Bronchiectasis, Pathophysiology, Disease management and Advanced therapies
Creators: name: Fatima, Zarrien
name: Suleman, Aleeza
name: Mansoor, Palvisha
name: Khaliq, Hafiz Muhammad Haseeb
Publisher: name: Zenodo openAIRE, Google Scholar Indexed
Year: 2024

description: The word "bronchiectasis" is derived from the Greek words “bronkia”  which means “bronchial tubes”, “ek” which means “out” and  and “tasis”  which means “stretching”. Its literal meaning is “bronchi stretching”.  It is a clinical illness which is characterized by persistent, irreversible bronchial wall dilatation and aberrant thickening that are both detectable on lung imaging (1). The incidence, prevalence, and clinical characteristics of bronchiectasis vary somewhat geographically and are age-related. Elderly people are experiencing a significant rise in the prevalence of disease, particularly serious disease. Moreover, Indigenous children in Canada, Alaska, New Zealand and Australia have the most significant diversity in bronchiectasis epidemiology. When compared with non-indigenous populations, paediatric groups show unusually high prevalence, with neonatal or childhood pneumonia being mentioned as the major cause. These findings taken together suggest that pathogenesis, specifically in certain indigenous communities, may be influenced by genetic predisposition, early childhood infection, and general poorer socioeconomic backgrounds (2).

Risk factors of Bronchiectasis:

·         Postinfective : tuberclusis (mycobacterial infection),  whooping cough, postpneumonia,

·         Aspiration syndromes

·         Defective mucociliary clearance: Immotile cilia, Young's syndrome & Kartagener's syndrome

·         Anatomical abnormalities: intraluminal airway obstruction, intramural obstruction, External airway compression 

·         Chronic obstructive pulmonary disease

·         Immune dysfunction: HIV infection, allergic bronchopulmonary aspergillosis, detection of hypogammaglobulinemia, cancer, late stages of lung transplant rejection

·         Genetic syndromes: Yellow nail syndrome

·         Inflammatoy conditions: Inflammatory bowel disease, Rheumatoid arthritis

·         Aging

·         Malnutrition and a poor socioeconomic situation

·         Gene mutations: Alpha1-antitrypsin deficiency, mutations of  CF transmembrane regulator (6)

Pathophysiology:

The interrelated ideas of persistent infection, inflammatory condition, decreased mucociliary clearance, & structural lung destruction are used to understand the pathophysiology of Bronchiectasis.

Airway impairment, an inflammation, structural illness, and infection follow an initial insult. Once the pattern is established, it progresses over time and gets past the host's local and systemic protection mechanisms. From patient to patient, the initial injury or infection differs and is frequently unknown. Some patients' airways are abnormal in and of themselves due to underlying conditions like infection or ciliary dysfunction, whereas in others, the mucus itself exhibits atypical properties that induce stasis and blockage (7). 

The Vicious Cycle and Vicious Vortex 

The "Vicious cycle hypothesis," which Peter Cole first proposed in 1986, is the most widely accepted theory of how bronchiectasis develops. According to this hypothesis, poor mucociliary clearance causes an accumulation of airway secretions, which compromises the body's natural defences and makes the patient more susceptible to infection. Inflammation brought on by a persistent infection leads to aberrant remodelling of the airways and structural harm. This series of circumstances leads to a persistent and worsening condition with a "entry point" that can be connected to the underlying cause of bronchiectasis. Inflammatory bowel disease, for instance, causes localised swelling and structural damage; Cystic Fibrosis and Primary Ciliary Dyskinesia patients have reduced mucociliary clearance, increasing their vulnerability to infections; and immunosuppression can lead to persistent infections.

Due to the connections between airway dysfunction, airway inflammation, infection, and structural damage, Flume et al. further altered this model to depict a vicious vortex. For instance, Pseudomonas aeruginosa infection causes neutrophilic inflammation by promoting the release of chemotactic factors like CXCL-8, interleukin (IL)-1, and some others, but it also negatively impacts mucociliary clearance by slowing ciliary beat frequency through the intervention of ciliotoxins like pyocyanin. Lung structure may be directly harmed by pseudomonas elastase. Therefore, an interdependent vortex model instead of a cyclic model represents a more appropriate portrayal of bronchiectasis pathogenesis. P. aeruginosa infection is just one manifestation of this (8). 

Bronchial infection:

One of the essential elements of pathophysiology of Bronchiectasis is the formation of airway chronic bronchial infection which is linked to poor quality of life, greater exacerbations, and increased fatality. The most frequent microorganisms associated with chronic bronchial infection are Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenza.  Additionally present during clinical stability are non-tuberculous mycobacteria, fungi, and bronchial viruses, all of which raise the possibility of an acute exacerbation (9).

 

Chronic inflammation:

A critical element of the pathophysiology of bronchiectasis is chronic inflammation. The condition is characterised by neutrophilic inflammation, and worse outcomes have been linked to higher concentrations of damaging proteases like neutrophil elastase. Recent research suggests that the main mechanism causing protease release and severe bronchiectasis may be neutrophil extracellular trap production. The bronchial elastin and other lung support structures are destroyed by mediators released by neutrophils, including inflammatory cytokines, elastases, and matrix metalloproteinases, which results in bronchial dilatation that is permanent. The structural cartilage in proximal airways may deteriorate, resulting in less supporting structure.

