Bronchiectasis – A Timeless Condition with Recent Developments

Bronchiectasis – A Timeless Condition with Recent Developments

Ana Pedro Cunha Craveiro*1, Eunice Magalhães2; Juliana Barata3, Maria La Salete Valente4.

1,2,3,4. Pulmonology Department, Centro Hospitalar Universitário Cova da Beira, Covilhã, Portugal.

Correspondence to: Ana Pedro Cunha Craveiro, Pulmonology Department, Centro Hospitalar Universitário Cova da Beira, Covilhã, Portugal.


Copyright

© 2024 A. Craveiro. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 18 March 2024

Published: 01 April 2024


Abstract

Radiologically defined as abnormal and irreversible bronchial dilatations, bronchiectasis are a chronic, progressive respiratory disease clinically characterized by persistent cough and sputum, with a non-negligible impact on quality of life. High-resolution computed tomography of the chest – through the identification of direct and indirect signs – is the gold-standard for its diagnosis.

Marked by heterogeneity in its etiology, evolution and prognosis, bronchiectasis represents the culmination of several factors. Recently, the classical pathophysiological explanation in the form of a cycle has given way to the concept of a vortex, in an unprecedented recognition of the continuous and mutual interrelationship between the various underlying elements.

This review article seeks to define and characterize the concept of bronchiectasis, reflect on the main pathophysiological elements involved, and provide updated data on its diagnostic and therapeutic approach.

Key words: Bronchiectasis, aetiology, pathophysiological vortex, treatable trait.


Bronchiectasis – A Timeless Condition with Recent Developments

1.Introduction

Bronchiectasis (BCs) are a chronic and progressive respiratory disease(1) characterized radiologically by abnormal and permanent bronchial dilatation and, clinically, by persistent cough and sputum(2). As a chronic lung disease characterised by such irreversible anatomical changes associated with cough, sputum and recurrent respiratory infections(3, 4, 5), they are the final common pathway of several pathological processes(6).

Identifiable by thoracic high-resolution computed tomography (HRCT)(7, 8) and diagnosed based on imaging and clinical criteria(3, 8), BCs are a chronic inflammatory disease (4) marked by heterogeneity in their etiology, clinical manifestations, radiological appearance, frequency of acute exacerbations (AE), impaired pulmonary function, microbiology and prognosis(3).

In a highly variable and often poorly understood combination, BCs can have numerous causes in their genesis, namely involving processes of infection and inflammation of the airways(7, 8) and different factors that contribute to their progression.

Several aspects of BCs – prevalence, underlying etiology, presentation – vary in different parts of the world(9), but there is a consensus that their incidence and prevalence are increasing globally(10, 11, 12), despite greater infectious control achieved in recent years. This is due to greater diagnostic accuracy, recognition of the association with different systemic diseases, increased population survival, among other factors.

Nevertheless, there has been a change in the epidemiology of the disease, with fewer post- infection cases and more older patients with other prevalent comorbidities, such as Chronic Obstructive Pulmonary Disease (COPD)(13). Thus, they are the 3rd most common disease among airways (after COPD and Asthma)(12), being more frequent with advancing age and among females(5, 14).

 

2.Clinical and Imaging Presentation

2.1. Clinical Presentation

Although there is no specific patient type due to the heterogeneity of the condition(1), BCs are a clinical syndrome characterized by cough, sputum, and/or recurrent respiratory infections, commonly with progressive development of exertional dyspnea(2, 5).

Complaints of tiredness, episodes of fever, hemoptysis, and thoracalgia may occur daily, intermittently, or only during exacerbations. When the pathological process extends to the upper airways (e.g., cases of Primary Ciliary Dyskinesia [PCD]), complaints consistent with rhinosinusitis and nasal polyposis (NP) may also be frequent(5, 14).

Other clinical features include extrapulmonary manifestations of peripheral muscle weakness (reduced functional capacity for exercise and physical activity), anxiety, depression, decreased exercise tolerance, all of which contribute to impaired quality of life (QOL)(2).

