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INTRODUÇÃO
A maioria das exacerbações da doença pulmonar obstrutiva crônica (DPOC) são devidas a
infecções do trato respiratório. Uma parte importante da avaliação é determinar quais
pacientes têm uma causa tratável de infecção e quando realizar testes microbiológicos.
O papel da infecção nas exacerbações da DPOC será revisto aqui. O manejo da infecção nas
exacerbações da DPOC é apresentado separadamente. Precipitantes, fatores de risco e
outras intervenções (por exemplo, broncodilatadores, glicocorticóides, oxigênio e ventilação
mecânica) também são discutidos separadamente. (Consulte “Manejo da infecção nas
exacerbações da doença pulmonar obstrutiva crônica” e “Exacerbações da DPOC: manejo” .)
DEFINIÇÃO
As diretrizes da Iniciativa Global para Doença Pulmonar Obstrutiva Crônica definem uma
exacerbação da DPOC como um evento caracterizado por dispneia e/ou tosse e
expectoração que piora ao longo de ≤14 dias, que pode ser acompanhada por taquipneia
e/ou taquicardia, e está frequentemente associada a aumento inflamação local e sistêmica
causada por infecção das vias aéreas, poluição ou outro insulto às vias aéreas [ 1,2 ].
ETIOLOGIA
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Estima-se que 70 a 80 por cento das exacerbações da DPOC sejam devidas a infecções
respiratórias. Os 20 a 30 por cento restantes são devidos à inflamação eosinofílica [ 3 ],
poluição ambiental, não adesão à medicação de manutenção ou têm etiologia desconhecida
[ 4 ]. As infecções virais e bacterianas causam a maioria das exacerbações, enquanto as
bactérias atípicas são uma causa relativamente incomum [ 5,6 ].
Vírus — Os vírus podem ser detectados em um terço a dois terços das exacerbações
usando métodos baseados em cultura, sorologia e reação em cadeia da polimerase (PCR). Os
vírus mais comuns associados às exacerbações da DPOC são os rinovírus [ 7 ]. Influenza,
parainfluenza, coronavírus e adenovírus também são comuns durante as exacerbações [ 7–
15 ]. O vírus sincicial respiratório e o metapneumovírus humano foram mais recentemente
associados a exacerbações [ 16,17 ].
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● Exacerbations with new bacterial strains are more likely to be associated with a humoral
immune response – In one study, exacerbations with a new strain of H. influenzae were
significantly more likely to be associated with a humoral immune response than
exacerbations with pre-existing strains of H. influenzae (61 versus 21 percent) [35].
These new antibodies were strain specific. M. catarrhalis, S. pneumoniae, and P.
aeruginosa also induce an antibody response that is measurable following an
exacerbation of COPD [33,36-38].
● Exacerbations with new bacterial strains are associated with a more robust
inflammatory response – Exacerbations of COPD with a new strain of bacteria have
been associated with more intense neutrophilic airway inflammation and systemic
inflammation than exacerbations not associated with a change in pre-existing bacterial
strains or recovery of pathogenic bacteria [39]. Resolution of the airway inflammation is
related to eradication of pathogenic bacteria from sputum and resolution of clinical
symptoms. In an animal model, new strains of H. influenzae that were known to be
associated with COPD exacerbation caused significantly more airway neutrophil
recruitment than colonizing strains of H. influenzae [40].
Most of the human studies were performed in patients with COPD who had chronic
bronchitis because expectorated sputum could be obtained easily. Thus, the degree to which
the data can be generalized to exacerbations in patients with COPD who do not have chronic
bronchitis is unknown. (See "Chronic obstructive pulmonary disease: Diagnosis and staging",
section on 'Definitions'.)
The idea that exacerbations of COPD are due to acquisition of a new strain of bacteria has
largely replaced the older hypothesis that increases in the concentration of colonizing
bacteria are the primary cause of exacerbations. The older theory was largely disproven by a
comprehensive analysis of the relationship among sputum bacterial concentrations,
exacerbation occurrence, and new pathogen acquisition [41]. The analysis demonstrated that
an increase in bacterial load is not a cause of exacerbation.
Molecular diagnostics, specifically 16S ribosomal ribonucleic acid (rRNA) sequencing, have
been extensively employed in the study of the airway microbiome at exacerbations and in
stable COPD [15,42-45]. A reduction in diversity and an increase in Proteobacteria with
increasing severity of COPD and at exacerbation have been consistently described. Another
intriguing observation suggests that even exacerbations with a dominant pathogen could be
polymicrobial. When known pathogens such as H. influenzae increased during acute
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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.
CLINICAL FEATURES
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● Increased dyspnea
● Increased sputum volume and/or viscosity
● Increased sputum purulence
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].
