REVIEW URRENT C OPINION
Role of infection in exacerbations of chronic obstructive pulmonary disease Marc Miravitlles a and Antonio Anzueto b
Purpose of review In this review, we present the latest findings on the cause, pathogenesis and management of patients with chronic obstructive pulmonary disease (COPD) and an infective phenotype. Recent findings More than half of COPD exacerbations are infective. Bacteria are isolated in 70% of them, but viruses also play an important role, both alone and in combination with bacteria. Furthermore, in many cases, viral infection can be followed by bacterial infection in patients with COPD but not in individuals with normal lung function. Viral infection may produce changes in the lung microbiome that may precipitate subsequent bacterial infection. Research on the lung microbiome is providing new insight into the pathogenesis of infection in healthy and diseased lungs. Summary COPD patients have alterations in their lung microbiome that may result in chronic infection with potentially pathogenic microorganisms (PPMs) even in periods of clinical stability and associated with a higher frequency of bacterial exacerbations. Patients with this infective phenotype may require a personalized approach to therapy with the use of short-term or long-term antibiotic treatment in addition to the usual treatment for COPD. Keywords antibiotics, chronic obstructive pulmonary disease, exacerbations, infection, microbiome
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is characterized by recurrent episodes of exacerbations defined by an acute increase in respiratory symptoms [1]. Among the multiple causes of exacerbations, infection is by far the most frequent. However, understanding of the role of infection in COPD is still incomplete. Thus, in stable COPD patients, potentially pathogenic microorganisms (PPMs) can be isolated in respiratory samples in between 20 and 60% of cases [2,3]. These bacteria contribute to chronic airway inflammation leading to COPD progression [2,4,5] and may be associated with exacerbations when they increase in concentrations in the airways, when there is a change in these strains or after a viral respiratory infection. These different mechanisms may be responsible for the development of a bacterial exacerbation of COPD [6]. In the past decade, novel culture-independent techniques have shown that the lower respiratory tract, previously deemed sterile, contains diverse communities of microbes, even without clinical www.co-pulmonarymedicine.com
evidence of infection, These studies have demonstrated the importance of the human microbiota for our health [7]. The role of the lung microbiota in COPD is currently a subject of intense investigation.
CAUSE AND PHENOTYPES OF EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Several studies have demonstrated that approximately 70% of exacerbations are caused by a
Pneumology Department, Hospital Universitari Vall d’Hebron, Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain and bDeDepartment of Medicine, Division of Pulmonary Diseases/Critical Care Medicine, The University of Texas Health Science Center at San Antonio and The South Texas Veterans Healthcare System, Audie L, Murphy Memorial Veterans Hospital Division, San Antonio, Texas, USA Correspondence to Marc Miravitlles, Pneumology Department, Hospital Universitari Vall d’Hebron, P. Vall d’Hebron 119-129, 08035 Barcelona, Spain. Tel: +93 2746157; fax: +93 2746083; e-mail: mmiravitlles@ vhebron.net Curr Opin Pulm Med 2015, 21:278–283 DOI:10.1097/MCP.0000000000000154 Volume 21 Number 3 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Infection in COPD Miravitlles and Anzueto
KEY POINTS Chronic bronchial infection is associated with increased pulmonary and systemic inflammation and is a risk factor for accelerated progression of COPD.
who experience frequent exacerbations requiring multiple antibiotic treatments despite optimal bronchodilator and anti-inflammatory therapy and are followed in specialized centres [19].
Viruses are a frequent cause of exacerbations, both alone and in combination with bacteria, and viral infection may be followed by bacterial infection after a few days.
MECHANISMS OF INFECTION IN BACTERIAL EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
The usual treatment of COPD with bronchodilators and inhaled corticosteroids may not be sufficient to prevent exacerbations in patients with COPD and an ‘infective phenotype’.
