Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity

doi:10.1016/S0140-6736(18)31767-7

The Lancet

Volume 392, Issue 10150, 8–14 September 2018, Pages 880-890

https://doi.org/10.1016/S0140-6736(18)31767-7 Get rights and content

Summary

Bronchiectasis is characterised by pathological dilation of the airways. More specifically, the radiographic demonstration of airway enlargement is the common feature of a heterogeneous set of conditions and clinical presentations. No approved therapies exist for the condition other than for bronchiectasis caused by cystic fibrosis. The heterogeneity of bronchiectasis is a major challenge in clinical practice and the main reason for difficulty in achieving endpoints in clinical trials. Recent observations of the past 2 years have improved the understanding of physicians regarding bronchiectasis, and have indicated that it might be more effective to classify patients in a different way. Patients could be categorised according to a heterogeneous group of endotypes (defined by a distinct functional or pathobiological mechanism) or by clinical phenotypes (defined by relevant and common features of the disease). In doing so, more specific therapies needed to effectively treat patients might finally be developed. Here, we describe some of the recent advances in endotyping, genetics, and disease heterogeneity of bronchiectasis including observations related to the microbiome.

Introduction

Bronchiectasis is defined as permanent enlargement of the airways,¹ and is mostly the result of an intrinsic airway pathology resulting in dilation. Multiple causes of bronchiectasis and a broad array of clinical presentations exist.² The extent of bronchiectasis can range from focal disease (limited to one segment or lobe) to diffuse disease (involving both lungs and all lobes). Bronchiectatic findings range from subtle dilation to cystic changes in the airways. Some patients will be asymptomatic and the bronchiectasis is discovered unexpectedly, whereas others will have daily symptoms of cough and sputum production with periodic exacerbations.³ The diagnosis of bronchiectasis is increasing worldwide. Previously classified as a rare or orphan disease, bronchiectasis has now been reported at rates of up to 566 per 100 000 population with an incidence that has increased by 40% in the past 10 years.⁴

Despite having its own diagnostic code, there are no medications or therapies approved by regulatory authorities in the USA or Europe for most cases of bronchiectasis. The exception is bronchiectasis due to cystic fibrosis, for which several approved medications exist, but none are approved as treatments for bronchiectasis of other causes.⁵ However, guidelines that recommend treatments for bronchiectasis are available,⁵ and reports have shown that some therapies are associated with clinical benefit,6, 7 suggesting that we need to improve our ability to identify those patients with bronchiectasis.8, 9 The pathway to more precise treatment will require a better understanding of patients beyond imaging studies. Here, we review recent studies, particularly focusing on the past 2 years, that have attempted to better describe patients according to a heterogeneous group of endotypes (defined by a distinct functional or pathobiological mechanism¹⁰) or clinical phenotypes (defined by relevant and common features of the disease¹¹).

Section snippets

Pathophysiology of disease

The list of conditions known to cause or be associated with bronchiectasis is long, but most have common features that lead to the remodelling and dilation of the airways. A useful pathophysiological pathway has described the process as a cycle of events promoting impaired mucociliary clearance and retention of airway secretions. These events disrupt the host's defences and render the airways more susceptible to establishment of chronic infection. The persistence of bacterial pathogens incites

Endotypes and genotypes

Although most patients will be diagnosed with idio-pathic bronchiectasis, indicating that the cause could not be found following testing, reviewing conditions with well known, genetics-based pathways offers insights into understanding the underlying mechanisms of bronchiectasis pathogenesis. These insights can aid in the development of specific treatment regimens. However, the interactions between genetics, endotypes, environment, and therapeutic interventions can vary. In asthma, for example,

Disease heterogeneity beyond causes: clinical phenotypes

Assessing patients with bronchiectasis requires knowledge of the heterogeneity of clinical presentation and variable clinical course. Patients with apparently mild symptoms at presentation could still have adverse prognostic factors and have rapid progression of disease, whereas others with seemingly severe symptoms at the outset might be easily managed and have a good prognosis.⁵³ A multidimensional approach to patient assessment should incorporate clinical history, physical examination,

Microbiology and the microbiome

Chronic bacterial infection is a characteristic in many patients with bronchiectasis. The term chronic infection is preferred to colonisation because colonisation implies a benign process whereas chronic infection is more reflective of the long-term interaction between microorganisms and the host leading to progressive tissue damage. Sputum culture remains an important part of management because the presence of some organisms has prognostic implications. This information can help guide