Some patients may be asymptomatic, while others have daily symptoms and frequent AEs(11). Two patients with similar complaints may differ completely in risk factors, comorbidities, lung function, imaging disorders, microbiology, disease severity, lung inflammation, expectations, adherence and social context(1).

 

Briefly, the cardinal complaints of the disease are:

•           Chronic productive cough (most common symptom – 96% of patients);

•           Abundant sputum;

•           Recurrent respiratory infections;

•           Exertional dyspnea;

•           Episodes of haemoptoic sputum/haemoptysis in the context of infection(2).

 2.2. Radiological Presentation

The gold standard test for imaging diagnosis of BCs is the thoracic HRC which, through ≤1mm slices, allows the detection of direct and indirect signs of the disease(14, 15). Direct signs manifest as bronchial dilatation(14) and consist of: 1) bronchial lumen-arterial ratio >1 ("Signet Ring Sign") when the bronchi are perpendicular to the image section; 2) absence of distant bronchial tapering; 3) visibility of peripheral airways ≤1 cm from the costal pleural or in contact with the mediastinal pleura(9, 14, 15). Indirect signs include: bronchial wall thickening, mucoid impaction (with focal opacities, in a "glove finger"), areas of mosaic attenuation (due to air trapping associated with bronchiolar subocclusion due to inflammation/fibrosis), atelectasis, and consolidations(9, 14, 15, 16, 17).

Since a significant percentage of healthy people have discrete BCs in some lung segment(14), imaging findings should always be interpreted in conjunction with clinical practice. Not all radiologically identified BCs are clinically relevant and therefore require treatment(11).

The radiological appearance can be highly influenced by the underlying etiology (e.g., in Cystic Fibrosis [CF] there are usually multilobar BCs with a predominance in the upper lobes, in Allergic Bronchopulmonary Aspergillosis [ABPA] the middle and upper lobes are more affected, among cases of Connective Tissue Disease [CTD], recurrent infections and/or aspiration, the disease predominates in the lower lobes)(9).

Still with regard to the radiological presentation, globally there are 3 morphological types of BCs according to their degree and type of dilation: Cylindrical (tubular; more frequent; bronchi of uniform caliber; due to the absence of normal bronchial tapering in the periphery; signs of the "rail rail" and "signet ring"); Varicose (bronchi dilated and constricted according to an irregular pattern; rosary-like appearance, which may be associated with pulmonary fibrosis) and Cystic (more severe form; dilated bronchi in a blind bottom; possibly with air-fluid levels)(9, 14, 15, 18) – Table 1.

 

 

3. Pathogenesis

Underlying a wide variety of pathological conditions that are not always understood (as discussed below), the pathogenesis of BCs involves key components, namely: impaired mucociliary clearance, bronchial inflammation and infection, and structural changes(8, 19, 20).

Two theoretical models are presented below that aim to reconcile the relative collaboration of each of these elements in the development and perpetuation of the disease.

 

3.1. Theoretical models:

On the classic explanatory model of this condition developed by Peter Cole – the Vicious Cycle Hypothesis – more holistic views of the problem are now emerging, namely with the replacement of the concept of cycle by that of vortex.

 

3.1.1. Vicious Cycle Hypothesis:

Historically older, the Vicious Cycle Hypothesis describes the pathogenesis of BCs as a circle of events – dysfunction, inflammation, infection, and structural changes in airways(5, 6). A certain aggressive stimulus, involving any of the aforementioned components, activates a cycle that results in the development and perpetuation of BCs(3).

Varying the "entry point into the cycle" depending on the etiology of BCs(6), this hypothesis considers that the disruption of any of the elements results in disease(8). A succession of events in which each step generates the next, culminating in a persistent and progressive process over time(21).

For example, compromised lung defenses and/or clearance facilitates infection, which in turn triggers a chronic inflammatory reaction and structural changes, further compromising the clearance of AWs, ending the cycle and favoring disease progression(13, 14).

 

3.1.2.   Vicious Vortex Hypothesis:

Considering that the dynamic and mutual interaction between the various key components of the pathophysiology of BCs could not be represented as a circle, emerged the Vicious Vortex hypothesis(1, 6, 21). It presents itself as a more holistic view of the disease, affirming a continuous interrelationship between the key elements, in which all they interact and are influenced by each other, probably to different extents, in different patients or etiologies and at different levels of severity(22).

