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Defining severity in non-cystic fibrosis bronchiectasis Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Korea University on 01/11/15 For personal use only.

Expert Rev. Respir. Med. 8(2), 249–262 (2014)

Lucy Poppelwell and James D Chalmers* Tayside Respiratory Research Group, University of Dundee, Dundee, DD1 9SY UK *Author for correspondence: Tel.: +44 0138 2386 339 [email protected]

Bronchiectasis is a common disease with important impacts on patient’s quality of life and on healthcare systems in terms of healthcare costs, hospitalisations and mortality. After decades of being regarded as an orphan disease there are an increasing numbers of treatments available, or in late-stage clinical trials. Assessment of disease severity is fundamental to clinical management. To date, however, there is no agreed definition of what constitutes mild, moderate or severe bronchiectasis. These terms are often applied to radiological appearances, but while important, computed tomography findings are not sufficiently precise to capture the complex impact of the disease. Studies are beginning to define the risk factors for mortality, hospital admissions, exacerbations and impaired quality of life in bronchiectasis, allowing us to propose new definitions of what constitutes severe bronchiectasis. An improved understanding of severity and prognosis in this disease will aid clinical decision making and the application of new therapies. KEYWORDS: bacteria • bronchiectasis • exacerbations • infection • mortality • neutrophil • prognosis • severity

Non-cystic fibrosis (CF) bronchiectasis (hereafter simply referred to as bronchiectasis) is defined radiologically as irreversible dilatation of the bronchi, often associated with inflammation and thickening of the bronchial walls. Clinically, the syndrome of bronchiectasis presents with cough, chronic sputum production and recurrent respiratory infections [1]. The pathophysiology of bronchiectasis is currently understood in terms of the vicious cycle hypothesis [2]. As originally proposed by Cole, this suggests that impaired mucociliary clearance of secretions leads to colonization of the airway with bacteria [2]. This leads to neutrophil-dominated airway inflammation and further structural damage to the bronchial tree leading to a vicious cycle of recurrent infections, progressing loss of lung function and exacerbations of bronchiectasis [3]. This vicious cycle hypothesis is shown in FIGURE 1. This vicious cycle can also be useful ‘aid memoir’ for the underlying causes of bronchiectasis, also shown in FIGURE 1, although it is the authors’ view that this probably represents a gross-oversimplification of the pathophysiology of many of these conditions. Once regarded as an orphan disease, bronchiectasis is a relatively common disease, estimated to effect 1 in 1000 people in the UK [4]. informahealthcare.com

10.1586/17476348.2014.896204

Although some patients are often described as having mild, moderate or severe bronchiectasis, there is no generally accepted definition of these terms. As the disease is increasingly recognized and more treatments become available, there is a need to identify patients at risk of long-term morbidity and complications and a need to define what we mean by severity in the context of bronchiectasis. This article explores current data about the predictors of outcome in bronchiectasis and the importance of developing disease stratification systems or tools to guide management in bronchiectasis. Why is there a need to define severity in bronchiectasis?

Most respiratory diseases, and indeed most common diseases, use a stratified approach to management. In chronic obstructive pulmonary disease (COPD), the Global Initiative for Chronic Obstructive Lung Disease classification system allows stratification of disease severity on the basis of lung function, although this has now been updated to a multidimensional scoring system incorporating symptoms and exacerbations alongside forced expiratory volume in 1 s (FEV1) [5]. This classification system is used to guide treatment because clinical trials have demonstrated the benefit of

 2014 Informa UK Ltd

ISSN 1747-6348

249

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Poppelwell & Chalmers

Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Korea University on 01/11/15 For personal use only.

Primary ciliary dyskinesia Congenital airway structural abnormality (e.g. WilliamsCampbell syndrome, MounierKuhn syndrome) Foreign body

Airway structural abnormalities/ damage

Infection

Pneumonia Mycobacterium tuberculosis Atypical Mycobacterium Viruses (pertussis, measles, adenovirus) Immunodeficiency

Airway inflammation

Connective tissue disease Allergic bronchopulmonary aspergillosis Inflammatory bowel disease

Figure 1. The vicious cycle hypothesis of bronchiectasis with the associated underlying causes.

