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A brief incursion into bronchiectasis – COPD overlap literature

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Ancuța Alina Constantin1,2, Anca Macri1, Florin Dumitru Mihălțan

Abstract: 

Bronchiectasis and COPD, two chronic respiratory diseases, share common features but also present many differences, the pattern of this association evoking different scientific assumptions. Although with a similar inflammatory profile, frequently adopting the same clinical course and functional abnormalities, their diagnosis, treatment, and evolution have differentiated them. Originally neglected, this association gave rise to a great deal of interest given the fact that over the last decade, the similarity between them was more than just a matter of chance. Researchers approaching these subjects tried to establish a connection between them in order to discover a therapeutic condition that addresses both of them. The development of new technologies and working techniques allowed improved results, but further studies are needed to complete this task.

 

Keywords: 
BCOS, bronchiectasis, COPD, overlap syndrome

Introduction

Bronchiectasis (BE) and chronic obstructive pulmo-nary disease (COPD) are highly prevalent inflammatory airway diseases, which raised interest both separately and taken together. Although mentioned for the first time by Barker in 2002(1), the overlap of these two condi-tions was a neglected area of research, not covered by guidelines for clinical practice.

The relationship between COPD and bronchiectasis has been particularly discussed in recent years because, although it is accepted that bronchiectasis have become more prevalent in patients with COPD, there are still very few reports on the consequences of this association or the existence of any pos-sible causal relationship between the two diseases(2).

The aim of this article is to review the available litera-ture on the different types of relationships between the two diseases and the impact of this relationship, also bringing into discussion the therapeutic considerations and the future challenges of this subject.

Definitions

Bronchiectasis (from the Greek “bronkhos”, meaning wind pipe or latterly bronchial tubes, and “ektasis”, meaning stretching out or extension) is a structural diag-nosis, with airway dilatation and airway wall thickening on CT scan, defined by imaging abnormalities (Figure 1a), associated with symptoms of persistent or recurrent bronchial infection(3,4).

COPD is a functional definition diagnosed on the basis of poorly reversible airflow obstruction, defined when an objective measure of airflow obstruction is associated with an abnormal inflammatory response of the lung to noxious stimuli, (cigarette smoke being the most common exposure in the developed world), associating or not air-way wall changes on CT scan (Figure 1b). Furthermore, both diseases share a similar neutrophilic inflammatory profile, as well as many clinical and functional character-istics, from common symptoms of cough with sputum production to susceptibility to recurrent exacerbations driven by new or persistent infections(2,4).

Moreover, the physiological criteria for the diagnosis of COPD and the structural criteria for the diagnosis of bronchiectasis create the possibility for individual patients to fulfill both of them, resulting conceptually in either co-diagnosis or an overlap syndrome between the two conditions – BCOS(4).

Epidemiology

Accurately estimating the incidence and prevalence of bronchiectasis proved to be challenging. As common structural endpoint of a number of disease processes, it is often not reported separately from the more severe or primary pathology(5).

It is now estimated that we are witnessing an increase in the number of cases of bronchiectasis, possibly due to factors such as the progressively increasing longevity of the population, the chronic nature of the diseases that cause bronchiectasis and, above all, the huge improvement in image-based diagnosis brought about by the routine use of chest HRCT. The real prevalence of bronchiectasis is still unknown, although some recent data highlighted on its epidemiological impact: the number of diagnoses has quadrupled in the last two decades and its epidemio-logical pattern has changed, with the elderly being most affected and an increasing number of hospitalisations and mortalities in recent years. Earlier mortality is also evi-dent, along with a reduced pulmonary function, a poorer quality of life and significant health costs(2).

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Chronic obstructive pulmonary disease (COPD) rep-resents a major public health problem that in the latest Global Burden of Disease report has risen to the third most frequent cause of death worldwide(6).

Based on current trajectories, by 2030 COPD, esti-mated by World Health Organization (WHO) at about 5% of all deaths worldwide, will still be the third leading cause of death globally, a rank already reported in the United States and Southeast Asia. Interestingly, COPD incidence remains the highest in Asia, three times more prevalent when compared to other continents(1).

The prevalence of this overlap will vary depending on the respective prevalence of COPD and bronchiectasis in the population under consideration(4).

The subject raises a real interest and a preoccupation at a global level, due to its increasing prevalence and, at the same time, a unitary effort of international health systems, through the working groups The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) and European Respiratory Society (ERS) Clinical Research Collaboration, funded by ERS to promote high-quality research in bronchiectasis.