The concept of Vortex may clarify why treatments alone have only modest effects on clinical outcomes in BCs (21). Targeting only one aspect (e.g., antibiotic therapy for an AE) only blocks one of the disease pathways and is likely to have insufficient clinical results(6, 8, 21). Rather than breaking a vicious cycle (which would be expected to stop the disease), a therapeutic approach directed to a single target will not contain the other elements that perpetuate the problem(21).

The concept of the "vicious vortex" highlights the complexity of the interaction between the various elements involved(6, 23) and advocates a multimodality treatment capable of involving all aspects of the disease(21).

 

3.2. Key components in the development of bronchiectasis:

As mentioned, there is a consensus among the various explanatory models that there are key aspects in the pathophysiology of the disease – dysfunction of mucociliary clearance, infection of AWs, bronchial inflammation and structural lung injury(1) – which are discussed below.

 

3.2.1.   Impairment of mucociliary clearance:

The term mucociliary clearance includes all the mechanisms by which mucus (composed of water, salt and proteins) and the respective cellular debris, particles and pathogens involved by it, are removed from airways – involving coordinated actions and synchronous movements of the cilia of respiratory epithelial cells(1).

Thus, the correct functioning of the entire system implies a balance between the composition and volume of mucus and periciliary fluid and the frequency and orientation of ciliary beats(24). Mucus and cilia form a "mucociliary escalator" that ensures that foreign agents in airways are transported and swallowed or expelled by cough(25).

In patients with BCs, often exists dysregulation of mucus secretion (with higher amounts of MUC5B mucin), increased osmotic pressure and mucus with a higher percentage of solids (dehydration index) and DNA content(3, 12). These factors change the physical properties of the mucus, with an increase in its viscosity and elasticity and impaired mucociliary clearance(3, 11).

Poor mucociliary clearance can cause sputum retention in airways, leading to chronic infection and inflammation(12, 14).

The mucociliary cleaning process may be impaired by primary cilia dysfunction, secondary to inflammatory injury, or by direct toxicity of bacterial proteins. Some patients have genetic causes for impaired mucociliary clearance (e.g., PCD), but it is usually the combined effects of chronic inflammation and infection of the airways that continually impair this process(10, 26).

 

3.2.2.   Inflammation:

Persistent inflammation is a key aspect of BCs(27), which is not limited to the coexistence of infection, but can be related to dysregulation of the immune response(14). The available evidence suggests an exuberant inflammatory response among patients with BCs – which will be at least partly responsible for lung damage ('collateral damage')(3) and, at the same time, may have important systemic repercussions.

The inflammatory response in BCs is predominantly localized at the pulmonary level, but several studies report elevated levels of systemic inflammatory markers (in phases of stability or exacerbations)(25, 27). Such high levels of pro-inflammatory cells and mediators, oxidative stress and nutritional deficiencies among these patients can have notable systemic repercussions – namely metabolic and/or cardiovascular(20, 28).

Due to the strong relationship with clinical phenotypes and results, knowledge of the associated inflammatory profile may be an important element to subclassify the disease(1).

Recent studies evaluating inflammatory markers and their association with disease heterogeneity have described 3 major categories of inflammation in BCs: Eosinophilic and epithelial inflammation; systemic inflammation; neutrophilic inflammation of airways(11).

In order to promote the control of the underlying inflammatory process (namely with targeted therapy), there is currently an attempt to classify patients into inflammatory endotypes according to their cellular profile – more neutrophilic, eosinophilic or mixed(19).

 

– Neutrophilic Inflammation:

Neutrophilic inflammation is the dominant inflammatory profile in BCs(1, 6, 12, 19, 27). In response to multiple cytokines and chemokines (Leukotriene B4, Interleukins 8 and 1β, TNF-α), neutrophils are continuously recruited to the AWs, where they perform several functions: bacterial phagocytosis; degranulation and release of proteases and reactive oxygen species (ROS); generation of neutrophil extracellular traps (NETs – i.e., "webs"/networks of DNA and opsonizating proteins of microorganisms that aim to prevent their dissemination and degrade virulence factors), among others(1). However, although they are known to be decisive in immune defence, in excessive amounts, these cells can cause significant tissue damage, particularly with their proteases(14, 19, 22).

