.84).

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Patients who received azithromycin had a significantly higher rate of nasopharyngeal colonization with macrolide-resistant bacteria (Staphylococcus aureus, S. pneumoniae, Haemophilus spp, Moraxella spp) than those who received placebo (81 versus 41 percent). Lower airway and enteric microbiology were not monitored, so the emergence of macrolide-resistant strains in these relevant sites was not assessed.

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Hearing decrements (assessed by audiometry) were more common in the azithromycin group than the placebo group (25 versus 20 percent). However, hearing loss associated with azithromycin usually results from long-term use and is reversible.

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Patients with resting tachycardia, hearing impairment, and those with or at risk for a prolonged QT interval were excluded from participating. Thus, the risks of long-term use may be higher when used in the general COPD population.

Other antibiotics, particularly moxifloxacin, also have demonstrated some efficacy for preventing COPD exacerbations [17]. However, we typically reserve their use for the treatment of infections in order to avoid fluoroquinolone-related adverse effects and the selection of fluoroquinolone-resistant bacteria [60]. In one trial comparing pulsed moxifloxacin (400 mg orally daily for five days every eight weeks for six cycles [total duration of 48 weeks]) in 1157 patients with COPD at high risk for recurrent exacerbations, the risk of COPD exacerbation was lower with moxifloxacin, both in the per-protocol analysis (OR 0.75, 95% CI 0.565-0.994) and in the intent-to-treat analysis (OR 0.81, 95% CI 0.645-1.008) [17]. A larger benefit was observed in those with purulent or mucopurulent sputum production (OR 0.55, 95% CI 0.36-0.84) in post-hoc analysis. Gastrointestinal adverse effects were more frequent with moxifloxacin; however, C. difficile infections were not observed. Sustained emergence of moxifloxacin-resistant strains was not observed in sputum or in enteric flora.

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

Background – Most exacerbations of chronic obstructive pulmonary disease (COPD) are caused by respiratory tract infections. Empiric antibiotic therapy is indicated for patients who are most likely to have a bacterial infection causing the exacerbation and for those who are most ill. (See 'Introduction' above.)

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Clinical characteristics – An exacerbation of COPD is an event characterized by dyspnea and/or cough and sputum that worsens over ≤14 days and is often associated with increased airway or systemic inflammation. Most exacerbations of COPD are due to respiratory infection. Cardinal symptoms of a COPD exacerbation include (see 'Introduction' above and 'Definitions' above):

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Increase in dyspnea• Increase in sputum volume and/or viscosity•

Increase in sputum purulence•

When to treat with antibiotics – We typically determine the need for antibiotics based on the number of cardinal symptoms present and the need for hospitalization and/or ventilatory support. The benefit of empiric antibiotic treatment is greatest in severely ill patients and those with a greater number of symptoms but appears to diminish as the severity of illness declines. (See 'Indications for antibacterial therapy' above.)

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We suggest empiric antibiotic treatment in patients with a COPD exacerbation and ≥2 of 3 cardinal symptoms: increased dyspnea, increased sputum volume/viscosity, or increased sputum purulence or a COPD exacerbation requiring hospitalization and/or ventilatory support (either invasive or noninvasive) (Grade 2C).

•

We do not initiate antibiotic therapy in patients with a COPD exacerbation and only one of three cardinal symptoms who do not require hospitalization or ventilatory support. New onset of increased wheezing may serve as an additional negative predictor for bacterial infection; therefore, if it is a prominent finding, it steers us away from antibiotic use.

•

Risk stratification to guide antibiotic selection – We use a "risk stratification" approach when selecting initial empiric antibiotic therapy for the treatment of acute exacerbations of COPD. We categorize patients based on treatment setting (eg, outpatient versus inpatient), risk for poor clinical outcomes ( table 2), and risk for infection with Pseudomonas ( table 3). (See 'Risk stratification' above.)

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Empiric antibiotic regimens – Empiric antibiotic regimens are designed to target the most likely infecting pathogens ( table 1); specific selection varies based on the patient's risk status ( algorithm 1A-B). When selecting an antibiotic, we take into account the patient's prior antibiotic exposure, prior clinical response to specific antibiotics, allergies and intolerances, drug interactions, the drug's adverse event profile, and the susceptibility pattern of organisms isolated in recent sputum cultures (if available). (See 'Antibiotic selection' above.)

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Duration of antibiotics – The duration of therapy is generally five days for outpatients and five to seven days for most hospitalized patients. However, azithromycin can be given for as few as three days when administered at a dose of 500 mg orally daily because of its long half-life. (See 'Duration' above.)

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Antiviral treatment – Patients with COPD are at increased risk for complications of influenza, so antiviral therapy (eg, oral oseltamivir or an intravenous agent) may be

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ACKNOWLEDGMENT

UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

Use of UpToDate is subject to the Terms of Use.

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49. Falagas ME, Avgeri SG, Matthaiou DK, et al. Short- versus long-duration antimicrobial treatment for exacerbations of chronic bronchitis: a meta-analysis. J Antimicrob Chemother 2008; 62:442.

50. Halpin DMG, Criner GJ, Papi A, et al. Global Initiative for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease. The 2020 GOLD Science Committee Report on COVID-19 and Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2021; 203:24.

51. Poole PJ, Chacko E, Wood-Baker RW, Cates CJ. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006; :CD002733.

52. Walters JA, Tang JN, Poole P, Wood-Baker R. Pneumococcal vaccines for preventing pneumonia in chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2017; 1:CD001390.

53. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011; 365:689.

54. Uzun S, Djamin RS, Kluytmans JA, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2014; 2:361.

55. Blasi F, Bonardi D, Aliberti S, et al. Long-term azithromycin use in patients with chronic obstructive pulmonary disease and tracheostomy. Pulm Pharmacol Ther 2010; 23:200.

56. Pomares X, Montón C, Espasa M, et al. Long-term azithromycin therapy in patients with severe COPD and repeated exacerbations. Int J Chron Obstruct Pulmon Dis 2011; 6:449.

57. Berkhof FF, Doornewaard-ten Hertog NE, Uil SM, et al. Azithromycin and cough-specific health status in patients with chronic obstructive pulmonary disease and chronic cough: a randomised controlled trial. Respir Res 2013; 14:125.

58. Herath SC, Normansell R, Maisey S, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev 2018; 10:CD009764.

59. Huckle AW, Fairclough LC, Todd I. Prophylactic Antibiotic Use in COPD and the Potential Anti-Inflammatory Activities of Antibiotics. Respir Care 2018; 63:609.

60. Brill SE, Law M, El-Emir E, et al. Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial. Thorax 2015; 70:930.

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GRAPHICS

Our approach to empiric antibacterial treatment of COPD exacerbations in out

Prompt and appropriate antibiotic use has been associated with improved clinical outcomes in patients with severe COPD exacerbations. Empiric regimens are designed to target the most likely pathogens (Haemophilu Moraxella catarrhalis, and Streptococcus pneumoniae) and should be broadened to target drug-resistant path difficult-to-eradicate pathogens (eg, macrolide-resistant S. pneumoniae, nontypeable strains of H. influenzae) poor outcomes. Coverage for Pseudomonas is indicated in patients with risk factors for infection with this pa patients should be evaluated for clinical response in approximately 72 hours, and sputum Gram stain and cu considered for those who fail to response to empiric treatment. Modifications to this approach may be need with a history of colonization or infection with drug-resistant pathogens (including Pseudomonas) or when a is suspected.

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

* Antiviral therapy for influenza is also indicated for exacerbations triggered by influenza infection.

¶ Suspicion for other cardiopulmonary disorders (heart failure, pneumothorax) and more severe infections ( should be absent for the diagnosis of an acute COPD exacerbation.

Δ Age alone is not a strict risk factor but should be considered as additive to other risk factors.

◊ Selection among antibiotic choices is based on local microbial sensitivity patterns, patient comorbidities, p organisms, potential adverse events and drug interactions, and also provider and patient preferences. In pa modifications to this regimen may be needed for patients with a history of drug-resistant Pseudomonas base illness, degree of suspicion for Pseudomonas, and prior susceptibility profiles of pseudomonal isolates.

§ If recent antibiotic exposure (eg, within the past 3 months), select an antibiotic from a different class than agent used.

¥ Trimethoprim-sulfamethoxazole is a reasonable alternative when macrolides and cephalosporins cannot b allergy, potential adverse effects, or availability.

‡ Some experts add amoxicillin or another agent with better activity against S. pneumoniae to ciprofloxacin f treatment.

† Because fluoroquinolone resistance is prevalent among Pseudomonas aeruginosa strains, we obtain a sput and culture with susceptibility testing for these patients to help guide subsequent management decisions. F outpatients, obtaining a sputum culture is not needed unless the patient fails to respond to empiric treatme

** Levofloxacin has lesser activity against Pseudomonas than ciprofloxacin but has greater activity against S. M. catarrhalis is thus a reasonable alternative to ciprofloxacin for patients who are at increased risk of Pseud but lack microbiologic evidence of Pseudomonas infection or colonization.

References: 1. Sethi S, Murphy TF. Acute exacerbations of chronic bronchitis: New developments concerning microbiology and pathophysiolog

approaches to risk stratification and therapy. Infect Dis Clin N Am 2004; 18:861. 2. Sethi S, Anzueto A, Miravitlles M, et al. Determinants of bacteriological outcomes in exacerbations of chronic obstructive pulmo

2016; 44:65. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary disease: cha

factors. BMC Pulm Med 2014; 14:103.

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Our approach to empiric antibacterial treatment of COPD exacerbations in hospitalized patients*

Prompt and appropriate antibiotic use has been associated with improved clinical outcomes in patients hospitalized for COPD exacerbations. Empiric regimens are designed to target the most likely pathogens (Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae). Pseudomonas should be targeted in those with risk factors for infection with this pathogen. Generally, a sputum Gram stain and culture with susceptibility testing should be obtained for hospitalized patients. Modifications to the empiric regimen may be needed based on sputum Gram stain and culture results, particularly for patients who do not respond to the initial empiric regimen within 48 to 72 hours of starting treatment. Modifications to this approach may be needed for

patients with a history of colonization or infection with drug-resistant pathogens (including Pseudomonas) or when a specific pathogen is suspected.

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

* Antiviral therapy for influenza is also indicated for exacerbations triggered by influenza infection.

¶ Selection among antibiotic choices is based on local microbial sensitivity patterns, patient comorbidities, prior infecting organisms, potential adverse events and drug interactions, and also provider and patient preferences. Modifications to these regimens may be needed for patients with suspicion for specific pathogens and/or history of drug-resistant organisms (eg, drug-resistant Pseudomonas).

Δ For those who cannot tolerate these agents, alternatives include ciprofloxacin, aztreonam, certain carbapenems (eg, meropenem, imipenem), and aminoglycosides. We generally select among them based on local epidemiology, prior susceptibility testing results, drug interactions, and patient comorbidities or intolerances. Two agents are often needed for empiric treatment. Refer to the UpToDate content for detail.

◊ If recent antibiotic exposure (eg, within the past 3 months), select an antibiotic from a different class than the most recent agent used.

References: 1. Sethi S, Murphy TF. Acute exacerbations of chronic bronchitis: New developments concerning microbiology and

pathophysiology–impact on approaches to risk stratification and therapy. Infect Dis Clin N Am 2004; 18:861. 2. Sethi S, Anzueto A, Miravitlles M, et al. Determinants of bacteriological outcomes in exacerbations of chronic

obstructive pulmonary disease. Infection 2016; 44:65. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary

disease: characterization and risk factors. BMC Pulm Med 2014; 14:103.

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Relative frequency of bacterial pathogens isolated from 14 antibiotic comparison trials in exacerbations of chronic obstructive pulmonary disease*

Pathogen Percentage of bacterial isolates (range)

Haemophilus influenzae 13 to 50

Moraxella catarrhalis 9 to 21

Streptococcus pneumoniae 7 to 26

Pseudomonas aeruginosa 1 to 13

* Enterobacteriaceae have been isolated from the respiratory tract of 3 to 19 percent of patients with chronic obstructive pulmonary disease (COPD) exacerbations and Staphylococcus aureus has been isolated from the respiratory tract of 1 to 20 percent of patients with COPD exacerbations, but their pathogenic significance in this setting has not been defined. Haemophilus parainfluenzae has been isolated from the respiratory tract of 2 to 32 percent of patients with COPD exacerbations, but these organisms are unlikely to cause COPD exacerbations.

Modified with permission from the American Thoracic Society. Copyright © 2004 American Thoracic Society. Sethi S. Bacteria in exacerbations of chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society 2004; 1:109. Official Journal of the American Thoracic Society.

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Risk factors for poor outcomes in patients with acute COPD exacerbations

Comorbid conditions (especially heart failure or ischemic heart disease)

Severe underlying COPD (eg, FEV <50%)

Frequent exacerbations of COPD (ie, ≥2 exacerbations per year)

Hospitalization for an exacerbation within the past 3 months

Receipt of continuous supplemental oxygen

Age ≥65 years*

Patients with greater underlying COPD severity are at higher risk for poor outcomes if initial antibiotic therapy is inadequate. We thus use a broader empiric regimen for such patients.

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

* Older age (eg, age ≥65 years) is also associated with poorer outcomes and/or risk of infection with drug-resistant pathogens. While not a strict indication for broadening antibiotic therapy, we consider older age as additive to the risk factors listed above.

References: 1. Balter MS, La Forge J, Low DE, et al. Canadian guidelines for the management of acute exacerbations of chronic

bronchitis. Can Respir J 2003; 10 Suppl B:3B. 2. Miravitlles M, Murio C, Guerrero T. Factors associated with relapse after ambulatory treatment of acute exacerbations

of chronic bronchitis. DAFNE Study Group. Eur Respir J 2001; 17:928. 3. Wilson R, Jones P, Schaberg T, et al. Antibiotic treatment and factors influencing short and long term outcomes of

acute exacerbations of chronic bronchitis. Thorax 2006; 61:337. 4. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation:

a prospective study. Eur Respir J 2009; 34:1072. 5. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012;

7:1129.

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Risk factors for infection with Pseudomonas aeruginosa in patients with acute COPD exacerbations

Chronic colonization or previous isolation of Pseudomonas aeruginosa from sputum (particularly in the past 12 months)

Very severe COPD (FEV <30% predicted)

Bronchiectasis on chest imaging

Broad-spectrum antibiotic use within the past 3 months

Chronic systemic glucocorticoid use

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

References: 1. Garcia-Vidal C, Almagro P, Romaní V, et al. Pseudomonas aeruginosa in patients hospitalised for COPD exacerbation:

a prospective study. Eur Respir J 2009; 34:1072. 2. Parameswaran GI, Sethi S. Pseudomonas infection in chronic obstructive pulmonary disease. Future Microbiol 2012;

7:1129. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary

disease: characterization and risk factors. BMC Pulm Med 2014; 14:103. 4. Boixeda R, Almagro P, Díez-Manglano J, et al. Bacterial flora in the sputum and comorbidity in patients with acute

exacerbations of COPD. Int J Chron Obstruct Pulmon Dis 2015; 10:2581.

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Alternatives to anti-pneumococcal beta-lactams for the empiric treatment of Pseudomonas inpatients with AECOPD

Antibiotic or antibiotic class

Comment

Ciprofloxacin Active against Pseudomonas but does not have strong activity against Streptococcus pneumoniae and Moraxella catarrhalis, which are also common causes of COPD exacerbations One of the few oral agents with anti-pseudomonal activity, thus, use is often reserved for the outpatient setting

Aztreonam Lacks activity against S. pneumoniae and other gram-positive pathogens Resistance to aztreonam among pseudomonal isolates is also common

Anti-pseudomonal carbapenems (eg, meropenem, doripenem)

Active against Pseudomonas and other common COPD pathogens Spectrum of activity often broader than necessary

Aminoglycosides (eg, tobramycin, gentamicin, amikacin, plazomicin)

Active against Pseudomonas aeruginosa but generally not used as single agents because of inadequate clinical efficacy

For patients who cannot tolerate anti-pneumococcal beta-lactams (eg, cefepime, piperacillin- tazobactam), alternatives include ciprofloxacin, aztreonam, certain carbapenems, and aminoglycosides. Each comes with relative disadvantages when compared with the anti- pseudomonal beta-lactams. We generally select among them based on local epidemiology, prior susceptibility testing results, drug interactions, and patient comorbidities or intolerances. For empiric treatment, two agents are often needed. The treatment of Pseudomonas is discussed in detail in the UpToDate text.

AECOPD: acute exacerbation of chronic obstructive pulmonary disease.

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Indications for pneumococcal vaccination in adults in the United States

All adults ≥65 years of age

Adults 19 to 64 years of age with any of the following: Predisposing medical conditions:

Alcohol use disorder Chronic heart disease Chronic lung disease Chronic liver disease Diabetes mellitus Sickle cell disease or other hemoglobinopathies Current cigarette smoking

Increased risk of meningitis: Cerebrospinal fluid leak Cochlear implant

Immunocompromising conditions and other conditions associated with altered immunocompetence :

Congenital or acquired immunodeficiency Generalized active malignancy Human immunodeficiency virus infection Iatrogenic immunosuppression Hodgkin disease Leukemia Lymphoma Multiple myeloma Solid organ transplant Chronic kidney disease and nephrotic syndrome Functional or anatomic asplenia

History of invasive pneumococcal disease

Pneumococcal vaccination is indicated for adults with risk factors for acquisition of or severe adverse outcomes from pneumococcal disease. These adults should receive either PCV20 alone or PCV15 followed by PPSV23. When administering the PCV15 and PPSV23 combination, PCV15 should be given first when possible. The recommended intervals between the two vaccines vary based on sequence and indication. Refer to the UpToDate topic on pneumococcal vaccination in adults for additional detail.

ACIP: Advisory Committee on Immunization Practices; HIV: human immunodeficiency virus; PCV20: 20-valent pneumococcal conjugate vaccine; PCV15: 15-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine.

* Including congestive heart failure and cardiomyopathies, excluding hypertension.

*

¶

Δ

◊

§

¥

‡

†

¶ Including chronic obstructive pulmonary disease, emphysema, and asthma.

Δ Some UpToDate authors differ from ACIP guidance on vaccine selection for immunocompromised individuals. Refer to the UpToDate topic on pneumococcal vaccination in adults for additional information.

◊ Includes B (humoral) or T lymphocyte deficiency, complement deficiencies (particularly C1, C2, C3, and C4 deficiencies), and phagocytic disorders (excluding chronic granulomatous disease).

§ HIV infection is an indication for pneumococcal vaccination, regardless of CD4 cell count.

¥ Treatment with any immunosuppressive drugs (including long-term glucocorticoids, tumor necrosis factor alpha inhibitors, cancer chemotherapy, and other cytokine inhibitors) or radiation therapy.

‡ Chronic kidney disease is defined as glomerular filtration rate <60 mL/min/1.73 m for ≥3 months.

† The United States Centers for Disease Control and Prevention ACIP does not mention individuals with a prior history of invasive pneumococcal disease in their recommendations on pneumococcal vaccinations. We suggest pneumococcal vaccination in this population due to their increased risk for recurrent pneumococcal disease. Refer to the UpToDate topic on pneumococcal vaccination in adults for additional detail.

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Recommended adult immunization schedule by medical condition and other in

Administer recommended vaccines if vaccination history is incomplete or unknown. Do not restart or add do use of trade names is for identification purposes only and does not imply endorsement by the ACIP or CDC.

Polio vaccination Routine vaccination:

Routine poliovirus vaccination of adults residing in the United States is not necessary. Special situations:

Adults at increased risk of exposure to poliovirus with: No evidence of a complete polio vaccination series (ie, at least 3 doses): Administer remain Evidence of completed polio vaccination series (ie, at least 3 doses): May administer one life

For detailed information, refer to www.cdc.gov/vaccines/vpd/polio/hcp/recommendations.html.

HSCT: hematopoietic stem cell transplant.

* Precaution for LAIV4 does not apply to alcoholism.

¶ COVID-19 vaccination Routine vaccination:

Primary series: 2-dose series at 0, 4 to 8 weeks (Moderna) or 2-dose series at 0, 3 to 8 weeks (Nov Booster dose: Refer to www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerati

Special situations: Persons who are moderately or severely immunocompromised.

Primary series: 3-dose series at 0, 4, 8 weeks (Moderna) or 3-dose series at 0, 3, 7 weeks (Pfizer-BioNTech). 2-dose series at 0, 3 weeks (Novavax).

Booster dose: Refer to www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-conside Pre-exposure prophylaxis (eg, monoclonal antibodies) may be considered to complement C considerations/interim-considerations-us.html#immunocompromised.

For Janssen COVID-19 Vaccine recipients refer to COVID-19 schedule at www.cdc.gov/vaccines/c NOTE: Current COVID-19 schedule available at www.cdc.gov/vaccines/covid-19/downloads/COVID- information on Emergency Use Authorization (EUA) indications for COVID-19 vaccines, please visit disease-2019-covid-19/covid-19-vaccines.

Contraindications and precautions: Refer to contraindications and precautions to COVID-19 vaccination.

Δ Influenza vaccination Routine vaccination:

Age 19 years or older: 1 dose any influenza vaccine appropriate for age and health status annual Age 65 years or older: Any one of quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), adjuvanted inactivated influenza vaccine (aIIV4) is preferred. If none of these three vaccines is ava For the 2022–2023 season, refer to www.cdc.gov/mmwr/volumes/71/rr/rr7101a1.htm. For the 2023–2024 season, refer to the 2023–2024 ACIP influenza vaccine recommendations.

Special situations: Egg allergy, hives only: Any influenza vaccine appropriate for age and health status annually. Egg allergy–any symptom other than hives (eg, angioedema, respiratory distress, or required e vaccine appropriate for age and health status may be administered. If using egg-based IIV4 or LAI provider who can recognize and manage severe allergic reactions. Close contacts (eg, caregivers, health care workers) of severely immunosuppressed persons receive LAIV4. If LAIV4 is given, they should avoid contact with/caring for such immunosuppressed Severe allergic reaction (eg, anaphylaxis) to a vaccine component or a previous dose of any i precautions. History of Guillain-Barré syndrome within 6 weeks after previous dose of influenza vaccine: risks for those at higher risk for severe complications from influenza.

Contraindications and precautions: For contraindications and precautions to influenza vaccination, refer to IIV4 Appendix, LAIV4 Appe

◊ Tetanus, diphtheria, and pertussis (Tdap) vaccination Routine vaccination:

Previously did not receive Tdap at or after age 11 years: 1 dose Tdap, then Td or Tdap every 10 Special situations:

Previously did not receive primary vaccination series for tetanus, diphtheria, or pertussis: 1 dose of Td or Tdap 6 to 12 months later (Tdap can be substituted for any Td dose, but preferred as Pregnancy: 1 dose Tdap during each pregnancy, preferably in early part of gestational weeks 27 t Wound management: Persons with 3 or more doses of tetanus-toxoid-containing vaccine: For cle last dose of tetanus-toxoid-containing vaccine; for all other wounds, administer Tdap or Td if more preferred for persons who have not previously received Tdap or whose Tdap history is unknown. I use Tdap. For detailed information, refer to www.cdc.gov/mmwr/volumes/69/wr/mm6903a5.htm.

Contraindications and precautions: For contraindications and precautions to tetanus, diphtheria, and acellular pertussis (Tdap), refer t

§ Measles, mumps, and rubella vaccination Routine vaccination:

No evidence of immunity to measles, mumps, or rubella: 1 dose. Evidence of immunity: Born before 1957 (health care personnel, refer below), documentation (diagnosis of disease without laboratory confirmation is not evidence of immunity).

Special situations: Pregnancy with no evidence of immunity to rubella: MMR contraindicated during pregnancy; a Nonpregnant women of childbearing age with no evidence of immunity to rubella: 1 dose. HIV infection with CD4 percentages ≥15% and CD4 count ≥200 cells/mm for at least 6 mon dose series at least 4 weeks apart; MMR contraindicated for HIV infection with CD4 percentage <1 Severe immunocompromising conditions: MMR contraindicated. Students in postsecondary educational institutions, international travelers, and household o evidence of immunity to measles, mumps, or rubella: 2-dose series at least 4 weeks apart if pre 1 dose MMR. In mumps outbreak settings, for information about additional doses of MMR (including 3rd dose Health care personnel:

Born before 1957 with no evidence of immunity to measles, mumps, or rubella: Consider rubella. Born in 1957 or later with no evidence of immunity to measles, mumps, or rubella: 2-dose rubella.

Contraindications and precautions: For contraindications and precautions to measles, mumps, rubella (MMR), refer to MMR Appendix

¥ Varicella vaccination Routine vaccination:

No evidence of immunity to varicella: 2-dose series 4 to 8 weeks apart if previously did not rece varicella vaccine] for children); if previously received 1 dose varicella-containing vaccine, 1 dose at

Evidence of immunity: US-born before 1980 (except for pregnant women and health care per vaccine at least 4 weeks apart, diagnosis or verification of history of varicella or herpes zoster

Special situations: Pregnancy with no evidence of immunity to varicella: VAR contraindicated during pregnancy; a previously received 1 dose varicella-containing vaccine or dose 1 of 2-dose series (dose 2: 4 to 8 w regardless of whether US-born before 1980.

3

Health care personnel with no evidence of immunity to varicella: 1 dose if previously received previously did not receive any varicella-containing vaccine, regardless of whether US-born before HIV infection with CD4 percentages ≥15% and CD4 count ≥200 cells/mm with no evidence VAR contraindicated for HIV infection with CD4 percentage <15% or CD4 count <200 cells/mm . Severe immunocompromising conditions: VAR contraindicated.

Contraindications and precautions: For contraindications and precautions to varicella (VAR), refer to VAR Appendix.

‡ Zoster vaccination Routine vaccination:

Age 50 years or older (NOTE: Serologic evidence of prior varicella is not necessary for zoster vacc available, providers should follow ACIP guidelines for varicella vaccination first. RZV is not indicate RZV in persons without a history of varicella or varicella vaccination): 2-dose series recombinant zo weeks; repeat dose if administered too soon), regardless of previous herpes zoster or history of zo

Special situations: Pregnancy: There is currently no ACIP recommendation for RZV use in pregnancy. Consider delay Immunocompromising conditions (including persons with HIV regardless of CD4 count; NOTE: I herpes zoster, providers should refer to the clinical considerations for use of RZV in immunocomp recommendations for further guidance: www.cdc.gov/mmwr/volumes/71/wr/mm7103a2.htm): 2-d (minimum interval: 4 weeks; repeat dose if administered too soon). For detailed information, refer

Contraindications and precautions: For contraindications and precautions to zoster recombinant vaccine (RZV), refer to RZV Appendix

† Human papillomavirus vaccination Routine vaccination:

HPV vaccination recommended for all persons through age 26 years: 2- or 3-dose series depen Age 15 years or older at initial vaccination: 3-dose series at 0, 1 to 2 months, 6 months (min dose 1 to dose 3: 5 months; repeat dose if administered too soon). Age 9 to 14 years at initial vaccination and received 1 dose or 2 doses less than 5 months Age 9 to 14 years at initial vaccination and received 2 doses at least 5 months apart: HPV

Interrupted schedules: If vaccination schedule is interrupted, the series does not need to be rest No additional dose recommended when any HPV vaccine series has been completed using th

Shared clinical decision-making: Some adults age 27 to 45 years: Based on shared clinical decision-making, 2- or 3-dose series as

Special situations: Age ranges recommended above for routine and catch-up vaccination or shared clinical deci

Immunocompromising conditions, including HIV infection: 3-dose series, even for those w Pregnancy: Pregnancy testing is not needed before vaccination; HPV vaccination is not recom vaccinated while pregnant.