Conclusion

Ultimately, clinical variables can only provide modest predictive accuracy for bronchiectasis outcomes and provide little information about the underlying biology of the disease. Recent progress in understanding genotypes and endotypes, the process of defining groups of patients by pathobiology often with use of biomarkers, is at an early stage in bronchiectasis but offers promising approaches to develop therapeutic interventions for some patients with bronchiectasis. Hopefully, in the near

Search strategy and selection criteria

We searched PubMed using the search terms ”bronchiectasis”, ”endotype”, ”genotype”, ”microbiome”, and ”heterogeneity”. We focused on papers and reviews published from Jan 1, 2010 to March 1, 2018 in English. We also searched author names of key people in the bronchiectasis field. From key papers, we reviewed reference lists to find additional pertinent papers and to redefine search terms. For the concept of endotyping, we searched this term in combination with other major pulmonary diseases

References (89)

GP Anderson
Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease
Lancet
(2008)
JA Driscoll et al.
Autosomal dominant polycystic kidney disease is associated with an increased prevalence of radiographic bronchiectasis
Chest
(2008)
MJ Welsh et al.
Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis
Cell
(1993)
SI Sheikh et al.
Computed tomography correlates with improvement with ivacaftor in cystic fibrosis patients with G551D mutation
J Cyst Fibros
(2015)
A Horani et al.
Genetics and biology of primary ciliary dyskinesia
Paediatr Respir Rev
(2016)
RH Buckley
Pulmonary complications of primary immunodeficiencies
Paediatr Respir Rev
(2004)
A Broides et al.
Genotype/phenotype correlations in X-linked agammaglobulinemia
Clin Immunol
(2006)
TI Coulter et al.
Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study
J Allergy Clin Immunol
(2017)
JM Reich et al.
Mycobacterium avium complex pulmonary disease presenting as an isolated lingular or middle lobe pattern. The Lady Windermere syndrome
Chest
(1992)
TM Ziedalski et al.
Prospective analysis of cystic fibrosis transmembrane regulator mutations in adults with bronchiectasis or pulmonary nontuberculous mycobacterial infection
Chest
(2006)

A De Soyza et al.

Bronchiectasis rheumatoid overlap syndrome is an independent risk factor for mortality in patients with bronchiectasis: a multicenter cohort study

Chest

(2017)

A Shoemark et al.

Aetiology in adult patients with bronchiectasis

Respir Med

(2007)

PJ McShane et al.

Bronchiectasis in a diverse US population: effects of ethnicity on etiology and sputum culture

Chest

(2012)

DR VanDevanter et al.

IV-treated pulmonary exacerbations in the prior year: an important independent risk factor for future pulmonary exacerbation in cystic fibrosis

J Cyst Fibros

(2016)

TR Aksamit et al.

Adult patients with bronchiectasis: a first look at the US bronchiectasis research registry

Chest

(2017)

GB Rogers et al.

The effect of long-term macrolide treatment on respiratory microbiota composition in non-cystic fibrosis bronchiectasis: an analysis from the randomised, double-blind, placebo-controlled BLESS trial

Lancet Respir Med

(2014)

JD Chalmers et al.

Management of bronchiectasis in adults

Eur Respir J

(2015)

D Araujo et al.

Standardised classification of the aetiology of bronchiectasis using an objective algorithm

Eur Respir J

(2017)

A Spinou et al.

The development and validation of the Bronchiectasis Health Questionnaire

Eur Respir J

(2017)

JK Quint et al.

Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study

Eur Respir J

(2016)

E Polverino et al.

European Respiratory Society guidelines for the management of adult bronchiectasis

Eur Respir J

(2017)

TR Nadig et al.

Aerosolized antibiotics for patients with bronchiectasis

Am J Respir Crit Care Med

(2016)

DJ Serisier et al.

Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial

JAMA

(2013)

T Aksamit et al.

RESPIRE 2: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

Eur Respir J

(2018)

A De Soyza et al.

RESPIRE 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

Eur Respir J

(2018)

MK Han et al.

Chronic obstructive pulmonary disease phenotypes: the future of COPD

Am J Respir Crit Care Med

(2010)

HC Chapin et al.

The cell biology of polycystic kidney disease

J Cell Biol

(2010)

SK Gilley et al.

Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways

Am J Physiol Lung Cell Mol Physiol

(2014)

S Svenningsen et al.

Asthma endotypes and an overview of targeted therapy for asthma

Front Med

(2017)

PM Farrell et al.

Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation

J Pediatr

(2017)

JM Rommens et al.

Identification of the cystic fibrosis gene: chromosome walking and jumping

Science

(1989)

M Lopes-Pacheco

CFTR modulators: shedding light on precision medicine for cystic fibrosis

Front Pharmacol

(2016)

SL Heltshe et al.

Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor

Clin Infect Dis

(2015)

AJ Shapiro et al.

Accuracy of nasal nitric oxide measurement as a diagnostic test for primary ciliary dyskinesia. A systematic review and meta-analysis

Ann Am Thorac Soc

(2017)

A Shoemark et al.

High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations

Thorax

(2018)

CJ Fowler et al.

Abnormal nasal nitric oxide production, ciliary beat frequency, and toll-like receptor response in pulmonary nontuberculous mycobacterial disease epithelium

Am J Respir Crit Care Med

(2013)

A Horani et al.

Primary ciliary dyskinesia and associated sensory ciliopathies

Expert Rev Respir Med

(2016)

R Ameratunga et al.

Review: diagnosing common variable immunodeficiency disorder in the era of genome sequencing

Clin Rev Allergy Immunol

(2018)

D Vetrie et al.

The gene involved in X-linked agammaglobulinaemia is a member of the Src family of protein-tyrosine kinases

Nature

(1993)

SM Holland et al.

STAT3 mutations in the hyper-IgE syndrome

N Engl J Med

(2007)

Y Minegishi et al.

Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome

J Exp Med

(2009)

AP Hsu et al.

IL2RG reversion event in a common lymphoid progenitor leads to delayed diagnosis and milder phenotype

J Clin Immunol

(2015)

JP Egan et al.

Successful treatment of ulcerative bronchiolitis in a woman with refractory Mycobacterium intracellulare infection

BMJ Case Rep

(2015)

BD Ye et al.

Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

Expert Rev Clin Immunol

(2016)

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Severity of bronchiectasis predicts use of and adherence to high frequency chest wall oscillation therapy - Analysis from the United States Bronchiectasis and NTM research registry; Severity of BE predicts HFCWO use and adherence
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High frequency chest wall oscillation (HFCWO) is a form of airway clearance therapy that has been available since the mid-1990s and is routinely used by patients suffering from retained pulmonary secretions. Patients with cystic fibrosis (CF), neuromuscular disease (NMD), and other disorders, including bronchiectasis (BE) and COPD (without BE), are commonly prescribed this therapy. Limited evidence exists describing HFCWO use in the BE population, its impact on long-term management of disease, and the specific patient populations most likely to benefit from this therapy. This study sought to characterize the clinical characteristics of patients with BE who have documented use of HFCWO at baseline and 1-year follow-up.
An analysis from a large national database registry of patients with BE was performed. Demographic and clinical characteristics of all patients receiving HFCWO therapy at baseline are reported. Patients were stratified into two groups based on continued or discontinued use of HFCWO therapy at 1-year follow-up.
Over half (54.8 %) of patients who reported using HFCWO therapy had a Modified Bronchiectasis Severity Index (m-BSI) classified as severe, and the majority (81.4 %) experienced an exacerbation in the prior two years. Of patients with 1-year follow-up data, 73 % reported continued use of HFCWO. Compared to patients who discontinued therapy, these patients were more severe at baseline and at follow-up suggesting that patients with more severe disease are more likely to continue HFCWO therapy.
Patients who have more severe disease and continue to experience exacerbations and hospitalizations are more likely to continue HFCWO therapy.
NA.
Impact of primary ciliary dyskinesia: Beyond sinobronchial syndrome in Japan
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Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by impaired motile cilia function, particularly in the upper and lower airways. To date, more than 50 causative genes related to the movement, development, and maintenance of cilia have been identified. PCD mostly follows an autosomal recessive inheritance pattern, in which PCD symptoms manifest only in the presence of pathogenic variants in both alleles.
Several genes causing PCD have been recently identified that neither lead to situs inversus nor cause definitive abnormalities in ciliary ultrastructure. Importantly, the distribution of disease-causing genes and pathogenic variants varies depending on ethnicity. In Japan, homozygosity for a ∼27.7-kb deletion of DRC1 is estimated to be the most common cause of PCD, presumably as a founder mutation. The clinical picture of PCD is similar to that of sinobronchial syndrome, thus making its differentiation from diffuse panbronchiolitis and other related disorders difficult. Given the diagnostic challenges, many cases remain undiagnosed or misdiagnosed, particularly in adults. While no fundamental cure is currently available, lifelong medical subsidies are provided in Japan, and proper respiratory management, along with continued prevention and treatment of infections, is believed to mitigate the decline in respiratory function. Timely action will be necessary when specific treatments for PCD become available in the future. This narrative review focuses on variations in the disease status of PCD in a non-Western country.
Reliability of blood eosinophil count in steady-state bronchiectasis
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The baseline value of eosinophils in peripheral blood (BEC) has been associated with different degrees of severity, prognosis and response to treatment in patients with bronchiectasis. It is not known, however, if this basal value remains constant over time.
The aim of this study was to assess whether the BEC remains stable in the long term in patients with bronchiectasis.
Patients from the RIBRON registry of bronchiectasis diagnosed by computed tomography with at least 2 BEC measurements one year apart were included in the study. Patients with asthma and those taking anti-eosinophilic drugs were excluded. Reliability was assessed using the intra-class correlation coefficient (ICC). A patient with a BEC of at least 300 cells/uL or less than 100 cells/uL was considered eosinophilic or eosinopenic, respectively. Group changes over time were also calculated.
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SeriesAdvances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity

Summary

Introduction

Section snippets

Pathophysiology of disease

Endotypes and genotypes

Disease heterogeneity beyond causes: clinical phenotypes

Microbiology and the microbiome

Conclusion

Search strategy and selection criteria

Lancet

Chest

Cell

J Cyst Fibros

Paediatr Respir Rev

Paediatr Respir Rev

Clin Immunol

J Allergy Clin Immunol

Chest

Chest

Chest

Respir Med

Chest

J Cyst Fibros

Chest

Lancet Respir Med

Management of bronchiectasis in adults

Eur Respir J

Standardised classification of the aetiology of bronchiectasis using an objective algorithm

Eur Respir J

The development and validation of the Bronchiectasis Health Questionnaire

Eur Respir J

Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study

Eur Respir J

European Respiratory Society guidelines for the management of adult bronchiectasis

Eur Respir J

Aerosolized antibiotics for patients with bronchiectasis

Am J Respir Crit Care Med

Effect of long-term, low-dose erythromycin on pulmonary exacerbations among patients with non-cystic fibrosis bronchiectasis: the BLESS randomized controlled trial

JAMA

RESPIRE 2: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

Eur Respir J

RESPIRE 1: a phase III placebo-controlled randomised trial of ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis

Eur Respir J

Chronic obstructive pulmonary disease phenotypes: the future of COPD

Am J Respir Crit Care Med

The cell biology of polycystic kidney disease

J Cell Biol

Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways

Am J Physiol Lung Cell Mol Physiol

Asthma endotypes and an overview of targeted therapy for asthma

Front Med

Diagnosis of cystic fibrosis: consensus guidelines from the cystic fibrosis foundation

J Pediatr

Identification of the cystic fibrosis gene: chromosome walking and jumping

Science

CFTR modulators: shedding light on precision medicine for cystic fibrosis

Front Pharmacol

Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor

Clin Infect Dis

Accuracy of nasal nitric oxide measurement as a diagnostic test for primary ciliary dyskinesia. A systematic review and meta-analysis

Ann Am Thorac Soc

High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations

Thorax

Abnormal nasal nitric oxide production, ciliary beat frequency, and toll-like receptor response in pulmonary nontuberculous mycobacterial disease epithelium

Am J Respir Crit Care Med

Primary ciliary dyskinesia and associated sensory ciliopathies

Expert Rev Respir Med

Review: diagnosing common variable immunodeficiency disorder in the era of genome sequencing

Clin Rev Allergy Immunol

The gene involved in X-linked agammaglobulinaemia is a member of the Src family of protein-tyrosine kinases

Nature

STAT3 mutations in the hyper-IgE syndrome

N Engl J Med

Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome

J Exp Med

IL2RG reversion event in a common lymphoid progenitor leads to delayed diagnosis and milder phenotype

J Clin Immunol

Successful treatment of ulcerative bronchiolitis in a woman with refractory Mycobacterium intracellulare infection

BMJ Case Rep

Series
Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity