Bronchiectasis is a common feature of severe inherited and acquired pulmonary disease conditions. Among inherited diseases, cystic fibrosis CF is the major disorder associated with bronchiectasis, while acquired conditions frequently featuring bronchiectasis include post-infective bronchiectasis and chronic obstructive pulmonary disease COPD.
Mechanistically, bronchiectasis is driven by a complex interplay of inflammation and infection with neutrophilic inflammation playing a predominant role. The clinical characterization and management of bronchiectasis should involve a precise diagnostic workup, tailored therapeutic strategies and pulmonary imaging that has become an essential tool for the diagnosis and follow-up of bronchiectasis. Prospective future studies are required to optimize the diagnostic and therapeutic management of bronchiectasis, particularly in heterogeneous non-CF bronchiectasis populations.
Bronchiectasis is a condition Bronchiectasis in cf patients dating which an area of the bronchial lumen is permanently and abnormally widened, with accompanying infection. Bronchiectasis is found in a variety of pulmonary diseases, both genetically caused and acquired, such as severe pulmonary infections and cystic fibrosis CFbut is also a feature of Kartagener syndrome, chronic obstructive pulmonary diseases COPDalpha 1-antitrypsin deficiency, asthma, or primary immunodeficiencies [ 1 — 3 ].
Bronchietasis is caused by long-term excessive inflammatory damage to the airways, which results in tissue breakdown, enlargement of the affected airways and the key clinical symptoms of chronic productive cough and shortness of breath. Globally, in up to half of all cases Bronchiectasis in cf patients dating cause cannot be identified idiopathic. Here we discuss the key features of both CF and non-CF related bronchiectasis with respect to their pathogenesis, imaging and clinical management.
Bronchiectasis mechanistically results from chronic inflammatory microenvironments that trigger airway tissue breakdown. In both CF and non-CF bronchiectasis, the complex interplay between infection and inflammation feeds a pro-inflammatory vicious circle that progressively drives the generation of bronchiectasis and the destruction of the pulmonary architecture [ 5 ]. Inflammatory immune cells mainly activated macrophages and neutrophils represent the major infiltrating population in disease conditions associated with bronchiectasis and contribute significantly to tissue damage and bronchiectasis generation through the release of their harmful cellular ingredients.
Particularly, cell-derived proteases and reactive oxygen species represent key mediators in the degradation and destruction of extracellular pulmonary tissue components, leading to bronchiectasis formation. The precise early immune-mediated mechanisms that trigger and maintain the formation of bronchiectasis remain yet incompletely understood.
Regulated immune homeostasis seems to be essential since both immune deficiencies as well as hyper-active immune are associated with bronchiectasis. Particularly, the protease-antiprotease imbalance [ 67 ], as found in CF and COPD airways, is considered as key pathogenic component in degrading extracellular matrix.
Mutations in the Bronchiectasis in cf patients dating fibrosis transmembrane conductance regulator CFTR gene are causative for CF lung disease and drive the earliest pathogenic events in epithelial cells that ultimately lead to the genesis of bronchiectasis.
Pseudomonas aeruginosa is a common and dominant pathogen found in the airways of both CF and non-CF bronchiectasis patients [ 9 — 13 ]. Chronic infection has been associated with more severe decline in lung function [ 14 — 19 ], increased hospitalizations [ 2021 ], frequent exacerbations [ 22 ] and disease severity [ 2324 ].
Although clinical manifestations between the two settings vary, their core airway microbiota is largely analogous [ 25 ]. Along with Pseudomonasbacteria belonging to other genera such as Haemophilus, Streptococcus, StaphylococcusVeillonella, Prevotella and Achromobacter also make up the core microbiota observed in bronchiectasis [ 92627 ].
Mycobacterium avium complex MAC and Mycobacterium abscessus are most frequently isolated in CF [ 3233 ] with high rates of multi-drug resistance in these species making them notoriously difficult to treat [ 34 ]. This group of organisms are surprisingly poorly associated with disease severity and exacerbations in the non-CF setting when compared to Pseudomonas [ 3738 ].
Interestingly, bacterial populations do not drastically change between stable and exacerbation states in bronchiectasis. However, viral load has been positively correlated with exacerbations in both CF and non-CF bronchiectasis patients.
Most attention towards understanding the microbiome in bronchiectasis is directed at the bacteriome. Although Bronchiectasis in cf patients dating are frequently isolated from the same airways, the role of the pulmonary mycobiome in the pathogenesis of these disease states remains largely elusive [ 47 — 49 ].