inhaled corticosteroids in patients with FEV1 less than 60% predicted [6]. Treatment decisions, including pharmacotherapy, are based on formal and objective assessments of exacerbation risk, lung function and symptoms, using either the St Georges Respiratory Questionnaire or the COPD assessment test [5]. In asthma, national and international guidelines recommend a stepwise approach to therapy, with new therapies added, if there is a failure to control symptoms on existing treatment [7]. In community-acquired pneumonia, multiple severity assessment scoring systems have been developed to guide several aspects of management [8]. The British Thoracic Society (BTS) recommend using the CURB65 (Confusion, Urea, Respiratory rate, Blood pressure and age 65 years) score to determine whether patients require admission to hospital and to determine the choice of empirical antibiotic treatment [9]. Implementation of similar scoring systems has been shown to improve patient outcome in terms of increasing safe discharges from hospital or improving empirical antibiotic prescribing [9,10]. Similarly, stratifying severity of disease in idiopathic pulmonary fibrosis can be achieved through scoring, and the requirement for treatment can be assessed in terms of severity of lung function impairment (total lung capacity [TLC]) and carbon monoxide diffusing capacity) or the decline in lung function variables over time, because these correlate with prognosis [11]. Therefore, nearly all common respiratory disorders practice, to a greater or lesser extent, a stratified approach to treatment and recommend an assessment of future risk as part of planning future management. Similar principles apply in bronchiectasis but without any guidelines recommendations on how to objectively classify severity. Effective management requires an understanding of prognosis. As a wide range of therapies including long-term antibiotics, physiotherapy adjuncts, anti-inflammatory treatments 250

and bronchodilators become available, identifying which patients are most likely to benefit becomes critical. Defining severity in bronchiectasis: what clinical parameters predict outcome?

Key end points that have been used to define severity in bronchiectasis include mortality, hospital admissions, exacerbation frequency, symptoms, quality of life (QoL) and lung function decline. There are limited data available for most of these end points. The data regarding predictors of these end points are discussed below. Mortality

Until recently, there were very few studies describing the underlying causes of death and the predictors of mortality in bronchiectasis. It has been suggested in the past that bronchiectasis is a relatively benign disease in many cases with little direct mortality, but recent data have clearly disproved this assertion. To date, perhaps the most comprehensive data published describing risk factors for mortality are from the Royal Brompton Hospital group [12]. Loebinger et al. followed up a cohort of patients originally enrolled in 1994 for a study validating the St George’s respiratory questionnaire (SGRQ) in bronchiectasis [12]. Using the subsequent 14 years follow-up data, the authors were able to describe the impact of bronchiectasis on mortality in great detail: 29.7% of patients died during follow-up, a significant finding in itself as this is more than double the expected mortality based on UK life expectancy data, suggesting that bronchiectasis, when severe, shortens life; 70.4% of patients died from respiratory causes, again indicating that bronchiectasis is fatal in a proportion of patients. In a multivariable analysis, the strongest predictors of mortality in this group were increasing age, the presence of Pseudomonas aeruginosa colonization, male gender, residual volume/TLC Expert Rev. Respir. Med. 8(2), (2014)

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Defining severity in non-cystic fibrosis bronchiectasis

ratio, TLC itself and KCO. In addition, the baseline score in the activities domain of the SGRQ was also independently associated with mortality [12]. Interestingly, although this study utilized the Bhalla scoring system for looking at radiological severity of disease, no independent association of radiological features with mortality was observed [13]. In the unadjusted analysis, bronchial wall thickening, mosaicism and emphysema appeared to be the best predictors of mortality, which is an interesting finding as recent studies have focused primarily on the extent of disease and the degree of bronchial dilatation [14]. Onen et al. reported data from 98 patients with bronchiectasis, with 16 deaths, and found age, body mass index and severity of dyspnea to be the strongest predictors of mortality [15]. Greater degrees of hypoxia and hypercapnia were also reported to be associated with mortality. There was also a very strong relationship between cystic bronchial dilatation and mortality with 14 out of 16 deaths having cystic changes, compared with 32/82 survivors. All 16 deaths were reported to be secondary to bronchiectasis [15]. More recent data confirm that a significant proportion of deaths are directly related to bronchiectasis, with 32/62 deaths over 4 years being directly related to bronchiectasis in our longitudinal study of bronchiectasis patients (n = 608) in the UK [16]. A recent Spanish study by Martinez-Garcia et al., which will be discussed in more detail in the section ‘Scoring systems specific for non-CF bronchiectasis’, identified independent predictors of mortality to be FEV1, increasing age, three or more lobes involved on CT scan, the Medical Research Council (MRC) Dyspnea score and P. aeruginosa colonization [17]. This study also confirmed that an important proportion of deaths is related to bronchiectasis, with 42.9% of deaths in this large cohort being due to respiratory causes [17]. Patients with COPD-associated bronchiectasis appear to be at a significantly increased risk of death compared with patients with bronchiectasis without COPD [18]. The most recent study to demonstrate this was a longitudinal analysis from Goeminne et al. This analysis included 568 patients followedup in a specialist bronchiectasis clinic in Belgium over a period of 76 months. In this study, 56% of deaths were due to respiratory disease and the strongest risk factor for death was bronchiectasis associated with COPD [19,20]. Interestingly, the bacteria most associated with increased death in this study were the Gram-negative pathogen Escherichia coli, along with Aspergillus, but mortality was also higher in those growing P. aeruginosa. Lower FEV1 and forced vital capacity (FVC) and the presence of pulmonary hypertension were also clear risk factors [19,20]. Therefore, we have a much clearer picture of the factors associated with mortality in patients with bronchiectasis, but much larger registries with detailed clinical phenotyping and long-term follow-up are needed. Hospital admissions