Patients with COPD present significant impairment in lung defence mechanisms, which enables the proliferation of PPMs in their bronchial secretions. Alterations to the normal microbiome can lead to colonization by different PPMs. Nontypeable Haemophilus influenzae is the most frequent bacterium found in distal airways of patients with COPD both in stable periods and in exacerbations [20]. The relationship between bronchial colonization and the evolution of COPD has been shown in a study by Wilkinson et al. [4] who observed that patients with higher bronchial bacterial loads presented a faster decline in lung function during a 1-year follow-up. The lung damage associated with bronchial colonization has been related to an increase in inflammation basically related to H. influenzae [21]. Therefore, it has been suggested that the term chronic bronchial infection would be more appropriate when addressing the presence of significant concentrations of PPMs in the lower airways of stable COPD patients [2,17]. These patients with chronic bronchial infection may constitute an infective phenotype [17]. Similarly, the predominant microorganisms causing exacerbations are nontypeable H. influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Bacteria are more frequently the cause of exacerbations in frequent exacerbators and the same microorganisms isolated during the exacerbation may persist after recovery in up to 50% of cases [22,23]. In patients with the most severe exacerbations requiring mechanical ventilation, other bacteria such as Pseudomonas aeruginosa and enteric Gram-negative bacilli (e.g. Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae) may be more frequent [24]. In fact, the severity of COPD measured by the FEV1 is an important determinant of the type of microorganisms [25,26]. P. aeruginosa and enteric Gramnegative bacteria appear more frequently in patients with the most severely impaired lung function. The definition of risk factors for P. aeruginosa infection is a potentially important issue because of the difference in the preferred antibiotic treatment and the risk of an unfavourable clinical course if appropriate antibiotics are not given. Different
The lung microbiome is a promising new field of research into the bacterial community in the lungs and the effects of treatment.
respiratory infections, including bacteria (40–60%), respiratory viruses (about 30%) and atypical bacteria (5–10%) [8,9]. Polymicrobial cause may affect up to 33% of cases, being particularly important in the most severe patients [10]. In patients admitted to hospital for an exacerbation of COPD, viral and/or bacterial infection was detected in as high as 78% of cases associated with longer hospitalization [10]. Multifactor cause is not uncommon [10,11], and in a certain proportion of exacerbations, the cause remains unknown. Microbiological studies have identified a change in colour and an increase in purulence as good surrogate markers for the presence of bacterial infection [12,13]. Among biomarkers, the most extensively studied is C-reactive protein (CRP), which can be used as a point-of-care test and is elevated in bacterial exacerbations [14 ]. Recent studies have further characterized the different types of exacerbations and identified bacterial, viral, inflammatory (eosinophilic) and pauciinflammatory phenotypes of exacerbations, with most (59%) exacerbations being bacterial or viral [15]. Interestingly, the phenotype of the exacerbation remains constant in a given patient [15]. This is particularly important not only for treatment of the exacerbations but especially for the selection of the best preventive measures that are guided by the phenotype of the patient [16]. In this respect, patients with the infective phenotype characterized by frequent bacterial exacerbations [17] may require a specific approach, and the additional use of longterm antibiotics has been advocated in these patients [18]. However, concerns about potential side effects and increased antibiotic resistance indicate that until further well controlled studies are conducted, such treatment should be reserved for patients with COPD &
1070-5287 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-pulmonarymedicine.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
279
Infectious diseases
studies [25–31] indicate a percentage of Pseudomonas infection of around 10–35% and have identified some of the risk factors associated with this microorganism (Table 1). Viruses account for approximately 30% of exacerbations, either alone or as copathogens, with the most frequent being picornavirus (especially rhinovirus), influenza virus and respiratory syncytial virus [32,33]. The causal relationship between upper-respiratory viral infection and COPD exacerbations has been demonstrated by Mallia et al. [34] in a study with experimental rhinovirus infection in COPD patients and healthy individuals. After being infected with rhinovirus, COPD patients developed more severe and prolonged respiratory symptoms, greater lung function impairment and increased airway inflammation, all of which resembled naturally occurring exacerbations [34]. In addition, there is growing evidence that the interaction between viruses and bacteria is crucial for the development of infective exacerbations, and in a significant number of cases, viral infection can be the precipitating factor for a subsequent bacterial episode. Rhinovirus infection induces impairment of antibacterial host defence [35] with a subsequent rise in bacterial burden and an outgrowth from bacteria present at baseline that precipitates bacterial infection. This has been confirmed by George et al. [36 ] in their cohort of patients in which the exacerbations that were positive for human rhinovirus but negative for bacteria at presentation &
