Bronchiectasis

Bronchiectasis pathophysiology is heterogeneous, complex and poorly understood. Cole's vicious cycle hypothesis has been central to our understanding of the development and progression of bronchiectasis since the 1980s. This concept allowed us to focus on four different components: inflammation, airway structural damage, impaired mucociliary clearance and infection. Infection is the dominant stimulus for neutrophil recruitment to the airway and is considered to be a major driver of disease progression in bronchiectasis. Although bacterial pathogens are the most clinically important, mycobacteria, viruses and fungi are also identified in stable bronchiectasis, and contribute to disease phenotype and progression. Exacerbations in bronchiectasis are likely to be heterogeneous events with multiple potential causative factors. Dysfunction of cilia and an increase of mucus leaves the respiratory epithelium vulnerable to infection. Ciliary dysfunction can be primary or acquired through inflammation and infection. New technologies including whole-genome sequencing, metagenomics and big data are increasing our ability to cut through the heterogeneity of disease. Significant progress has been made in our understanding of the pathophysiology of bronchiectasis; however, there are many unanswered questions necessitating a renewed effort by the scientific community.

Cite as: Boaventura R, Shoemark A, Chalmers JD. Pathophysiology. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 8–28 [https://doi.org/10.1183/2312508X.10021218].

Comorbidities are common and significant in bronchiectasis, often contributing to symptoms, exacerbations, hospital admissions and mortality. In this chapter, we provide a state-of-the-art summary of key comorbidities observed in bronchiectasis patients in terms of their prevalence, impact, pathophysiology and prognosis. We discuss clinical tools used to quantify comorbidity and predict prognosis in bronchiectasis and outline the implications of multimorbidity in the clinical management of bronchiectasis patients to maximise outcome and reduce the illness burden associated with the disease.

Cite as: McDonnell MJ, Ward C, Rutherford RM. Comorbidities and their impact. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 45–61 [https://doi.org/10.1183/2312508X.10015417].

Non-CF bronchiectasis is characterised by dysregulated immunity and impaired airway clearance. Mucus accumulation results in an increased susceptibility to persistent lung infections by pathogens such as Haemophilus influenzae, Pseudomonas aeruginosa and Aspergillus fumigatus. The presence of these microbes within the lower airways contributes to a “vicious circle” of impaired mucociliary function, bronchial inflammation and progressive lung injury. The importance of pathogen detection as a guide to antimicrobial therapy has led to the use of narrowly focused diagnostic practices. However, extended culture techniques and DNA sequencing technologies have revealed a more diverse airway microbiota, including an abundance of species that are refractory to common diagnostic protocols. Interactions that occur between these microbial species can profoundly affect the expression of pathogenicity and virulence by important airway pathogens, such as P. aeruginosa. This chapter sets out current hypotheses regarding the contribution of the respiratory microbiome to non-CF bronchiectasis, and discusses how the insight gained using emerging analytical technologies can inform clinical care.

Cite as: Rogers GB. The bronchiectasis microbiome. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 82–98 [https://doi.org/10.1183/2312508X.10015617].

Phenotypes refer to observable characteristics in patients that link to meaningful clinical outcomes while endotypes refer to distinct biological mechanisms that may link to clinical phenotype, clinical outcomes or treatment response. Phenotyping and endotyping could be extremely useful in cutting through the heterogeneity of bronchiectasis and leading to personalised treatment. These approaches are at an early stage but this chapter reviews the progress made to date and the potential to implement stratified approaches into clinical practice in future.

Cite as: Chalmers JD. Phenotypes and endotypes. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 133–152 [https://doi.org/10.1183/2312508X.10017118].

The association of COPD and asthma with bronchiectasis is well known but the prevalence of these combinations varies.

COPD and bronchiectasis share common risk factors, clinical features and functional abnormalities. In clinical practice, it is common to identify patients with both COPD and bronchiectasis. In these patients, it can be unclear whether recurrent bronchiectasis exacerbations have led to the obstructive pattern, or whether COPD with frequent exacerbations has led to the development of bronchiectasis. The COPD/bronchiectasis overlap should be identified as a specific phenotype as it requires a different therapeutic approach.

The association between asthma and bronchiectasis is more complex. Bronchiectasis has been detected in severe asthma in ≤40% of patients who experience frequent exacerbations; it usually has a non-eosinophilic inflammatory pattern that is poorly responsive to standard asthma treatment. These patients require a different kind of pharmacological treatment (antibiotic therapy and/or physiotherapy). In patients with bronchiectasis without a history of asthma, some “asthma-like features” may be observed.

The definition of these “bronchietasis phenotypes” has a strong impact on prompt diagnosis and personalised therapy.

Cite as: Dente FL, Roggi MA, Del Cesta R, Polverino E, Paggiaro P. COPD and asthma overlap with bronchiectasis. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 167–185 [https://doi.org/10.1183/2312508X.10016017].

NTM are ubiquitous environmental organisms that have been postulated as a cause of progressive bronchiectasis in their own right and also commonly colonise and infect patients with pre-existing bronchiectasis from other causes. The interplay can be complex pathophysiologically and it is not always clear which came first in the individual patient. Clinicians need to be astutely aware of the primary disease process, how to assess the significance of NTM isolation in sputum of bronchiectasis patients, particularly when co-infection with other organisms is present, understand when and how NTM should be treated, and at the same time, deliver optimal management of the underlying bronchiectasis.

Cite as: Baird TM, Thomson R. Diagnosis, classification and epidemiology of pulmonary nontuberculous mycobacterial disease. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 204–221 [https://doi.org/10.1183/2312508X.10014818].