Filamentous fungi belonging to genus Aspergillus are frequently isolated fungal organisms in sputum samples from CF patients [ 5051 ]. Among the different species of AspergillusA. Only a single study to date has shown that fungi belonging to the Aspergillus spp. Importantly, in a study of severe asthma patients, Aspergillus fumigatus sensitization has also been associated with poorer lung function and an increased incidence of bronchiectasis, a likely cause and consequence for this anatomical airway distortion [ 5859 ].
Among yeasts, Candida spp.
Isolation of Candida albicans from such airways is shown to be a predictor for frequent hospital-exacerbations and declines in lung function [ 61 ]. Compared to bacteria, our present understanding of fungal pathogenesis in the context of both CF and non-CF bronchiectasis remains limited and further work is required to determine their prevalence, colonization frequency, host-pathogen interaction and risk factor profile in this key patient group.
Neutrophil-dominant inflammation is a key feature of bronchiectasis. Sputum neutrophils are higher in bronchiectasis patients versus healthy controls and this correlates with an increased disease severity [ 62 — 64 ]. Both interleukin-8 IL-8 and leukotriene-B4 LTB4 are key chemo-attractants required for migration and infiltration of neutrophils into bronchiectatic airways [ 65 ].
High systemic IL-8 levels are detectable in individuals with "Bronchiectasis in cf patients dating" [ 66 — 68 ]. Antibacterial neutrophil responses such as reactive oxygen species ROS formation are activated through the ILCXCR1 axis, but proteolytic cleavage mediated by neutrophil elastase NEwhich itself is associated with exacerbations and lung function decline in bronchiectasis, impairs antibacterial Bronchiectasis in cf patients dating functions [ 6970 ].
Uncontrolled NE activity, as found in CF airways, causes further respiratory tissue damage through degradation of extracellular proteins such Bronchiectasis in cf patients dating surfactant proteins [ 71 — 73 ] and cellular surface receptors such as complement receptors [ 74 ] ; high NE levels correlating with disease severity and poorer lung function are described in both CF and non-CF bronchiectasis settings [ 7576 ].
In this context, CXCR receptor antagonists are hypothesized to inhibit neutrophil airway influx and have been shown to be effective in modulating the Bronchiectasis in cf patients dating state in bronchiectasis [ 7778 ]. Airway neutrophils in CF illustrate an impaired phagocytic ability [ 79 ]. This is in line with the observation that CF neutrophils have an impaired ROS production, a critical mediator of antimicrobial host defense [ 80 ].
Neutrophils defective in their oxidative abilities obtained from non-CF bronchiectasis patients were poorer at bacterial killing when compared to those of healthy controls [ 81 ].
They degrade proteoglycans in the respiratory epithelium subsequently inducing airway damage [ 82 ]. In bronchiectasis, activated airway neutrophils Bronchiectasis in cf patients dating an abundance of human neutrophil peptides HNPswhich have been described to inhibit their phagocytic ability. Importantly, high concentrations of HNPs are detected in both CF and non-CF airways, which in turn may contribute to the decreased phagocytic abilities and higher rates of infection described in both conditions [ 83 ].
Poorer clearance of neutrophils by alveolar macrophages further augments the inflammatory state in bronchiectasis [ 63 ]. Eosinophils contribute to tissue injury in CF and the presence of eosinophil cationic protein ECP heralds the cell activation state. ECP levels are elevated both in the airway and systemically in bronchiectasis [ 84 — 86 ]. Other eosinophilic markers including eosinophil protein X and peroxidase follow a similar pattern and like ECP contribute to poorer pulmonary function [ 87 ].
Importantly, eosinophilic granule release in CF may be triggered by NE illustrating the cross-granulocyte talk that occurs in the setting of bronchiectasis [ 88 ]. T-cells constitute another key component of the inflammatory response in bronchiectasis [ 89 ]. Th17 cells, neutrophils and NKT cells are found in abundance in all-cause bronchiectasis compared to healthy controls [ 92 ].
While high Th17 infiltrates independently associate with poorer lung function in CF [ 93 ], activation of Th17 antigen-specific pathways have been described in non-CF bronchiectasis [ 94 ].
IL, a central mediator of the Th17 pathway lacks correlation with disease phenotypes suggestive of the more prominent role that neutrophil-mediated inflammation likely plays in the pathogenesis of bronchiectasis [ 94 ].
A seminal study in CF children identified the key risk factors for bronchiectasis: Exacerbations of both CF and non-CF bronchiectasis increases inflammation irrespective of bacterial, viral or fungal causation [ 43, ].