Both the US and European data suggest an increase in hospitalization rates for bronchiectasis, an effect that is likely to be informahealthcare.com

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related to increased recognition of the disease [21,22]. In a large German database of 61,838 patients, the rate of hospital admissions was reported at 9.4 per 100,000. The risk of hospitalization increased with age, peaking in men aged 75–84 years [22]. Predictors of hospital admissions for bronchiectasis have not been extensively described. In the large German database study by Ringshausen et al., patients with COPD accounted for 39.2% of hospital admissions, mirroring the data for mortality that suggests a greater healthcare burden for COPD-associated bronchiectasis compared with bronchiectasis without COPD [18–22]. Roberts et al. reported in a retrospective study from New Zealand and found that hospital admissions were correlated with the Bhalla score [23]. Apart from these studies, there are little data available on the predictors of hospital admissions in bronchiectasis. Exacerbations

Exacerbations are an important outcome in bronchiectasis and thus far have been regarded as the key outcome in clinical trials. Exacerbations are a major driver of healthcare costs associated with bronchiectasis [24], as well as impact on patients’ QoL and possibly their long-term outcome [25,26]. They are not, however, a universal finding. In the largest tertiary referral center cohort to be reported thus far, the Bronchiectasis Research Registry in the USA reported 29% of patients had no exacerbations in the year prior to enrolment [27]. In contrast, some patients have multiple exacerbations per year despite treatment. Identification of a frequent exacerbator phenotype, as has been described in COPD [28], has not been described in bronchiectasis, although clinical experience suggests these patients do exist. Further research to identify patients at risk of exacerbations, and mechanistic work to determine what actually triggers exacerbations (including the role of bacteria load, acquisition of new bacterial strains and viral infections) is urgently needed. Health-related QoL & symptoms

The most widely used method for assessing health-related QoL in bronchiectasis has been the SGRQ [29]. Validated by Wilson and colleagues for use in bronchiectasis, the total score of this questionnaire correlates well with other markers of disease activity such as exacerbation frequency, radiological extent, breathlessness using the MRC dyspnea score and FEV1 [29]. Investigating determinants of quality-of-life impairment, the SGRQ score was shown to be most closely correlated with chronic sputum production, dyspnea and FEV1, although this analysis has some limitations and these predictors only explained 55% of the SGRQ variability [26]. A disease-specific QoL instrument for bronchiectasis, QoL-B, has recently been developed and data regarding this are awaited with interest [30]. Cough is clearly a prominent and in some cases disabling symptom for patients. The Leicester cough questionnaire (LCQ) is a well-validated and accepted symptom questionnaire for patients with chronic cough and has been validated in bronchiectasis [31,32]. The severity of cough measured by the LCQ correlated with the presence of cystic or varicose 251

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Table 1. Modifiers of disease severity in bronchiectasis. Clinical parameters

Features of mild bronchiectasis or good prognosis

Features of severe bronchiectasis or poor prognosis

Bacteriology

No pathogens Haemophilus influenzae colonization

Pseudomonas aeruginosa MRSA Enteric Gram-negative pathogens Higher bacterial load

Radiology

3 lobes involved Cystic dilatation Bronchial wall thickening Large airway plugging Mosaicism Emphysema

Pulmonary function tests

Normal spirometry

Airflow obstruction Restriction Increased RV/TLC ratio Reduced KCO

Exercise capacity/dyspnea

No dyspnea

MRC dyspnea score 4/5

Symptoms

25 ml/day sputum Purulent sputum when stable Severe cough

Etiology

No co-morbidities

COPD-associated bronchiectasis Rheumatoid arthritis-associated bronchiectasis

Exacerbations

18.5

>80%

No

0–2

1–3

Not colonized

Defining severity in non-cystic fibrosis bronchiectasis.

Bronchiectasis is a common disease with important impacts on patient's quality of life and on healthcare systems in terms of healthcare costs, hospita...
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