Pathophysiology

In an attempt to explain a possible causal relation-ship between COPD and bronchiectasis from a patho-physiological point of view, three different potential scenarios can be identified: 1) COPD leads to the devel-opment of bronchiectasis through a variation of the classic “vicious cycle” hypothesis of airway inflammation and repeated infections; 2) bronchiectasis caused by other etiologies in a non-smoker leads to a fixed airway

obstruction and, thus, leads to the diagnosis of COPD;3) COPD and bronchiectasis are two independent dis-eases that may coexist in the same patient(6).

Years ago, Cole proposed the hypothesis of a patho-genic vicious circle originating from chronic bronchial infection caused by potentially pathogenic microorgan-isms (PPMs) and the consequent chronic inflammation resulting in remodeling of the airways and damage to the local defense mechanisms, which in turn facilitate the persistence of PPMs in the bronchial tree despite treatment. Chronic bronchial infection is also frequently found in patients with COPD and would provide a link between the two diseases(7).

This pathophysiological hypothesis could explain a possible causal relationship between COPD and bron-chiectasis but, somehow, after all, the discussion wheth-er bronchiectasis in COPD is a cause or a consequence remains, however, unanswered.

An overall view…

The possible relationship between these two entities raised a real interest among researchers, being the aim of different profile studies and approaches, and it seems to require several research directions in an attempt to establish a causal relationship: endotype, phenotype or comorbidity.

Reviewing the article of Franceso Blasi et al.(6), “COPD and Bronchiectasis: Phenotype, Endotype or Comorbidiy?”, from Journal of Chronic Obstructive Pulmonary Disease, we conclude that bronchiectasis are common in COPD, being associated with more severe clinical disease, sustaining phenotype, also neutrophilic inflammation and persistent bacterial infection that advocate the endotype and eventu-ally may be caused by COPD, but must exclude other eti-ologies or comorbidities.

Starting from the idea that early detection of bron-chiectasis among patients with COPD could lead to a better disease management and, in the long run, better survival, several studies were undertaken, attempting to establish the prevalence this way. The results obtained in these studies are conflicting, ranging from 4% to 72%(7). The lowest percentaje was revealed by the ECLIPSE study, which aimed to identify predictive mark-ers in COPD patients. In Spain, an examination of patients with moderate to severe COPD showed that 57.6% had bronchiectasis, while in Turkey, researchers reported 33 percent. Two Chinese studies found that 34.7% and, respectively, 45.8% of patients with stable COPD also had bronchiectasis(8), and we can get more information from Miguel Martinez Garcia et al. study(2), who collected data from 17 studies from 2000 to 2017, also identifying the differences between the variables used in each study (Table 1).

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In june 2017, Diaz et al.(9) published in Chest Journal a key observation which will modify in the current views(3). In a study analyzing 21 smokers with a radiological diag-nosis of bronchiectasis, including 17 subjects with COPD and 21 never-smoking control subjects, he used quantita-tive CT scanning to objectively measure airway and vas-cular size and associated features. His findings reveal that in bronchiectasis diagnosed smokers, the bronchial/arte-rial ratio is increased by the decreased artery diameter. Oxygen saturations correlated with the diameters of the bronchial arteries, which led the authors to speculate that the reduced size of the vessel may indicate hypoxic vaso-constriction(3). Subjects with “bronchiectasis” did not have major increases in bronchial diameter compared with healthy subjects at the same level, but had smaller blood vessels, giving the “artificial” appearance of bronchiecta-sis (Table 2, Table 3).

Relying on Diaz’s study and on the fundamental idea that the radiographic diagnosis of bronchiectasis is defined by the diameter of the bronchus smaller than of the adjacent vessel, and therefore a bronchial/arterial (BA)>1 ratio indicates radiological bronchiectasis, James Chalmers(3) assumed that many of the aforementioned studies showed a high prevalence of bronchiectasis in COPD, missing the fact that a high percentage of these are not clinically significant.

To strengthen this idea, we also mention the study of Tan et al.(10), who found the presence of bronchiectasis in 19.9% of the healthy population versus 35.1% in patients diagnosed with severe COPD using the same age segment(3).

These studies indicate that the prevalence of bron-chiectasis in patients with COPD is overestimated and requires deeper studies to make use of other imaging features to differentiate between true bronchiectasis associated with COPD, bronchiectasis caused by aging or the altered BA ratio due to vasoconstriction.

Finally, the question arises, that many patients with COPD overlap bronchiectasis syndrome might be mis-diagnosed, also highlighting the need for extensive studies, the clinical implications being substantial.

