Download Acute and chronic infection in chronic obstructive pulmonary disease

Acute and chronic infection in chronic obstructive pulmonary disease
Dr Marc Miravitlles
Pneumology Department
Hospital Vall d'Hebron
P. Vall d'Hebron 119
08035 Barcelona
SPAIN
[email protected]
AIMS: To discuss the main clinical challenges associated with acute and chronic infection in
patients with chronic obstructive pulmonary disease (COPD).
TARGET AUDIENCE: Clinician, Nurse, Pulmonologist, Physiotherapist
AIMS
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Define the concepts of acute and chronic infection in COPD
Describe the impact of infection in the natural course of COPD
Strategies for prevention and treatment of acute infection
Discuss the treatment options for chronic infection in COPD
SUMMARY
Patients with COPD may present with different clinical characteristics, prognosis and response to
treatment (1). This has resulted in increased efforts to identify subgroups of patients with similar clinical
characteristics and prognosis, the so-called clinical phenotypes, in order provide more individualized
and effective therapy (2,3). One of these phenotypes is the frequent exacerbator and in most cases these
exacerbations are caused by bronchial infection.
The concept of chronic bronchial infection in COPD
Subjects with COPD present different forms of impaired immunity, including reduced mucociliary
clearance, defective phagocytosis and hyporesponsiveness of alveolar macrophages to bacterial
antigens, with a subsequent predisposition to infection (4,5). Among the defense mechanisms, airway
mucus plays a leading role; under normal circumstances it protects the epithelial lining by entrapping
harmful particles and clearing them from the airway through the mucociliary clearance (4). Cigarette
smoke, bacterial infection, cold air, and various irritants and allergens cause mucus secretion by
inducing the release of inflammatory mediators or nerve activation (4). The vicious circle of bacterial
infection and mucus hypersecretion is further complicated by the fact that a reduction in the numbers
of serous and Club cells (caused by globet cell hyperplasia) results in low concentrations of their
protective molecules in respiratory secretions and may also explain the increased propensity for
bacterial growth in the lower airways of patients with mucus hypersecretion (4,6). Consequently,
microbiological cultures of sputum are positive for PPMs in about 40-70% of patients with stable COPD
(7).
The PPMs most frequently recovered from respiratory samples in stable COPD include non-typeable
Haemophilus influenza (NTHi), Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus
parainfluenzae Multibacterial colonization is not uncommon, while Pseudomonas spp. is predominately
found in patients with more severe functional impairment (7).
The relationship between the isolation of PPMs in bronchial secretions and the evolution of COPD has
been demonstrated in a study by Wilkinson et al (8), who observed that patients with higher bronchial
bacterial loads and those experiencing changes in colonising bacterial type over time, presented a faster
decline in lung function during a one-year follow-up. These results were confirmed by Marin et al (9)
in a series of 79 COPD patients, of which 47 were chronically infected by H.influenzae, P. aeruginosa,
or enterobacteria. These authors found increased neutrophilic inflammation associated with isolation of
these microorganisms and a statistically significant relationship with accelerated FEV1 decline. More
recently, Bafadhel et al (10) observed that persistence of bacteria in the airways, whether defined by
culture, quantitative polymerase chain reaction (qPCR), or both, was associated with lower forced
expiratory volume in 1 second (FEV1). Moreover, the increased inflammation associated with the
presence of PPMs in the lower airways results in more respiratory symptoms (11) and a significant
impairment in health-related quality of life (11,12).
There is therefore sufficient evidence to maintain that PPMs play an important role in the pathogenesis
and progression of COPD. The usual term, “colonisation”, suggests passive and harmless coexistence
of bacteria on the mucous membranes of an asymptomatic host. However, not only are PPMs far from
being passive bystanders, they in fact contribute actively to airway and systemic inflammation, with all
the subsequent negative consequences. On the basis of the evidence available, a change in the
terminology has been suggested in favour of the term “chronic bronchial infection” to describe the
isolation of a significant load of PPMs in the airways in stable COPD patients (13,14). This syndrome
can be accompanied by recurrent infective exacerbations, an increase in respiratory symptoms, and a
significant impairment to health status, even in the absence of an exacerbation.
Further evidence of the impact of chronic bronchial infection on the natural history of COPD derives
from its relationship with increased frequency and severity of exacerbations. Patel et al (15)
demonstrated that chronic bronchial infection, mainly from H.influenzae, was associated with more
frequent exacerbations and more symptoms and increased sputum purulence during exacerbations,
compared with patients not infected in a stable state. These results have been confirmed in subsequent
studies using molecular techniques to identify microorganisms such as qPCR (10).
In fact, most patients with severe COPD and chronic bronchial infection have significant bronchiectasis
when studied by high resolution CT (HRCT) scan. In the study by Martinez-Garcia et al. (16), the
isolation of a PPM in the sputum of a patient with stable COPD, together with a FEV1<50% predicted
and a history of at least one hospital admission for an exacerbation in the previous year, were associated
with a 99% probability of presenting bronchiectasis in an HRCT scan.
The relationship between chronic and acute bronchial infection in COPD
The balance between microorganisms and their host may be altered by several factors that determine an
uncontrolled increase in bacterial load and associated inflammation, giving rise to the symptoms of an
exacerbation. This is suggested by the observation that PPMs are more frequently isolated and have
higher loads during exacerbations when compared to the stable state, both in traditional cultures and in
qPCR (7). All these findings, and the fact that the severity of bronchial inflammation is directly
correlated with bacterial load, support the “fall and rise” or quantitative hypothesis of bacterial
exacerbations of COPD (17). According to this hypothesis, symptoms of exacerbation appear when the
inflammatory reaction caused by the increasing bacterial load in the airways exceeds a certain threshold.
Furthermore, findings based on molecular typing of bacterial isolates have demonstrated that the
acquisition of new strains of bacteria or antigenic change in pre-existing strains play a crucial role in
the pathogenesis of bacterial exacerbations, and that a change in the bacterial load, with a subsequent
increase in inflammation, is merely a secondary phenomenon (18). It has been suggested that after a
new strain is acquired, due to the absence of an effective host immune response, bacteria may proliferate
in the airways, resulting in a greater bacterial load, more severe local and systemic inflammation, and
the development of symptoms of exacerbation (18). There is also the possibility that a viral infection
could trigger an increase in bacterial load and a bacterial exacerbation.
Antibiotic therapy for chronic bronchial infection
There are several studies of long-term macrolide therapy in COPD with the objective to prevent
exacerbations. Recently, in a large pivotal study, Albert et al (19) reported the use of 12-month treatment
with daily azithromycin. In this study, the addition of azithromycin to standard therapy was associated
with a 27% decrease in the frequency of exacerbations and an increased in the median time to
exacerbation (266 days vs. 174 days, respectively; p<0.001). In addition, patients treated with
azithromycin showed a significant reduction. In another 12-month retrospective study, azithromycin
was also shown to reduce exacerbations, hospitalizations, and length of hospital stay (20).
The risk of increasing bacterial resistance with long-term use of macrolides is a concern. In view of the
large patient population affected by COPD, widespread use of macrolides, particularly azithromycin,
has the potential to substantially influence antimicrobial resistance rates of a range of respiratory
microorganisms (21). Another concern is the possible superinfection by non-tuberculous mycobacteria
that has been observed in some cases of patients with bronchiectasis treated with macrolides long-term.
There is also the possibility of hearing loss associated with long-term use of macrolides, this effect may
have been related to the high dose used in the study by Albert et al (19) (250 mg/day for one year).
Intermittent, pulsed fluoroquinolone antibiotic therapy in COPD patients was reported by Sethi et al
(22) In this study, moxifloxacin was given once daily for 5 days, and the treatment was repeated every
8 weeks for a total of six courses. Pulsed therapy with moxifloxacin reduced the odds of an exacerbation
by 25% in the primary population for efficacy analysis (per protocol population as pre-specified in the
protocol) in patients with moderate-to-severe COPD, while in a post hoc analysis, this reduction was
45% in patients with purulent or mucopurulent sputum at baseline. As with macrolides, the use of
quinolones has also been associated with a prolonged QTc interval, and the same concerns about the
prolongation of the QTc interval are valid.
The use of prophylactic antibiotics in COPD is a clear example of a decision that has to be made based
on a careful evaluation of a risk-benefit analysis. There is no doubt that antibiotic prophylaxis reduces
exacerbation frequency in selected populations of COPD patients, but it is also clear that long-term use
of antibiotics is associated with potentially serious adverse events and increased risk of bacterial
resistance; therefore, both pros and cons must be evaluated in a case by case indication.
The clinical data suggest that a small population of COPD patients may benefit from the use of longterm antibiotics. The real challenge is to provide this treatment to the right patient and prevent the
excessive use of long-term antibiotics in the community. Most guidelines do not recommend the use of
long-term antibiotics based on a limited benefit and potential harm, but they fail to consider the selected
population in which may benefit (23). The recent Spanish COPD guidelines suggest that long-term
treatment with macrolides can be considered in patients with severe COPD and frequent exacerbations
or hospital admissions, despite optimal pharmacologic and non pharmacologic treatment and always
with an accurate clinical and bacteriological control (24).
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1341-1351.
2. Han MK, Agusti A, Calverley PMA, et al. Chronic obstructive pulmonary disease phenotypes. The
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Agustí A, Antó JM, Monsó E, on behalf of the PAC-COPD study group. Effect of bronchial
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disease. N Engl J Med 2008; 359: 2355-2365.
14. Matkovic Z, Miravitlles M. Chronic bronchial infection in COPD. Is there an infective
phenotype? Respir Med 2013; 107: 10-22.
15. Patel IS, Seemungal TAR, Wilks M, et al. Relationship between bacterial colonisation and the
frequency, character, and severity of COPD exacerbations. Thorax 2002; 57: 759-764.
16. Martinez-Garcia MA, Soler-Cataluna JJ, Donat-Sanz Y, et al. Factors associated with
bronchiectasis in chronic obstructive pulmonary disease patients. Chest 2011; 140: 1130-1137.
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20. Pomares X, Montón C, Espasa M, Casabon J, Monsó E, Gallego M. Long-term azithromycin
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FACULTY DISCLOSURE
Dr Marc Miravitlles has received speaker fees from AstraZeneca, Boehringer Ingelheim, Novartis,
Pfizer, Grifols, Menarini, Gebro and Teva. He has also received consulting fees from AstraZeneca,
Boehringer Ingelheim, GlaxoSmithKline, Novartis, Grifols, Gebro, Teva and Cipla
EVALUATION
1. Which of the following is not correct regarding infection in COPD
a. Bacteria can be found in sputum in up to 50% of patients with exacerbations
b. Viruses are also frequent pathogens in exacerbations of COPD
c. Bacteria and viruses can not be found simultaneously in exacerbated patients
d. Bacterial etiology is associated with a darker colour of sputum
2. Which of the following is not correct regarding macrolide treatment in COPD
a. Macrolides have antibacterial and anti-inflammatory effects in COPD
b. Macrolides can eradicate Pseudomonas aeruginosa en colonized patients with COPD
c. Macrolides may cause hearing problems when used long-term
d. The use of long-term macrolides is associated with increases risk of development of bacterial
resistance
3. Which of the following bacteria is not a common cause of bronchial infection in COPD?
a. Serratia marcescens
b. Pseudomonas aeruginosa
c. Haemphilus influenza
d. Moraxella catarrhalis
4. Which of the following criteria is useful for the identification of exacerbations that require an
antibiotic?
a. FEV1
b. Blood eosinophilia
c. Color or sputum
d. Peak flow
5. Which of the following is not a consequence of the chronic bronchial infection in COPD?
a. Faster decline in FEV1
b. Reduced response to bronchodilators
c. Increased bronchial inflammation
d. Impaired quality of life