Contraindications and precautions: For contraindications and precautions to human papillomavirus (HPV) vaccination, refer to HPV Ap

** Pneumococcal vaccination Routine vaccination:

Age 65 years or older who have: Not previously received a dose of PCV13, PCV15, or PCV20 or whose previous vaccination this should be followed by a dose of PPSV23 given at least 1 year after the PCV15 dose. A min for adults with an immunocompromising condition (NOTE: Immunocompromising conditions

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3

iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, Ho transplants, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies invasive pneumococcal disease caused by serotypes unique to PPSV23 in these vulnerable gro Previously received only PCV7: Follow the recommendation above. Previously received only PCV13: 1 dose PCV20 at least 1 year after the PCV13 dose OR comp www.cdc.gov/vaccines/vpd/pneumo/downloads/pneumo-vaccine-timing.pdf. Previously received only PPSV23: 1 dose PCV15 OR 1 dose PCV20 at least 1 year after the PP PPSV23. Previously received both PCV13 and PPSV23 but NO PPSV23 was received at age 65 years vaccine dose OR complete the recommended PPSV23 series as described here: www.cdc.gov/ Previously received both PCV13 and PPSV23, AND PPSV23 was received at age 65 years o least 5 years after the last pneumococcal vaccine dose. For guidance on determining which pneumococcal vaccines a patient needs and when, pleas www.cdc.gov/vaccines/vpd/pneumo/hcp/pneumoapp.html.

Special situations: Age 19 to 64 years with certain underlying medical conditions or other risk factors who hav alcoholism, chronic heart/liver/lung disease, chronic renal failure, cigarette smoking, cochlear im generalized malignancy, HIV, Hodgkin disease, immunodeficiency, iatrogenic immunosuppressio organ transplants, or sickle cell disease, or other hemoglobinopathies):

Not previously received a PCV13, PCV15, or PCV20 or whose previous vaccination history should be followed by a dose of PPSV23 given at least 1 year after the PCV15 dose. A minimum adults with an immunocompromising condition(NOTE: Immunocompromising conditions inc iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, Ho transplants, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies Previously received only PCV7: Follow the recommendation above. Previously received only PCV13: 1 dose PCV20 at least 1 year after the PCV13 dose OR comp www.cdc.gov/vaccines/vpd/pneumo/downloads/pneumo-vaccine-timing.pdf. Previously received only PPSV23: 1 dose PCV15 OR 1 dose PCV20 at least 1 year after the PP PPSV23. Previously received both PCV13 and PPSV23 but have not completed the recommended dose OR complete the recommended PPSV23 series as described here: www.cdc.gov/vaccines

For guidance on determining which pneumococcal vaccines a patient needs and when, please re www.cdc.gov/vaccines/vpd/pneumo/hcp/pneumoapp.html.

Contraindications and precautions: For contraindications and precautions to Pneumococcal conjugate (PCV15 and PCV20), refer to PC PPSV23 Appendix.

¶¶ Hepatitis A vaccination Routine vaccination:

Not at risk but want protection from hepatitis A (identification of risk factor not required): apart [minimum interval: 6 months]) or 3-dose series HepA-HepB (Twinrix at 0, 1, 6 months [mini

Special situations: At risk for hepatitis A virus infection: 2-dose series HepA or 3-dose series HepA-HepB as above

Chronic liver disease (eg, persons with hepatitis B, hepatitis C, cirrhosis, fatty liver disease, a [ALT] or aspartate aminotransferase [AST] level greater than twice the upper limit of normal). HIV infection. Men who have sex with men.

Injection or noninjection drug use. Persons experiencing homelessness. Work with hepatitis A virus in research laboratory or with nonhuman primates with hepatit Travel in countries with high or intermediate endemic hepatitis A (HepA-HepB [Twinrix] m to 30 days, followed by a booster dose at 12 months). Close, personal contact with international adoptee (eg, household or regular babysitting) endemic hepatitis A (administer dose 1 as soon as adoption is planned, at least 2 weeks befor Pregnancy if at risk for infection or severe outcome from infection during pregnancy. Settings for exposure, including health care settings targeting services to injection or noninj for developmentally disabled persons (individual risk factor screening not required).

Contraindications and precautions: For contraindications and precautions to hepatitis A (HepA) vaccination, refer to HepA Appendix.

ΔΔ Hepatitis B vaccination Routine vaccination:

Age 19 through 59 years: Complete a 2- or 3-, or 4-dose series. 2-dose series only applies when 2 doses of Heplisav-B (NOTE: Heplisav-B and PreHevbrio are persons) are used at least 4 weeks apart. 3-dose series Engerix-B, PreHevbrio (NOTE: Heplisav-B and PreHevbrio are not recommended Recombivax HB at 0, 1, 6 months [minimum intervals: dose 1 to dose 2: 4 weeks / dose 2 to d 3-dose series HepA-HepB (Twinrix at 0, 1, 6 months [minimum intervals: dose 1 to dose 2: 4 w 4-dose series HepA-HepB (Twinrix) accelerated schedule of 3 doses at 0, 7, and 21 to 30 days,

Age 60 years or older with known risk factors for hepatitis B virus infection should complete a H Age 60 years or older without known risk factors for hepatitis B virus infection may complete a

Risk factors for hepatitis B virus infection include: Chronic liver disease (eg, persons with hepatitis C, cirrhosis, fatty liver disease, alcoholic aspartate aminotransferase [AST] level greater than twice upper limit of normal). HIV infection. Sexual exposure risk (eg, sex partners of hepatitis B surface antigen [HBsAg]-positive pe persons seeking evaluation or treatment for a sexually transmitted infection; men who ha Current or recent injection drug use. Percutaneous or mucosal risk for exposure to blood (eg, household contacts of HBsAg disabled persons; health care and public safety personnel with reasonably anticipated risk maintenance dialysis, including in-center or home hemodialysis and peritoneal dialysis, a Incarceration. Travel in countries with high or intermediate endemic hepatitis B.

Special situations: Patients on dialysis: complete a 3- or 4-dose series.

3-dose series Recombivax HB at 0, 1, 6 months (NOTE: use Dialysis Formulation 1 mL = 40 mc 4-dose series Engerix-B at 0, 1, 2, and 6 months (NOTE: use 2 mL dose instead of the normal a

Contraindications and precautions: For contraindications and precautions to hepatitis B (HepB) vaccination, refer to HepB Appendix.

◊◊ Meningococcal vaccination Special situations for MenACWY:

Anatomical or functional asplenia (including sickle cell disease), HIV infection, persistent co eculizumab, ravulizumab) use: 2-dose series MenACWY-D (Menactra, Menveo, or MenQuadfi) a

Travel in countries with hyperendemic or epidemic meningococcal disease, or microbiologi (Menactra, Menveo, or MenQuadfi) and revaccinate every 5 years if risk remains. First-year college students who live in residential housing (if not previously vaccinated at a Menveo, or MenQuadfi). For MenACWY booster dose recommendations for groups listed under "Special situations" and among men who have sex with men) and additional meningococcal vaccination information, refe

Shared clinical decision-making for MenB: Adolescents and young adults age 16 to 23 years (age 16 to 18 years preferred) not at increa making, 2-dose series MenB-4C (Bexsero) at least 1 month apart or 2-dose series MenB-FHbp (Tru after dose 1, administer dose 3 at least 4 months after dose 2); MenB-4C and MenB-FHbp are not

Special situations for MenB: Anatomical or functional asplenia (including sickle cell disease), persistent complement co ravulizumab) use, or microbiologists routinely exposed to Neisseria meningitidis (NOTE: Men if indicated, but at a different anatomic site, if feasible): 2-dose primary series MenB-4C (Bexsero) at 0, 1 to 2, 6 months (if dose 2 was administered at least 6 months after dose 1, dose 3 not need dose should be administered at least 4 months after dose 3); MenB-4C and MenB-FHbp are not in booster 1 year after primary series and revaccinate every 2 to 3 years if risk remains. Pregnancy: Delay MenB until after pregnancy unless at increased risk and vaccination benefits o For MenB booster dose recommendations for groups listed under "Special situations" and in an among men who have sex with men) and additional meningococcal vaccination information, refe

Contraindications and precautions: For contraindications and precautions to meningococcal ACWY (MenACWY) [MenACWY-CRM (Men MenACWY Appendix. For contraindications and precautions to meningococcal B (MenB) [MenB-4C (Bexsero); MenB-FH

§§ Haemophilus influenzae type b vaccination Special situations:

Anatomical or functional asplenia (including sickle cell disease): 1 dose if previously did not r before splenectomy. Hematopoietic stem cell transplant (HSCT): 3-dose series 4 weeks apart starting 6 to 12 month

Contraindications and precautions: For contraindications and precautions to Haemophilus influenzae type b (Hib) vaccination, refer to

¥¥ Vaccinate after pregnancy.

Reproduced from: Advisory Committee on Immunization Practices. Recommended Adult Immunization Schedule for ages 19 years or https://www.cdc.gov/vaccines/schedules/hcp/imz/adult-conditions.html (Accessed on February 15, 2023).

Contributor Disclosures

Sanjay Sethi, MD Grant/Research/Clinical Trial Support: Astra Zeneca [COPD]; Regeneron [COPD]; Theravance [COPD]. Consultant/Advisory Boards: Astra Zeneca [COPD]; BI [COPD]; Chiesi [COPD]; GSK [Asthma, COPD]; Nuvaira [COPD]; Pulmonx [COPD]. Speaker's Bureau: AstraZeneca [COPD]; BI [COPD]; GSK [COPD]. All of the relevant financial relationships listed have been mitigated. Timothy F Murphy, MD No relevant financial relationship(s) with ineligible companies to disclose. Julio A Ramirez, MD, FACP Grant/Research/Clinical Trial Support: Eli Lilly [Monoclonal antibodies]; Janssen [Vaccines]; Pfizer [Vaccines]. Consultant/Advisory Boards: Dompe [Infectious diseases]; Nabriva [Respiratory infections]; Paratek [Respiratory infections]; Pfizer [Vaccines]. All of the relevant financial relationships listed have been mitigated. Sheila Bond, MD No relevant financial relationship(s) with ineligible companies to disclose. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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COPD exacerbations: Prognosis, discharge planning, and prevention

INTRODUCTION

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" by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), a report produced by the National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO) [1,2]. This generally includes an acute change in one or more of the following cardinal symptoms:

The prognosis after a COPD exacerbation and strategies for prevention of future exacerbations will be discussed here. The risk factors, clinical manifestations, diagnosis, and management of COPD exacerbations are discussed separately. (See "COPD exacerbations: Clinical manifestations and evaluation" and "COPD exacerbations: Management" and "Management of infection in exacerbations of chronic obstructive pulmonary disease".)

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All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2023. This topic last updated: Nov 06, 2023.

Cough increases in frequency and severity●

Sputum production increases in volume and/or changes character●

Dyspnea increases●

PROGNOSIS AFTER AN EXACERBATION

Exacerbations of COPD are associated with increased morbidity and mortality [1,3-5]. Individuals who have experienced a single moderate COPD exacerbation, compared with those without exacerbation, have an increased risk of respiratory and all-cause mortality (hazard ratios 2.98 [95% CI 1.14-7.83] and 1.34 [95% CI 0.79-2.29], respectively) [4].

A number of factors influence mortality following hospital discharge after an exacerbation of COPD, including older age, the severity of the underlying COPD, requirement for long-term oxygen at discharge, presence of comorbidities (eg, cardiovascular disease or lung cancer), and the presence of Pseudomonas aeruginosa in the patient's sputum, as described in the following studies [6-14]:

Even if the COPD exacerbation resolves, many patients never return to their baseline level of health [5].

COMPREHENSIVE DISCHARGE PLANNING

For patients who have required hospitalization for a COPD exacerbation, formal criteria for discharge and a comprehensive discharge plan may help to reduce readmissions and recurrent exacerbations, although supportive data are mixed [1,16-18]. Nonetheless, the following discharge planning steps appear sensible and are consistent with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy [1]. (See "Hospital discharge and readmission".)

For patients hospitalized with a COPD exacerbation, in-hospital mortality ranges from three to nine percent [12-14]. In a separate study of patients who required noninvasive ventilation, in-hospital mortality was 11 percent [15].

●

In a study of 260 patients admitted with a COPD exacerbation, the one year mortality was 28 percent [9]. Independent risk factors for mortality were age, male sex, prior hospitalization for COPD, arterial tension of carbon dioxide (PaCO ) ≥45 mmHg (6 kPa), and blood urea >8 mmol/L (BUN 22 mg/dL).

●

2

Patients hospitalized for a COPD exacerbation who have Pseudomonas aeruginosa in their sputum have a higher risk of mortality at three years than those without (59 versus 35 percent; HR 2.33, 95% CI 1.29-3.86), independent of age, comorbidity, or COPD severity [10].

●

Criteria for discharge — Criteria for discharge generally depend on sufficient improvement in the manifestations of COPD such that the patient’s condition has stabilized, and frequent nebulizer treatments are no longer required. If the patient is near their prehospital baseline, discharge to home is likely appropriate. However, some patients no longer require hospital-level care but are unable to manage at home due to frailty or severe exercise intolerance; for these patients, a period of inpatient rehabilitation may be more suitable. Patients requiring nocturnal noninvasive ventilation may benefit from a rehabilitation hospital stay. (See "Hospital discharge and readmission", section on 'Determining the post-discharge site of care'.)

When deciding whether a patient can be discharged to home, the patient’s ability to manage activities of daily living (ADLs) at home should be assessed along with the need for assistive devices such as a walker, elevated toilet seat, bedside commode, or shower chair. (See "Comprehensive geriatric assessment", section on 'Activities of daily living'.)

Discharge to home checklist — A number of issues pertaining to COPD exacerbations in particular and hospitalizations in general must be assessed as part of discharge planning, such as: the transition from hospital to home (eg, oxygen en route, stairs to climb), the patient’s ability to obtain and self-administer medications, meal preparation and self-feeding, and the need for visiting nurse, in-home services, and hospice.

A checklist can ensure that important steps to enable a smooth transition to home are not overlooked. Checklists may be general ( table 1) or specific to COPD ( form 1). Components that are thought to improve discharge success include the following [1]:

Explain diagnosis and planned postdischarge therapy with patient/caregiver; ensure understanding and agreement with the regimen

●

Review with patient the technique(s) of all inhaler devices that will be used at discharge and assess their technique

●

Review management plans for comorbidities (eg, heart failure, coronary heart disease, arrhythmia, lung cancer screening, sleep-related breathing disorders, metabolic syndrome, anxiety, depression)

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Ensure that patient understands written and verbal directions for withdrawal of acute medications (eg, antibiotics, systemic glucocorticoids) used to treat exacerbation

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Confirm that patient has received appropriate vaccinations for seasonal influenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and S. pneumococcus (See "Pneumococcal vaccination in adults" and "Standard immunizations for children and adolescents: Overview".)

●

Provide smoking cessation education and medication to patients who smoke●

Patients who have a new prescription for long-term oxygen typically need additional instruction on the use of oxygen delivery systems (eg, tanks, concentrators, portable systems) and safe practices regarding oxygen tubing as a tripping hazard and avoiding exposure to open flames (see "Long-term supplemental oxygen therapy" and "Portable oxygen delivery and oxygen conserving devices"). Such patients should be reassessed two to three months after discharge regarding whether supplemental oxygen is still needed and, if so, at what dose.

Palliative care planning — The disease trajectory in COPD is heterogenous and ranges from gradual worsening of exercise tolerance and oxygenation to a sudden and unanticipated end- of-life. Given the difficulties in predicting the clinical course, an exacerbation requiring hospitalization, particularly one requiring intensive care, creates an opportunity to discuss a palliative care consultation. Criteria for considering a palliative care referral are listed in the table ( table 2). (See "Palliative care for adults with nonmalignant chronic lung disease", section on 'What are the indications for a palliative care consultation?'.)

The primary care provider or pulmonary specialist can raise the possibility of a palliative care approach and obtain a palliative care consultation, if needed. Important components of palliative care include exploring the patient’s understanding about their illness and prognosis, assessing and managing symptoms, discussing goals of care and advance care planning, coordinating care, and helping to plan end-of-life care, including determining the need and timing of hospice care ( table 3). (See "Palliative care for adults with nonmalignant chronic lung disease".)

For patients with advanced COPD, it may be reasonable to discuss hospice care at home. Disease specific guidelines are listed in the table and discussed separately ( table 4). (See "Palliative care for adults with nonmalignant chronic lung disease" and "Hospice: Philosophy of care and appropriate utilization in the United States".)

PREVENTION

Assess need for supplemental oxygen and prescribe if indicated; ensure that supplemental oxygen will be available for transfer to home and in the home before the patient arrives

●

Assess need for home nebulizer treatments and arrange for nebulizer if needed●

Arrange for out-patient pulmonary rehabilitation program, as appropriate●

Advise patient regarding any pending test results or planned follow-up testing (eg, lung cancer screening)

●

Confirm follow-up visits at approximately one and four weeks, and as indicated●

General measures — Several measures can reduce the frequency of COPD exacerbations including the following [1,19-21]:

Pulmonary rehabilitation — Pulmonary rehabilitation has a number of benefits; it significantly reduces future hospital admissions and mortality and improves exercise tolerance and quality of life, compared with usual community care [22]. After a COPD exacerbation, we encourage patients to participate in a pulmonary rehabilitation program, if they have not yet done so. The optimal timing for initiating pulmonary rehabilitation after a COPD exacerbation has not been determined and likely needs to be individualized; patients need to have recovered sufficiently to maximize the benefits of exercise training. (See "Pulmonary rehabilitation", section on 'Benefits' and "Pulmonary rehabilitation", section on 'Setting'.)

Physical activity — While pulmonary rehabilitation programs are preferred, if one is not available, physical activity (exercising two to three times per week for 30 minutes to a level that causes mild shortness of breath) may reduce hospitalizations for COPD exacerbations based on observational data [19]. Further study is needed on alternatives to pulmonary rehabilitation programs in under-resourced settings.

Optimizing medications for COPD — A number of medications for COPD reduce the frequency of COPD exacerbations. A personalized approach to medication selection should be based on the patient’s severity of COPD symptoms and exacerbation frequency, noting that certain medications may be of greater benefit for some patients than others [1]. As an example, inhaled glucocorticoids reduce exacerbations in patients with a history of exacerbations but are not likely to be of benefit in patients with low blood eosinophils. (See "Stable COPD: Follow-up pharmacologic management", section on 'Persistent exacerbations with or without dyspnea'.)

The selection among these medications and their efficacy in reducing exacerbations are reviewed separately ( algorithm 1 and table 9):

Smoking cessation (see "Overview of smoking cessation management in adults")• Proper use of medications (including inhaler technique) ( table 5 and table 6 and

table 7 and table 8) (see "The use of inhaler devices in adults") •

Vaccination against seasonal influenza (see "Seasonal influenza vaccination in adults")• Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see "COVID-19: Vaccines")

•

Pneumococcal vaccination ( figure 1) (see "Pneumococcal vaccination in adults")• Vaccination against respiratory syncytial virus (suspected benefit, which will be revisited as data emerge) (see "Overview of preventive care in adults", section on 'Immunization')

•

For patients whose medications are changed during a hospitalization, it is important to reevaluate discharge medications at office visits in the next one to four weeks. This is a good time to consolidate inhaled medications into a single inhaler if possible or to select inhaler devices that use the same technique. The proper technique should be reviewed for every inhaler that the patient is using. If the patient has poor inspiratory flow or is unable to demonstrate proper technique, nebulized medication from the appropriate class can be substituted: LAMAs (revefenacin), LABAs (formoterol and arformoterol), and glucocorticoid (budesonide).

Prophylactic azithromycin — For patients with recurrent exacerbations (≥2 per year) despite optimal therapy (eg, long-acting bronchodilators with or without inhaled glucocorticoids, smoking cessation, vaccinations, and pulmonary rehabilitation), prophylactic azithromycin may

Long-acting muscarinic antagonists (LAMA). (See "Stable COPD: Initial pharmacologic management", section on 'Long-acting muscarinic antagonists'.)

●

Long-acting beta-agonists (LABA). (See "Stable COPD: Initial pharmacologic management", section on 'Long-acting beta-agonists'.)

●

LAMA-LABA combination inhalers. (See "Stable COPD: Initial pharmacologic management", section on 'Use of dual bronchodilator therapy'.)

●

LABA-glucocorticoid combination inhalers. (See "Stable COPD: Initial pharmacologic management", section on 'Alternative approaches'.)

●

LAMA-LABA-glucocorticoid combination inhalers. (See "Stable COPD: Follow-up pharmacologic management".)

●

Roflumilast, an oral PDE-4 inhibitor, reduces the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of frequent COPD exacerbations (eg, at least two per year or one requiring hospitalization). (See "Management of refractory chronic obstructive pulmonary disease", section on 'Phosphodiesterase-4 inhibitors (Roflumilast)'.)

●

Oral thiol derivatives, such as N-acetylcysteine (NAC), erdosteine, and carbocysteine, are used to thin secretions in patients with bothersome sputum production, but studies have not demonstrated a reduction in exacerbations. (See "Role of mucoactive agents and secretion clearance techniques in COPD", section on 'Thiols and thiol derivatives' and "Management of refractory chronic obstructive pulmonary disease", section on 'Mucoactive agents'.)

●

reduce the frequency of exacerbations. The dosing, potential adverse effects, and evidence in support of prophylaxis with azithromycin are described separately. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prophylactic macrolides' and "Management of refractory chronic obstructive pulmonary disease", section on 'Macrolides and other chronic antibiotic therapy'.)

GLP-1 receptor agonists and SGLT-2 inhibitors, for diabetic patients — Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide) and sodium-glucose cotransporter 2 (SGLT- 2) inhibitors (eg, dapagliflozin) may offer some protection against exacerbations in patients with diabetes and COPD, although further data are needed to confirm these findings.

The mechanism underlying the potential benefits of these agents is unclear. GLP-1 receptor agonists have been shown to reduce inflammation and result in weight loss, with improvements in lung function in small clinical trials [25,26]. SGLT-2 inhibitors decrease endogenous carbon dioxide production via metabolic effects and appear to decrease risk of pneumonia based on meta-analyses of cardiovascular trials [27].

Future trials are needed to determine whether use of GLP-1 receptor agonists or SGLT-2 inhibitors are preferable to other antihyperglycemic agents in patients with DM and risk for COPD exacerbations.

Noninvasive ventilation — For patients who require noninvasive ventilation (NIV) during a hospitalization for a COPD exacerbation and who remain hypercapnic, nocturnal NIV at home significantly reduces the risk of rehospitalization. (See "Nocturnal ventilatory support in COPD".)

In one population-based cohort study of patients with COPD and new initiation of an antihyperglycemic agent, 1252 patients who began GLP-1 receptor agonists and 2956 patients who began SGLT-2 inhibitors were matched with similar patients who received sulfonylureas instead [23]. Compared with patients receiving sulfonylureas, those on GLP- 1 receptor agonists were less likely to be hospitalized for COPD exacerbations (3.5 versus 5.0 percent of patients per year [HR 0.7, 95% CI 0.49-0.99]); similar results were seen for those on SGLT-2 inhibitors (2.4 versus 3.9 percent per year [HR 0.62, 95% CI 0.48-0.81]).

●

In a separate retrospective database analysis, 1642 patients with COPD initiating new oral agents for DM were evaluated over six months following treatment initiation [24]. The adjusted incidence rates of moderate or severe exacerbations were improved with GLP- 1RA inhibitors compared with dipeptidyl peptidase-4 inhibitors (incidence rate ratio [IRR] 0.67, 95% CI 0.49-0.93) or sulfonylureas (IRR 0.49, 95% CI 0.37-0.62); there was no difference compared with SGLT-2 inhibitors.

●

Vitamin D supplementation — Adhering to current guidelines regarding vitamin D supplementation in patients with a 25-hydroxyvitamin D level <20 or 30 ng/mL (50 or 75 nmol/L) reduces COPD exacerbations in addition to benefits in reducing falls and fractures (see "Overview of vitamin D"). While randomized trials were conflicting [28-31], a systematic review and meta-analysis used individual patient data from three of the four randomized trials to examine the role of supplementation in patients with 25-hydroxyvitamin D (25[OH]D) levels <25 nmol/L [32].

In the meta-analysis, vitamin D supplementation did not reduce the rate of moderate-to-severe COPD exacerbations overall, but a prespecified subgroup analysis revealed protective effects in patients with a baseline serum 25[OH]D level <10 ng/mL (<25 nmol/L; adjusted rate ratio 0.55, 95% CI 0.36-0.84). The trial that was not included in the analysis had separately found a benefit to vitamin D supplementation in this setting, so its exclusion was unlikely to affect the results. No increase in adverse events was noted with vitamin D supplementation.

The serum 25(OH)D level <10 ng/mL (<25 nmol/L) used as a threshold in the meta-analysis is well below the minimum level of 20 or 30 ng/mL (50 or 75 nmol/L) advised by national and international guidelines to prevent falls and fracture. Estimates of vitamin D requirements to achieve sufficient levels vary and depend in part upon sun exposure. The optimal intake of vitamin D to prevent deficiency is discussed separately. (See "Overview of vitamin D" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Optimal intake to prevent deficiency'.)

Separate studies suggest that vitamin D supplementation prevents acute respiratory tract infections, particularly in patients who are vitamin D deficient, which might contribute to the benefit in preventing COPD exacerbations [33].

INEFFECTIVE INTERVENTIONS

Selective beta-blockers — Preliminary data and a meta-analysis of 15 observational studies suggested that therapy with selective beta-blockers (given for comorbid cardiovascular disease) might reduce COPD exacerbations [34-36]. However, a randomized trial that included 532 patients with COPD and an increased risk of exacerbation (eg, moderate airflow limitation, exacerbation in the previous year, prescribed use of oxygen), but no cardiac indication for beta- blocker therapy, found that extended release metoprolol (25 to 100 mg/day) did not decrease the time to first exacerbation compared with placebo (hazard ratio 1.05, 95% CI 0.84 to 1.32) [37]. The study was stopped early for safety concerns. Metoprolol was associated with an increased risk of an exacerbation leading to hospitalization (hazard ratio 1.91, 95% CI 1.29 to

2.83), although the reason for this increase was unclear. There was no between group difference in forced expiratory volume in one second (FEV ).