Microbiological aspects

Another important aspect analyzed in most studies published on this topic is about airway microbiome. Special attention should be given to the colonization or chronic bronchial infection by Pseudomonas aeruginosa in COPD and bronchiectasis patients. In his study “The Overlap with bronchiectasis”(2), published in ERS Monograph in 2015, Martinez stressed that, although its significance may be uncertain in patients with COPD without bronchiectasis (even if the literature increas-ingly points towards a worsened prognosis), in patients with bronchiectasis (with or without COPD) its presence definitely results in a poorer prognosis.

In patients diagnosed with COPD, the colonization with P. aeruginosa was associated with various factors, such as a greater number and severity of exacerbations, greater airflow obstruction, recent hospitalisations, a more severe state according to the BODE index, a need for mechanical ventilation, frequent intake of antibiotics and consumption of steroids in the months prior to its isolation and greater extension of the bronchiectasis.

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In patients with bronchiectasis, chronic bronchial infection with P. aeruginosa is a sign of worse prognosis, associated with an accelerated functional decline, poor quality of life, a greater number of affected lung lobes, frequent exacerbations and increased severity and mortality(2).

The variable most consistently associated with the presence of bronchiectasis in patients with COPD is chronic bronchial infection by PPMs, particularly Pseudomonas aeruginosa, along with the existence of a greater bacterial load(7).

Another possibility to consider is the non-tuberculous mycobacterial infection (NTM). In a case study(11), Andrejak reported that COPD increased the risk of NTM infection by 16-fold, and with an increase of 29 times in the presence of COPD and inhaled corticosteroid therapy. This problem’s importance lies in the fact that a growing number of patients receive a macrolide long-term treat-ment, and therefore have the potential to induce mac-rolide resistance in TNM(3).

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Regarding the variety of the microbioma present in the association of these two diseases, COPD and bronchiectasis, Martinez and colleagues(12) performed a study that high-lighted the main PPMs isolated in COPD with and without bronchiectasis (Figure 3). In this prospective study, in a group of 92 patients diagnosed with moderate (50%<FEV1≤70%) to severe (FEV1≤50%) COPD, who underwent a HRCT, the presence of bronchiectasis was identified in 53 patients. Monthly microbiological analysis of spontaneous sputum was required from each patient within 6 months subsequent to the inclusion in the study, isolated bacterial agents being classified in PPM strains, such as Haemophilus influenzae,

Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus parainfluenzae, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae and other Gram-negative strains. The presence of a single PPM in at least three different monthly sputum samples without concomitant antibiotic treatment was considered chronic colonization. The authors conclude that the presence of PPM positive culture in at least one sputum sample is a factor associated with the presence of bronchiectasis in patients with COPD, which is consistent with the reports of Patel et al.(13) and Cole et al(14).

Therapeutic management

There is no consensus about the management strategies for COPD coexistent with bronchiectasis(15,16). It is impor-tant to assess whether COPD or bronchiectasis is the pri-mary diagnosis in order to guide investigative strategy and treatment. In those patients, where this is not possible, investigating both conditions may be necessary(4).

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The treatments used in COPD may not be appropriate for bronchiectasis and viceversa. The use of inhaled corticosteroids in bronchiectasis is controversial, but they are widely used in COPD. GOLD strategy suggested that treatment of bronchiectasis in patients with COPD should be according to conventional lines for bronchi-ectasis with the addition of usual COPD strategies where indicated(15).

The primary goal of the bronchiectasis treatment is to suppress bacterial airway infection (e.g., P. aeruginosa), using inhaled antibiotic or anti-inflammatory and anti-microbial treatments such as long-term treatment with macrolides, but we need to be careful about the potential macrolide resistance in NTM if used inappropriately(3). At the same time, the use of macrolides raise questions about both antimicrobial resistance and potential side effects, so they may not be suitable for all patients with COPD, but they may be reserved for the subgroup of patients associating bronchiectasis. Treatment options targeted at COPD, including inhaled corticosteroids and bronchodila-tors, may be indicated in BCOS, particularly if patients frequently exacerbate.

In conclusion, therapeutic implications, such as the apparently poorer response to inhaled corticosteroids, are complex and unclear, and the role of long-term and inhaled antibiotics in BCOS is still debated.

Conclusions

We can conclude from this review that the prevalence of the association between these two conditions is extreme-ly various and largely depends on a wide range of variables, such as demographic criteria and patient inclusion criteria in these studies.

What is clear from most studies is that the simultaneity of these diseases is a high-risk factor for mortality, often involving frequent and severe exacerbations, a higher number of long-term hospitalizations, and impaired quality of life. Reviewing the various studies from literature, the major con-clusion is that COPD-related bronchiectasis is a true clinical entity with real implications for the clincal course of COPD.

Understanding the etiology and pathogenesis of bron-chiectasis in COPD in order to discover prevention and treatment strategies requires further studies and a contin-ued consistency of researchers on this topic.

 

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