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● Patients with risk factors for Pseudomonas infection – Risk factors for Pseudomonas
infection include recent hospitalization (≥2 days' duration during the past 90 days),
frequent administration of antibiotics (≥4 courses within the past year), advanced COPD
(FEV1 <30 percent of predicted), isolation of P. aeruginosa during a previous
exacerbation, Pseudomonas colonization during a stable period, and systemic
glucocorticoid use ( table 2) [1,57,58].
● 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.
The evidence demonstrating the limited utility of routine sputum Gram stain and culture
includes the following:
● Gram stain and culture of expectorated sputum yield similar results during
exacerbations and stable disease [8]. In other words, they do not distinguish between
true pathogens and colonizing flora. The molecular testing studies cited in the
preceding section showed that newly acquired bacterial strains are often associated
with exacerbations, but identification of these strains requires sequential cultures and
specialized tests that are not available for routine clinical use [41] (see 'Bacteria' above).
Additional supporting evidence is the presence of a likely pathogen seen on Gram stain
and recovered from culture with heavy growth. Also, the failure to grow an easily
cultured pathogen such as gram-negative bacilli or S. aureus from a purulent
pretreatment specimen is evidence against their role in the exacerbation.
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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].
● Studies comparing culture to quantitative polymerase chain reaction (PCR) for the three
most common bacterial pathogens (H. influenzae, M. catarrhalis, S. pneumoniae) also
demonstrated a doubling of pathogen detection with the latter technique, confirming
the low sensitivity of sputum culture [60,61]. However, the detection of these organisms
by PCR can be misleading given its high sensitivity and the fact that these organisms
can be part of the colonizing oropharyngeal flora.
Detection of respiratory viruses — A key step in evaluating for viral infection is to detect
influenza, as it is amenable to antiviral treatment. We therefore test for influenza in all
patients with COPD exacerbations when influenza is suspected (eg, during influenza season).
Test selection (eg, rapid diagnostic test, PCR) depends on the treatment setting and available
resources ( table 3) (see "Seasonal influenza in adults: Clinical manifestations and
diagnosis").
During the pandemic, we test all patients with new or worsening respiratory symptoms,
regardless of vaccination status. (See "COVID-19: Diagnosis".)
The role of testing for other respiratory viruses in patients with a COPD exacerbation is less
clear, as these are not amenable to specific antiviral treatment. PCR-based diagnostic panels
that can detect multiple respiratory viruses simultaneously and can be performed in two to
three hours in hospital laboratories have been developed [62-66]. Viruses detected by such
panels include influenza, adenovirus, parainfluenza virus, respiratory syncytial virus, human
metapneumovirus, coronavirus, and rhinovirus [66]. The impact of detection of these viruses
(other than influenza) on clinical decision making is minimal, as they can be detected in a
stable state, concomitant bacterial infection is not excluded and specific antiviral treatment is
not available. We do not routinely use these panels in immunocompetent COPD patients
presenting with an exacerbation. (See "Management of infection in exacerbations of chronic
obstructive pulmonary disease", section on 'Respiratory virus treatment' and "Clinical
evaluation and diagnostic testing for community-acquired pneumonia in adults", section on
'Other respiratory viruses'.)
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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.
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Chronic obstructive
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pulmonary disease".)
● 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.)
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.)
• When to obtain sputum studies – For most patients, obtaining sputum Gram stain
and culture for microbiologic diagnosis is not necessary. We reserve testing for
patients with COPD exacerbations with risk factors for Pseudomonas infection
( table 2), failure to improve on initial empiric antibiotics, and in hospitalized
patients (particularly those with impending or actual acute respiratory failure due to
an exacerbation of COPD). (See 'When to obtain sputum studies' above.)
• Testing for respiratory viruses – We test for influenza in all patients with COPD
exacerbations when influenza is suspected (eg, the patient presents during influenza
season and has a clinical picture suggestive of influenza). (See 'Detection of
respiratory viruses' above.)
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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.)
ACKNOWLEDGMENT
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GRAPHICS
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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COPD: chronic obstructive pulmonary disease; FEV1: 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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Time to
Test Comments
results
Recommended tests
Additional tests
Rapid influenza diagnostic tests <15 minutes Low to moderate sensitivity; high
(antigen detection) specificity
Viral culture
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.
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
influenza. Clin Infect Dis 2019; 68:895.
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2. Centros de Controle e Prevenção de Doenças dos Estados Unidos. Métodos de teste do vírus influenza. Disponível
em: https://www.cdc.gov/flu/professionals/diagnosis/table-testing-methods.htm (Acessado em 31 de agosto de
2021).
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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.
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evidência do UpToDate.
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