Based on this study, selective beta-blockers do not have a role in prevention of COPD exacerbations but continue to be used for patients with a cardiovascular indication. (See "Management of the patient with COPD and cardiovascular disease".)

Statins — Statins (hydroxymethylglutaryl [HMG] CoA reductase inhibitors) do not diminish COPD exacerbations, although they may have other health benefits. In observational studies of COPD, statins were associated with a reduced rate and severity of exacerbations, rate of hospitalizations, and mortality [38-41]. However, these beneficial effects were not supported in a trial that randomly assigned 885 participants with COPD, but without other indications or contraindications for statin therapy, to simvastatin 40 mg daily or placebo for up to 36 months [42]. Simvastatin did not reduce the rate of exacerbations or the time to first exacerbation. A systematic review found no clear benefit to statins in terms of lung function, exercise capacity, or mortality, but deemed evidence to be low quality [43]. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

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" and "Society guideline links: Pulmonary rehabilitation".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

1

th th

th th

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

Basics topics (see "Patient education: Pulmonary rehabilitation (The Basics)")●

Prognosis after exacerbations – Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of mortality. For patients hospitalized with a COPD exacerbation, in-hospital mortality ranges from 3 to 9 percent and one-year mortality of approximately 25 percent. (See 'Prognosis after an exacerbation' above.)

●

General measures – Several general measures can help reduce the frequency of COPD exacerbations, including smoking cessation, pulmonary rehabilitation and increased physical activity, proper use of medications (including correct inhaler technique), and vaccination against seasonal influenza, SARS-CoV-2, and pneumococcus ( figure 1). (See 'General measures' above.)

●

Pharmacologic interventions – Most medications for COPD reduce the frequency of COPD exacerbations, including long-acting muscarinic antagonists (LAMAs), long-acting beta-agonists (LABAs), inhaled glucocorticoids, and roflumilast. The selection among these medications is based on the patient’s severity of symptoms and risk of exacerbations and is discussed separately. (See 'Optimizing medications for COPD' above.)

●

Chronic azithromycin – For patients with recurrent exacerbations (≥2 per year) despite optimal therapy with long-acting bronchodilator and glucocorticoid inhalers, prophylactic azithromycin may also reduce the frequency of exacerbations. (See 'Prophylactic azithromycin' above and "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prophylactic macrolides' and "Management of refractory chronic obstructive pulmonary disease", section on 'For patients with frequent exacerbations'.)

•

Noninvasive ventilation, for hypercapnic patients – For patients who require noninvasive ventilation (NIV) during a hospitalization for a COPD exacerbation and who remain hypercapnic, nocturnal NIV at home significantly reduces the risk of rehospitalization. (See 'Noninvasive ventilation' above and "Nocturnal ventilatory support in COPD".)

●

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REFERENCES

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Comprehensive discharge planning – After hospitalization for a COPD exacerbation, formal criteria for discharge and a comprehensive discharge plan may help to reduce readmissions and recurrent exacerbations after hospitalization for a COPD exacerbation ( form 1). (See 'Comprehensive discharge planning' above.)

●

11. Piquet J, Chavaillon JM, David P, et al. High-risk patients following hospitalisation for an acute exacerbation of COPD. Eur Respir J 2013; 42:946.

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30. Rafiq R, Prins HJ, Boersma WG, et al. Effects of daily vitamin D supplementation on respiratory muscle strength and physical performance in vitamin D-deficient COPD patients: a pilot trial. Int J Chron Obstruct Pulmon Dis 2017; 12:2583.

31. Zendedel A, Gholami M, Anbari K, et al. Effects of Vitamin D Intake on FEV1 and COPD Exacerbation: A Randomized Clinical Trial Study. Glob J Health Sci 2015; 7:243.

32. Jolliffe DA, Greenberg L, Hooper RL, et al. Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials. Thorax 2019; 74:337.

33. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017; 356:i6583.

34. Du Q, Sun Y, Ding N, et al. Beta-blockers reduced the risk of mortality and exacerbation in patients with COPD: a meta-analysis of observational studies. PLoS One 2014; 9:e113048.

35. Bhatt SP, Wells JM, Kinney GL, et al. β-Blockers are associated with a reduction in COPD exacerbations. Thorax 2016; 71:8.

36. Suissa S, Ernst P. Beta-Blockers in COPD: A Methodological Review of the Observational Studies. COPD 2018; 15:520.

37. Dransfield MT, Voelker H, Bhatt SP, et al. Metoprolol for the Prevention of Acute Exacerbations of COPD. N Engl J Med 2019; 381:2304.

38. Wang MT, Lo YW, Tsai CL, et al. Statin use and risk of COPD exacerbation requiring hospitalization. Am J Med 2013; 126:598.

39. Janda S, Park K, FitzGerald JM, et al. Statins in COPD: a systematic review. Chest 2009; 136:734.

40. Sharif R, Parekh TM, Pierson KS, et al. Predictors of early readmission among patients 40 to 64 years of age hospitalized for chronic obstructive pulmonary disease. Ann Am Thorac Soc 2014; 11:685.

41. Lawes CM, Thornley S, Young R, et al. Statin use in COPD patients is associated with a reduction in mortality: a national cohort study. Prim Care Respir J 2012; 21:35.

42. Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med 2014; 370:2201.

43. Walsh A, Perrem L, Khashan AS, et al. Statins versus placebo for people with chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2019.

Topic 122145 Version 16.0

GRAPHICS

Ideal discharge of the older adult patient: A hospitalist checklist

Data elements

Processes

Discharge summary

Patient instructions

Communication to follow-up clinician on

day of discharge

Presenting problem that precipitated hospitalization

x x x

Key findings and test results x   x

Final primary and secondary diagnoses

x x x

Brief hospital course x   x

Condition at discharge, including functional status and cognitive status if relevant

x – functional status

o – cognitive status

Discharge destination (and rationale if not obvious)

x   x

Discharge medications:

Written schedule x x x

Include purpose and cautions (if appropriate) for each

o x o

Comparison with pre-admission medications (new, changes in dose/frequency, unchanged, meds should no longer take)

x x x

Follow-up appointments with name of provider, date, address, phone number, visit purpose, suggested management plan

x x x

All pending labs or tests, responsible person to whom results will be sent

x   x

Recommendations of any sub- specialty consultants

x   o

Documentation of patient education and understanding

x    

Any anticipated problems and suggested interventions

x x x

24/7 call-back number x x  

Identify referring and receiving providers

x x  

Resuscitation status and any other pertinent end-of-life issues

o    

x: required element; o: optional element.

Derived and expanded from: Halasyamani L, Kripalani S, Coleman E, et al. Transition of care for hospitalized elderly patients: Development of a discharge checklist for hospitalists. J Hosp Med 2006; 1:354.

Graphic 54279 Version 6.0

COPD exacerbation discharge to home checklist

COPD: chronic obstructive pulmonary disease; MDI: metered dose inhaler; DPI: dry powder inhaler; SMI: soft mist inhaler; NIV: noninvasive ventilation.

Graphic 130525 Version 1.0

Criteria for considering a palliative care referral in patients with chronic lung disease

Patient characteristics Social circumstances or issues related to

anticipatory bereavement

Limited options for treatment Limited access to care

Physical symptoms, such as pain, dyspnea, or cough, that are refractory to conventional management

Familial factors, including: Limitations of the family/caregiver Inadequate family support Family discord History of intensely dependent relationship(s) Parental concerns regarding care of dependents

High symptom burden or distress score Financial limitations

Inability to engage in advance care planning and care plan

Unresolved grief or multiple prior losses

Uncertainty as to prognosis or disease trajectory Spiritual or existential crisis

Cognitive impairment Need for coordination of care at multiple sites

Severe or multiple comorbid conditions  

Communication barriers related to language, literacy, or physical issues

Request for hastened death  

Homebound  

Adapted from: NCCN Guidelines Version 2.2012, Palliative Care.

Graphic 103284 Version 2.0

Primary palliative care assessment of patients with chronic lung disease

Understanding of illness/prognosis and treatment options

Does the patient/family/surrogate understand the current illness, their prognosis for quantity and quality of life, expected disease trajectory/uncertainty about disease trajectory, and treatment options?

Symptom management

Does the patient have uncontrolled/distressing symptoms? In particular, does the patient have any of the following?

Pulmonary symptoms (cough, dyspnea) with daily activities Pain Fatigue and sleep disturbance Distressing psychological symptoms (depression and anxiety) Constitutional symptoms (anorexia and weight loss)

Social/spiritual assessment

Are there significant social or spiritual concerns affecting daily life?

Decision making

Is the patient comfortable making health care decisions? Or, does the patient rely on family members, friends, or health care professionals to make decisions?

Has the patient identified a surrogate decision-maker and talked with this person about their goals and values?

Would the patient/family/surrogate like help with treatment decision-making?

Identification of patient-centered goals of care

What are the goals for care, as identified by the patient/family/surrogate?

Are treatment options matched to informed patient-centered goals?

Has the patient participated in an advance care planning process?

Has the patient completed an advance care planning document?

Coping with life-threatening illness

How is the patient coping with their illness?

How are the family/family caregivers coping with the illness?

Coordination of care

Are there barriers to safe and sustainable transitions from one setting to another (eg, transportation to appointments)?

Are systems in place to enable good communication between multiple providers?

Adapted from: 1. Jacobsen J, Jackson V, Dahlin C, et al. Components of early outpatient palliative care consultation in patients with

metastatic nonsmall cell lung cancer. J Palliat Medicine 2011; 14:459. 2. Weissman DE, Meier DE. Identifying patients in need of a palliative care assessment in the hospital setting. J Palliat

Med 2011; 14:17.

Graphic 103286 Version 1.0

Medical guidelines for determining appropriateness of hospice referral: Disease-specific guidelines

A patient will be considered to have a life expectancy of 6 months and be eligible for hospice services if they meet criteria for the following disease-specific baseline guidelines as well as evidence of decline as outlined in non-disease-specific baseline guidelines (shown on a separate table):

Cancer diagnoses

Disease with metastases at presentation OR

Progression from an earlier stage of disease to metastatic disease with either continued decline in spite of therapy or patient declines further disease-directed therapy.

NOTE: Certain cancers with poor prognoses (eg, small-cell lung cancer, brain cancer, and pancreatic cancer) may be hospice eligible without fulfilling the other criteria in this section

Dementia due to Alzheimer disease and related disorders

Patients will be considered to be in the terminal stage of dementia (life expectancy of 6 months or less) if they meet all of the following criteria:

Stage 7 or beyond according to the Functional Assessment Staging Scale; unable to walk, dress, and bathe without assistance; urinary and fecal incontinence (intermittent or constant); no consistently meaningful verbal communication (stereotypical phrases only or the ability to speak is limited to 6 or fewer intelligible words); AND

At least 1 medical complication within the past 12 months: aspiration pneumonia, pyelonephritis, septicemia, multiple stage 3 to 4 decubitus ulcers, recurrent fever after antibiotics, inability to maintain sufficient fluid and calorie intake (≥10% weight loss over previous 6 months or serum albumin <2.5 g/dL).

NOTE: This section is specific for Alzheimer disease and related disorders and is not appropriate for other types of dementia.

Heart disease

Patients will be considered to be in the terminal stage of heart disease (life expectancy of 6 months or less) if they meet the following criteria (1 and 2 should be present; factors from 3 will add supporting documentation):

1. At the time of initial certification or recertification for hospice, the patient is or has been already optimally treated for heart disease, or the patient is either not a candidate for surgical procedures or they decline those procedures. (Optimally treated means that patients who are not on vasodilators have a medical reason for not being on these drugs, eg, hypotension or kidney disease.)

2. Patients with congestive heart failure or angina should meet the criteria for the New York Heart Association (NYHA) Class IV. (Class IV patients with heart disease have an inability to carry on any physical activity. Symptoms of heart failure or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased.)

Significant congestive heart failure may be documented by an ejection fraction of ≤20%, but assessment of ejection fraction is not required if not already available.

3. Documentation of the following factors supports but is not required to establish eligibility for hospice care: treatment-resistant symptomatic supraventricular or ventricular arrhythmias, history of cardiac arrest or resuscitation, history of unexplained syncope, brain embolism of cardiac origin, or concomitant HIV disease.

HIV disease

Patients will be considered to be in the terminal stage of their illness (life expectancy of 6 months or less) if they meet the following criteria (1 and 2 should be present; factors from 3 will add supporting documentation):

1. CD4 count <25 cells per microliter or persistent (2 or more assays at least 1 month apart) viral load >100,000 copies/mL, plus 1 of the following:

Central nervous system (CNS) lymphoma, untreated or persistent despite treatment; wasting (loss of at least 10% lean body mass); mycobacterium avium complex (MAC) bacteremia, untreated, unresponsive to treatment, or treatment refused; progressive multifocal leukoencephalopathy; systemic lymphoma, with advanced HIV disease and partial response to chemotherapy; visceral Kaposi sarcoma, unresponsive to therapy; kidney failure in the absence of dialysis; cryptosporidium infection; toxoplasmosis, unresponsive to therapy.

2. Decreased performance status, as measured by the Karnofsky Performance Status (KPS) scale, ≤50%.

3. Documentation of the following factors will support eligibility for hospice care: chronic persistent diarrhea for 1 year; persistent serum albumin <2.5 g/dL; concomitant, active substance abuse; age >50 years; absence of or resistance to effective antiretroviral, chemotherapeutic, and prophylactic drug therapy related specifically to HIV disease; advanced AIDS dementia complex; toxoplasmosis; congestive heart failure, symptomatic at rest; advanced liver disease.

Liver disease

Patients will be considered to be in the terminal stage of liver disease (life expectancy of 6 months or less) if they meet the following criteria (1 and 2 should be present; factors from 3 will lend supporting documentation):

1. Both prolonged prothrombin time (more than 5 seconds over control or INR >1.5) AND serum albumin <2.5 g/dL.

2. End-stage liver disease with at least 1 of the following: ascites, refractory to treatment or patient noncompliant; spontaneous bacterial peritonitis; hepatorenal syndrome (elevated creatinine and BUN with oliguria [<400 mL/day] and urine sodium concentration <10 mEq/L); hepatic encephalopathy, refractory to treatment or patient noncompliant; recurrent variceal bleeding, despite intensive therapy.

3. Documentation of the following factors will support eligibility for hospice care: progressive malnutrition; muscle wasting with reduced strength and endurance; continued active alcoholism (>80 g ethanol/day); hepatocellular carcinoma; chronic hepatitis B virus infection (HBsAg-positive); hepatitis C infection, refractory to interferon treatment.

Pulmonary disease

Patients will be considered to be in the terminal stage of pulmonary disease (life expectancy of 6 months or less) if they meet the following criteria. The criteria refer to patients with various forms of advanced pulmonary disease who eventually follow a final common pathway for end-stage pulmonary disease (1 and 2 should be present; documentation of 3, 4, and 5 will lend supporting documentation):

1. Severe chronic lung disease as documented by both of the following:

Disabling dyspnea at rest, poorly responsive or unresponsive to bronchodilators, resulting in decreased functional capacity, eg, bed to chair existence, fatigue, and cough (documentation of forced expiratory volume in 1 second [FEV1], <30% predicted value after bronchodilator, is objective evidence for disabling dyspnea but is not necessary to obtain). Progression of end-stage pulmonary disease, as evidenced by increasing visits to the emergency department or hospitalizations for pulmonary infections and/or respiratory failure or increasing clinician home visits prior to initial certification (documentation of serial decrease of FEV1 >40 mL/year is objective evidence for disease progression but is not necessary to obtain).

2. Hypoxemia at rest on room air, as evidenced by pO ≤55 mmHg, or oxygen saturation ≤88%, determined either by arterial blood gases or oxygen saturation monitors (these values may be obtained from recent hospital records), OR hypercapnia, as evidenced by pCO ≥50 mmHg (this value may be obtained from recent [within 3 months] hospital records).

3. Right heart failure (RHF) secondary to pulmonary disease (Cor pulmonale, eg, not secondary to left heart disease or valvulopathy).

4. Unintentional progressive weight loss >10% of body weight over the preceding 6 months.

5. Resting tachycardia >100/minute.

Kidney disease (acute and chronic)

Patients will be considered to be in the terminal stage of kidney disease (life expectancy of 6 months or less) if they meet the following criteria:

Acute kidney failure (1 and either 2, 3, or 4 should be present; factors from 5 will lend supporting documentation):

1. The patient is not seeking dialysis or kidney transplant or is discontinuing dialysis. As with any other condition, an individual with kidney disease is eligible for the hospice benefit if that individual has a prognosis of 6 months or less, if the illness runs its normal course.

2

2

There is no regulation precluding patients on dialysis from electing hospice care. However, the continuation of dialysis will significantly alter a patient's prognosis and thus potentially impact that individual's eligibility.

When an individual elects hospice care for end-stage kidney disease (ESKD) or for a condition to which the need for dialysis is related, the hospice agency is financially responsible for the dialysis. In such cases, there is no additional reimbursement beyond the per diem rate. The only situation in which a beneficiary may access both the hospice benefit and the ESKD benefit is when the need for dialysis is not related to the patient's terminal illness.

2. Creatinine clearance <10 cc/minute (<15 cc/minute for diabetics), or <15 cc/minute (<20 cc/minute for diabetics) with comorbidity of congestive heart failure.

3. Serum creatinine >8.0 mg/dL (>6.0 mg/dL for diabetics).

4. Estimated glomerular filtration rate (GFR) <10 mL/minute.

5. Comorbid conditions: mechanical ventilation, malignancy (other organ system), chronic lung disease, advanced cardiac disease, advanced liver disease, immunosuppression/AIDS, albumin <3.5 g/dL, platelet count <25,000/microL, disseminated intravascular coagulation, gastrointestinal bleeding.

Chronic kidney disease (1 and either 2 or 3 should be present; factors from 4 will lend supporting documentation):

1. The patient is not seeking dialysis or kidney transplant or is discontinuing dialysis; as with any other condition, an individual with kidney disease is eligible for the hospice benefit if that individual has a prognosis of 6 months or less, if the illness runs its normal course. There is no regulation precluding patients on dialysis from electing hospice care. However, the continuation of dialysis will significantly alter a patient's prognosis and thus potentially impact that individual's eligibility.

When an individual elects hospice care for ESKD or for a condition to which the need for dialysis is related, the hospice agency is financially responsible for the dialysis. In such cases, there is no additional reimbursement beyond the per diem rate. The only situation in which a beneficiary may access both the hospice benefit and the ESKD benefit is when the need for dialysis is not related to the patient's terminal illness.

2. Creatinine clearance <10 cc/minute (<15 cc/minute for diabetics), or <15 cc/minute (<20 cc/minute for diabetics) with comorbidity of congestive heart failure.

3. Serum creatinine >8.0 mg/dL (>6.0 mg/dL for diabetics).

4. Signs and symptoms of kidney failure: uremia; oliguria (<400 cc/24 hours); intractable hyperkalemia (>7.0 mEq/L), not responsive to treatment; uremic pericarditis; hepatorenal syndrome; intractable fluid overload, not responsive to treatment.

Stroke or coma

Patients will be considered to be in the terminal stages of stroke or coma (life expectancy of 6 months or less) if they meet the following criteria:

Stroke:

KPS or Palliative Performance Scale of 40% or less. Inability to maintain hydration and caloric intake with 1 of the following: weight loss >10% in the last 6 months or >7.5% in the last 3 months; serum albumin <2.5 g/dL; current history of pulmonary aspiration, not responsive to speech-language pathology intervention; sequential calorie counts documenting inadequate caloric/fluid intake; dysphagia severe enough to prevent the patient from continuing food and fluids necessary to sustain life, in a patient who does not receive artificial nutrition and hydration.

Coma (any etiology): Comatose patients with any 3 of the following on day 3 of the coma: abnormal brain stem response, absent verbal response, absent withdrawal response to pain, serum creatinine >1.5 mg/dL.

Documentation of the following factors will support eligibility for hospice care:

Documentation of medical complications, in the context of progressive clinical decline, within the previous 12 months, that support a terminal prognosis:

Aspiration pneumonia, upper urinary tract infection (pyelonephritis), refractory stage 3 to 4 decubitus ulcers, fever recurrent after antibiotics.

For stroke patients, documentation of diagnostic imaging factors that support poor prognosis after stroke include:

For non-traumatic hemorrhagic stroke: large-volume hemorrhage on CT (≥20 mL if intratentorial, ≥50 mL if supratentorial), ventricular extension of hemorrhage, surface area of involvement of hemorrhage ≥30% of cerebrum, midline shift ≥1.5 cm, obstructive hydrocephalus in a patient who declines or is not a candidate for ventriculoperitoneal shunt. For thrombotic/embolic stroke: large anterior infarcts with both cortical/subcortical involvement, large bihemispheric infarcts, basilar artery occlusion, bilateral vertebral artery occlusion.

Amyotrophic lateral sclerosis (ALS)

Patients are considered eligible for hospice care if they do not elect tracheostomy and invasive ventilation and display evidence of critically impaired respiratory function (with or without use of noninvasive positive pressure ventilation [NIPPV]) and/or severe nutritional insufficiency (with or without use of a gastrostomy tube).

Critically impaired respiratory function is as defined by:

Forced vital capacity (FVC) <40% predicted (seated or supine) and 2 or more of the following symptoms and/or signs: dyspnea at rest, orthopnea, use of accessory respiratory musculature, paradoxical abdominal motion, respiratory rate >20/minute, reduced speech/vocal volume, weakened cough, symptoms of sleep-disordered breathing, frequent awakening, daytime somnolence/excessive daytime sleepiness, unexplained headaches, unexplained confusion, unexplained anxiety, unexplained nausea.

If unable to perform the FVC test, patients meet this criterion if they manifest 3 or more of the above symptoms/signs. Severe nutritional insufficiency is defined as dysphagia with progressive weight loss of at least 5% of body weight with or without election for gastrostomy tube insertion. These revised criteria rely less on the measured FVC and, as such, reflect the reality that not all patients with ALS can or will undertake regular pulmonary function tests.

KPS = 50: Requires considerable assistance and frequent medical care.

KPS <50: Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly.

HIV: human immunodeficiency virus; CD4: cluster of differentiation 4; AIDS: acquired immunodeficiency syndrome; INR: international normalized ratio; BUN: blood urea nitrogen; HBsAg: hepatitis B surface antigen; pO : partial pressure of oxygen; pCO : partial pressure of carbon dioxide; CT: computed tomography.

Sources: 1. The NHO medical guidelines for non-cancer disease and local medical review policy: hospice access for patients with

diseases other than cancer. Hosp J 1999. 2. Centers for Medicare & Medicaid Services. Medicare Coverage Database. Available at: https://www.cms.gov/medicare-

coverage-database/details/lcd-details.aspx?LCDId=34538 (Accessed on January 5, 2021).

Graphic 61282 Version 21.0

2 2

Technique for use of a pressurized metered dose inhaler (MDI) with a spacer or chamber*

Uncap mouthpiece and check for loose objects in the device.

Prime your inhaler if this is the first time you are using it, if you have not used it for several days, or if you have dropped it. Priming an MDI usually involves shaking it and spraying it into the air (away from your face) a total of up to 4 times. See the information that came with your inhaler for exact instructions.

Insert MDI into spacer.

Shake canister vigorously for approximately 5 seconds.

Hold the MDI upright with your index finger on the top of the medication canister and your thumb supporting the bottom of the inhaler. You may need to use the other hand to hold the spacer.

Breathe out normally through your mouth.

Put the mouthpiece between your teeth and close your lips tightly around mouthpiece of spacer. (If using a mask attached to the chamber, place the mask completely over your nose and mouth.)

Make sure your tongue does not block the opening of the mouthpiece of the spacer.

Press down the top of the canister with your index finger to release the medicine.

At the same time, breathe in deeply and slowly through your mouth until your lungs are completely filled; this should take 3 to 5 seconds.

Hold the medicine in your lungs for approximately 5 to 10 seconds. If you did not get a full breath or cannot hold your breath long enough, you can inhale a second time to fully empty the chamber and hold your breath again for approximately 5 seconds. For infants and young children, or if unable to cooperate with a deep breath or breath-holding, 5 to 6 normal breaths will allow complete emptying of the chamber.

If you need more than one puff, wait approximately 15 to 30 seconds between puffs. Shake canister again before the next puff. Do not load both puffs into the chamber and then empty the chamber with a single inhalation.

When finished, recap mouthpiece.

If your inhaler contains a steroid medicine (sometimes called glucocorticoid or corticosteroid), rinse your mouth and gargle with water after you use it. Then spit out the water. Do not swallow it.

You can use your spacer for more than 1 medication. Just remove the first MDI and insert the other one.

These instructions do not apply to dry powder or soft mist inhalers. Cleaning instructions are provided separately.

* We prefer to use a "valved holding chamber" for the spacer (eg, AeroChamber, Easivent, Optichamber, Vortex). The valve holds the medicine in the chamber until you take your deep breath

in. This helps get the medicine into your lungs. Also, when you breathe out into the mouthpiece, the valve prevents your breath from going into the chamber. If your spacer does not have this valve, you should breathe out through your nose or remove the spacer from your mouth before breathing out.

Graphic 103303 Version 9.0

Technique for use of a metered dose inhaler (MDI) without a spacer or chamber

Remove the cover of the mouthpiece.

Prime your inhaler if this is the first time you are using it, if you have not used it for several days, or if you have dropped it. Priming a metered dose inhaler usually involves shaking it and spraying it into the air (away from your face) up to 4 times. See the information that came with your inhaler for exact instructions.

Check the number of doses remaining in the MDI.

Sit or stand up straight with the chi tilted up and neck slightly extended.

Shake MDI canister vigorously for 5 seconds.

Hold the MDI upright with your index finger on the top of the canister and your thumb supporting the bottom of the inhaler.

Breathe out normally.

Put the mouthpiece between your teeth and close your lips around mouthpiece or position mouthpiece about 4 cm (about the width of 2 fingers) from your mouth.

Keep your tongue away from the opening of the mouthpiece.

Press down the top of the canister with the index finger to release the medicine.

At the same time as the canister is pressed, breathe in deeply and slowly through your mouth until your lungs are completely full. This should take 3 to 5 seconds.

Hold the medicine in your lungs for as long as comfortable (about 5 to 10 seconds).

Remove the inhaler from your mouth and exhale normally.

If you need a second puff, wait about 15 to 30 seconds between puffs. Shake the canister again before the next puff.

When finished, put the mouthpiece cover back on.

If your inhaler contains a steroid medicine (sometimes called a "glucocorticoid" or "corticosteroid"), rinse your mouth and gargle with water after you use it. Then spit out the water. Do not swallow it.

We prefer to use metered dose inhalers (MDIs) with a spacer or holding chamber. Instructions for use of MDIs with these devices is provided in a separate graphic.

These instructions do not apply to dry powder or soft mist inhalers. Cleaning instructions are provided separately.

More detailed information about individual medicines can be found at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

MDI: metered dose inhaler.