Bacterial infection is a common cause of bronchiectasis and persistent microbial colonisation is thought to be a central component of the ongoing pathophysiology of the disease. Many bronchiectasis patients also have underlying immune-mediated inflammatory diseases that require treatment with immunosuppressive medications. Examples of these medications include nonbiologic disease-modifying antirheumatic drugs, such as methotrexate or leflunomide, and biologic disease-modifying antirheumatic drugs, such as etanercept or infliximab. These medications are known to place all patients at greater risk of infection, and theoretically can contribute to persistent bacterial colonisation and recurrent pulmonary infections in bronchiectasis patients. Ultimately, this can lead to bronchiectasis progression. With the increasing use of these medications, the safety of their use in patients with bronchiectasis remains a question. In this chapter, we discuss the infection risk of immunosuppressive medications in patients with bronchiectasis, the management of these infections (paying special focus to pulmonary NTM infections) and how to balance the need for continued immunosuppression with further infection risk.

Cite as: Ranches GP, Winthrop KL. Nontuberculous mycobacteria infections in patients receiving immunosuppressive agents. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 238–253 [https://doi.org/10.1183/2312508X.10016417].

PCD is a genetically and clinically heterogeneous condition. It is characterised by inherited abnormality of motile ciliary function. Symptoms include recurrent upper and lower respiratory tract infections from an early age, usually resulting in bronchiectasis as an adult. Approximately 50% of people with PCD have situs inversus. Diagnosis of PCD is complex and requires a multi-test approach since no test has complete sensitivity or specificity. This chapter describes the central aspects of PCD diagnosis, based on evidence from the 2017 European Respiratory Society guidelines. Diagnostic investigations include measurement of nasal nitric oxide, genetic testing and sampling the nasal epithelium to conduct microscopic analysis of cilia. Laboratory microscopy investigations include ciliary beat frequency and pattern by high-speed video microscopy, ciliary protein expression by immunofluorescence, and ciliary ultrastructure by transmission electron microscopy. A diagnosis is confirmed by the presence of a hallmark defect of ciliary ultrastructure observed by electron microscopy or bi-allelic pathogenic mutations in a known PCD gene.

Cite as: Shoemark A, Lucas JS. Diagnosis of primary ciliary dyskinesia: current practice and future perspectives. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 267–281 [https://doi.org/10.1183/2312508X.10016617].

Pulmonary exacerbations are key events in the natural history of bronchiectasis, and determinants of mortality and healthcare costs. Recent literature shows that “frequent exacerbator” is a valid clinical phenotype, with more frequent hospitalisations, impaired quality of life and increased 5-year mortality. As a consequence, exacerbation rate and time to first exacerbation are fundamental end-points in clinical research and targets for therapy. Society recommendations have, to some degree, addressed the clinical management of frequently exacerbating patients. After improvement of any treatable underlying causes and optimisation of airway clearance, long-term inhaled antibiotics are suggested for patients with chronic Pseudomonas aeruginosa respiratory infection. Depending on whether lack of efficacy or intolerance occurs, second-line treatment is represented by an add-on or switch to long-term macrolide therapy. On the contrary, macrolides represent first-line treatment in frequent exacerbators without chronic P. aeruginosa infection. However, most of these approaches lack strong evidence from RCTs in a large target population and multiple factors in patients with recurrent exacerbations should be considered in clinical management.

Cite as: Gramegna A, Di Pasquale M, Blasi F. Management of frequently exacerbating patients. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 300–311 [https://doi.org/10.1183/2312508X.10015218].

People with bronchiectasis are characterised by a combination of an impaired mucociliary clearance system with functional limitation and lower physical activity levels; hence, physiotherapy interventions should be a priority strategy for the management of this population. ACTs used regularly reduce the respiratory symptoms related to cough and, therefore, improve health-related quality of life (HRQoL). Short-term clinical benefits in people with bronchiectasis are observed for functional exercise capacity, symptoms and HRQoL after completing a pulmonary rehabilitation programme, but these improvements are not maintained long term. Consequently, interventions to increase physical activity and reduce sedentary time may be incorporated in pulmonary rehabilitation programmes and in the overall management of people with bronchiectasis. Furthermore, strategies to promote behavioural change and adherence are needed to ensure successful implementation of these interventions in clinical practice. Further research is needed to explore the effects of physiotherapy interventions during an acute exacerbation and continued beyond discharge, and their impact on disease severity.

Cite as: Herrero-Cortina B, Lee AL, O'Neill B, et al. Airway clearance techniques, pulmonary rehabilitation and physical activity. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 331–352 [https://doi.org/10.1183/2312508X.10017017].

A palpable recognition of the growing global importance of bronchiectasis is evident. This is paralleled by increases in the quantity and quality of research in the field. To ensure we make progress, continue on an upward trajectory and draft a realistic roadmap for bronchiectasis research over the next decade, it is imperative to learn from past works and fully understand the current research state. Most research performed to date is clinical and a need exists to go back to basics and establish strong platforms for basic science and translational studies focused on understanding pathophysiological mechanisms that drive disease onset and progression. Such approaches will allow attempts at resolution of the unresolved heterogeneity that persists in disease which has negatively influenced many clinical trial outcomes. Elucidating specific disease endo-phenotypes, clarifying ethno-geographic variation and building upon the strong clinical foundations already set for this devastating disease should all be key priorities over the coming decade of bronchiectasis research.

Cite as: Chotirmall SH. Future directions: the next 10 years in research. In: Chalmers JD, Polverino E, Aliberti S, eds. Bronchiectasis (ERS Monograph). Sheffield, European Respiratory Society, 2018; pp. 371–387 [https://doi.org/10.1183/2312508X.10017217].