Despite the fact that neutrophilic illness predominates, there are documented eosinophilic subtypes as well. Elevated bacterial populations and persistent infection with Pseudomonas aeruginosa are linked to neutrophilic inflammation. Severe bronchiectasis is characterised by a loss of the normal lung microbiota's variety and a predominance of proteobacteria like Pseudomonas and Haemophilus, which is associated with poor outcomes (10).

Primary Ciliary Dyskinesia:

The rare hereditary disease known as primary ciliary dyskinesia serves as an excellent example of ciliary malfunction. A variety of disorders where cilia are missing, immotile or dysmotile cause the airway epithelium to be prone to infection. These problems are caused by mutations in genes coding for proteins responsible for ciliary biogenesis, structure, and function. Mucus accumulation, airway obstruction, and infection susceptibility are all effects of impaired mucociliary clearance.

Patients with bronchiectasis who do not have documented PCD may experience ciliary dyskinesia. The serine protease known as neutrophil elastase (NE), which is generated by neutrophils in response to bacterial infection, can be harmful to the airway epithelium. As a result of ciliary beat frequency reduction and extracellular matrix degradation, NE can decrease the effectiveness of clearance (11).

Pathology:

Based on histology, bronchiectasis can be divided into four groups: 

1.      Tubular: A thick tubular structure with a homogeneous appearance that extends toward the lung periphery is a sign of tubular bronchiectasis, which causes bronchial and bronchiolar dilatation 

2.      Varicose: The bronchi in varicose bronchiectasis exhibit uneven shapes, round and protruding ends, and alternately constricted and dilated portions 

3.      Cystic (saccular): The bronchi become substantially dilated and develop enormous cysts that are fluid and air-filled in cystic bronchiectasis .

4.      Follicular:  There is increased lymphoid follicle development along the bronchial and bronchiole walls as well as interstitial pneumonia in follicular bronchiectasis (12).

In a study, the analysis of 200 consecutive surgical lung specimens provided the clearest picture of the bronchiectasis pathology. This investigation showed pronounced bronchial wall inflammation, especially in the smaller airways. Elastin deficit or loss and more chronic illness, including bronchial dilation, were both characterised by the breakdown of muscle and cartilage. It is unknown what exact process causes this tissue loss to result in bronchial dilatation. Atelectasis, peribronchial pneumonic change, and varied bronchial wall fibrosis were present. 

Lymphoid follicles in the bronchial wall were a defining feature of follicular bronchiectasis. The tiny airway was the site of the initial inflammation. Due to the minor airway inflammation, mediators such proteases were released, damaging the larger airways and resulting in the loss of elastin as well as other components like muscle and cartilage, which led to bronchial dilatation. As the illness worsened, lymphoid follicles became larger and obstructed the little airways' ability to breathe. The final occurrence was the interstitial pneumonia caused when the inflammation progressed outside of the airways. 

The discovery of airflow obstruction in bronchiectasis is also explained by the pathology research. Findings demonstrate that while the medium and small airways exhibit airflow blockage primarily brought on by bronchial wall thickness, the big airways get dilated. Since medium and small airways make up the majority of the respiratory system, bronchiectasis' inflammatory process ultimately results in airflow blockage.

Distribution of bronchiectasis: There are two types of bronchiectasis: localized which is limited to one lobe and generalized. It is normally generalized and appears to be more prevalent in the lower lobes.  Lower lobes may be involved due to the contaminated fluids being retained due to gravity. Additionally, the proximal bronchus is surrounded by a collar of lymph nodes, and any disorder that results in a protracted swelling of these nodes may produce blockage and secondary bronchiectasis (13).

Recent Advancements in the management of Bronchiectasis:

Advancement in Pathophysiology:

The pathogenesis of bronchiectasis is now better understood than it was previously. According to Cole's "vicious cycle hypothesis," an airway insult would set off a series of events on the basis of host sensitivity and/or immunological deficiency. A damaging and never-ending "cycle" that hinders mucociliary clearance, encourages mucus accumulation, establishes chronic infection, and causes inflammation leads to bronchial wall loss, dilatation, and airway remodelling as a result. The development of bronchiectasis in patients with mucociliary defects, following infection, or in immune-deficient conditions is depicted in this model, but it falls short of adequately explaining why treatments "targeted" at a particular aspect of the cycle such as antibiotics or anti-inflammatories do not 'break it' rather than offer significant benefit. Therefore, the recent description of a "vicious vortex" where interaction happens constantly and nonsequentially between all elements of the initial cycle, with each step having an impact on all others, is a significant advancement. This justifies the little clinical benefit shown after addressing just one facet of the initial cycle and promotes the use of a multimodal strategy to slow disease development (14).

Recent trial of Brensocatib (INS 1007):

In a 24-week experiment, brensocatib treatment reduced neutrophil serine protease activity in bronchiectasis patients, and this was correlated with better clinical outcomes.