In addition, several studies have shown that neutrophils in BCs are dysfunctional(6, 25, 27) – a concept of "Neutrophilic Paradox"(6) –, presenting deficient phagocytosis; excessive activation, degranulation and release of serine proteases (Neutrophil Elastase [NE], Proteinase 3, Cathepsin G) – overcoming anti-protease defense(1, 3, 6); apoptosis long; excessive formation of NETs(9). With regard to the latter, their formation has been strongly associated with the severity of BCs(1, 12).

The function of NETs is to eliminate pathogenic microorganisms but their overproduction leads to tissue injury and persistent inflammation of airways. NETs release neutrophil DNA into AWs with large amounts of enzymes (namely NE)(25). These proteases, antimicrobial proteins, DNA and histones released culminate in excessive inflammation, tissue damage, impaired mucociliary clearance and inability to eliminate pathogens(9).

Regarding NE, several data indicate that it contributes to the production of pro- inflammatory cytokines and mucus, has cilium and cytotoxic properties, and inhibits many innate defenses(14). Studies have shown that patients with BCs often have higher levels of NE in their sputum(6). This serine protease can cleave and inactivate host proteins (including cell receptors involved in eferocytosis, antimicrobial peptides, and extracellular matrix proteins)(1), impair ciliary beat, phagocytosis, and bacterial death, promote extracellular matrix destruction, mucous gland hyperplasia, and increase mucus production, as well as directly injure airways(8).

Therefore, high levels of NE in the AWs and lungs correlate with early development of BCs(1). Excessive neutrophilic inflammation is related to increased frequency of AE and rapid decline in lung function, namely by degradation of elastin in airways(8). In addition, it is associated with a high bacterial load and loss of lung microbiome diversity(1, 12).

 

–          Eosinophilic Inflammation:

In up to 25% of patients with BCs there is eosinophilic inflammation of the airways contributing to their disease(1, 6) and being able to targeted therapy(19, 27). Eosinophils have bactericidal and antiviral properties against pathogenic microorganisms commonly found BCs(12). Nowadays, eosinophilic inflammation is considered an important factor in the occurrence of BCs unrelated to other diagnoses(1), and has been described in 20-30% of patients with BCs without concomitant asthma(25, 27).

Considering the hypothesis that eosinophilic inflammation could be a driver of BCs pathogenesis and not only a co-factor, in some patients, targeting this pathway could modify the natural history of the disease(27).

 

–          Macrophages:

The number of macrophages in lung biopsies of patients with BCs is increased, although their function is altered(12). These cells are crucial to the immune response against pathogens and to the clearance of apoptotic cells (eferocytosis). Through eferocytosis, they regulate the number of neutrophils in the airways, preventing post-apoptotic necrosis. Impairment in the clearance of necrotic cells promotes the release of inflammatory cytokines, proteases, and ROS, contributing to the persistence of inflammation in airways(6, 12).

Further studies are needed to understand the exact role of macrophages in BCs – in the stability phase and in AE(6).

 

3.2.3.   Bronchial Infection and Microbiome:

Bronchial infection remains a key component in BCs, during AE and in periods of clinical stability(19). It triggers, signalizes, and promotes the inflammatory response, and is one of the main causes for neutrophil migration to the respiratory tract. It creates favorable conditions for the survival of microorganisms – whose persistence results in lesion and abnormal remodeling of airways(1, 14) – and is considered a major factor for disease progression(12).

Infections by bacteria, viruses, fungi or mycobacteria are associated with the development of BCs and with AE of the disease(1). On the other hand, commensal agents may have a beneficial effect on inflammation(19). Thus, the designation of patients chronically infected by pathogens has given way to the notion of microbial dysbiosis – i.e., loss of microbiological diversity, with domination of the microbiome by specific organisms(25).