Graphic 72362 Version 13.0

Technique for use of various dry powder inhalers*

Load a dose of medicine

For single-dose inhalers, load a dose by taking a pill out of its packaging and putting the pill into the inhaler. Then push 1 or more buttons on the inhaler to poke holes in the pill.

For multiple-dose inhalers, load a dose by sliding a lever or twisting part of the inhaler. Loading a dose should decrease the counter on the device by one. This means a dose is ready to be inhaled.

Once the dose is loaded, maintain your inhaler in the correct position – some inhalers need to be held upright, but others need to be horizontal. The dose may be lost or spilled if the inhaler is tipped over after loading.

Medication delivery

Open the device or take off the cap to expose the mouthpiece, if necessary.

While holding the inhaler away from your mouth, breathe out (exhale) fully. Do not exhale into the mouthpiece.

Put the mouthpiece between your lips. Breathe in quickly and steadily through your mouth, as deeply as possible. Do not breathe in through your nose. You might not taste or feel the medicine, even when you are using the inhaler correctly. If your device has air vent holes, do not cover those holes while inhaling through the device.

Remove the device from your mouth and hold your breath for about 10 seconds (or as long as you comfortably can).

Breathe out slowly (away from the mouthpiece).

If you are supposed to take 2 puffs of your inhaler, load/activate another dose and breathe it in.

Rinse your mouth out with water, gargle, and spit out the water.

Device maintenance and storage

After use, close your inhaler or replace the cover or cap. Make sure the device is fully closed before storing.

For single dose inhalers, you often need to dispose of the used dose. Please refer to the package insert.

Pay attention to the number of doses you have remaining. For multi-dose devices, observe the counter to determine when you need a refill on the device. For single dose devices, monitor the number of individual doses remaining.

Store your inhaler in a cool, dry place.

Dry powder inhalers generally do not require internal cleaning. The mouthpiece may be wiped off with a dry cloth. Please refer to the package insert for additional device-specific instructions.

* Each dry powder inhaler comes with its own directions. Although the general technique is similar, various devices are loaded and activated differently. Some devices load each dose separately, while others contain a month's worth of medication and do not require loading. Refer to the package insert of each device or to the manufacturer website for additional instructions.

Graphic 51020 Version 13.0

Technique for use of soft mist inhalers (SMIs)*

The first time you use a soft mist inhaler, you will need to insert the cartridge.

Keep the cap on the mouthpiece closed. Press the safety catch on the side of the inhaler and pull off the clear plastic base.

Write the discard date on the label. This is 3 months from the date you put in the cartridge.

Push the narrow end of the cartridge into the inhaler.

Push the cartridge against a firm surface or table top to be sure it has gone all the way in. You will know the cartridge is in all the way when it clicks. You will still be able to see a little bit of the cartridge.

Do not remove the cartridge after it has been inserted.

Put the clear base back on. Press until you hear a click.

Do not remove the clear base again.

Prime the inhaler before the first dose.

Hold the inhaler upright with the cap closed. Turn the clear base clockwise (to the right) half a turn until it clicks.

Open the cap by pushing on the small, round opening tab. Then point the inhaler at the floor, away from your face.

Press the dose release button on the side. Check to see if a mist comes out. Close the cap.

If you did not see a mist, repeat the priming steps above until you see a mist come out.

After you see a mist come out, repeat these steps 3 more times until you see a total of 4 sprays of medicine.

Your inhaler is now primed and ready for daily use.

If you do not use the inhaler for more than 3 days, repeat the priming steps 1 time to release 1 spray of medicine.

If you do not use the inhaler for more than 3 weeks, repeat the priming steps 4 times to release 4 sprays of medicine.

Take a dose of medicine.

Hold the inhaler upright with 1 hand, with the cap closed. You do not need to shake it. Use your other hand to turn the clear base clockwise half a turn in the direction of the arrows. This prepares the dose of medicine.

Open the cap by pushing on the small round opening tab.

Breathe out slowly and fully.

Put the mouthpiece in your mouth, and hold the inhaler horizontally. This means it should point toward the back of your throat.

Close your lips around the inhaler, but do not cover the air vents (holes) on the sides.

Take a slow, deep breath in. As you start to inhale, press the button on the side of the inhaler and inhale the mist.

When your lungs are full, hold your breath for 10 seconds to keep the medicine in your lungs.

Remove inhaler from your mouth and breathe out slowly. Put the cap back on the mouthpiece.

You should clean your inhaler once a week. To do this, wipe the inside and outside of the mouthpiece with a clean, damp cloth.

The inhaler has a dose counter (also called a "dose indicator") on the side. When the arrow is in the red zone, the inhaler is almost empty. When the inhaler is completely empty, the arrow will point to "0," and you will not be able to turn the base of the inhaler. Throw away the inhaler when the counter reads "0" or you reach the discard date, whichever is first. Make sure you always have another inhaler available before you need it.

* Soft mist inhalers are also known as Respimat inhalers.

Graphic 93600 Version 6.0

Recommended adult immunization schedule by medical condition and other in

Administer recommended vaccines if vaccination history is incomplete or unknown. Do not restart or add do use of trade names is for identification purposes only and does not imply endorsement by the ACIP or CDC.

Polio vaccination Routine vaccination:

Routine poliovirus vaccination of adults residing in the United States is not necessary. Special situations:

Adults at increased risk of exposure to poliovirus with: No evidence of a complete polio vaccination series (ie, at least 3 doses): Administer remain Evidence of completed polio vaccination series (ie, at least 3 doses): May administer one life

For detailed information, refer to www.cdc.gov/vaccines/vpd/polio/hcp/recommendations.html.

HSCT: hematopoietic stem cell transplant.

* Precaution for LAIV4 does not apply to alcoholism.

¶ COVID-19 vaccination Routine vaccination:

Primary series: 2-dose series at 0, 4 to 8 weeks (Moderna) or 2-dose series at 0, 3 to 8 weeks (Nov Booster dose: Refer to www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerati

Special situations: Persons who are moderately or severely immunocompromised.

Primary series: 3-dose series at 0, 4, 8 weeks (Moderna) or 3-dose series at 0, 3, 7 weeks (Pfizer-BioNTech). 2-dose series at 0, 3 weeks (Novavax).

Booster dose: Refer to www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-conside Pre-exposure prophylaxis (eg, monoclonal antibodies) may be considered to complement C considerations/interim-considerations-us.html#immunocompromised.

For Janssen COVID-19 Vaccine recipients refer to COVID-19 schedule at www.cdc.gov/vaccines/c NOTE: Current COVID-19 schedule available at www.cdc.gov/vaccines/covid-19/downloads/COVID- information on Emergency Use Authorization (EUA) indications for COVID-19 vaccines, please visit disease-2019-covid-19/covid-19-vaccines.

Contraindications and precautions: Refer to contraindications and precautions to COVID-19 vaccination.

Δ Influenza vaccination Routine vaccination:

Age 19 years or older: 1 dose any influenza vaccine appropriate for age and health status annual Age 65 years or older: Any one of quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), adjuvanted inactivated influenza vaccine (aIIV4) is preferred. If none of these three vaccines is ava For the 2022–2023 season, refer to www.cdc.gov/mmwr/volumes/71/rr/rr7101a1.htm. For the 2023–2024 season, refer to the 2023–2024 ACIP influenza vaccine recommendations.

Special situations: Egg allergy, hives only: Any influenza vaccine appropriate for age and health status annually. Egg allergy–any symptom other than hives (eg, angioedema, respiratory distress, or required e vaccine appropriate for age and health status may be administered. If using egg-based IIV4 or LAI provider who can recognize and manage severe allergic reactions. Close contacts (eg, caregivers, health care workers) of severely immunosuppressed persons receive LAIV4. If LAIV4 is given, they should avoid contact with/caring for such immunosuppressed Severe allergic reaction (eg, anaphylaxis) to a vaccine component or a previous dose of any i precautions. History of Guillain-Barré syndrome within 6 weeks after previous dose of influenza vaccine: risks for those at higher risk for severe complications from influenza.

Contraindications and precautions: For contraindications and precautions to influenza vaccination, refer to IIV4 Appendix, LAIV4 Appe

◊ Tetanus, diphtheria, and pertussis (Tdap) vaccination Routine vaccination:

Previously did not receive Tdap at or after age 11 years: 1 dose Tdap, then Td or Tdap every 10 Special situations:

Previously did not receive primary vaccination series for tetanus, diphtheria, or pertussis: 1 dose of Td or Tdap 6 to 12 months later (Tdap can be substituted for any Td dose, but preferred as Pregnancy: 1 dose Tdap during each pregnancy, preferably in early part of gestational weeks 27 t Wound management: Persons with 3 or more doses of tetanus-toxoid-containing vaccine: For cle last dose of tetanus-toxoid-containing vaccine; for all other wounds, administer Tdap or Td if more preferred for persons who have not previously received Tdap or whose Tdap history is unknown. I use Tdap. For detailed information, refer to www.cdc.gov/mmwr/volumes/69/wr/mm6903a5.htm.

Contraindications and precautions: For contraindications and precautions to tetanus, diphtheria, and acellular pertussis (Tdap), refer t

§ Measles, mumps, and rubella vaccination Routine vaccination:

No evidence of immunity to measles, mumps, or rubella: 1 dose. Evidence of immunity: Born before 1957 (health care personnel, refer below), documentation (diagnosis of disease without laboratory confirmation is not evidence of immunity).

Special situations: Pregnancy with no evidence of immunity to rubella: MMR contraindicated during pregnancy; a Nonpregnant women of childbearing age with no evidence of immunity to rubella: 1 dose. HIV infection with CD4 percentages ≥15% and CD4 count ≥200 cells/mm for at least 6 mon dose series at least 4 weeks apart; MMR contraindicated for HIV infection with CD4 percentage <1 Severe immunocompromising conditions: MMR contraindicated. Students in postsecondary educational institutions, international travelers, and household o evidence of immunity to measles, mumps, or rubella: 2-dose series at least 4 weeks apart if pre 1 dose MMR. In mumps outbreak settings, for information about additional doses of MMR (including 3rd dose Health care personnel:

Born before 1957 with no evidence of immunity to measles, mumps, or rubella: Consider rubella. Born in 1957 or later with no evidence of immunity to measles, mumps, or rubella: 2-dose rubella.

Contraindications and precautions: For contraindications and precautions to measles, mumps, rubella (MMR), refer to MMR Appendix

¥ Varicella vaccination Routine vaccination:

No evidence of immunity to varicella: 2-dose series 4 to 8 weeks apart if previously did not rece varicella vaccine] for children); if previously received 1 dose varicella-containing vaccine, 1 dose at

Evidence of immunity: US-born before 1980 (except for pregnant women and health care per vaccine at least 4 weeks apart, diagnosis or verification of history of varicella or herpes zoster

Special situations: Pregnancy with no evidence of immunity to varicella: VAR contraindicated during pregnancy; a previously received 1 dose varicella-containing vaccine or dose 1 of 2-dose series (dose 2: 4 to 8 w regardless of whether US-born before 1980.

3

Health care personnel with no evidence of immunity to varicella: 1 dose if previously received previously did not receive any varicella-containing vaccine, regardless of whether US-born before HIV infection with CD4 percentages ≥15% and CD4 count ≥200 cells/mm with no evidence VAR contraindicated for HIV infection with CD4 percentage <15% or CD4 count <200 cells/mm . Severe immunocompromising conditions: VAR contraindicated.

Contraindications and precautions: For contraindications and precautions to varicella (VAR), refer to VAR Appendix.

‡ Zoster vaccination Routine vaccination:

Age 50 years or older (NOTE: Serologic evidence of prior varicella is not necessary for zoster vacc available, providers should follow ACIP guidelines for varicella vaccination first. RZV is not indicate RZV in persons without a history of varicella or varicella vaccination): 2-dose series recombinant zo weeks; repeat dose if administered too soon), regardless of previous herpes zoster or history of zo

Special situations: Pregnancy: There is currently no ACIP recommendation for RZV use in pregnancy. Consider delay Immunocompromising conditions (including persons with HIV regardless of CD4 count; NOTE: I herpes zoster, providers should refer to the clinical considerations for use of RZV in immunocomp recommendations for further guidance: www.cdc.gov/mmwr/volumes/71/wr/mm7103a2.htm): 2-d (minimum interval: 4 weeks; repeat dose if administered too soon). For detailed information, refer

Contraindications and precautions: For contraindications and precautions to zoster recombinant vaccine (RZV), refer to RZV Appendix

† Human papillomavirus vaccination Routine vaccination:

HPV vaccination recommended for all persons through age 26 years: 2- or 3-dose series depen Age 15 years or older at initial vaccination: 3-dose series at 0, 1 to 2 months, 6 months (min dose 1 to dose 3: 5 months; repeat dose if administered too soon). Age 9 to 14 years at initial vaccination and received 1 dose or 2 doses less than 5 months Age 9 to 14 years at initial vaccination and received 2 doses at least 5 months apart: HPV

Interrupted schedules: If vaccination schedule is interrupted, the series does not need to be rest No additional dose recommended when any HPV vaccine series has been completed using th

Shared clinical decision-making: Some adults age 27 to 45 years: Based on shared clinical decision-making, 2- or 3-dose series as

Special situations: Age ranges recommended above for routine and catch-up vaccination or shared clinical deci

Immunocompromising conditions, including HIV infection: 3-dose series, even for those w Pregnancy: Pregnancy testing is not needed before vaccination; HPV vaccination is not recom vaccinated while pregnant.

Contraindications and precautions: For contraindications and precautions to human papillomavirus (HPV) vaccination, refer to HPV Ap

** Pneumococcal vaccination Routine vaccination:

Age 65 years or older who have: Not previously received a dose of PCV13, PCV15, or PCV20 or whose previous vaccination this should be followed by a dose of PPSV23 given at least 1 year after the PCV15 dose. A min for adults with an immunocompromising condition (NOTE: Immunocompromising conditions

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3

iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, Ho transplants, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies invasive pneumococcal disease caused by serotypes unique to PPSV23 in these vulnerable gro Previously received only PCV7: Follow the recommendation above. Previously received only PCV13: 1 dose PCV20 at least 1 year after the PCV13 dose OR comp www.cdc.gov/vaccines/vpd/pneumo/downloads/pneumo-vaccine-timing.pdf. Previously received only PPSV23: 1 dose PCV15 OR 1 dose PCV20 at least 1 year after the PP PPSV23. Previously received both PCV13 and PPSV23 but NO PPSV23 was received at age 65 years vaccine dose OR complete the recommended PPSV23 series as described here: www.cdc.gov/ Previously received both PCV13 and PPSV23, AND PPSV23 was received at age 65 years o least 5 years after the last pneumococcal vaccine dose. For guidance on determining which pneumococcal vaccines a patient needs and when, pleas www.cdc.gov/vaccines/vpd/pneumo/hcp/pneumoapp.html.

Special situations: Age 19 to 64 years with certain underlying medical conditions or other risk factors who hav alcoholism, chronic heart/liver/lung disease, chronic renal failure, cigarette smoking, cochlear im generalized malignancy, HIV, Hodgkin disease, immunodeficiency, iatrogenic immunosuppressio organ transplants, or sickle cell disease, or other hemoglobinopathies):

Not previously received a PCV13, PCV15, or PCV20 or whose previous vaccination history should be followed by a dose of PPSV23 given at least 1 year after the PCV15 dose. A minimum adults with an immunocompromising condition(NOTE: Immunocompromising conditions inc iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, Ho transplants, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies Previously received only PCV7: Follow the recommendation above. Previously received only PCV13: 1 dose PCV20 at least 1 year after the PCV13 dose OR comp www.cdc.gov/vaccines/vpd/pneumo/downloads/pneumo-vaccine-timing.pdf. Previously received only PPSV23: 1 dose PCV15 OR 1 dose PCV20 at least 1 year after the PP PPSV23. Previously received both PCV13 and PPSV23 but have not completed the recommended dose OR complete the recommended PPSV23 series as described here: www.cdc.gov/vaccines

For guidance on determining which pneumococcal vaccines a patient needs and when, please re www.cdc.gov/vaccines/vpd/pneumo/hcp/pneumoapp.html.

Contraindications and precautions: For contraindications and precautions to Pneumococcal conjugate (PCV15 and PCV20), refer to PC PPSV23 Appendix.

¶¶ Hepatitis A vaccination Routine vaccination:

Not at risk but want protection from hepatitis A (identification of risk factor not required): apart [minimum interval: 6 months]) or 3-dose series HepA-HepB (Twinrix at 0, 1, 6 months [mini

Special situations: At risk for hepatitis A virus infection: 2-dose series HepA or 3-dose series HepA-HepB as above

Chronic liver disease (eg, persons with hepatitis B, hepatitis C, cirrhosis, fatty liver disease, a [ALT] or aspartate aminotransferase [AST] level greater than twice the upper limit of normal). HIV infection. Men who have sex with men.

Injection or noninjection drug use. Persons experiencing homelessness. Work with hepatitis A virus in research laboratory or with nonhuman primates with hepatit Travel in countries with high or intermediate endemic hepatitis A (HepA-HepB [Twinrix] m to 30 days, followed by a booster dose at 12 months). Close, personal contact with international adoptee (eg, household or regular babysitting) endemic hepatitis A (administer dose 1 as soon as adoption is planned, at least 2 weeks befor Pregnancy if at risk for infection or severe outcome from infection during pregnancy. Settings for exposure, including health care settings targeting services to injection or noninj for developmentally disabled persons (individual risk factor screening not required).

Contraindications and precautions: For contraindications and precautions to hepatitis A (HepA) vaccination, refer to HepA Appendix.

ΔΔ Hepatitis B vaccination Routine vaccination:

Age 19 through 59 years: Complete a 2- or 3-, or 4-dose series. 2-dose series only applies when 2 doses of Heplisav-B (NOTE: Heplisav-B and PreHevbrio are persons) are used at least 4 weeks apart. 3-dose series Engerix-B, PreHevbrio (NOTE: Heplisav-B and PreHevbrio are not recommended Recombivax HB at 0, 1, 6 months [minimum intervals: dose 1 to dose 2: 4 weeks / dose 2 to d 3-dose series HepA-HepB (Twinrix at 0, 1, 6 months [minimum intervals: dose 1 to dose 2: 4 w 4-dose series HepA-HepB (Twinrix) accelerated schedule of 3 doses at 0, 7, and 21 to 30 days,

Age 60 years or older with known risk factors for hepatitis B virus infection should complete a H Age 60 years or older without known risk factors for hepatitis B virus infection may complete a

Risk factors for hepatitis B virus infection include: Chronic liver disease (eg, persons with hepatitis C, cirrhosis, fatty liver disease, alcoholic aspartate aminotransferase [AST] level greater than twice upper limit of normal). HIV infection. Sexual exposure risk (eg, sex partners of hepatitis B surface antigen [HBsAg]-positive pe persons seeking evaluation or treatment for a sexually transmitted infection; men who ha Current or recent injection drug use. Percutaneous or mucosal risk for exposure to blood (eg, household contacts of HBsAg disabled persons; health care and public safety personnel with reasonably anticipated risk maintenance dialysis, including in-center or home hemodialysis and peritoneal dialysis, a Incarceration. Travel in countries with high or intermediate endemic hepatitis B.

Special situations: Patients on dialysis: complete a 3- or 4-dose series.

3-dose series Recombivax HB at 0, 1, 6 months (NOTE: use Dialysis Formulation 1 mL = 40 mc 4-dose series Engerix-B at 0, 1, 2, and 6 months (NOTE: use 2 mL dose instead of the normal a

Contraindications and precautions: For contraindications and precautions to hepatitis B (HepB) vaccination, refer to HepB Appendix.

◊◊ Meningococcal vaccination Special situations for MenACWY:

Anatomical or functional asplenia (including sickle cell disease), HIV infection, persistent co eculizumab, ravulizumab) use: 2-dose series MenACWY-D (Menactra, Menveo, or MenQuadfi) a

Travel in countries with hyperendemic or epidemic meningococcal disease, or microbiologi (Menactra, Menveo, or MenQuadfi) and revaccinate every 5 years if risk remains. First-year college students who live in residential housing (if not previously vaccinated at a Menveo, or MenQuadfi). For MenACWY booster dose recommendations for groups listed under "Special situations" and among men who have sex with men) and additional meningococcal vaccination information, refe

Shared clinical decision-making for MenB: Adolescents and young adults age 16 to 23 years (age 16 to 18 years preferred) not at increa making, 2-dose series MenB-4C (Bexsero) at least 1 month apart or 2-dose series MenB-FHbp (Tru after dose 1, administer dose 3 at least 4 months after dose 2); MenB-4C and MenB-FHbp are not

Special situations for MenB: Anatomical or functional asplenia (including sickle cell disease), persistent complement co ravulizumab) use, or microbiologists routinely exposed to Neisseria meningitidis (NOTE: Men if indicated, but at a different anatomic site, if feasible): 2-dose primary series MenB-4C (Bexsero) at 0, 1 to 2, 6 months (if dose 2 was administered at least 6 months after dose 1, dose 3 not need dose should be administered at least 4 months after dose 3); MenB-4C and MenB-FHbp are not in booster 1 year after primary series and revaccinate every 2 to 3 years if risk remains. Pregnancy: Delay MenB until after pregnancy unless at increased risk and vaccination benefits o For MenB booster dose recommendations for groups listed under "Special situations" and in an among men who have sex with men) and additional meningococcal vaccination information, refe

Contraindications and precautions: For contraindications and precautions to meningococcal ACWY (MenACWY) [MenACWY-CRM (Men MenACWY Appendix. For contraindications and precautions to meningococcal B (MenB) [MenB-4C (Bexsero); MenB-FH

§§ Haemophilus influenzae type b vaccination Special situations:

Anatomical or functional asplenia (including sickle cell disease): 1 dose if previously did not r before splenectomy. Hematopoietic stem cell transplant (HSCT): 3-dose series 4 weeks apart starting 6 to 12 month

Contraindications and precautions: For contraindications and precautions to Haemophilus influenzae type b (Hib) vaccination, refer to

¥¥ Vaccinate after pregnancy.

Reproduced from: Advisory Committee on Immunization Practices. Recommended Adult Immunization Schedule for ages 19 years or https://www.cdc.gov/vaccines/schedules/hcp/imz/adult-conditions.html (Accessed on February 15, 2023).

Graphic 62130 Version 23.0

New diagnosis of COPD

COPD: chronic obstructive pulmonary disease; COVID-19: coronavirus disease 2019; GOLD: Global Initiative f CAT: COPD Assessment Test; SABA: short-acting beta-agonist; SAMA: short-acting muscarinic antagonist; LAM (anticholinergic); LABA: long-acting beta-agonist; mMRC: Modified Medical Research Council; FEV : forced ex forced vital capacity.

* COPD is diagnosed based on the presence of chronic respiratory symptoms (dyspnea, cough, sputum prod limitation. All patients with COPD defined by GOLD have airflow limitation based on a reduced FEV /FVC ratio is determined by the reduction in FEV .

¶ An exacerbation of COPD is characterized by increased dyspnea and/or cough and sputum that worsens in accompanied by tachypnea or tachycardia, and is often caused by infection, environmental irritation, or othe exacerbations" are typically defined as those which require treatment with systemic glucocorticoids. More o been proposed but are difficult to establish via patient history. Please refer to UpToDate content on "COPD e and evaluation" for additional information.

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1

Δ CAT: http://www.catestonline.org (Accessed on January 12, 2023).

◊ For those prescribed a LABA alone, SAMA-SABA combination therapy is likely to be most potent but will ha LAMA. For those prescribed a LAMA, SAMA should generally not be used concomitantly, so SABA alone is pre

§ Occasional patients with only minimal intermittent symptoms are appropriate for only as-needed rescue th acting bronchodilators.

Graphic 54300 Version 13.0

Follow-up management of COPD*

No exacerbations and no dyspnea/low COPD impact (ie, mMRC 0 to 1 or CAT <10)

Current therapy Actions

SABA or SABA-SAMA as needed

Continue current therapy

LAMA, LABA, or LAMA-LABA Continue current therapy

LABA-ICS or LABA-LAMA-ICS Taper or discontinue ICS dose to reduce adverse effects of ICS

Persistent dyspnea or high COPD impact (ie, mMRC ≥2 or CAT ≥10) with no exacerbations

Current therapy Actions

SABA or SABA-SAMA as needed

Add LAMA or LABA

LAMA or LABA monotherapy Change to LAMA-LABA

LABA-ICS LAMA-LABA-ICS LAMA-LABA if lack of response to ICS or adverse effects from ICS

LAMA-LABA Substitute alternate delivery system or different LAMA- LABA agents Trial of LAMA-LABA-ICS, in patients with blood eosinophils ≥100 cells/microL Additional interventions may include low-dose theophylline, repeat pulmonary rehabilitation, and nonpharmacologic therapies

LAMA-LABA-ICS Continue LAMA-LABA-ICS Additional interventions may include low-dose theophylline, repeat pulmonary rehabilitation, and nonpharmacologic therapies for COPD Stop ICS, if initial indication unclear, lack of response, or adverse effect to ICS

1 or more exacerbations in past year +/– persistent dyspnea or high COPD impact (ie, mMRC ≥2 or CAT ≥10)

Current therapy Actions

SABA or SABA-SAMA as needed

Add LAMA

¶

Δ

¶

◊

§

§

Δ

¶

§

LAMA or LABA monotherapy LAMA-LABA, if blood eosinophil count <300/microL

or

LAMA-LABA-ICS, if blood eosinophil count ≥300/microL or hospitalization for COPD exacerbation

or

LABA-ICS, if blood eosinophil count ≥100/microL and LAMA contraindicated

LAMA-LABA LAMA-LABA-ICS, if blood eosinophil count ≥100/microL

or

Continue LAMA-LABA, if blood eosinophil count <100/microL

Add roflumilast

or

Add azithromycin

LABA-ICS LAMA-LABA-ICS

or

LAMA-LABA if lack of response to ICS or adverse effects from ICS

LAMA-LABA-ICS Continue LAMA-LABA-ICS Add roflumilast

or

Add azithromycin Stop ICS if initial indication unclear, lack of response, or adverse effects of ICS

COPD: chronic obstructive pulmonary disease; mMRC: modified Medical Research Council; CAT: COPD Assessment Test; SABA: short-acting beta-agonist; SAMA: short-acting muscarinic-antagonist; LAMA: long-acting muscarinic-antagonist; LABA: long-acting beta-agonist; ICS: inhaled corticosteroids (glucocorticoids); BMI: body mass index; SpO : pulse oxygen saturation; FEV : forced expiratory volume in one second.

* Adjustments to pharmacologic therapy for COPD are based on an assessment of dyspnea/exercise limitation (mMRC or CAT), frequency of exacerbations, and peripheral blood eosinophil counts. Follow-up visits are also an opportunity to assess and reinforce nonpharmacologic interventions for COPD, including: smoking cessation; inhaler technique and adherence to medications; administration of pneumococcal and seasonal influenza vaccinations; pulmonary rehabilitation; and nutrition counselling regarding healthy diet and normal BMI. All patients with COPD should have a rapid relief inhaler available, either a SABA or a SABA-SAMA (SABA preferred for patients using a LAMA). Refer to UpToDate content on the overview of management for stable COPD.