Table 1. Risk factors for Pseudomonas aeruginosa infection in chronic obstructive pulmonary disease Reference
Risk factors
Allegra et al. [27]
FEV1
Role of infection in exacerbations of chronic obstructive pulmonary disease Marc Miravitlles a and Antonio Anzueto b
Purpose of review In this review, we present the latest findings on the cause, pathogenesis and management of patients with chronic obstructive pulmonary disease (COPD) and an infective phenotype. Recent findings More than half of COPD exacerbations are infective. Bacteria are isolated in 70% of them, but viruses also play an important role, both alone and in combination with bacteria. Furthermore, in many cases, viral infection can be followed by bacterial infection in patients with COPD but not in individuals with normal lung function. Viral infection may produce changes in the lung microbiome that may precipitate subsequent bacterial infection. Research on the lung microbiome is providing new insight into the pathogenesis of infection in healthy and diseased lungs. Summary COPD patients have alterations in their lung microbiome that may result in chronic infection with potentially pathogenic microorganisms (PPMs) even in periods of clinical stability and associated with a higher frequency of bacterial exacerbations. Patients with this infective phenotype may require a personalized approach to therapy with the use of short-term or long-term antibiotic treatment in addition to the usual treatment for COPD. Keywords antibiotics, chronic obstructive pulmonary disease, exacerbations, infection, microbiome
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is characterized by recurrent episodes of exacerbations defined by an acute increase in respiratory symptoms [1]. Among the multiple causes of exacerbations, infection is by far the most frequent. However, understanding of the role of infection in COPD is still incomplete. Thus, in stable COPD patients, potentially pathogenic microorganisms (PPMs) can be isolated in respiratory samples in between 20 and 60% of cases [2,3]. These bacteria contribute to chronic airway inflammation leading to COPD progression [2,4,5] and may be associated with exacerbations when they increase in concentrations in the airways, when there is a change in these strains or after a viral respiratory infection. These different mechanisms may be responsible for the development of a bacterial exacerbation of COPD [6]. In the past decade, novel culture-independent techniques have shown that the lower respiratory tract, previously deemed sterile, contains diverse communities of microbes, even without clinical www.co-pulmonarymedicine.com
evidence of infection, These studies have demonstrated the importance of the human microbiota for our health [7]. The role of the lung microbiota in COPD is currently a subject of intense investigation.
CAUSE AND PHENOTYPES OF EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE Several studies have demonstrated that approximately 70% of exacerbations are caused by a
Pneumology Department, Hospital Universitari Vall d’Hebron, Ciber de Enfermedades Respiratorias (CIBERES), Barcelona, Spain and bDeDepartment of Medicine, Division of Pulmonary Diseases/Critical Care Medicine, The University of Texas Health Science Center at San Antonio and The South Texas Veterans Healthcare System, Audie L, Murphy Memorial Veterans Hospital Division, San Antonio, Texas, USA Correspondence to Marc Miravitlles, Pneumology Department, Hospital Universitari Vall d’Hebron, P. Vall d’Hebron 119-129, 08035 Barcelona, Spain. Tel: +93 2746157; fax: +93 2746083; e-mail: mmiravitlles@ vhebron.net Curr Opin Pulm Med 2015, 21:278–283 DOI:10.1097/MCP.0000000000000154 Volume 21 Number 3 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Infection in COPD Miravitlles and Anzueto
KEY POINTS Chronic bronchial infection is associated with increased pulmonary and systemic inflammation and is a risk factor for accelerated progression of COPD.
who experience frequent exacerbations requiring multiple antibiotic treatments despite optimal bronchodilator and anti-inflammatory therapy and are followed in specialized centres [19].
Viruses are a frequent cause of exacerbations, both alone and in combination with bacteria, and viral infection may be followed by bacterial infection after a few days.
MECHANISMS OF INFECTION IN BACTERIAL EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
The usual treatment of COPD with bronchodilators and inhaled corticosteroids may not be sufficient to prevent exacerbations in patients with COPD and an ‘infective phenotype’.