The development of the microbiome depends on several factors. In the case of the respiratory system, this may include translocation of agents from the upper airways, microaspirations  and  host  defenses,  which  make  heterogeneity  a  hallmark  of  the microbiome(6). Its loss – in a process of dysbiosis – can have implications for lung function, inflammatory pattern and disease occurrence.

In BCs, as in other pathological conditions, there is a loss of microbial diversity (with a predominance of small groups of microorganisms)(6, 29). Thus, while the healthy bacterioma of AWs includes Prevotella, Veillonella, Fusobacterium, Streptococcus, Porphyromonas, Neisseria, among others (which reach lower airways through microaspirations of the upper respiratory tract)(25), the organisms that most commonly chronically infect AWs of patients with BCs are Gram-negative pathogens of the Proteobacteria phylum (Pseudomonas aeruginosa [PSAE], Haemophilus influenzae, Moraxella catarrhalis, Enterobacteriaceae) or pathogens from the Firmicutes phylum (Staphylococcus aureus, Streptococcus pneumoniae)(1, 3, 6, 12, 14, 25, 30).

Proteobacterial dysbiome of the microbiome, defined by its dominance (mainly by PSAE and Haemophilus), is associated with more severe disease and worse clinical outcomes(25). In fact, sequencing of the lung microbiome indicated that patients dominated by proteobacteria (PSAE in particular) had more severe disease and that was clearly distinct from that dominated by Firmicutes(1).

PSAE, in particular, is the most identified bacterium worldwide among patients with BCs, being associated with increased frequency of AE, risk of hospitalization and death, and worse QOL. By inducing the formation of NETs, PSAE acquires survival advantage, as these neutrophil "nets/traps" inhibit and eliminate competing microorganisms, and PSAE is able to persist and degrade them, evading inflammatory cells. Patients with PSAE are considered a stable and distinct phenotype, with worse outcomes(2, 25).

 

3.2.4.   Structural changes:

Genetic conditions (such as CF or PCD), congenital malformations, bronchial obstruction, CTD, post-infectious lesions (tuberculosis, pneumonia) can culminate in important structural changes, namely with the development of BCs. On the other hand, in view of the existence of BCs, the overlapping of disease/other processes can result in the aggravation and progression of structural changes. Examples include the occurrence of infections (e.g., due to the effect of bacterial products on cilia function and cytotoxicity), inflammatory effects (especially with high levels of NE and ineffective NETs), acquired dysfunction of mucociliary clearance due to infection and inflammation.

Regardless of the initial process, BCs are associated with progressive loss of Elastin and Collagen (mediated by Serines, Cysteines, Metalloproteinases) and, therefore, with permanent structural changes(1).

 

4. Etiology And Diagnostic Approach

As mentioned, BCs are characterized by great heterogeneity in their etiology, form of presentation, and evolution(1). They can result from a variety of conditions – local or systemic, genetic or acquired – but often no one cause is identified(3, 14, 13).

Nevertheless, and given that the specific treatment of a minority of underlying conditions is associated with a better prognosis, in addition to its clinical and imaging diagnosis, BCs require a systematic search for possible underlying etiologies(1, 13).

 

4.1. Etiological Classification of Bronchiectasis

In order to conduct a sufficiently comprehensive and simultaneously targeted study, it is important to consider the following etiological classification list of BCs (Table 2):

Table 2 – Main etiological groups underlying the development of BCs

A. Post-infections BCs:

Infections are the most frequently reported cause of BCs in the literature(12). A post- infectious aetiology of BCs is often assumed when symptoms begin after a severe infection. However, there are cases in which they only appear several years later, when another predisposing factor coexists (e.g., some degree of immunodeficiency). Thus, it is important to ask about respiratory complaints prior to infection, since they may be related to a first exacerbation of a disease that was not previously diagnosed(13). Respiratory infections cause direct structural damage and contribute to the chronic inflammatory process(12). The associated enlargement of peribronchial lymph nodes may result in bronchial obstruction and, secondarily, structural injury(18).

It is widely recognized that sequelae BCs of tuberculosis are associated with more severe disease, greater pulmonary involvement on HRCT-Chest scans, and a predominance of upper lobe affection. Patients generally have a lower body mass index (BMI) and worse lung function(28).