◊

◊

◊

◊

¥

‡

†

Δ

‡

†

Δ

2 1

¶ mMRC dyspnea scale: https://www.pcrs-uk.org/mrc-dyspnoea-scale; CAT evaluates health impact of COPD: https://www.catestonline.org.

Δ If blood eosinophil count ≥300 cells/microL, patient is more likely to experience exacerbations after ICS withdrawal. Close patient monitoring is required if ICS are withdrawn.

◊ In patients with exacerbations and blood eosinophil count ≥300 cells/microL, the addition of ICS is likely to be of benefit. For patients with eosinophil counts ≥100 but <300 cells/microL, ICS may improve exacerbation rates and pulmonary function.

§ Nonpharmacologic measures (eg, oxygen therapy if SpO ≤88%, pulmonary rehabilitation, bronchoscopic or surgical lung volume reduction, lung transplantation) can help reduce dyspnea and exacerbations. Contributing comorbidities should be evaluated and treated. Not all patients achieve control of dyspnea or exacerbations despite optimal available pharmacotherapy.

¥ For patients with a blood eosinophil count <100 cells/microL, there is a low likelihood that addition of ICS will be beneficial and higher risk of pneumonia after the addition of ICS.

‡ Roflumilast is used for patients with chronic bronchitis and FEV <50% predicted, particularly if there has been at least 1 hospitalization for an exacerbation in the past year. Potential adverse effects may limit use.

† Azithromycin preventive therapy is more effective in patients who are not current smokers. However, it may lead to development of resistant organisms.

Adapted from: Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease (2023 Report). Available at: www.goldcopd.org (Accessed on December 13, 2022).

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Contributor Disclosures

James K Stoller, MD, MS Grant/Research/Clinical Trial Support: Alpha-1 Foundation [Alpha-1 antitrypsin detection]. Consultant/Advisory Boards: 23andMe [Alpha-1 antitrypsin deficiency]; 4DMT [Alpha-1 antitrypsin deficiency]; Alpha-1 Foundation [Member, Board of Directors]; Bridgebio [Alpha-1 antitrypsin deficiency]; CSL Behring [Alpha-1 antitrypsin detection]; Dicerna [Alpha-1 antitrypsin deficiency]; Grifols [Alpha-1 antitrypsin detection]; InhibRx [Alpha-1 antitrypsin deficiency]; Insmed [Alpha-1 antitrypsin deficiency]; Korro [Alpha-1 antitrypsin deficiency]; Takeda [Alpha-1 antitrypsin detection]; Vertex [Alpha-1 antitrypsin deficiency]. All of the relevant financial relationships listed have been mitigated. Peter J Barnes, DM, DSc, FRCP, FRS Grant/Research/Clinical Trial Support: AstraZeneca [Asthma, COPD]; Boehringer [COPD]; Novartis [COPD]. Consultant/Advisory Boards: AstraZeneca [Asthma, COPD]; Boehringer [COPD]; Epi-Endo [Asthma, COPD]; Novartis [COPD]; Teva [COPD]. Speaker's Bureau: AstraZeneca [Asthma]; Boehringer [COPD]; Novartis [COPD]; Teva [Asthma]. All of the relevant financial relationships listed have been mitigated. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

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Official reprint from UpToDate www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

COPD exacerbations: Management

INTRODUCTION

The Global Initiative for Chronic Obstructive Lung Disease (GOLD), a report produced by the National Heart, Lung, and Blood Institute (NHLBI) and the World Health Organization (WHO), defines an exacerbation of chronic obstructive pulmonary disease (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]. This generally includes an acute change in one or more of the following cardinal symptoms:

The management of patients with exacerbations of COPD is discussed here. A table to assist with emergency management of severe acute exacerbations of COPD is provided ( table 1). The diagnosis and treatment of infection in exacerbations and the management of stable COPD are discussed separately.

®

������: James K Stoller, MD, MS ������� ������: Peter J Barnes, DM, DSc, FRCP, FRS ������ ������: Paul Dieffenbach, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2023. This topic last updated: Sep 19, 2023.

Cough increases in frequency and severity●

Sputum production increases in volume and/or changes character●

Dyspnea increases●

(See "COPD exacerbations: Clinical manifestations and evaluation".)●

(See "COPD exacerbations: Prognosis, discharge planning, and prevention".)●

(See "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease".)●

TRIAGE TO HOME OR HOSPITAL

An important step in the initial evaluation is to determine whether the patient needs hospitalization or can be safely managed at home ( algorithm 1) [1,3]. More than 80 percent of exacerbations of COPD can be managed on an outpatient basis, sometimes after initial treatment in the office or emergency department. If the exacerbation appears life-threatening or if there are indications for ventilatory support (eg, hypoxemic or hypercapnic respiratory failure), the patient should be admitted to the intensive care unit as quickly as possible. (See 'Ventilatory support' below.)

Other criteria that might lead to a decision to hospitalize the patient have been proposed in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines and international consensus statements include [1,2,4]:

Prior guidelines have also included severe airflow limitation, a history of frequent or severe exacerbations, and frailty as factors associated with increased risk for severe exacerbations. These factors may also be considered in triaging COPD patients for hospital admission.

Intensive home care, which generally includes nurse visits, home oxygen, and physical therapy, may be an alternative to hospitalizations in certain locations (eg, United Kingdom, Europe) for selected patients with an exacerbation of COPD [5-9]. A meta-analysis of seven trials noted that intensive home care resulted in equivalent clinical outcomes and substantial cost savings compared to hospitalization [10]. However, these trials excluded sicker patients with an

(See "Management of infection in exacerbations of chronic obstructive pulmonary disease".)

●

(See "Stable COPD: Overview of management".)●

Inadequate response to outpatient or emergency department management●

Onset of new signs (eg, cyanosis, altered mental status, peripheral edema)●

Marked increase in intensity of symptoms over baseline (eg, new onset resting dyspnea) accompanied by increased oxygen requirement

●

Signs of respiratory distress (use of accessory respiratory muscles or paradoxical chest wall movements, or both)

●

Serious comorbidities including pneumonia, cardiac arrhythmia, heart failure, diabetes mellitus, renal failure, or liver failure

●

Hemodynamic instability●

Insufficient home support●

impaired level of consciousness, respiratory acidosis (arterial pH <7.35), acute electrocardiographic or chest radiographic changes, or coexisting medical morbidities. Although care at home is feasible in highly selected patients without these characteristics, implementation requires a dedicated support team to conduct ongoing clinical assessments and provide home care. In general, home management of the patient who satisfies criteria for hospitalization should be considered infrequently and only when optimal home care is available.

HOME OR OFFICE MANAGEMENT OF COPD EXACERBATIONS

Home management of COPD exacerbations generally includes intensification of bronchodilator therapy and initiation of a course of oral glucocorticoids; oral antibiotics are added based on individual characteristics.

Home/office short-acting bronchodilator treatments — We recommend that all patients with a COPD exacerbation receive inhaled short-acting bronchodilator therapy.

Beta-adrenergic agonists – Inhaled short-acting beta- (adrenergic) agonists (SABA; eg, albuterol, levalbuterol) are the mainstay of therapy for an acute exacerbation of COPD because of their rapid onset of action and efficacy in producing bronchodilation [1,11,12]. Albuterol is sometimes combined with an additional short-acting bronchodilator (the short-acting muscarinic antagonist [SAMA] ipratropium) in a soft mist inhaler (SMI).

●

Occasional patients with more severe COPD or difficulty with inhaler technique may take albuterol or levalbuterol by nebulization at home. The usual dose of albuterol for nebulization is 2.5 mg (diluted to a total of 3 mL with sterile normal saline, resulting in 2.5 mg/3 mL or 0.083 percent). For COPD exacerbations, this dose can be repeated every 20 to 60 minutes for two to three doses and then every two to four hours as needed based on the patient’s response. Levalbuterol dosing for nebulization is 0.63 to 1.25 mg (diluted to 3 mL) and administered at the same intervals as noted for albuterol.

Patients who already have a nebulizer at home frequently report that bronchodilator administration via nebulizer is helpful during COPD exacerbations. However, most studies have not supported a greater effect from nebulizer treatments over properly administered metered dose inhaler medication. Nebulized albuterol can be combined with ipratropium. (See 'Hospital-based bronchodilator therapies' below and "Delivery of inhaled medication in adults", section on 'Home use'.)

Continued use of long-acting bronchodilators during exacerbations — While continuation of ongoing therapy with long-acting beta agonists (LABAs) or LAMAs has not been specifically studied, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy advises their continuation [1].

Home oral glucocorticoid therapy — For outpatients with a COPD exacerbation characterized by breathlessness that interferes with daily activities, systemic glucocorticoid therapy appears to have a small but beneficial effect with a reduction in rate of relapse. Our practice reflects current guidelines, which suggest using a dose that is the equivalent of prednisone 40 mg per day for 5 to 14 days [1,3,12]. Occasional patients may benefit from a higher dose or a longer course depending on the severity of the exacerbation and response to prior courses of glucocorticoids.

The benefit of oral glucocorticoids in the outpatient management of COPD exacerbations was examined in a randomized trial of 147 patients discharged from the emergency department

Muscarinic antagonists – Ipratropium bromide, an inhaled SAMA (also known as a short- acting anticholinergic agent) is often used in combination with inhaled SABA [1]. It is generally not used as monotherapy due to the longer time to onset of action compared with SABAs.

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The usual dose of ipratropium for an acute exacerbation of COPD is two inhalations by metered dose inhaler (MDI) every four to six hours. The usual dose of a combination ipratropium and albuterol SMI is one inhalation by SMI (Respimat) every four to six hours. When administering by nebulizer, the dose of ipratropium is 0.5 mg/2.5 mL (0.02 percent; one unit-dose vial) every 6 to 8 hours. Alternatively, ipratropium 0.5 mg/2.5 mL can be combined with albuterol 2.5 mg/0.5 mL (total 3 mL).

The evidence for adding a SAMA to SABA comes from a few studies in which combination therapy produced bronchodilation in excess of that achieved by either agent alone in patients with a COPD exacerbation or stable COPD [13,14]. However, this finding has not been universal, and other studies not found an additive effect in COPD exacerbations [15,16]. A longer duration of bronchodilation has been observed with the addition of ipratropium to albuterol in stable COPD [17].

For patients who have a history of benign prostatic hypertrophy or prior urinary retention, the addition of ipratropium to a long-acting muscarinic antagonist (LAMA; eg, aclidinium, glycopyrrolate, tiotropium, umeclidinium) may increase the risk of acute urinary retention, although data are conflicting. (See "Role of muscarinic antagonist therapy in COPD", section on 'Acute urinary retention'.)

after presenting with an acute exacerbation of COPD [18]. Patients received oral prednisone (40 mg) or placebo for 10 days. Patients who received prednisone were less likely to return to the emergency department or their clinician with increasing dyspnea within 30 days (27 versus 43 percent, p = 0.05) ( figure 1). In addition to a lower rate of relapse (the primary end point of the study), prednisone therapy was associated with decreased dyspnea and a greater improvement in forced expiratory volume in one second (FEV ; 34 versus 15 percent) on day 10.

The REDUCE trial showed that a five-day course of methylprednisolone (day one intravenously, orally thereafter) was noninferior to a 14-day course regarding the risk of recurrent exacerbation over six months of follow-up [19]. Although over 90 percent of the patients in the trial were initially admitted, these findings can likely be extrapolated to the less ill outpatient population. (See 'Glucocorticoids in moderate to severe exacerbations' below.)

Patients should be warned of potential adverse effects of systemic glucocorticoids that may require mitigation, particularly hyperglycemia (in patients with diabetes mellitus), fluid retention, and hypertension. (See "Major adverse effects of systemic glucocorticoids".)

Inhaled glucocorticoids as an alternative approach — A few trials have examined high-dose budesonide as an alternative to systemic glucocorticoids for COPD exacerbations, but have largely studied hospitalized patients who did not require intensive care unit (ICU) admission and have examined physiologic outcomes, such as FEV improvement [20,21]. Further study is needed to establish efficacy before this strategy is broadly used.

In a systematic review and meta-analysis (9 studies, nearly 1000 patients), high-dose nebulized budesonide (4 to 8 mg/day) had a similar effect to oral glucocorticoids in patients hospitalized for a COPD exacerbation for change in FEV (weighted mean difference 0.05 L/sec [95% CI -0.01– 0.12]) or arterial tension of carbon dioxide (PaCO ), but was slightly inferior for oxygenation improvement [20].

A separate trial in 109 out-patients with a COPD exacerbation found that use of the high-dose combination inhaler, budesonide-formoterol (320 mcg-9 mcg) 1 inhalation four times daily, resulted in a similar change in FEV compared with oral prednisolone 30 mg daily plus inhaled formoterol [22].

Antimicrobial therapy, in selected outpatients

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Antibiotics – To try to maximize the benefit of antibiotic therapy, clinical practice guidelines recommend antibiotic therapy only for those patients who are most likely to have bacterial infection or are most ill. The role of antibiotics in exacerbations of COPD, including antibiotic selection, is discussed in detail separately. (See "Management of

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Adjunctive care — For patients being managed at home, supportive care often includes advice regarding cigarette smoking cessation and medication adherence. Some patients may need nutritional support and a review of goals of care. Patients who have a new requirement for supplemental oxygen are usually managed in the hospital, at least initially. (See 'Triage to home or hospital' above and "Overview of smoking cessation management in adults" and "Malnutrition in advanced lung disease" and "Pulmonary rehabilitation".)

EMERGENCY DEPARTMENT AND HOSPITAL MANAGEMENT

infection in exacerbations of chronic obstructive pulmonary disease", section on 'Summary and recommendations' and "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'Summary and recommendations'.)

In brief, the GOLD strategy recommends empiric antibiotics for patients with COPD exacerbations who have increased sputum purulence and either increased sputum volume or increased dyspnea, or for patients who require ventilatory assistance [1]. Patients without these risk factors should not receive up-front antibiotic therapy without radiographic or microbiologic evidence of pulmonary infection. The choice of empiric therapy varies based on both patient-specific factors and local resistance patterns ( algorithm 2).

Antiviral agents – For patients with a COPD exacerbation during influenza season, we screen for influenza infection, with a preference for molecular assays over rapid antigen tests. If influenza infection is suspected, we initiate empiric antiviral therapy without waiting for laboratory confirmation. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Respiratory virus treatment' and "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

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Severe acute respiratory syndrome coronavirus (SARS-CoV)-2, the cause of coronavirus disease-2019 (COVID-2019), can mimic or result in a COPD exacerbation. When an exacerbation of COPD occurs in the course of COVID-19, the usual guidelines for prompt initiation of systemic glucocorticoids for a COPD exacerbation should be followed, as delaying therapy can increase the risk of a life-threatening exacerbation. Patients with COPD are at increased risk for severe respiratory illness associated with COVID-19 and therefore qualify for prioritized outpatient therapy. Diagnosis and treatment of COVID-19 are discussed separately. (See "COVID-19: Diagnosis" and 'Antiviral and antimicrobial agents' below and "COVID-19: Management of adults with acute illness in the outpatient setting".)

Similar to at-home management, the major components of emergency department or in- hospital management of exacerbations of COPD include reversing airflow limitation with inhaled short-acting bronchodilators and systemic glucocorticoids, treating infection, ensuring appropriate oxygenation, and averting intubation and mechanical ventilation [1,23]. An approach to emergency management of severe exacerbations of COPD is summarized in the table ( table 1).

For patients who are admitted to the hospital, the severity of the exacerbation is classified based on clinical signs [1,2]:

Monitoring — In-hospital monitoring typically includes frequent assessment of respiratory status (eg, respiratory rate and effort, wheezing, pulse oxygen saturation), heart rate and rhythm, blood pressure, and also fluid status. Patients who require admission to the intensive care unit (ICU) should have continuous monitoring of vital signs and oxygenation. Arterial blood gas measurement is performed to assess for respiratory acidosis (eg, prior hypercapnia, severe exacerbation, or deterioration of patient's respiratory status during treatment), confirm the accuracy of pulse oxygen saturation, and to monitor known hypercapnia. (See "Simple and mixed acid-base disorders", section on 'Respiratory acid-base disorders'.)

Initial pharmacologic therapy

Hospital-based bronchodilator therapies — We recommend that all patients with an exacerbation of COPD receive prompt treatment with an inhaled short-acting beta- (adrenergic) agonist (SABAs; eg, albuterol, levalbuterol) because of their rapid onset of action and efficacy in producing bronchodilation in COPD [1,3]. We further suggest use of the combination of a short-

No respiratory failure – Respiratory rate ≤24 breaths per minute; heart rate (HR) <95 beats per minute; no use of accessory respiratory muscles; no change in mental status; pulse oxygen saturation (SpO ) 88 to 92 percent with Venturi mask 24 to 35 percent inspired oxygen (or equivalent); no hypercapnia.

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Acute nonlife-threatening respiratory failure – Respiratory rate >24 breaths per minute; use of accessory muscles of respiration; no change in mental status; SpO 88 to 92 percent with Venturi mask 24 to 35 percent (or equivalent); arterial tension of carbon dioxide (PaCO ) 50 to 60 mmHg or increased over baseline.

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Acute life-threatening respiratory failure – Respiratory rate >24 breaths per minute; use of accessory muscles of respiration; acute change in mental status; requiring fraction of inspired oxygen (FiO ) ≥40 percent to maintain SpO 88 to 92 percent; PaCO increased compared with baseline or >60 mmHg or associated with acidosis (pH ≤7.25).

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acting muscarinic antagonist (SAMA; eg, ipratropium) and SABA for exacerbations that require emergency department or hospital-based treatment, based on the benefit of dual therapy in stable COPD [1,16,24].

SAMA-SABA combination therapy – When combined with albuterol for nebulization, ipratropium 0.5 mg (500 mcg) is mixed with albuterol 2.5 mg in 3 mL and given every hour for two or three doses and then every two to four hours as needed. In patients with potential viral infections resulting in COPD exacerbation, particularly SARS-CoV-2, nebulized medications should ideally be avoided or limited to use in negative pressure rooms to decrease disease spread.

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Alternatively, a combination ipratropium-albuterol soft mist inhaler (SMI) can be used, one inhalation, approximately every 20 to 60 minutes for two to three doses and then every two to four hours as needed, guided by the response to therapy [25]. Ipratropium is also available in a metered dose inhaler (MDI) that can be used with a spacer, two to four inhalations every hour for two to three doses, and then every two to four hours as needed. (See "Role of muscarinic antagonist therapy in COPD".)

Combination therapy with albuterol and ipratropium is clearly superior to albuterol alone in stable COPD, but studies in acute exacerbations are limited [14,16]. A systematic review identified a small number of trials that compared a combination of SAMA (ipratropium) plus SABA (albuterol, metaproterenol, fenoterol) with SABA alone and did not find an added benefit to the combination when assessed at 90 minutes [16]. Nevertheless, this combination is often used to treat COPD exacerbations given extensive evidence of superior bronchodilation in longer term studies.

SABA therapy alone – Typical doses of albuterol in this setting are 2.5 mg (diluted to a total of 3 mL with sterile normal saline) by nebulizer or one to two inhalations (most commonly two, occasionally four; 90 mcg per inhalation) by MDI with a spacer every 20 to 60 minutes for two to three doses and then every two to four hours as needed, guided by the response to therapy [1]. For patients requiring mechanical ventilation, up to eight inhalations may be given if needed. Levalbuterol is given at equipotent doses (ie, 1.25 mg in 3 mL sterile saline for nebulization and 45 mcg per inhalation via MDI).

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Despite evidence that MDI devices have equal efficacy during exacerbations of COPD, many clinicians prefer nebulized therapy on the presumption of more reliable delivery of drug to the airway [1]. We favor nebulized therapy because many patients with COPD have difficulty using proper MDI technique in the setting of an exacerbation. Air-driven nebulizers are preferred over oxygen delivered nebulizers to minimize the risk of

Magnesium sulfate — For patients who present with a severe exacerbation that is not responding promptly to short-acting inhaled bronchodilators, we suggest intravenous administration of a single dose of magnesium sulfate (2 g infused over 20 minutes). Intravenous magnesium sulfate has bronchodilator activity thought to arise from inhibition of calcium influx into airway smooth muscle cells [30]. The best evidence for benefit in COPD exacerbations comes from a systematic review (3 studies, 170 participants) that found a decrease in hospitalizations with intravenous magnesium compared with placebo (odds ratio [OR] 0.45, 95% CI 0.23-0.88) [31], which is similar to or better than the effect seen in severe asthma exacerbations [32]. (See "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Magnesium sulfate'.)

Intravenous magnesium has an excellent safety profile; however, it is contraindicated in the presence of renal insufficiency, and hypermagnesemia can result in muscle weakness. (See "Hypermagnesemia: Causes, symptoms, and treatment", section on 'Symptoms of hypermagnesemia'.)

Continuing long-acting bronchodilators — While continuation of ongoing therapy with long- acting beta agonists (LABAs) and/or long-acting muscarinic agents (LAMAs) has not been specifically studied, the GOLD strategy advises their continuation during exacerbations [1].

Glucocorticoids in moderate to severe exacerbations — For patients requiring emergency department or hospital-based treatment for a COPD exacerbation, we recommend a course of systemic glucocorticoids.

increasing PaCO [26,27]. In patients with potential viral infections resulting in COPD exacerbation, particularly SARS-CoV-2, nebulized medications should ideally be avoided or limited to use in negative pressure rooms in order to decrease disease spread.

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Placebo-controlled trials are lacking for SABAs in acute COPD exacerbation, so the main evidence comes from long-term clinical experience and extrapolation from the treatment of asthma and stable COPD. Increasing the dose of nebulized albuterol to 5 mg does not have a significant benefit on spirometry or clinical outcomes [28]. Similarly, continuously nebulized beta-agonists have not been shown to confer an advantage in COPD and may increase adverse effects.

It is not known whether a rapid-onset, long-acting beta-agonist, like indacaterol, would be a reasonable substitute for albuterol nebulizer treatments in patients not already using indacaterol [29].

Route – Oral glucocorticoids are rapidly absorbed (peak serum levels achieved at one hour after ingestion) with virtually complete bioavailability and appear equally efficacious to intravenous glucocorticoids for treating most exacerbations of COPD [11,33,34]. In a systematic review, parenteral glucocorticoids were compared with oral glucocorticoids and no significant differences were noted in the primary outcomes of treatment failure, relapse, or mortality or for any secondary outcomes [33]. However, intravenous glucocorticoids are typically administered to patients who present with a severe exacerbation, who have not responded to oral glucocorticoids at home, who are unable to take oral medication, or who may have impaired absorption due to decreased splanchnic perfusion (eg, patients in shock).

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Dose – The optimal dose of systemic glucocorticoids for treating a COPD exacerbation is unknown [1,11]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines advise using the equivalent of prednisone 40 mg once daily for the majority of COPD exacerbations ( table 2) [1]. Frequently used regimens range from prednisone 30 to 60 mg, once daily, to methylprednisolone 60 to 125 mg, two to four times daily, depending on the severity of the exacerbation [19,34,35]. A growing body of evidence favors using a moderate, rather than high dose of glucocorticoids, for most patients with an exacerbation of COPD. As an example, a comparative analysis of glucocorticoid dosing examined outcomes of 79,985 patients admitted to the hospital with an exacerbation of COPD, excluding those requiring intensive care [35]. The median glucocorticoid dose administered in the first two days was 60 mg for those on oral therapy and 556 mg for intravenous therapy. The risk of treatment failure was no greater with the lower dose. As this was an observational study and did not include objective measures of airflow limitation, it is possible that less ill patients were more likely to receive oral treatment.

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On the other hand, for patients with impending or actual acute respiratory failure due to a COPD exacerbation, many clinicians use an intravenous formulation at a higher dose, such as the equivalent of methylprednisolone 60 mg intravenously, one to four times daily, although outcomes data to support this practice are limited. In an observational cohort study, among 17,239 patients admitted to an intensive care unit with an exacerbation of COPD, a dose of methylprednisolone of 240 mg/day or less, compared with a higher dose (methylprednisolone >240 mg/day), was not associated with a mortality benefit, but was associated with slightly shorter hospital (-0.44 days; 95% CI -0.67 to -0.21) and ICU (-0.31 days; 95% CI -0.46 to -0.16) lengths of stay [36]. Length of mechanical ventilation and need for insulin therapy were also lower in the lower dose group. As this was an observational study, further research is needed to determine the optimal glucocorticoid dose in this setting.

Duration – The optimal duration of systemic glucocorticoid therapy is not clearly established and often depends on the severity of the exacerbation and the observed response to therapy [1,11,37-39]. The GOLD guidelines suggest that glucocorticoids (eg, prednisone 30 to 40 mg/day) be given for five days [1], while the European Respiratory Society/American Thoracic Society guidelines suggest a course of therapy up to 14 days in duration [11]. Thus, a range of 5 to 14 days appears reasonable.

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Data in support of a 14-day course, rather than a longer duration, come from the Systemic Corticosteroids in COPD Exacerbations (SCCOPE) trial, which compared two and eight week regimens and did not find any additional benefit to the longer course [40]. Patients in the eight week group experienced more glucocorticoid-related side effects.

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Other studies have examined whether courses shorter than 14 days are also effective for COPD exacerbations. As an example, the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial randomly assigned 314 patients with exacerbations of COPD, of whom 289 required hospitalization, to prednisone 40 mg daily for 5 or 14 days [19]. No difference was noted in the time to the next exacerbation, the likelihood of an exacerbation in the subsequent 180 days, or the recovery of lung function. The mean cumulative prednisone dose was significantly higher in the 14-day group, but treatment-related adverse effects, such as hyperglycemia and hypertension, were not different between the groups. While this study suggests that a five-day course may be comparable to 14 days for many patients, further study is needed to determine whether some patients might do better with the longer course.

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A systematic review compared different durations of systemic glucocorticoid therapy (eight studies, 457 participants) and found no difference in the risk of treatment failure with courses of three to seven days compared with longer courses of 10 to 15 days (OR 1.04, 95% CI 0.70-1.56) [37]. Including the data from the REDUCE trial above, the systematic review concluded that a five-day course of oral glucocorticoids is probably comparable to a 14-day or longer course, but that further research is needed to conclude equivalence.