Patients with COPD present significant impairment in lung defence mechanisms, which enables the proliferation of PPMs in their bronchial secretions. Alterations to the normal microbiome can lead to colonization by different PPMs. Nontypeable Haemophilus influenzae is the most frequent bacterium found in distal airways of patients with COPD both in stable periods and in exacerbations [20]. The relationship between bronchial colonization and the evolution of COPD has been shown in a study by Wilkinson et al. [4] who observed that patients with higher bronchial bacterial loads presented a faster decline in lung function during a 1-year follow-up. The lung damage associated with bronchial colonization has been related to an increase in inflammation basically related to H. influenzae [21]. Therefore, it has been suggested that the term chronic bronchial infection would be more appropriate when addressing the presence of significant concentrations of PPMs in the lower airways of stable COPD patients [2,17]. These patients with chronic bronchial infection may constitute an infective phenotype [17]. Similarly, the predominant microorganisms causing exacerbations are nontypeable H. influenzae, Streptococcus pneumoniae and Moraxella catarrhalis. Bacteria are more frequently the cause of exacerbations in frequent exacerbators and the same microorganisms isolated during the exacerbation may persist after recovery in up to 50% of cases [22,23]. In patients with the most severe exacerbations requiring mechanical ventilation, other bacteria such as Pseudomonas aeruginosa and enteric Gram-negative bacilli (e.g. Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Serratia marcescens, Enterobacter cloacae) may be more frequent [24]. In fact, the severity of COPD measured by the FEV1 is an important determinant of the type of microorganisms [25,26]. P. aeruginosa and enteric Gramnegative bacteria appear more frequently in patients with the most severely impaired lung function. The definition of risk factors for P. aeruginosa infection is a potentially important issue because of the difference in the preferred antibiotic treatment and the risk of an unfavourable clinical course if appropriate antibiotics are not given. Different
The lung microbiome is a promising new field of research into the bacterial community in the lungs and the effects of treatment.
respiratory infections, including bacteria (40–60%), respiratory viruses (about 30%) and atypical bacteria (5–10%) [8,9]. Polymicrobial cause may affect up to 33% of cases, being particularly important in the most severe patients [10]. In patients admitted to hospital for an exacerbation of COPD, viral and/or bacterial infection was detected in as high as 78% of cases associated with longer hospitalization [10]. Multifactor cause is not uncommon [10,11], and in a certain proportion of exacerbations, the cause remains unknown. Microbiological studies have identified a change in colour and an increase in purulence as good surrogate markers for the presence of bacterial infection [12,13]. Among biomarkers, the most extensively studied is C-reactive protein (CRP), which can be used as a point-of-care test and is elevated in bacterial exacerbations [14 ]. Recent studies have further characterized the different types of exacerbations and identified bacterial, viral, inflammatory (eosinophilic) and pauciinflammatory phenotypes of exacerbations, with most (59%) exacerbations being bacterial or viral [15]. Interestingly, the phenotype of the exacerbation remains constant in a given patient [15]. This is particularly important not only for treatment of the exacerbations but especially for the selection of the best preventive measures that are guided by the phenotype of the patient [16]. In this respect, patients with the infective phenotype characterized by frequent bacterial exacerbations [17] may require a specific approach, and the additional use of longterm antibiotics has been advocated in these patients [18]. However, concerns about potential side effects and increased antibiotic resistance indicate that until further well controlled studies are conducted, such treatment should be reserved for patients with COPD &
1070-5287 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.co-pulmonarymedicine.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
279
Infectious diseases
studies [25–31] indicate a percentage of Pseudomonas infection of around 10–35% and have identified some of the risk factors associated with this microorganism (Table 1). Viruses account for approximately 30% of exacerbations, either alone or as copathogens, with the most frequent being picornavirus (especially rhinovirus), influenza virus and respiratory syncytial virus [32,33]. The causal relationship between upper-respiratory viral infection and COPD exacerbations has been demonstrated by Mallia et al. [34] in a study with experimental rhinovirus infection in COPD patients and healthy individuals. After being infected with rhinovirus, COPD patients developed more severe and prolonged respiratory symptoms, greater lung function impairment and increased airway inflammation, all of which resembled naturally occurring exacerbations [34]. In addition, there is growing evidence that the interaction between viruses and bacteria is crucial for the development of infective exacerbations, and in a significant number of cases, viral infection can be the precipitating factor for a subsequent bacterial episode. Rhinovirus infection induces impairment of antibacterial host defence [35] with a subsequent rise in bacterial burden and an outgrowth from bacteria present at baseline that precipitates bacterial infection. This has been confirmed by George et al. [36 ] in their cohort of patients in which the exacerbations that were positive for human rhinovirus but negative for bacteria at presentation &
Table 1. Risk factors for Pseudomonas aeruginosa infection in chronic obstructive pulmonary disease Reference
Risk factors
Allegra et al. [27]
FEV1