With regard to NTMs, since they are ubiquitous, the development of disease requires some degree of immunodeficiency in the host. Pulmonary involvement is the most common manifestation of the disease and usually progresses. Rarely, hypersensitivity pneumonitis (hot tub lung) may be present. Two major clinical patterns can coexist: older patients with pre- existing structural alterations (BCs and/or cavitations due to previous lung disease); individuals without preexisting pulmonary pathology, usually non-smoking women, with rib cage anomalies and low BMI, who develop nodular, multifocal BCs(13). Lady Windermere Syndrome occurs with BCs in segments of the middle lobe (ML) or lingula due to infection by Mycobacterium avium intracellulare and often occurs in older women who suppress cough(9).

 

B. BCs and Immunodeficiencies:

The close relationship between these diagnoses stems from the greater vulnerability to recurrent infections that immunodeficiencies confer(12). Immunodeficiencies are a broad and heterogeneous group of diseases, fortunately of low prevalence, resulting from dysfunction of the immune system. The most prevalent group is relates to deficient antibody production (Acs), which includes immunodeficiencies that present with BCs following recurrent infections: IDCV, specific Acs deficiency, autosomal recessive/X-linked agammaglobulinemia, IgA deficit and Good's Syndrome(13).

CVID is the most prevalent immunodeficiency in adulthood. It presents with clinical infections, recurrent/prolonged diarrhoea and different expressions of autoimmune pathology (AI) and/or lymphoid proliferation. Specific Acs deficiency is much rarer, involving often complicated BCs and recurrent chest infections with normal total Immunoglobulin (Ig) G levels.

Agammaglobulinemia results from a delay in B cell differentiation, culminating in a small amount of these cells and much lower serum Ig levels. Infections develop from about 3-6 months of age (when maternal IgG levels begin to decrease), and immunoglobulin replacement is recommended. IgA deficiency is the most frequent immunodeficiency and tends to be asymptomatic. In view of its diagnosis in patients with BCs, it is important to quantify IgG subclasses and to test specific Acs, since IgA deficiency can progress to CVID/specific Acs deficiency(13).

Finally, Good's Syndrome represents the coexistence of thymoma and immunodeficiency diagnoses and is a rare cause of combined T-cell and B-cell deficiency. Generally identified between the 4th and 5th decades of life, it confers greater susceptibility to bacterial infections with encapsulated, viral and fungal microorganisms. Approximately 75% of patients have BCs, and are associated with more frequent and/or recurrent respiratory infections, pneumonia and inflammatory dysregulation(13).

 

C.  BCs and other chronic respiratory diseases:

BCs can be associated with chronic respiratory diseases – namely bronchial asthma, COPD or ABPA(11). In fact, many patients with BCs have some other respiratory pathology(9), with around 50% of patients with moderate-severe COPD having BCs, and asthma also being one of the most associated comorbidities. Severe asthma is particularly related to the existence of eosinophilic inflammation and BCs with mucus plugs(12, 25, 29).

– COPD: Similar to what happens among patients with BCs, in COPD the neutrophilic inflammatory pattern tends to predominate(29). The respiratory microbiome includes more proteobacteria, and there is overexpression of pro-inflammatory mucins (MUC5AC) and neutrophil dysregulation pathway proteins(25). As they are associated with increased systemic inflammation, worse lung function and QOL, more sputum and poor prognosis, it is importante to look for the existence of BCs in patients with COPD and very common AE. BCs are usually cylindrical, small, and multiple, dominating in the lung bases(13, 29).

– Bronchial asthma: there is a frequent and clinically significant association between asthma and BCs(29), with BCs estimated to be present in approximately 18-30% of asthmatic patients(13).

Asthma can be considered a comorbidity in patients with BCs, but it is also recognized that the latter can result from the former, particularly in cases of severe asthma. BCs are more common in patients with long-standing asthma, frequent AE and advanced age. Patients with overlap tend to be less atopic and have lower levels of Fractional exhaled nitric oxide (FeNO)(29).

 – Alpha-1-Antitripsin Deficiency: as an effective inhibitor of NE, Alpha-1-Antitrypsin (AAT) performs lung protection functions. Therefore, it is recommended to test for DAAT in all patients with BCs(13).