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At the end of the treatment course, glucocorticoid therapy may be discontinued rather than tapered, if the patient has substantially recovered. Alternatively, the dose is tapered over another seven days, as a trial to determine whether a longer course of glucocorticoid therapy is required. However, long-term systemic glucocorticoids should rarely be used for stable COPD if therapy is otherwise optimized. Tapering solely because of concerns about adrenal suppression is not necessary if the duration of

Antiviral and antimicrobial agents — Most clinical practice guidelines recommend antibiotics for patients having a moderate to severe COPD exacerbation that requires hospitalization [1,11,43]. The optimal antibiotic regimen for the treatment of exacerbations of COPD has not been determined. We use a "risk stratification" approach when selecting initial antibiotic therapy, providing a broader antibiotic regimen for patients at risk for resistant organisms ( algorithm 3). The rationale, diagnosis, and treatment of infection in exacerbations of COPD, including antibiotic selection, are discussed separately. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Summary and

therapy is less than three weeks (a duration too brief to cause adrenal atrophy). (See "Glucocorticoid withdrawal", section on 'Recommended tapering regimen' and "Management of refractory chronic obstructive pulmonary disease", section on 'The limited role for systemic glucocorticoids in refractory disease'.)

Efficacy – Systemic glucocorticoids, when added to the bronchodilator therapies described above, improve symptoms and lung function, and decrease the length of hospital stay [1,19,33,40,41]. In a systematic review and meta-analysis of nine studies (n = 917), systemic glucocorticoids reduced the risk of treatment failure by over 50 percent compared with placebo (OR 0.48, 95% CI 0.35-0.67) and, in two studies (n = 415), reduced the risk of relapse at one month (hazard ratio 0.78, 95% CI 0.63-0.97) [33]. For each nine treated subjects, one treatment failure was avoided. The forced expiratory volume in one second (FEV ) showed significant improvement in the glucocorticoid group up to 72 hours after initiation, but not after that time point. Hospital stay was significantly shorter with glucocorticoid treatment (mean difference -1.22 days, 95% CI -2.26 to -0.18). Mortality up to 30 days was not decreased by systemic glucocorticoids. The risk of hyperglycemia was significantly increased with glucocorticoids compared with placebo (odds ratio 2.79, 95% CI 1.86-4.19).

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Preliminary evidence suggests that using total serum eosinophil counts to guide systemic glucocorticoid therapy may reduce the duration of glucocorticoid exposure [42]. After an initial intravenous dose of methylprednisolone 80 mg, subsequent doses were only given when the eosinophil count was ≥0.3 x10 /L. Further study of this strategy is needed prior to implementation.

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Adverse events – Even short courses of systemic glucocorticoids are associated with an increased risk of harm, such as hyperglycemia, pneumonia, sepsis, venous thromboembolism, and fracture. The adverse effects of systemic glucocorticoids and their mitigation are discussed separately. (See "Major adverse effects of systemic glucocorticoids".)

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recommendations' and "Evaluation for infection in exacerbations of chronic obstructive pulmonary disease", section on 'Summary and recommendations'.)

Antiviral therapy is recommended for patients with clinical and laboratory evidence of influenza infection who require hospitalization for an exacerbation of COPD. Because of the risk of acute bronchoconstriction with inhalation of zanamivir, oseltamivir is preferred unless local resistance patterns suggest a likelihood of oseltamivir-resistant influenza. Antiviral treatment of influenza is discussed in greater detail separately. (See "Seasonal influenza in nonpregnant adults: Treatment".)

Information regarding antiviral resistance that emerges during the influenza season is available through the United States Centers for Disease Control and Prevention. Clinicians should review antiviral resistance patterns for updated antiviral recommendations should resistant strains emerge.

COPD is associated with a greater likelihood of intensive care unit admission, mechanical ventilation, or death among patients with COVID-19 due to SARS-CoV-2 [44-46]. Potential treatments for hospitalized patients with SARS-coronavirus-2 infection (COVID-19) are discussed separately. (See "COVID-19: Management in hospitalized adults" and "COVID-19: Management of the intubated adult".)

Supportive and palliative care — Supportive care for patients hospitalized with an exacerbation of COPD includes the following therapies, as needed:

General measures

Cigarette smoking cessation – Hospitalization can sometimes provide an opportunity for patients who continue to smoke to move towards cigarette smoking cessation. Nicotine replacement therapy can help reduce symptoms of nicotine withdrawal during hospitalization. (See "Overview of smoking cessation management in adults", section on 'Hospitalized patients' and "Pharmacotherapy for smoking cessation in adults".)

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Thromboprophylaxis – Hospitalization for exacerbations of COPD increases the risk for deep venous thrombosis and pulmonary embolism [1]. For patients without a risk factor for bleeding who require ICU admission, we recommend pharmacologic thromboprophylaxis; for those not requiring ICU admission, we suggest pharmacologic thromboprophylaxis. Low molecular weight heparin is generally preferred. Preventive measures are discussed in greater detail separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)

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Oxygen therapy — Supplemental oxygen is a critical component of acute therapy. Administration of supplemental oxygen should target an SpO of 88 to 92 percent or an arterial oxygen tension (PaO ) of approximately 60 to 70 mmHg, to minimize the risk of worsening hypercapnia with excess supplemental oxygen [1,23,47]. In two small randomized trials, titrating supplemental oxygen to SpO 88 to 92 percent resulted in a lower mortality compared with high-flow (nontitrated) oxygen [47]. (See "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure".)

There are numerous devices available to deliver supplemental oxygen during an exacerbation of COPD:

Nutritional support – Oral nutritional supplementation may be of benefit for malnourished patients hospitalized with a COPD exacerbation. (See "Malnutrition in advanced lung disease", section on 'Frequency of malnutrition'.)

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Venturi masks permit a precise upper limit for the FiO , which may be preferable for patients at risk of hypercapnia. Venturi masks can deliver an FiO of 24, 28, 31, 35, 40, or 60 percent.

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Nasal cannula can provide flow rates up to 6 L per minute with an associated FiO of approximately 40 percent ( table 3). They are more comfortable and convenient for the patient, especially during oral feedings.

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When a higher FiO is needed, simple facemasks can provide an FiO up to 55 percent using flow rates of 6 to 10 L per minute. However, variations in minute ventilation and inconsistent entrainment of room air affect the FiO when simple facemasks (or nasal cannula) are used.

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Non-rebreathing masks with a reservoir, one-way valves, and a tight face seal can deliver an inspired oxygen concentration up to 90 percent, but are generally not needed in this setting.

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High-flow nasal cannula (HFNC) provide supplemental oxygen (adjustable FiO ) at a high flow rate (up to 60 L/min that results in a low level of continuous positive airway pressure. The specific indications for HFNC remain unclear, and robust comparisons of HFNC with noninvasive ventilation (NIV) in patients with COPD exacerbations are lacking [1,48,49]. (See "Heated and humidified high-flow nasal oxygen in adults: Practical considerations and potential applications".)

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A high FiO is generally not required to correct the hypoxemia associated with exacerbations of COPD. Inability to correct hypoxemia with a relatively low FiO (eg, 4 L/min by nasal cannula or 35 percent by mask) should prompt consideration of an additional cause of hypoxemia, such as pulmonary emboli, acute respiratory distress syndrome, pulmonary edema, or severe pneumonia. (See "Measures of oxygenation and mechanisms of hypoxemia".)

Adequate oxygenation (ie, to achieve an oxygen saturation of 88 to 92 percent) must be assured, even if it leads to acute hypercapnia. Hypercapnia is generally well tolerated in patients whose PaCO is chronically elevated. However, mechanical ventilation may be required if hypercapnia is associated with depressed mental status, profound acidemia, or cardiac dysrhythmias. (See 'Ventilatory support' below and "The evaluation, diagnosis, and treatment of the adult patient with acute hypercapnic respiratory failure" and "Adverse effects of supplemental oxygen", section on 'Accentuation of hypercapnia'.)

Compared with oxygen-driven nebulization, air-driven nebulization of inhaled medications is less likely to cause an increase in PaCO and is therefore preferred [27]. (See 'Hospital-based bronchodilator therapies' above.)

Ventilatory support — For patients who fail supportive therapy with oxygen and medications, ventilatory support is necessary assuming this is consistent with the patient’s goals of care (see 'Palliative care' below). HFNC is not routinely administered in patients with acute exacerbations of COPD, although some experts administer it cautiously in this population prior to the application of NIV. (See "Heated and humidified high-flow nasal oxygen in adults: Practical considerations and potential applications".)

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Noninvasive ventilation – NIV (also known as noninvasive positive pressure ventilation [NPPV]) refers to mechanical ventilation delivered through a noninvasive interface, such as a face mask, nasal mask, orofacial mask, or nasal prongs (nasal pillows). NIV reduces mortality and the intubation rate and is the preferred method of ventilatory support in many patients with an exacerbation of COPD [11].

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Most commonly, NIV is initiated in the emergency department, intensive care unit (ICU), or a specialized respiratory unit to enable close monitoring, although this has not been formally studied and varies among hospitals. Patients who develop acute or acute-on- chronic respiratory acidosis (as characterized frequently by PaCO >45 mmHg [6 kPa] and pH <7.35) are the subgroup who are most likely to benefit from an initial trial of NIV. Bilevel positive airway pressure is typically used. For other patients with nonhypercapnic respiratory failure due to COPD exacerbation, a trial of NIV is also appropriate, although

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Palliative care — The goals of palliative care are to prevent and relieve suffering and aid in the end-of-life care of patients with advanced disease. Some patients may have had a goals of care discussion with their physician and will have an advance directive in place. For those who do not have an advance directive, it is helpful for patients, their families, and their healthcare providers to review the patient’s understanding of their diagnosis and expected disease course, and then reflect on the patient’s goals, values, and beliefs. This information is used to inform decision- making in the context of care that is medically reasonable and appropriate. (See "Discussing goals of care" and "Advance care planning and advance directives" and "Palliative care for adults with nonmalignant chronic lung disease" and "Palliative care: Issues in the intensive care unit in adults".)

For patients with COPD, an important component of decision-making is whether intubation and mechanical ventilation are appropriate and desirable in the event of respiratory failure. When discussing a potential trial of mechanical ventilation for an exacerbation of COPD, parameters for discontinuing mechanical ventilation should be included. The potential outcomes of intubation/mechanical ventilation should be described to help the patient’s decision-making. While prognostic uncertainty and variable trajectory of illness make communication about these issues difficult [50], it is important to incorporate this uncertainty into advance care planning.

Given the high one-year mortality rate after hospitalization for a COPD exacerbation, it may be appropriate to consider a palliative care referral during or shortly after a hospitalization for COPD. Palliative care consultation can help explore the patient's understanding of their illness and prognosis, assess and manage symptoms (eg, dyspnea, anxiety, panic, depression), discuss the patient's goals of care, place of death preferences, and advance directives, and help

the derived benefit may be considerably less. (See "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications".)

A reasonable approach is to initiate bilevel NIV in a spontaneously triggered mode with a backup respiratory rate (eg, 8 breaths/minute); typical initial settings include an inspiratory positive airway pressure (IPAP) of 8 to 12 cm H O and an expiratory pressure (EPAP) of 3 to 5 cm H O. NIV is discussed in detail separately. (See "Noninvasive ventilation in adults with acute respiratory failure: Practical aspects of initiation".)

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Invasive ventilation – Invasive mechanical ventilation should be administered when patients fail NIV, do not tolerate NIV, or have contraindications to NIV. Invasive mechanical ventilation for acute respiratory failure due to a COPD exacerbation is discussed separately. (See "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease".)

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implement end-of-life care. (See "Palliative care for adults with nonmalignant chronic lung disease" and "Assessment and management of dyspnea in palliative care".)

Adjusting therapy for poor response — Assess several potential contributors:

Discharge planning — It is hoped that comprehensive discharge planning will help speed symptom resolution and reduce readmissions for COPD exacerbations. However, the optimal components of discharge planning have not been determined, so discharge-related decision- making is largely guided by good medical practice, as described separately. (See "COPD exacerbations: Prognosis, discharge planning, and prevention".)

A meta-analysis of 13 randomized controlled trials of pulmonary rehabilitation within four weeks of hospitalization for acute exacerbation of COPD showed benefits of reduced mortality and hospital readmissions and enhanced healthcare-related quality of life and walking distance [51].

TREATMENTS WITHOUT DOCUMENTED BENEFIT

Mucoactive agents, methylxanthines, and mechanical techniques to augment sputum clearance have not been shown to confer benefit for patients with a COPD exacerbation.

Optimize schedule for delivery of inhaled medications to ensure doses are not being missed.

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Ask patients about continued smoking and discuss ways to reduce or stop smoking.●

Evaluate for conditions that might contribute to or mimic symptoms and signs of a COPD exacerbation, such as viral respiratory tract infection, pneumonia, pulmonary emboli, pneumothorax, heart failure, dysrhythmias, tracheomalacia, diaphragmatic dysfunction, and intraabdominal processes limiting diaphragmatic excursion. Testing may include complete blood count and differential, serum brain natriuretic peptide, microbiologic testing, lower extremity compression ultrasonography for deep venous thrombosis, transthoracic echocardiogram, chest radiograph, and/or computed tomography with or without pulmonary angiography. (See "COPD exacerbations: Clinical manifestations and evaluation", section on 'Differential diagnosis'.)

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Mucoactive agents – There is little evidence supporting the use of mucoactive agents (eg, N-acetylcysteine) in exacerbations of COPD [52-54]. Some mucoactive agents may worsen bronchospasm. (See "Role of mucoactive agents and secretion clearance techniques in COPD".)

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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" and "Society guideline links: Pulmonary rehabilitation".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer

The lack of efficacy of mucoactive agents in the treatment of COPD exacerbations was best demonstrated by a double-blind trial that randomly assigned 50 patients with a COPD exacerbation to receive N-acetylcysteine (600 mg, twice daily) or placebo for seven days [54]. There was no difference in the rate of change of forced expiratory volume in one second (FEV ), vital capacity, oxygen saturation, breathlessness, or length of stay between the two groups.

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Methylxanthines – The methylxanthines, aminophylline and theophylline, are considered second-line therapy for exacerbations of COPD [1]. Randomized trials of intravenous aminophylline in this setting have failed to show efficacy beyond that induced by inhaled bronchodilator and glucocorticoid therapy. In addition to lack of efficacy, methylxanthines caused significantly more nausea and vomiting than placebo and trended toward more frequent tremor, palpitations, and arrhythmias.

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Nebulized magnesium – Nebulized isotonic magnesium (151 mg per dose) had no effect on FEV when added to nebulized salbutamol (albuterol) in one study of patients with exacerbations of COPD [55]. A subsequent systematic review including four additional studies found no effect of nebulized magnesium on hospital admission or the need for invasive or noninvasive breathing support [31].

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Chest physiotherapy – Mechanical techniques to augment sputum clearance, such as directed coughing, chest physiotherapy with percussion and vibration, intermittent positive pressure breathing, and postural drainage, have not been shown to be beneficial in COPD and may provoke bronchoconstriction. Their use in exacerbations of COPD (in the absence of bronchiectasis) is not supported by clinical trials [1,52,53].

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short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

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Basics topics (see "Patient education: Chronic bronchitis (The Basics)" and "Patient education: Medicines for chronic obstructive pulmonary disease (COPD) (The Basics)")

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Beyond the Basics topics (see "Patient education: Chronic obstructive pulmonary disease (COPD) treatments (Beyond the Basics)")

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Triage and goals of therapy – A COPD exacerbation is characterized by dyspnea and/or cough and sputum that worsens over ≤14 days; it may be accompanied by tachypnea and/or tachycardia and is often associated with increased local and systemic inflammation caused by airway infection, pulmonary embolism, pollution, or other airway insult. (See 'Introduction' above.)

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Triage to determine site of care is based on signs and symptoms, vital signs, arterial blood gas (ABG), and response to initial office/emergency department care ( algorithm 1). (See 'Triage to home or hospital' above.)

Regardless of treatment location, management goals are to:

Reverse airflow limitation using short-acting inhaled bronchodilators and systemic glucocorticoids

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Treat infection, which is implicated in most exacerbations• Exclude other causes for which additional therapy is needed (eg, pulmonary embolism)• Ensure appropriate oxygenation• Avert intubation and mechanical ventilation•

Rapid overview of management for severe exacerbations – A rapid overview for the evaluation and management of severe exacerbations of chronic obstructive pulmonary disease (COPD) in the emergency department is provided in the table ( table 1). (See 'Emergency department and hospital management' above.)

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Short-acting bronchodilators – For all patients having a COPD exacerbation, we recommend inhaled short-acting bronchodilator therapy (Grade 1B).

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At home, patients should use their prescribed reliever medication, typically a short- acting beta-agonist (SABA; eg, albuterol, levalbuterol) or combined SABA plus short- acting muscarinic antagonist (SAMA; eg, ipratropium) ( algorithm 4). (See 'Home/office short-acting bronchodilator treatments' above.)

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In outpatient clinics and hospital settings, we suggest administration of SABA-SAMA combination therapy rather than SABA alone (Grade 2C). The combination is well tolerated and might achieve better bronchodilation. (See 'Hospital-based bronchodilator therapies' above.)

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We prefer nebulized therapy for reliable airway delivery, but delivery by soft mist inhaler (SMI), dry-powder inhaler (DPI), or metered dose inhaler (MDI) with spacer is equally effective when properly administered.

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The usual dose for acute symptom relief is two puffs (MDI/DPI), one inhalation (SMI), or 3 mL (nebulization solution) every 20 to 60 minutes for two to three doses, then every two to four hours based on the patient response. Standard solutions for nebulization contain 2.5 mg of albuterol with or without 0.5 mg of ipratropium in 3 mL sterile normal saline. (See 'Home/office short-acting bronchodilator treatments' above and 'Hospital-based bronchodilator therapies' above.)

For patients in emergency room or inpatient settings with limited benefit from short- acting inhaled bronchodilators, we suggest intravenous magnesium (Grade 2C). (See 'Magnesium sulfate' above.)

Systemic glucocorticoids – For patients hospitalized due to an acute exacerbation of COPD, we recommend a course of systemic glucocorticoids (Grade 1B); we also suggest glucocorticoids for patients who do not require hospitalization (Grade 2B). A reasonable dose for most patients is prednisone 40 to 60 mg once daily (or the equivalent) for 5 to 14 days. A higher dose of glucocorticoids may occasionally be used in patients with impending or actual respiratory failure. In general, results with oral dosing are similar to those with intravenous dosing. (See 'Home oral glucocorticoid therapy' above and 'Glucocorticoids in moderate to severe exacerbations' above.)

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Antibiotics and antiviral agents – Antibiotics are indicated for many patients having a COPD exacerbation, particularly those who require hospitalization for their exacerbation ( algorithm 2 and algorithm 3). Antiviral therapy may be appropriate for some

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REFERENCES

1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diag nosis, Management and Prevention of Chronic Obstructive Pulmonary Disease: 2023 Repor t. www.goldcopd.org www.goldcopd.org (Accessed on December 13, 2022).

2. Celli BR, Fabbri LM, Aaron SD, et al. An Updated Definition and Severity Classification of Chronic Obstructive Pulmonary Disease Exacerbations: The Rome Proposal. Am J Respir Crit Care Med 2021; 204:1251.

infections triggered by respiratory viruses. (See 'Antimicrobial therapy, in selected outpatients' above and 'Antiviral and antimicrobial agents' above and "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Summary and recommendations'.)

Titrating supplemental oxygen – Patients with hypoxemia due to an exacerbation of COPD should receive supplemental oxygen ( algorithm 1). We suggest that supplemental oxygen be titrated to a target of 88 to 92 percent pulse oxygen saturation, rather than using high-flow, nontitrated oxygen (Grade 2B). Lower oxygen targets may both improve monitoring for and prevent worsening of hypercapnia. (See 'Oxygen therapy' above.)

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Ventilatory support – Ventilatory support is necessary for patients who develop respiratory fatigue despite supportive therapy with medications and oxygen ( algorithm 1). Noninvasive ventilation (NIV) is the preferred method in most patients. (See 'Ventilatory support' above and "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications", section on 'Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) with hypercapnic respiratory acidosis'.)

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Invasive mechanical ventilation is required in patients with respiratory failure despite NIV, who do not tolerate NIV, or who have contraindications to NIV. (See 'Ventilatory support' above and "Invasive mechanical ventilation in acute respiratory failure complicating chronic obstructive pulmonary disease".)

Treatments without clear benefit – Mucoactive agents, methylxanthines, and mechanical techniques to augment sputum clearance have not been shown to confer benefit for COPD exacerbations. (See 'Treatments without documented benefit' above.)

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3. National Institute for Health and Care Excellence (NICE). Chronic obstructive pulmonary dis ease in over 16s: diagnosis and management (2018). https://www.nice.org.uk/guidance/ng 115/chapter/Recommendations#managing-exacerbations-of-copd (Accessed on February 0 3, 2020).

4. Stolz D, Mkorombindo T, Schumann DM, et al. Towards the elimination of chronic obstructive pulmonary disease: a Lancet Commission. Lancet 2022; 400:921.

5. Hernandez C, Casas A, Escarrabill J, et al. Home hospitalisation of exacerbated chronic obstructive pulmonary disease patients. Eur Respir J 2003; 21:58.

6. Ojoo JC, Moon T, McGlone S, et al. Patients' and carers' preferences in two models of care for acute exacerbations of COPD: results of a randomised controlled trial. Thorax 2002; 57:167.

7. Cotton MM, Bucknall CE, Dagg KD, et al. Early discharge for patients with exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Thorax 2000; 55:902.

8. Davies L, Wilkinson M, Bonner S, et al. "Hospital at home" versus hospital care in patients with exacerbations of chronic obstructive pulmonary disease: prospective randomised controlled trial. BMJ 2000; 321:1265.

9. Skwarska E, Cohen G, Skwarski KM, et al. Randomized controlled trial of supported discharge in patients with exacerbations of chronic obstructive pulmonary disease. Thorax 2000; 55:907.

10. Ram FS, Wedzicha JA, Wright J, Greenstone M. Hospital at home for patients with acute exacerbations of chronic obstructive pulmonary disease: systematic review of evidence. BMJ 2004; 329:315.

11. Wedzicha JA Ers Co-Chair, Miravitlles M, Hurst JR, et al. Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J 2017; 49.

12. National Institute for Health and Care Excellence (NICE). Chronic obstructive pulmonary dis ease in over 16s – Diagnosis and management (2018, updated 2019). https://www.nice.org. uk/guidance/ng115 (Accessed on March 23, 2020).

13. Cydulka RK, Emerman CL. Effects of combined treatment with glycopyrrolate and albuterol in acute exacerbation of chronic obstructive pulmonary disease. Ann Emerg Med 1995; 25:470.

14. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Chest 1994; 105:1411.

15. O'Driscoll BR, Taylor RJ, Horsley MG, et al. Nebulised salbutamol with and without ipratropium bromide in acute airflow obstruction. Lancet 1989; 1:1418.

16. McCrory DC, Brown CD. Anti-cholinergic bronchodilators versus beta2-sympathomimetic agents for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002; :CD003900.

17. Levin DC, Little KS, Laughlin KR, et al. Addition of anticholinergic solution prolongs bronchodilator effect of beta 2 agonists in patients with chronic obstructive pulmonary disease. Am J Med 1996; 100:40S.

18. Aaron SD, Vandemheen KL, Hebert P, et al. Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease. N Engl J Med 2003; 348:2618.

19. Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA 2013; 309:2223.

20. Pleasants RA, Wang T, Xu X, et al. Nebulized Corticosteroids in the Treatment of COPD Exacerbations: Systematic Review, Meta-Analysis, and Clinical Perspective. Respir Care 2018; 63:1302.

21. Ding Z, Li X, Lu Y, et al. A randomized, controlled multicentric study of inhaled budesonide and intravenous methylprednisolone in the treatment on acute exacerbation of chronic obstructive pulmonary disease. Respir Med 2016; 121:39.

22. Ställberg B, Selroos O, Vogelmeier C, et al. Budesonide/formoterol as effective as prednisolone plus formoterol in acute exacerbations of COPD. A double-blind, randomised, non-inferiority, parallel-group, multicentre study. Respir Res 2009; 10:11.

23. Stoller JK. Clinical practice. Acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002; 346:988.

24. Moayyedi P, Congleton J, Page RL, et al. Comparison of nebulised salbutamol and ipratropium bromide with salbutamol alone in the treatment of chronic obstructive pulmonary disease. Thorax 1995; 50:834.

25. van Geffen WH, Douma WR, Slebos DJ, Kerstjens HA. Bronchodilators delivered by nebuliser versus pMDI with spacer or DPI for exacerbations of COPD. Cochrane Database Syst Rev 2016; :CD011826.

26. Edwards L, Perrin K, Williams M, et al. Randomised controlled crossover trial of the effect on PtCO2 of oxygen-driven versus air-driven nebulisers in severe chronic obstructive pulmonary disease. Emerg Med J 2012; 29:894.

27. Bardsley G, Pilcher J, McKinstry S, et al. Oxygen versus air-driven nebulisers for exacerbations of chronic obstructive pulmonary disease: a randomised controlled trial. BMC Pulm Med 2018; 18:157.

28. Nair S, Thomas E, Pearson SB, Henry MT. A randomized controlled trial to assess the optimal dose and effect of nebulized albuterol in acute exacerbations of COPD. Chest 2005; 128:48.

29. Segreti A, Fiori E, Calzetta L, et al. The effect of indacaterol during an acute exacerbation of COPD. Pulm Pharmacol Ther 2013; 26:630.

30. Gourgoulianis KI, Chatziparasidis G, Chatziefthimiou A, Molyvdas PA. Magnesium as a relaxing factor of airway smooth muscles. J Aerosol Med 2001; 14:301.

31. Ni H, Aye SZ, Naing C. Magnesium sulfate for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2022; 5:CD013506.

32. Kew KM, Kirtchuk L, Michell CI. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department. Cochrane Database Syst Rev 2014; :CD010909.

33. Walters JA, Tan DJ, White CJ, et al. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2014; :CD001288.

34. de Jong YP, Uil SM, Grotjohan HP, et al. Oral or IV prednisolone in the treatment of COPD exacerbations: a randomized, controlled, double-blind study. Chest 2007; 132:1741.

35. Lindenauer PK, Pekow PS, Lahti MC, et al. Association of corticosteroid dose and route of administration with risk of treatment failure in acute exacerbation of chronic obstructive pulmonary disease. JAMA 2010; 303:2359.

36. Kiser TH, Allen RR, Valuck RJ, et al. Outcomes associated with corticosteroid dosage in critically ill patients with acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2014; 189:1052.

37. 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 2018; 3:CD006897.

38. Long B, April MD. Are Shorter Courses of Corticosteroids as Effective as Longer Courses in Acute Exacerbations of Chronic Obstructive Pulmonary Disease? Ann Emerg Med 2018; 72:719.

39. Ma Z, Zhang W. Short-term versus longer duration of glucocorticoid therapy for exacerbations of chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2016; 40:84.

40. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs

Cooperative Study Group. N Engl J Med 1999; 340:1941.

41. Quon BS, Gan WQ, Sin DD. Contemporary management of acute exacerbations of COPD: a systematic review and metaanalysis. Chest 2008; 133:756.

42. Sivapalan P, Lapperre TS, Janner J, et al. Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): a multicentre, randomised, controlled, open-label, non-inferiority trial. Lancet Respir Med 2019; 7:699.