Exacerbations in bronchiectasis patients occur often and are likely to be caused by neutrophilic inflammation. Patients with bronchiectasis have higher levels of neutrophil serine proteases, such as neutrophil elastase, in their sputum both at rest and during exacerbations. Dipeptidyl peptidase 1 (DPP-1) is an enzyme that activates neutrophil serine proteases, and brensocatib (INS1007) is a reversible oral inhibitor of DPP-1. Clinical outcomes for patients with bronchiectasis who took brensocatib to lower neutrophil serine protease activity saw an improvement. In individuals with bronchiectasis who were regarded as frequent exacerbators, bronsocatib increased the time to the first exacerbation and reduced the number of exacerbations compared to placebo (15) 

Advancement in clinical diagnostics:

Imaging:

The "gold standard" for radiologically diagnosing bronchiectasis is high-resolution computed tomography (HRCT) of the chest. The severity of chest HRCT in bronchiectasis patients can be evaluated using a variety of scoring methods and objective criteria. To evaluate the degree of bronchiectasis, bronchi wall thickening, small-airway anomalies, and mosaic pattern, a unique quantitative HRCT procedure has been created. This technique exhibited a high level of interobserver reliability and low intraobserver variance. Airway obstruction had an inverse relationship with the severity of bronchiectasis, bronchial wall thickening, and mosaic attenuation. In addition, the Bhalla score might offer more clarity than the modified Reiff score. The kind of bronchiectasis and Bhalla score were found to be connected with the symptoms, lung function, frequency of exacerbations, and hospitalization in a multicenter research (16).

The prognosis is worse when bronchiectasis, COPD, and/or asthma are present. The identification of this phenotype was crucially aided by HRCT. In 34.7% of COPD patients, HRCT revealed bronchiectasis, with P. aeruginosa isolation serving as the main indicator. In addition, machine learning-based novel methods for HRCT image analysis have been developed by artificial intelligence. Artificial intelligence is currently being integrated into healthcare practice (2)

 

References:

1.         Aliberti S, Goeminne PC, O'Donnell AE, Aksamit TR, Al-Jahdali H, Barker AF, et al. Criteria and definitions for the radiological and clinical diagnosis of bronchiectasis in adults for use in clinical trials: international consensus recommendations. The Lancet Respiratory Medicine. 2022;10(3):298-306.

2.         Tiddens HA, Meerburg JJ, van der Eerden MM, Ciet P. The radiological diagnosis of bronchiectasis: what's in a name? European Respiratory Review. 2020;29(156).

3.         Aliberti S, Sotgiu G, Lapi F, Gramegna A, Cricelli C, Blasi F. Prevalence and incidence of bronchiectasis in Italy. BMC pulmonary medicine. 2020;20:1-6.

4.         Amaro R, Perea L, Sibila O. Future directions in bronchiectasis research. Clinics in Chest Medicine. 2022;43(1):179-87.

5.         Barbosa M, Chalmers JD. Bronchiectasis. La Presse Médicale. 2023;52(3):104174.

6.         Chalmers JD, Polverino E, Crichton ML, Ringshausen FC, De Soyza A, Vendrell M, et al. Bronchiectasis in Europe: data on disease characteristics from the European Bronchiectasis registry (EMBARC). The Lancet Respiratory Medicine. 2023.

7.         Cohen R, Shteinberg M. Diagnosis and evaluation of bronchiectasis. Clinics in Chest Medicine. 2022;43(1):7-22.

8.         Goyal V, Chang AB. Bronchiectasis in childhood. Clinics in Chest Medicine. 2022;43(1):71-88.

9.         Keir HR, Chalmers JD, editors. Pathophysiology of bronchiectasis. Seminars in respiratory and critical care medicine; 2021: Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY ….

10.       Li L, Mac Aogain M, Xu T, Jaggi TK, Chan LL, Qu J, et al. Neisseria species as pathobionts in bronchiectasis. Cell Host & Microbe. 2022;30(9):1311-27. e8.

11.       Mac Aogáin M, Narayana JK, Tiew PY, Ali NAtBM, Yong VFL, Jaggi TK, et al. Integrative microbiomics in bronchiectasis exacerbations. Nature medicine. 2021;27(4):688-99.

12.       Matsumoto H. Bronchiectasis in severe asthma and asthmatic components in bronchiectasis. Respiratory Investigation. 2022;60(2):187-96.

13.       O’Donnell AE. Bronchiectasis—a clinical review. New England Journal of Medicine. 2022;387(6):533-45.

14.       Shoemark A, Shteinberg M, De Soyza A, Haworth CS, Richardson H, Gao Y, et al. Characterization of eosinophilic bronchiectasis: a European multicohort study. American journal of respiratory and critical care medicine. 2022;205(8):894-902.

15.       Shteinberg M, Flume PA, Chalmers JD. Is bronchiectasis really a disease? European Respiratory Review. 2020;29(155).

16.       Solarat B, Perea L, Faner R, de La Rosa D, Martínez-García MÁ, Sibila O. Pathophysiology of chronic bronchial infection in bronchiectasis. Archivos de Bronconeumología. 2023;59(2):101-8.