 

D. BCs and mucociliary clearance defects:

–          Primary Ciliary Dyskinesia: PCD is a rare and clinically heterogeneous autosomal recessive genetic disorder characterised by abnormal ultrastructure and/or ciliary function. Ciliary motility impairment results in upper and lower airways disease, with recurrent respiratory infections due to faulty mucociliary clearance(25). The age of presentation is variable, from birth to adulthood. In the neonatal period, it can cause respiratory stress and/or pneumonia without obvious predisposing factors, continuous rhinorrhea from birth, laterality problems or complex congenital heart disease. In childhood/adolescence it tends to manifest itself in the form of chronic productive cough, recurrent respiratory infections, BCs, chronic rhinosinusitis (rarely with NP), otitis media with recurrent effusion, loss of hearing acuity and/or halitosis. In adulthood, NP and halitosis predominate, as well as the occurrence of ectopic pregnancy/subfertility in women and infertility in men (50%)(13, 16).

–          Cystic Fibrosis/ other diseases related to Cystic Fibrosis: as an autosomal recessive multisystem disease with several possible phenotypic expressions, most common among caucasians, CF results from mutations in the CFTR gene. Such mutations cause dysfunction of the apical membrane protein CFTR (regulator of Cl- and Na+ transport in secretory epithelial cells) and consequently result in abnormal ionic concentrations along the apical membranes of these cells. Clinically, it is responsible for the development of diffuse BCs (95%) – often colonized by S. aureus, B. cepacea, etc. –, sinus disease (90-100%), exocrine pancreatic insufficiency (85%; leading to malabsorption), salt loss by sweat glands (100%), male infertility (99%), meconium ileus (20%), distal intestinal obstruction syndrome (20%), CF-related diabetes (20%), liver disease (20%) and NP (10%)(13).

 

E. BCs and excessive immune response:

–          Allergic Bronchopulmonary Aspergillosis: a non-invasive disease caused by hypersensitivity to the ubiquitous fungus Aspergillus fumigatus after inhalation of its spores. It almost only occurs in patients with asthma or CF (2%, 1-15%, respectively). Occasionally, it can complicate other chronic lung diseases, such as idiopathic BCs or those secondary to other causes. Without gender predilection, it is more frequent between the 3rd and 4th decades of life. Most patients report fever, weight loss, severe wheezing and shortness of breath, productive cough with very thick sputum, and sometimes dark brown mucus plugs(13). They are, essentially, central BCs, whose development is believed to be secondary to the impaction of mucous plugs in the bronchial walls previously weakened by eosinophilic infiltration(31-33).

 

F. BCs and Post-inflammatory Pneumonitis:

Post-inflammatory BCs may develop after acute inhalation injury or be related to chronic aspiration and severe GERD(12).

– Gastroesophageal Reflux Disease: frequent comorbidity (26-75% of patients with BCs). It is believed to contribute to BCs by 2 major mechanisms: vagally mediated bronchoconstriction reflex and pulmonary microaspirations(25). The existence of a causal relationship between GERD and BCs is controversial, but it is known that GERD can negatively impact BCs(13).

 

H. BCs and Connective Tissue Disease: BCs are a frequent extra-articular feature of RA (prevalence ~20%)(25), and are associated with rapidly progressive disease and frequent AE(12). In SS, the prevalence varies between 7 and 54%. They are usually older patients, with hiatal hernia, higher frequency of anti-smooth muscle and anti-SSA Acs(25).

 

J. Other causes of BCs:

–          Inflammatory Bowel Disease: pathogenic mechanisms are poorly understood, and there is the theory of the "Lung-Gut Axis" which, by affirming a common derivation of the embryonic cell line, argues that the same inflammatory process occurs at the pulmonary and intestinal levels in certain patients(25).

–          Diffuse Panbronchiolitis: idiopathic inflammatory disease that mainly affects the respiratory bronchioles, causing severe suppurative obstructive pathology. More common among Asians and with 2/3 of patients being non-smokers, clinically present with productive cough, profuse sputum, exertional dyspnoea and chronic sinusitis(13).

 

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