43. National Institute for Health and Care Excellence (NICE) Guideline. Chronic obstructive pul monary disease (acute exacerbation): antimicrobial prescribing. https://www.nice.org.uk/g uidance/ng114 (Accessed on July 20, 2020).

44. Leung JM, Niikura M, Yang CWT, Sin DD. COVID-19 and COPD. Eur Respir J 2020; 56.

45. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA 2020; 323:2052.

46. Goyal P, Choi JJ, Pinheiro LC, et al. Clinical Characteristics of Covid-19 in New York City. N Engl J Med 2020; 382:2372.

47. Austin MA, Wills KE, Blizzard L, et al. Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial. BMJ 2010; 341:c5462.

48. Hill NS. High Flow Nasal Cannula, Is There a Role in COPD? Tanaffos 2017; 16:S12.

49. Lin SM, Liu KX, Lin ZH, Lin PH. Does high-flow nasal cannula oxygen improve outcome in acute hypoxemic respiratory failure? A systematic review and meta-analysis. Respir Med 2017; 131:58.

50. Murray SA, Kendall M, Boyd K, Sheikh A. Illness trajectories and palliative care. BMJ 2005; 330:1007.

51. Ryrsø CK, Godtfredsen NS, Kofod LM, et al. Lower mortality after early supervised pulmonary rehabilitation following COPD-exacerbations: a systematic review and meta- analysis. BMC Pulm Med 2018; 18:154.

52. Snow V, Lascher S, Mottur-Pilson C, Joint Expert Panel on Chronic Obstructive Pulmonary Disease of the American College of Chest Physicians and the American College of Physicians-American Society of Internal Medicine. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 2001; 134:595.

53. Bach PB, Brown C, Gelfand SE, et al. Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Ann Intern Med 2001; 134:600.

54. Black PN, Morgan-Day A, McMillan TE, et al. Randomised, controlled trial of N- acetylcysteine for treatment of acute exacerbations of chronic obstructive pulmonary disease [ISRCTN21676344]. BMC Pulm Med 2004; 4:13.

55. Edwards L, Shirtcliffe P, Wadsworth K, et al. Use of nebulised magnesium sulphate as an adjuvant in the treatment of acute exacerbations of COPD in adults: a randomised double- blind placebo-controlled trial. Thorax 2013; 68:338.

Topic 1461 Version 82.0

GRAPHICS

Initial emergency management of severe COPD exacerbations: Rapid overview of emergency management

Clinical features

Features of COPD exacerbation: Diffuse wheezing, distant breath sounds, barrel-shaped chest, tachypnea, tachycardia, smoking >20 pack years.

Features of severe respiratory insufficiency: Use of accessory muscles; brief, fragmented speech; inability to lie supine; profound diaphoresis; agitation; asynchrony between chest and abdominal motion with respiration; failure to improve with initial emergency treatment.

Features of impending respiratory arrest: Inability to maintain respiratory effort, cyanosis, hemodynamic instability, and depressed mental status

Features of cor pulmonale: Jugular venous distension, prominent left parasternal heave, peripheral edema.

COPD exacerbations are most often precipitated by infection (viral or bacterial).

Severe respiratory distress in a patient with known or presumed COPD can be due to an exacerbation of COPD or a comorbid process, such as acute coronary syndrome, decompensated heart failure, pulmonary embolism, pneumonia, pneumothorax, sepsis.

Management

Assess patient's airway, breathing, and circulation; secure as necessary.

Provide supplemental oxygen to target a pulse oxygen saturation of 88 to 92% or PaO of 60 to 70 mmHg (7.98 to 9.31 kPa); Venturi mask can be useful for titrating FiO ; high FiO usually not needed and can contribute to hypercapnia (high FiO requirement should prompt consideration of alternative diagnosis [eg, PE]).

Determine patient preferences regarding intubation based on direct questioning or advance directive whenever possible.

Provide combination of aggressive bronchodilator therapy and ventilatory support (NIV or invasive ventilation).

Noninvasive ventilation (NIV): Appropriate for the majority of patients with severe exacerbations of COPD unless immediate intubation is needed or NIV is otherwise contraindicated

Contraindications to NIV include: Severely impaired consciousness, inability to clear secretions or protect airway, high aspiration risk.

Initial settings for bilevel NIV: 8 cm H O inspiratory pressure (may increase up to 15 cm H O if needed to aid ventilation); 3 cm H O expiratory pressure.

Administer bronchodilators via nebulizer or MDI: Nebulizer usually requires interruption of NIV; MDIs can be delivered in line using adaptor (refer to dosing below).

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Obtain ABG after two hours of NIV and compare with baseline: Worsening or unimproved gas exchange and pH <7.25 are indications for invasive ventilation.

Tracheal intubation and mechanical ventilation: Indicated for patients with acute respiratory failure, hemodynamic instability (eg, heart rate <50/minute, uncontrolled arrhythmia) and those in whom NIV is contraindicated or who fail to improve with NIV and aggressive pharmacotherapy

Rapid sequence induction (eg, etomidate, ketamine, or propofol).

Intubate with #8 endotracheal tube (8 mm internal diameter) or larger, if possible.

Initial ventilator settings aim to maintain adequate oxygenation and ventilation while minimizing elevated airway pressures: SIMV, tidal volume 6 to 8 mL/kg, respiratory rate 10 to 12/minute, inspiratory flow rate 60 to 80 L/min (increase if needed to enable longer expiratory phase), PEEP 5 cm H O. May need to tolerate elevated PaCO to avoid barotrauma (ie, permissive hypercapnia). In patients with chronic hypercapnia, aim for PaCO close to baseline.

Administer inhaled bronchodilator therapy: Usually via MDI with in-line adaptor (refer to dosing below).

Diagnostic testing

Assess oxygen saturation with continuous pulse oximetry.

Obtain ABG in all patients with severe COPD exacerbation.

ETCO monitoring (capnography) has only moderate correlation with arterial PaCO in COPD exacerbations.

Do not assess peak expiratory flow or spirometry in acute severe COPD exacerbations as results are not accurate.

Obtain portable chest radiograph: Look for signs of pneumonia, acute heart failure, pneumothorax.

When evidence of acute infection (eg, purulent phlegm, pneumonia) is absent and chest radiograph is unrevealing, obtain CT pulmonary angiogram for possible pulmonary embolism.

Obtain complete blood count, electrolytes (Na+, K+, Cl–, HCO3–), BUN, and creatinine; also obtain cardiac troponin, BNP, or NT-proBNP, if diagnosis is uncertain.

Test for influenza infection during influenza season.*

Obtain ECG: Look for arrhythmia, ischemia, cor pulmonale.

Pharmacotherapy

Inhaled beta agonist: Albuterol 2.5 mg diluted to 3 mL via nebulizer or 2 to 4 inhalations from MDI every hour for 2 or 3 doses; up to 8 inhalations may be used for intubated patients, if needed.

Short-acting muscarinic antagonist (anticholinergic agent): Ipratropium 500 micrograms (can be combined with albuterol) in 3 mL via nebulizer or 2 to 4 inhalations from MDI every hour for 2 to 3 doses.

Intravenous glucocorticoid (eg, methylprednisolone 60 mg to 125 mg IV, repeat every 6 to 12

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hours).

Antibiotic therapy*: Appropriate for majority of severe COPD exacerbations; select antibiotic based on likelihood of particular pathogens (eg, Pseudomonas risk factors , prior sputum cultures, local patterns of resistance).

No Pseudomonas risk factor(s) : Ceftriaxone 1 to 2 grams IV, or cefotaxime 1 to 2 grams IV, or levofloxacin 500 mg IV or orally, or moxifloxacin 400 mg IV or orally

Pseudomonas risk factor(s) : Piperacillin-tazobactam 4.5 grams IV, or cefepime 2 grams IV, or ceftazidime 2 grams IV

Antiviral therapy (influenza suspected)*: Oseltamivir 75 mg orally every 12 hours or peramivir 600 mg IV once (for patients unable to take oral medication).

Monitoring

Perform continual monitoring of oxygen saturation, blood pressure, heart rate, respiratory rate.

Close monitoring of respiratory status.

Continuous ECG monitoring.

Monitor blood glucose.

Disposition

Criteria for ICU admission include:

Patients with high-risk comorbidities (pneumonia, cardiac arrhythmia, heart failure, diabetes mellitus, renal failure, liver failure)

Continued need for NIV or invasive ventilation

Hemodynamic instability

Need for frequent nebulizer treatments or monitoring

COPD: chronic obstructive pulmonary disease; PaO : arterial tension of oxygen; FiO : fraction of inspired oxygen; PE: pulmonary embolism; NIV: noninvasive ventilation; MDI: metered dose inhaler; ABG: arterial blood gas; SIMV: synchronized intermittent mechanical ventilation; PEEP: positive end- expiratory pressure; PaCO : arterial tension of carbon dioxide; ETCO : end-tidal carbon dioxide; BUN: blood urea nitrogen; BNP: brain natriuretic peptide; NT-ProBNP: N-terminal pro-BNP; ECG: electrocardiogram; IV: intravenous; ICU: intensive care unit.

* When influenza is suspected, therapy should not be delayed while awaiting results of testing. Doses shown are for patients with normal renal function. Some agents require dose adjustment for renal impairment; refer to separate UpToDate algorithms of antibiotic treatment of exacerbations of COPD.

¶ Pseudomonas infection risk factors: Broad spectrum antibiotic use in the past 3 months; chronic colonization or previous isolation of Pseudomonas aeruginosa from sputum (particularly in past 12 months); very severe underlying COPD (FE 1 <30% predicted); chronic systemic glucocorticoid use.

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Graphic 65420 Version 12.0

Algorithm for triage of patients presenting with COPD exacerbation*

COPD: chronic obstructive pulmonary disease; ICU: intensive care unit; SpO : pulse oxygen saturation; NIV: n ventilation via nasal mask, face mask, or nasal plugs; ABG: arterial blood gas; PaCO : arterial tension of carb expiratory volume in one second; PaO : arterial oxygen tension.

* This algorithm can be used to support decisions regarding hospitalization and ventilatory support, but clin employed in all cases. Prior goals of care and advance care planning discussions should be reviewed to ensu about invasive ventilation, are consistent with the patient's values and preferences. Short-acting bronchodila triage assessment; symptomatic improvement with bronchodilator administration may impact triage decisio

¶ Contraindications to NIV: Inability to protect the airway or clear secretions Severely impaired consciousness Nonrespiratory organ failure that is acutely life-threatening High aspiration risk Inability to cooperate Facial surgery, trauma, or deformity Recent esophageal anastomosis

Δ Indications for ICU admission vary among institutions and generally include (but are not limited to) the fol Hemodynamic instability requiring vasopressor support Unstable cardiac events (eg, acute myocardial infarction, complex arrhythmias, cardiogenic shock) Severe neurologic complications (eg, major acute intracranial hemorrhage or stroke, status epilepticu Persistent or worsening hypoxemia (eg, PaO <50 mmHg [6.62 kPa] despite supplemental oxygen) Need for monitoring or nursing care that exceeds the capacity of non-ICU settings

◊ Severe airflow limitation, a history of frequent or severe exacerbations, and frailty are additional factors th increased risk for severe exacerbation.

Graphic 114160 Version 3.0

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Kaplan-Meier estimates of the probability of remaining relapse-free at 30 days for outpatients with acute exacerbations of COPD treated with prednisone or placebo

Tick marks represent censored data. p=0.04 by the log-rank test.

Data from: N Engl J Med 2003; 348:2623.

Graphic 60719 Version 1.0

Our approach to empiric antibacterial treatment of COPD exacerbations in out

Prompt and appropriate antibiotic use has been associated with improved clinical outcomes in patients with severe COPD exacerbations. Empiric regimens are designed to target the most likely pathogens (Haemophilu Moraxella catarrhalis, and Streptococcus pneumoniae) and should be broadened to target drug-resistant path difficult-to-eradicate pathogens (eg, macrolide-resistant S. pneumoniae, nontypeable strains of H. influenzae) poor outcomes. Coverage for Pseudomonas is indicated in patients with risk factors for infection with this pa patients should be evaluated for clinical response in approximately 72 hours, and sputum Gram stain and cu considered for those who fail to response to empiric treatment. Modifications to this approach may be need with a history of colonization or infection with drug-resistant pathogens (including Pseudomonas) or when a is suspected.

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

* Antiviral therapy for influenza is also indicated for exacerbations triggered by influenza infection.

¶ Suspicion for other cardiopulmonary disorders (heart failure, pneumothorax) and more severe infections ( should be absent for the diagnosis of an acute COPD exacerbation.

Δ Age alone is not a strict risk factor but should be considered as additive to other risk factors.

◊ Selection among antibiotic choices is based on local microbial sensitivity patterns, patient comorbidities, p organisms, potential adverse events and drug interactions, and also provider and patient preferences. In pa modifications to this regimen may be needed for patients with a history of drug-resistant Pseudomonas base illness, degree of suspicion for Pseudomonas, and prior susceptibility profiles of pseudomonal isolates.

§ If recent antibiotic exposure (eg, within the past 3 months), select an antibiotic from a different class than agent used.

¥ Trimethoprim-sulfamethoxazole is a reasonable alternative when macrolides and cephalosporins cannot b allergy, potential adverse effects, or availability.

‡ Some experts add amoxicillin or another agent with better activity against S. pneumoniae to ciprofloxacin f treatment.

† Because fluoroquinolone resistance is prevalent among Pseudomonas aeruginosa strains, we obtain a sput and culture with susceptibility testing for these patients to help guide subsequent management decisions. F outpatients, obtaining a sputum culture is not needed unless the patient fails to respond to empiric treatme

** Levofloxacin has lesser activity against Pseudomonas than ciprofloxacin but has greater activity against S. M. catarrhalis is thus a reasonable alternative to ciprofloxacin for patients who are at increased risk of Pseud but lack microbiologic evidence of Pseudomonas infection or colonization.

References: 1. Sethi S, Murphy TF. Acute exacerbations of chronic bronchitis: New developments concerning microbiology and pathophysiolog

approaches to risk stratification and therapy. Infect Dis Clin N Am 2004; 18:861. 2. Sethi S, Anzueto A, Miravitlles M, et al. Determinants of bacteriological outcomes in exacerbations of chronic obstructive pulmo

2016; 44:65. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary disease: cha

factors. BMC Pulm Med 2014; 14:103.

Graphic 66357 Version 14.0

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Comparison of systemic glucocorticoid preparations

  Equivalent doses

(mg)

Antiinflammatory activity relative to hydrocortisone*

Duration of action (hours)

Glucocorticoids

Short acting

Hydrocortisone (cortisol)

20 1 8 to 12

Cortisone acetate 25 0.8 8 to 12

Intermediate acting

Prednisone 5 4 12 to 36

Prednisolone 5 4 12 to 36

Methylprednisolone 4 5 12 to 36

Triamcinolone 4 5 12 to 36

Long acting

Dexamethasone 0.75 30 36 to 72

Betamethasone 0.6 30 36 to 72

Mineralocorticoids

Fludrocortisone Not used for an antiinflammatory effect . The typical dose of fludrocortisone for mineralocorticoid replacement is 0.1 to 0.2 mg.

12 to 36

The mineralocorticoid effect of commonly administered glucocorticoids may be estimated as follows:

When given at replacement doses, triamcinolone, dexamethasone, and betamethasone have no clinically important mineralocorticoid activity. 20 mg hydrocortisone and 25 mg of cortisone acetate each provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg fludrocortisone. Prednisone or prednisolone given at antiinflammatory doses ≥50 mg per day provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg of fludrocortisone.

* Equivalent antiinflammatory dose shown is for oral or intravenous (IV) administration. Relative potency for intraarticular or intramuscular administration may vary considerably.

¶ The antiinflammatory potency is 10 to 15 times that of hydrocortisone; however, fludrocortisone is not used clinically as an antiinflammatory agent.

¶

Data from: 1. Schimmer BP, Funder JW. ACTH, Adrenal Steroids, and Pharmacology of the Adrenal Cortex. In: Goodman & Gilman's:

The Pharmacological Basis of Therapeutics, 12th ed, Brunton LL, Chabner BA, Knollmann BC (Eds), McGraw-Hill Education 2011.

2. Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol 2013, 9:30.

Graphic 64138 Version 22.0

Our approach to empiric antibacterial treatment of COPD exacerbations in hospitalized patients*

Prompt and appropriate antibiotic use has been associated with improved clinical outcomes in patients hospitalized for COPD exacerbations. Empiric regimens are designed to target the most likely pathogens (Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae). Pseudomonas should be targeted in those with risk factors for infection with this pathogen. Generally, a sputum Gram stain and culture with susceptibility testing should be obtained for hospitalized patients. Modifications to the empiric regimen may be needed based on sputum Gram stain and culture results, particularly for patients who do not respond to the initial empiric regimen within 48 to 72 hours of starting treatment. Modifications to this approach may be needed for

patients with a history of colonization or infection with drug-resistant pathogens (including Pseudomonas) or when a specific pathogen is suspected.

COPD: chronic obstructive pulmonary disease; FEV : forced expiratory volume in 1 second.

* Antiviral therapy for influenza is also indicated for exacerbations triggered by influenza infection.

¶ Selection among antibiotic choices is based on local microbial sensitivity patterns, patient comorbidities, prior infecting organisms, potential adverse events and drug interactions, and also provider and patient preferences. Modifications to these regimens may be needed for patients with suspicion for specific pathogens and/or history of drug-resistant organisms (eg, drug-resistant Pseudomonas).

Δ For those who cannot tolerate these agents, alternatives include ciprofloxacin, aztreonam, certain carbapenems (eg, meropenem, imipenem), and aminoglycosides. We generally select among them based on local epidemiology, prior susceptibility testing results, drug interactions, and patient comorbidities or intolerances. Two agents are often needed for empiric treatment. Refer to the UpToDate content for detail.

◊ If recent antibiotic exposure (eg, within the past 3 months), select an antibiotic from a different class than the most recent agent used.

References: 1. Sethi S, Murphy TF. Acute exacerbations of chronic bronchitis: New developments concerning microbiology and

pathophysiology–impact on approaches to risk stratification and therapy. Infect Dis Clin N Am 2004; 18:861. 2. Sethi S, Anzueto A, Miravitlles M, et al. Determinants of bacteriological outcomes in exacerbations of chronic

obstructive pulmonary disease. Infection 2016; 44:65. 3. Gallego M, Pomares X, Espasa M, et al. Pseudomonas aeruginosa isolates in severe chronic obstructive pulmonary

disease: characterization and risk factors. BMC Pulm Med 2014; 14:103.

Graphic 53537 Version 13.0

1

Oxygen delivery systems

System Percent oxygen

delivered* Indications Comments

Blow by Less than 30 percent

Use for spontaneously breathing children who require low doses of oxygen and do not tolerate a mask

Best delivered at a flow rate of at least 10 L/minute through a reservoir (ie, a simple mask or Styrofoam or paper drinking cup with oxygen tubing poked through the bottom) with the reservoir held near the patient's face by a parent or other caregiver

Low flow nasal cannula (1 to 4 L/min)

25 to 40 percent

Use to deliver low- dose oxygen to spontaneously breathing patients

Percent oxygen delivered affected by respiratory rate, tidal volume, and extent of mouth breathing. In infants, limit flow rate to 2 L/min or less to avoid inadvertent administration of positive airway pressure

Simple mask 35 to 50 percent

Use to deliver low- dose oxygen to spontaneously breathing patients

Percent oxygen delivered affected by mask fit and respiratory rate

Small diffuser (OxyMask)

25 to >80 percent

Use to provide low- or high-dose oxygen to spontaneously breathing patients

Range of oxygen delivery at different flow rates (approximately 25 percent at 1.5 L/min to >80 percent at ≥15 L/min). Open-mask design may be better tolerated by children. May provide equivalent oxygen delivery at lower flow rates than other mask devices.

Partial rebreather mask

50 to 60 percent

Use to conserve oxygen

Nonrebreather mask

65 to 95 percent

Use to deliver high- dose oxygen to spontaneously breathing patients

Tight mask fit required to deliver higher concentrations of oxygen

Hood 30 to 90 percent

Infants less than one year of age

Noisy for patient

Tent 25 to 50 percent

Use for children who require 30 percent oxygen or less

Mist may obscure view of patient. Noisy for patient. Low-flow nasal cannula or masks preferred.

Self-inflating ventilation bag

95 to 100 percent, with reservoir

Use to provide assisted ventilation and oxygen

Do not use to provide blow by. Must use with a reservoir to provide higher oxygen concentrations.

Flow-inflating ventilation bag

100 percent Use to provide assisted ventilation and oxygen

May use to provide blow by. Requires experience to use reliably.

*Actual percent oxygen delivered may vary widely depending on the type of delivery device, device manufacturer, oxygen flow rate provided to the device, and, for oxygen masks, mask fit. All patients receiving supplemental oxygen warrant monitoring with pulse oximetry.

Graphic 60610 Version 9.0

New diagnosis of COPD

COPD: chronic obstructive pulmonary disease; COVID-19: coronavirus disease 2019; GOLD: Global Initiative f CAT: COPD Assessment Test; SABA: short-acting beta-agonist; SAMA: short-acting muscarinic antagonist; LAM (anticholinergic); LABA: long-acting beta-agonist; mMRC: Modified Medical Research Council; FEV : forced ex forced vital capacity.

* COPD is diagnosed based on the presence of chronic respiratory symptoms (dyspnea, cough, sputum prod limitation. All patients with COPD defined by GOLD have airflow limitation based on a reduced FEV /FVC ratio is determined by the reduction in FEV .

¶ An exacerbation of COPD is characterized by increased dyspnea and/or cough and sputum that worsens in accompanied by tachypnea or tachycardia, and is often caused by infection, environmental irritation, or othe exacerbations" are typically defined as those which require treatment with systemic glucocorticoids. More o been proposed but are difficult to establish via patient history. Please refer to UpToDate content on "COPD e and evaluation" for additional information.

1

1

1

Δ CAT: http://www.catestonline.org (Accessed on January 12, 2023).

◊ For those prescribed a LABA alone, SAMA-SABA combination therapy is likely to be most potent but will ha LAMA. For those prescribed a LAMA, SAMA should generally not be used concomitantly, so SABA alone is pre

§ Occasional patients with only minimal intermittent symptoms are appropriate for only as-needed rescue th acting bronchodilators.

Contributor Disclosures

James K Stoller, MD, MS Grant/Research/Clinical Trial Support: Alpha-1 Foundation [Alpha-1 antitrypsin detection]. Consultant/Advisory Boards: 23andMe [Alpha-1 antitrypsin deficiency]; 4DMT [Alpha-1 antitrypsin deficiency]; Alpha-1 Foundation [Member, Board of Directors]; Bridgebio [Alpha-1 antitrypsin deficiency]; CSL Behring [Alpha-1 antitrypsin detection]; Dicerna [Alpha-1 antitrypsin deficiency]; Grifols [Alpha-1 antitrypsin detection]; InhibRx [Alpha-1 antitrypsin deficiency]; Insmed [Alpha-1 antitrypsin deficiency]; Korro [Alpha-1 antitrypsin deficiency]; Takeda [Alpha-1 antitrypsin detection]; Vertex [Alpha-1 antitrypsin deficiency]. All of the relevant financial relationships listed have been mitigated. Peter J Barnes, DM, DSc, FRCP, FRS Grant/Research/Clinical Trial Support: AstraZeneca [Asthma, COPD]; Boehringer [COPD]; Novartis [COPD]. Consultant/Advisory Boards: AstraZeneca [Asthma, COPD]; Boehringer [COPD]; Epi-Endo [Asthma, COPD]; Novartis [COPD]; Teva [COPD]. Speaker's Bureau: AstraZeneca [Asthma]; Boehringer [COPD]; Novartis [COPD]; Teva [Asthma]. All of the relevant financial relationships listed have been mitigated. Paul Dieffenbach, MD No relevant financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

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CHAPTER 4: MANAGEMENT OF EXACERBATIONS

KEY POINTS: • An exacerbation of COPD is defined as an event characterized by dyspnea and/or cough

and sputum that worsen over < 14 days. Exacerbations of COPD are often associated with increased local and systemic inflammation caused by airway infection, pollution, or other insults to the lungs.

• As the symptoms are not specific to COPD relevant differential diagnoses should be considered, particularly pneumonia, congestive heart failure and pulmonary embolism.

• The goals for treatment of COPD exacerbations are to minimize the negative impact of the current exacerbation and to prevent subsequent events.

• Short-acting inhaled beta2-agonists, with or without short-acting anticholinergics, are recommended as the initial bronchodilators to treat an exacerbation.

• Maintenance therapy with long-acting bronchodilators should be initiated as soon as possible. In patients with frequent exacerbations and elevated blood eosinophil levels addition of inhaled corticosteroids to the double bronchodilator regimen should be considered.

• In patients with severe exacerbations, systemic corticosteroids can improve lung function (FEV1), oxygenation and shorten recovery time including hospitalization duration. Duration of therapy should not normally be more than 5 days.

• Antibiotics, when indicated, can shorten recovery time, reduce the risk of early relapse, treatment failure, and hospitalization duration. Duration of therapy should be 5 days.

• Methylxanthines are not recommended due to increased side effect profiles.

• Non-invasive mechanical ventilation should be the first mode of ventilation used in COPD patients with acute respiratory failure who have no absolute contraindication because it improves gas exchange, reduces work of breathing and the need for intubation, decreases hospitalization duration and improves survival.

• Exacerbation recovery time varies, taking up to 4-6 weeks to recover, with some patients failing to return to the pre-exacerbation functional state. Following an exacerbation, appropriate measures for exacerbation prevention should be initiated (see Chapter 3).

DEFINITION

An exacerbation of chronic obstructive pulmonary disease (ECOPD) is defined as an event characterized by increased

dyspnea and/or cough and sputum that worsens in < 14 days which may be accompanied by tachypnea and/or

tachycardia and is often associated with increased local and systemic inflammation caused by infection, pollution, or

other insult to the airways.(304)

Considerations

Exacerbations of COPD are important events in the management of COPD because they negatively impact health

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status, rates of hospitalization and readmission, and disease progression.(435,436) COPD exacerbations are usually

associated with increased airway inflammation, increased mucus production and marked gas trapping. These changes

contribute to increased dyspnea that is the key symptom of an exacerbation. Other symptoms include increased

sputum purulence and volume, together with increased cough and wheeze.(1140,1141) Patients with COPD are at

increased risk of other acute events, particularly decompensated heart failure,(1142,1143) pneumonia,(1144,1145) pulmonary

embolism(1146,1147) that may also mimic or aggravate an ECOPD. Thus, while worsening of dyspnea, particularly if

associated with cough and, purulent sputum, and no other symptoms or signs in a patient with COPD may be diagnosed

as an ECOPD, other patients may have worsening of respiratory symptoms, particularly dyspnea without the classic

characteristics of ECOPD, that should prompt careful consideration and/or search of those potential confounders, or

contributors. In some patients one or more of these diagnoses may contribute to the clinical presentations and should

be addressed appropriately (Figure 4.1).

Currently, exacerbations are classified after the event has occurred as:

► Mild (treated with short acting bronchodilators only, SABDs)

► Moderate (treated with SABDs and oral corticosteroids ± antibiotics) or

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► Severe (patient requires hospitalization or visits the emergency room). Severe exacerbations may also be

associated with acute respiratory failure.

The current grading of the severity of an ECOPD, based on post facto use of healthcare resources, is a major limitation

of the current definition. Because of global variability in the available resources to treat patients and local customs

affecting the criteria for hospital visits and admissions, there is substantial variability in reported ECOPD outcomes.(1148)

Figure 4.2 shows a proposed clinical approach based on the current best available evidence.(304)

It has been proposed that these easy to obtain clinical variables can help define the severity of exacerbations on point

of contact (The ROME Proposal).(304) Using The ROME Proposal for exacerbations, hospitalized patients with acute

exacerbations can be further subclassified into mild, moderate and severe events with differences in mortality.(1149,1150)

Based on a thorough review of the available literature and using a Delphi approach to agree on the variable thresholds,

the severity classification is summarized in Figure 4.3.

In the primary care setting, where laboratories may not be available, severity can be determined with the easily

obtainable dyspnea intensity (using a VAS 0 to 10 dyspnea scale with zero being not short of breath at all and 10 the

worst shortness of breath you have ever experienced), respiratory rate, heart rate and oxygen saturation level. Where

available, blood C-reactive protein (CRP) level is recommended. To determine the need for ventilator support (usually

in the emergency room or hospital setting) arterial blood gases or equivalent should be measured. To move from a

mild to a moderate level, three of the variables need to exceed the established thresholds. It is hoped that prospective

validation will help better define exacerbations and their severity at point of contact, and that documented validation

may confirm or help modify the proposed thresholds of the variables now included. It is proposed that prospective

research can help determine a more specific marker of lung injury than the more generic CRP, as has been true for

other organs acute events.

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It is now recognized that many exacerbations are not reported to healthcare professionals for therapy and yet these

events, although often shorter in duration, also have a significant impact on health status.(1151,1152) Thus COPD patients

need to receive education about the importance of understanding exacerbation symptoms and when to seek

professional healthcare. The WHO has defined a minimum set of interventions for the management of

exacerbations.(742)

Exacerbations are mainly triggered by respiratory viral infections although bacterial infections and environmental

factors such as ambient air pollution and excess heat may also initiate and/or amplify these events.(1153,1154) Short-term

exposure to fine (PM2.5) and coarse (PM10) particulate matter is associated with increased hospitalizations, ER visits,

and outpatient visits,(1154) as well as increased mortality of COPD exacerbations.(1153,1155,1156) Another study also showed

that short-term exposure to ambient nitrogen dioxide and PM2.5 was associated with exacerbations in mild to

moderate COPD patients.(101) The most common viruses isolated are human rhinovirus (the cause of the common cold),

influenza, para-influenza and metapneumovirus which can be detected for up to a week after an exacerbation

onset.(1157,1158) When associated with viral infections, exacerbations are often more severe, last longer and precipitate

more hospitalizations, as seen during winter. Filamentous fungi, particularly Aspergillus species, may be identified in

sputum samples of patients during moderate or severe exacerbations(1159-1161) although their clinical relevance remains

unclear. Invasive pulmonary aspergillosis is rare (1.3%-3.9%)(1162) and more frequent in patients with more severe

baseline airflow obstruction, recent use of broad spectrum antibiotics or parenteral steroids, and

hypoalbuminemia.(1163) Aspergillus sensitization is also a marker of increased risk of exacerbations.(1164) The diagnostic

approach to invasive aspergillosis in this setting remains challenging.(1165)

Exacerbations can be associated with increased sputum production and, if purulent, they are most likely due to

bacterial infection(1141,1157,1166) There is reasonable evidence to support the concept that eosinophils are increased in

the airways, lung, and blood in a significant proportion of people with COPD.(1167-1169) The presence of sputum

eosinophilia has been related to susceptibility to viral infection.(1166) It has been suggested that exacerbations

associated with an increase in sputum or blood eosinophils may be more responsive to systemic steroids(1170) although

more prospective trials are needed to test this hypothesis.(1170)

During a COPD exacerbation, increased symptoms are usually present for 7 to 10 days, but some events may last

longer. At 8 weeks up to 20% of patients will not have recovered to their pre-exacerbation state.(1171) COPD

exacerbations contribute to disease progression,(1172) which is more likely if recovery from exacerbations is slow.(1173)

Exacerbations can also cluster in time and once they occur there is increased likelihood of another event(439,1174) (see

Chapter 2).

Some patients are susceptible to frequent exacerbations (defined as two or more exacerbations per year), and these

patients have worse health status and morbidity than patients with less frequent exacerbations.(436) The exact reason

for an individual’s increased susceptibility to exacerbation symptoms remains largely unknown. However, the

perception of breathlessness is greater in frequent exacerbators than infrequent exacerbators,(489) suggesting that a

perception of breathing difficulty may contribute to precipitating the respiratory symptoms rather than solely

physiological, or causative factors. The strongest predictor of a patient’s future exacerbation frequency remains the

number of exacerbations they have had in the prior year.(439) It is recognized that these patients form a moderately

stable phenotype, although some studies have shown that a significant proportion of patients change their

exacerbation frequency especially with worsening FEV1.(1175)

Other factors that have been associated with an increased risk of acute exacerbations and/or severity of exacerbations

include an increase in the ratio of the pulmonary artery to aorta cross sectional dimension (i.e., ratio > 1),(301) a greater

percentage of emphysema or airway wall thickness(1176) measured by chest CT imaging and the presence of chronic

bronchitis.(169,1177)

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Vitamin D has an immune-modulating role and has been implicated in the pathophysiology of exacerbations. As with

many chronic diseases vitamin D levels are lower in COPD than in health. Some, but not all studies have shown that

supplementation in people with severe deficiency results in a 50% reduction in episodes and hospital

admission.(896,1178) Therefore it is recommended that all patients hospitalized for exacerbations should be assessed and

investigated for severe deficiency (< 10 ng/ml or < 25 nM) followed by supplementation if required.

TREATMENT OPTIONS

Treatment setting

The goals of treatment for COPD exacerbations are to minimize the negative impact of the current exacerbation and

prevent the development of subsequent events.(1179) Depending on the severity of an exacerbation and/or the severity

of the underlying disease, an exacerbation can be managed in either the outpatient or inpatient setting. More than

80% of exacerbations are managed on an outpatient basis with pharmacological therapies including bronchodilators,

corticosteroids, and antibiotics.(439,740,1180)

The indications for assessing the need for hospitalization during a COPD exacerbation are shown in Figure 4.4. When

patients with a COPD exacerbation come to the emergency department, if hypoxemic they should be provided with

supplemental oxygen and undergo assessment to determine whether the exacerbation is life-threatening and if

increased work of breathing or impaired gas exchange requires consideration for non-invasive ventilation. If so,

healthcare providers should consider admission to an area where proper monitoring and care can be provided. In less

severe cases, the patient may be managed in the emergency department or hospital ward unit. In addition to

pharmacological therapy, hospital management of exacerbations includes respiratory support (oxygen therapy,

ventilation). The management of severe, but not life threatening, exacerbations is outlined in Figure 4.5.

The clinical presentation of COPD exacerbation is heterogeneous, thus we recommend that in hospitalized patients

the severity of the exacerbation should be based on the patient’s clinical signs and recommend the following

classification:(1181)

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No respiratory failure: Respiratory rate: ≤ 24 breaths per minute; heart rate < 95 beats per minute, no use of

accessory respiratory muscles; no changes in mental status; hypoxemia improved with supplemental oxygen given via

Venturi mask 24-35% inspired oxygen (FiO2); no increase in PaCO2.

Acute respiratory failure – non-life-threatening: Respiratory rate: > 24 breaths per minute; using accessory

respiratory muscles; no change in mental status; hypoxemia improved with supplemental oxygen via Venturi mask

> 35% FiO2; hypercarbia i.e., PaCO2 increased compared with baseline or elevated 50-60 mmHg.

Acute respiratory failure – life-threatening: Respiratory rate: > 24 breaths per minute; using accessory

respiratory muscles; acute changes in mental status; hypoxemia not improved with supplemental oxygen via Venturi

mask or requiring FiO2 > 40%; hypercarbia i.e., PaCO2 increased compared with baseline or elevated > 60 mmHg or the

presence of acidosis (pH ≤ 7.25).

Long-term prognosis following hospitalization for COPD exacerbation is poor, with a five-year mortality rate of about

50%.(1182) Factors independently associated with poor outcome include older age, lower BMI, comorbidities (e.g.,

cardiovascular disease or lung cancer), previous hospitalizations for COPD exacerbations, clinical severity of the index

exacerbation and need for long-term oxygen therapy at discharge.(1183-1185) Patients characterized by a higher

prevalence and severity of respiratory symptoms, poorer quality of life, worse lung function, lower exercise capacity,

lower lung density and thickened bronchial walls on CT-scan are also at increased risk for a higher mortality following

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an acute COPD exacerbation.(1186) Mortality risk may be heightened during spells of cold weather.(1187)

An updated Cochrane review concluded that the use of COPD exacerbation action plans with a single short educational

component, in conjunction with ongoing support, reduced in-hospital healthcare utilization. Such educational

interventions were also found to increase the treatment of COPD exacerbations with corticosteroids and

antibiotics.(1188)

Key points for the management of all exacerbations are given in Figure 4.6.

Pharmacological treatment

The three classes of medications most commonly used for COPD exacerbations are bronchodilators, corticosteroids,

and antibiotics.

Bronchodilators

Although there is no high-quality evidence from RCTs, it is recommended that short-acting inhaled beta2-agonists, with

or without short-acting anticholinergics, are the initial bronchodilators for acute treatment of a COPD

exacerbation.(1135,1189) A systematic review of the route of delivery of short-acting bronchodilators found no significant

differences in FEV1 between using metered dose inhalers (MDI) (with or without a spacer device) or nebulizers to

deliver the agent,(527,1190) although the latter may be an easier delivery method for sicker patients. It is recommended

that patients do not receive continuous nebulization but use the MDI inhaler one or two puffs every one hour for two

or three doses and then every 2-4 hours based on the patient’s response. Although, there are no clinical studies that

have evaluated the use of inhaled long-acting bronchodilators (either beta2-agonists or anticholinergics or

combinations) with or without ICS during an exacerbation, we recommend continuing these treatments during the

exacerbation or to start these medications as soon as possible before hospital discharge. Intravenous methylxanthines

(theophylline or aminophylline) are not recommended to use in these patients due to significant side effects.(1191,1192)

If a nebulizer is chosen to deliver the bronchodilator agent, air-driven bronchodilator nebulization is preferable to

oxygen-driven in acute exacerbations of COPD in order to avoid the potential risk of increasing the PaCO2 associated

with oxygen-driven bronchodilator administration.(1193)

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Glucocorticoids

Data from studies (mostly hospital based) indicate that systemic glucocorticoids in COPD exacerbations shorten

recovery time and improve lung function (FEV1). They also improve oxygenation,(1194-1197) the risk of early relapse,

treatment failure,(1198) and the length of hospitalization.(1194,1196,1199) A dose of 40 mg prednisone-equivalent per day

for 5 days is recommended.(1200) One observational study suggests that longer courses of oral corticosteroids for COPD

exacerbations are associated with an increased risk of pneumonia and mortality.(1201) Therapy with oral prednisolone

is equally effective to intravenous administration.(1202) Nebulized budesonide alone may be a suitable alternative for

treatment of exacerbations in some patients,(1195,1203,1204) and provides similar benefits to intravenous

methylprednisolone, although the choice between these options may depend on local cost issues.(1205,1206) Even short

bursts of corticosteroids are associated with subsequent increased risk of pneumonia, sepsis and death(1207) and use

should be confined to patients with significant exacerbations. Recent studies suggest that glucocorticoids may be less

efficacious to treat acute COPD exacerbations in patients with lower levels of blood eosinophils(439,1167,1170,1208) and

more trials of steroid-sparing treatment regimens are required.

Antibiotics

Although the infectious agents in COPD exacerbations can be viral or bacterial,(1158,1209) the use of antibiotics in

exacerbations remains controversial.(326,1210,1211) The uncertainties originate from studies that did not differentiate

between bronchitis (acute or chronic) and COPD exacerbations, studies without placebo-control, and/or studies

without chest X-rays that do not exclude that patients may have had underlying pneumonia. There is evidence

supporting the use of antibiotics in exacerbations when patients have clinical signs of a bacterial infection e.g.,

increased sputum purulence.(326,1211) Indeed the use of observed sputum color can safely modulate antibiotic therapy

with no adverse effects if sputum is white or clear in color. On the other hand observed sputum purulence has 94.4%

sensitivity and 52% specificity for high bacterial load, indicative of a causative relationship.(326)

A systematic review of placebo-controlled studies has shown that antibiotics reduce the risk of short-term mortality

by 77%, treatment failure by 53% and sputum purulence by 44%.(1212) The review provides evidence to treat

moderately or severely ill patients with COPD exacerbations and increased cough and sputum purulence with

antibiotics.(1212,1213) These data are supported by more RCTs in patients with diagnoses of moderate COPD.(1214) In an

RCT, the addition of doxycycline to oral corticosteroid an outpatient setting did not prolong time to next

exacerbation.(1215) In the outpatient setting, sputum cultures are not feasible as they take at least two days and

frequently do not give reliable results for technical reasons. Several biomarkers of airway infection are being studied

in exacerbations of COPD that have a better diagnostic profile. Earlier studies of C-reactive protein (CRP) have reported

contradictory findings.(1216,1217) A randomized trial found a marked reduction in antibiotic prescriptions without

impaired outcomes in UK primary care outpatients with ECOPD in whom antibiotics prescriptions were guided by

point-of-care CRP testing.(1218) Another trial in patients hospitalized for exacerbations of COPD in The Netherlands

found similar results (reduced antibiotic use with no increase in treatment failure). These findings need confirmation

in other settings before a recommendation to generalize this approach. However, data has indicated that antibiotic

usage can be safely reduced from 77.4% to 47.7% when CRP is low.(1219)

Procalcitonin is an acute phase reactant that increases in response to inflammation and infection and has been studied

to determine the use of antibiotics in COPD exacerbations.(1220) The efficacy of this biomarker is controversial. Several

studies, mainly done in the outpatient setting, suggested that procalcitonin-guided antibiotic treatment reduces

antibiotic exposure and side effects with the same clinical efficacy.(1221-1223) A systematic review and meta-analysis on

the use of procalcitonin in hospitalized patients with a COPD exacerbation found no significant reduction in overall

antibiotic exposure.(1224) In patients with COPD exacerbations treated in an ICU setting, the use of a procalcitonin-

based algorithm for initiating or stopping antibiotics was associated with a higher mortality rate when compared to

those receiving standard antibiotic regimens.(1225) Based on these conflicting results we cannot recommend at this

time the use of procalcitonin-based protocols to make the decision on using antibiotics in patient with COPD

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exacerbations; however, confirmatory trials with rigorous methodology are required.

In summary, antibiotics should be given to patients with exacerbations of COPD who have three cardinal symptoms:

increase in dyspnea, sputum volume, and sputum purulence; have two of the cardinal symptoms, if increased

purulence of sputum is one of the two symptoms; or require mechanical ventilation (invasive or noninvasive).(1141,1158)

A metanalysis demonstrated that ≤ 5 days of antibiotic treatment had the same clinical and bacteriological efficacy to

longer conventional treatment in outpatients with COPD exacerbations. Furthermore, shorter exposure to antibiotics

may decrease the risk developing antimicrobial resistance and complications associated with this therapy. The

recommended length of antibiotic therapy is 5-7 days.(1226) We recommend a duration of ≤ 5 days of antibiotic

treatment for outpatient treatment of COPD exacerbations.(1225,1227)

The choice of the antibiotic should be based on the local bacterial resistance pattern. Usually, initial empirical

treatment is an aminopenicillin with clavulanic acid, macrolide, tetracycline or, in selected patients, quinolone. In

patients with frequent exacerbations, severe airflow obstruction,(1228,1229) and/or exacerbations requiring mechanical

ventilation,(1230) cultures from sputum or other materials from the lung should be performed, as gram-negative

bacteria (e.g., Pseudomonas species) or resistant pathogens that are not sensitive to the above-mentioned antibiotics

may be present. The route of administration (oral or intravenous) depends on the patient’s ability to eat and the

pharmacokinetics of the antibiotic, although it is preferable that antibiotics be given orally. Improvements in dyspnea

and sputum purulence suggest clinical success.

Adjunct therapies

Depending on the clinical condition of the patient, an appropriate fluid balance, use of diuretics when clinically

indicated, anticoagulants, treatment of comorbidities and nutritional aspects should be considered. Among COPD

patients hospitalized with a suspected exacerbation, up to 5.9% were found to have pulmonary embolism.(1146)

Hospitalized patients with COPD are at an increased risk of deep vein thrombosis and pulmonary embolism(1231,1232)

and prophylactic measures for thromboembolism should be instituted.(1233,1234) At all times, healthcare providers

should strongly enforce the need for smoking cessation.

Respiratory support

Oxygen therapy

This is a key component of hospital treatment of an exacerbation. Supplemental oxygen should be titrated to improve

the patient’s hypoxemia with a target saturation of 88-92%.(1235) Once oxygen is started, blood gases should be checked

frequently, or as clinically indicated, to ensure satisfactory oxygenation without carbon dioxide retention and/or

worsening acidosis. Pulse oximetry is not as accurate as arterial blood gas(488) and in particular, may overestimate

blood oxygen content among individuals with darker skin tones.(1236) A study demonstrated that venous blood gas to

assess bicarbonate levels and pH is accurate when compared with arterial blood gas assessment.(1237) Additional data

are needed to clarify the utility of venous blood gas sampling to make clinical decisions in scenarios of acute respiratory

failure; most patients included had a pH > 7.30 on presentation, PCO2 levels were dissimilar when measured by venous

compared to arterial blood samples and the severity of airflow obstruction was not reported.(1237) Venturi masks offer

more accurate and controlled delivery of oxygen than do nasal prongs.(1135)

High-flow nasal therapy

High-flow nasal therapy (HFNT) delivers heated and humidified air-oxygen blends via special devices (e.g.,

Vapotherm®, Comfort Flo®, or Optiflow®) at rates up to 8 L/min in infants and up to 60 L/min in adults.(1238) HFNT has

been associated with decreased respiratory rate and effort, decreased work of breathing, improved gas exchange,

improved lung volume and dynamic compliance, transpulmonary pressures and homogeneity.(1239,1240) These

physiologic benefits positively improve oxygenation and clinical outcomes in patients with acute hypoxemic

respiratory failure.(1239-1242) HFNT has been reported to improve oxygenation and ventilation, decrease hypercarbia and

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improve health-related quality of life in patients with acute hypercapnia during an acute exacerbation, and also in

select patients with stable hypercapnic COPD.(1239,1243-1245) However, the small sample sizes, heterogeneity of the

patient populations and short duration of follow-up are current limitations in the interpretation of the value of HFNT

for the COPD patient population at large.(1246) A meta-analysis, based on poor quality studies, showed no clear

benefit.(1247) HFNT has been reported to improve oxygenation and ventilation, decrease hypercarbia, prolong the time

to next moderate exacerbation and improve health-related quality of life scores in patients with acute hypercapnia

during an exacerbation or in select patients with stable hypercapnic COPD receiving long term oxygen therapy.(1248)

HFNT did not prevent intubation in a RCT conducted in patients hospitalized with an acute exacerbation.(1249) It should

be noted that European Respiratory Society (ERS) Clinical Practice Guidelines recommend trialling NIV prior to use of

HFNT in patients with COPD and hypercapnic ARF.(1250) There is a need for well-designed, prospective, randomized and

controlled multicenter trials to study the effects of HFNT in people with COPD experiencing episodes of either acute

or chronic hypercapnic respiratory failure.

Ventilatory support

Some patients need immediate admission to the respiratory care or intensive care unit (ICU) (Figure 4.7). Admission

of patients with severe exacerbations to intermediate or special respiratory care units may be appropriate if adequate

personnel skills and equipment exist to identify and manage acute respiratory failure. Ventilatory support in an

exacerbation can be provided by either noninvasive (nasal or facial mask) or invasive (oro-tracheal tube or

tracheostomy) ventilation. Respiratory stimulants are not recommended for acute respiratory failure.(1189)

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Noninvasive mechanical ventilation

The use of noninvasive mechanical ventilation (NIV) is preferred over invasive ventilation (intubation and positive

pressure ventilation) as the initial mode of ventilation to treat acute respiratory failure in patients hospitalized for

acute exacerbations of COPD. NIV has been studied in RCTs showing a success rate of 80-85%.(641,1251-1254) NIV has been

shown to improve oxygenation and acute respiratory acidosis i.e., NIV increases pH and decreases PaCO2. NIV also

decreases respiratory rate, work of breathing and the severity of breathlessness but also decreases complications such

as ventilator associated pneumonia, and length of hospital stay. More importantly, mortality and intubation rates are

reduced by this intervention.(1252,1255-1257) Once patients improve and can tolerate at least 4 hours of unassisted

breathing, NIV can be directly discontinued without any need for a “weaning” period.(1258) The indications for NIV(1254)

are summarized in Figure 4.8.

Invasive mechanical ventilation

The indications for initiating invasive mechanical ventilation during an exacerbation are shown in Figure 4.9, and

include failure of an initial trial of NIV.(1259) As experience is gained with the generalized clinical use of NIV in COPD, a

number of indications for invasive mechanical ventilation are being successfully treated with NIV, thus eliminating

invasive mechanical ventilation as first line treatment of acute respiratory failure during hospitalization for COPD

exacerbation.(1259) In patients who fail non-invasive ventilation as initial therapy and receive invasive ventilation as

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subsequent rescue therapy, morbidity, hospital length of stay and mortality are greater.(641) The use of invasive

ventilation in patients with very severe COPD is influenced by the likely reversibility of the precipitating event, the

patient’s wishes, and the availability of intensive care facilities.(641) When possible, a clear statement of the patient’s

own treatment wishes, such as an advance directive or “living will”, makes these difficult decisions easier to resolve.

Major hazards include the risk of ventilator-acquired pneumonia (especially when multi-resistant organisms are

prevalent), barotrauma and volutrauma, and the risk of tracheostomy and consequential prolonged ventilation.

Acute mortality among COPD patients with respiratory failure is lower than mortality among patients ventilated for

non-COPD causes.(1260) Despite this, there is evidence that patients who might otherwise survive are frequently denied

admission to intensive care for intubation because of unwarranted prognostic pessimism.(1261) A large study of COPD

patients with acute respiratory failure reported in-hospital mortality of 17-49%.(1262) Further deaths were reported

over the next 12 months, particularly among those patients who had poor lung function before invasive ventilation

(FEV1 < 30% predicted), had a non-respiratory comorbidity, or were housebound. Patients who did not have a

previously diagnosed comorbidity, had respiratory failure due to a potentially reversible cause (such as an infection),

or were relatively mobile and not using long-term oxygen, did well after ventilator support.

Hospital discharge and follow-up

The cause, severity, impact, treatment and time course of exacerbations varies from patient to patient and facilities in

the community, and healthcare systems, differ from country to country. Accordingly, there are no standards that can

be applied to the timing and nature of discharge. However, it is recognized that recurrent exacerbations leading to

short-term readmission and increased all-cause mortality are associated with the initial hospitalization for an acute

episode of deterioration.(1263)

When features related to re-hospitalization and mortality have been studied, defects in perceived optimal

management have been identified including spirometric assessment and arterial blood gas analysis.(1264) A systematic

review has shown that comorbidities, previous exacerbations and hospitalization, and increased length of stay were

significant risk factors for 30- and 90-day all-cause readmission after an index hospitalization with an exacerbation of

COPD.(1265) Mortality relates to patient age, the presence of acidotic respiratory failure, the need for ventilatory

support and comorbidities including anxiety and depression.(1266)

The introduction of care bundles at hospital discharge to include education, optimization of medication, supervision

and correction of inhaler technique, assessment and optimal management of comorbidities, early rehabilitation,

telemonitoring and continued patient contact have all been investigated to address these issues (Figure 4.10).(1267)

While these measures all seem sensible there is insufficient data that they influence either readmission rates or short-

term mortality(1264,1266,1268,1269) and there is little evidence of cost-effectiveness.(1266) One RCT showed that

telemonitoring did not change hospitalization or exacerbation rates in people with COPD.(1270) Nevertheless, it remains

good clinical practice to cover these issues before discharge and their effectiveness on health status and readmission

rates may be increased if they are delivered with an approach that includes motivational interview-based health

coaching.(964)

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The only possible exception is early rehabilitation as there is some evidence that this factor is associated with increased

mortality, although the reasons remain unknown.(1269) However, other data suggest that early rehabilitation post

hospital discharge (i.e., < 4 weeks) may be associated with improved survival.(702)

Early follow-up (within one month) following discharge should be undertaken when possible and has been related to

less exacerbation-related readmissions.(1271) There are many patient issues that prevent early follow-up; those not

attending early follow-up have increased 90-day mortality. This may reflect both patient compliance, limited access to

medical care, poor social support, and/or the presence of more severe disease. Nevertheless, early follow-up permits

a careful review of discharge therapy and an opportunity to make any needed changes in therapy.

Additional follow-up at three months is recommended to ensure return to a stable clinical state and permit a review

of the patient’s symptoms, lung function (by spirometry), and where possible the assessment of prognosis using

multiple scoring systems such as BODE.(1272) In addition, arterial oxygen saturation and blood gas assessment will

determine the need for long-term oxygen therapy more accurately at prolonged follow-up compared to shortly after

discharge.(1273)

CT assessment to determine the presence of bronchiectasis and emphysema should be done in patients with recurrent

exacerbations and/or hospitalizations.(483,1274) A further detailed assessment of the presence and management of

comorbidities should also be undertaken (Figure 4.10).(1274)

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Prevention of exacerbations

After an acute exacerbation, appropriate measures for prevention of further exacerbations should be initiated (Figure

4.6 and Figure 4.11). For the following treatment modalities significant effects on exacerbation risk/frequency could

be shown in clinical trials. For details refer to Chapter 3.

Based on findings from observational studies in various countries(1275-1278) there was a major decrease in hospital

admissions for COPD exacerbations during the COVID-19 epidemic. It was hypothesized that this phenomenon may be

a consequence of shielding measures (e.g., wearing masks, avoiding social contact, regular hand washing etc). An

alternative explanation is that patients may not have been seeking medical assistance during an exacerbation due to

concern about becoming infected with the SARS-CoV-2 virus. If this was the case, then a corresponding increase in

COPD related mortality would be expected. However, two major studies from the US and the UK(1275,1279) did not report

increased COPD associated mortality during the pandemic. Accordingly, shielding measures could be considered

during the winter months (on top of established pharmacological and non-pharmacological measures) in patients at

risk of exacerbation.

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