Small Airway Disease in Pulmonary Fibrotic Diseases: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Georgios I Barkas.

Small airway disease (SAD) is a pathological condition that affects the bronchioles and non-cartilaginous airways 2 mm or less in diameter. These airways play a crucial role in respiratory function and are often implicated in various pulmonary disorders. Pulmonary fibrotic diseases are characterized by the thickening and scarring of lung tissue, leading to progressive respiratory failure. 

  • autoimmune disease
  • fibrosis
  • interstitial lung disease
  • small airways

1. Introduction

Interstitial lung disease, or interstitial lung disease (ILD), encompasses a variety of lung disorders that affect the pulmonary interstitium [1]. These conditions can have devastating consequences, including reduced exercise capacity, poor gas exchange, and a lower quality of life. Sadly, most patients with ILD have limited treatment options, and respiratory failure and death are often inevitable outcomes [1,2,3][1][2][3]. The body’s natural response to pathogens is the formation of fibrosis, but in cases of pulmonary fibrosis, excessive inflammation and fibrotic responses can occur, leading to tissue remodeling and matrix deposition. We urgently need better treatments for ILDs to improve patients’ lives and prevent these devastating outcomes.
Fibrosis is a serious issue caused by the excessive deposition of the extracellular matrix (ECM) during wound healing [4].The process of fibrogenesis is orchestrated by several types of cells and signaling mechanisms, and it can lead to a variety of health complications. It is crucial to understand that fibrosis is not a disease in itself but rather an outcome of dysregulation following many types of tissue injury [5,6][5][6]. During tissue injury, fibroblasts become activated and increase the secretion of inflammatory mediators, contractility, and the synthesis of ECM components. This process leads to a minor increase in ECM deposition, which is usually cleared from the wound site via apoptosis after injury repair [6,7][6][7]. However, in pulmonary fibrosis, myofibroblasts, resulting from fibroblasts and other mesenchymal cells, repeatedly secrete ECM components that fail to clear via apoptosis. These cells remain activated, leading to excessive ECM deposition [6,7,8][6][7][8]. The accumulation of ECM can disrupt normal tissue architecture, leading to lung failure, increased stiffness, cell damage, and oxygen diffusion obstructions [9]. Factors such as infectious agents, alcohol, environmental particles, gene mutations, and predispositions can cause fibrosis, while inflammation upregulates mediators of fibrosis [6,7,8,9][6][7][8][9].
Small airway obstruction, small airway dysfunction, and small airway disease (SAD) refer to pathophysiology within bronchioles and non-cartilaginous airways 2mm or less in diameter [10]. Measuring SAD function is crucial for determining pulmonary mechanics and general lung function in patients with respiratory diseases, where small airways are the predominant site of resistance [7,10][7][10]. Accessing and visualizing these smaller airways in clinical practice is complex and requires the use of non-invasive techniques such as spirometry, oscillometry, resistance measurements, plethysmography, nitrogen washout, alveolar nitric oxide, helium–oxygen flow–volume curves, and high-resolution computed tomography (HRCT) [7,8,9,10][7][8][9][10].

2. Small Airways in IPF

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that primarily affects older adults. It is characterized by the progressive worsening of dyspnea and lung function, leading to respiratory failure, and it has a poor prognosis. IPF is fibrosing interstitial pneumonia associated with radiological and histologic features of usual interstitial pneumonia (UIP). Despite extensive research, the cause of IPF remains unknown [5,33][5][11]. The pathogenesis of IPF is complex, involving a wound-healing process in response to lung injury. The disease is characterized by the scarring of lung tissue, which reduces gas exchange and leads to respiratory failure. IPF is considered a multi-factorial disease with a complicated pathogenesis influenced by environmental, aging, and genetic factors [34][12]. Persistent micro-injuries cause damage to alveolar epithelial tissues in IPF, leading to aberrant repair processes. Pathologically, the pulmonary interstitium is involved, but the disease may also affect the airways, pleura, and pulmonary circulation [35][13]. Bronchiolitis is an injury to the bronchioles resulting in inflammation and potentially fibrosis [36][14]. The current pathogenic paradigm supports the idea that the disease arises from the premature senescence of alveolar epithelial cells following repetitive alveolar injury in genetically susceptible individuals [37][15]. This provides a start to the ECM accumulation cascade, which results in the fibrosis of the tissue.

3. The Small Airway Disease in Other Fibrotic Diseases

Interstitial pulmonary disease, caused by the thickening and scarring of lung tissue, is characterized by a restrictive defect without evidence of obstruction to airflow [48][16]. Interstitial pneumonias are a group of diseases defined by their distinct histopathological features, with the histological pattern being the archetype of progressive fibrosis [49,50][17][18]. Nonspecific interstitial pneumonia (NSIP) is an ILD that can be categorized as either idiopathic or secondary due to connective tissue disease or caused by toxins or numerous other causes [49][17]. A study of biopsy and autopsy samples on usual interstitial pneumonia (UIP) and NSIP patients revealed that NSIP patients present increased bronchiolar and peribronchiolar inflammation, fibrosis, and decreased luminal areas, to conclude that small airways may take part in the lung remodeling process [52][19]. Hypersensitivity pneumonitis (HP), which is a complex syndrome characterized by inflammation and fibrosis in both the airways and the lung parenchyma, is caused by the inhalation of a variety of diverse antigens—which are mainly derived from bird protein and fungi in genetically susceptible and sensitized individuals [53,54][20][21]. According to the ATS/JRS/ALAT (2020) [55][22] and ACCP (2021) [56][23] classifications, we now distinguish “non-fibrotic HP” and “fibrotic” HP. It can progress to pulmonary fibrosis [57][24], while its connection to the small airways is extensive [57,58][24][25]. HP is one of the most frequent causes of distal airway disease. In several studies, patients with HP had small airway abnormalities as indicated by ultrasonic pneumography (UPG) and IOS, not found by spirometry and body plethysmography [57][24]. Abnormality within and/or around the small airways is a unique feature of HP that is observed in all patients with HP in histopathology [53,59][20][26]. It is associated with inflammation of the bronchioles predominantly by lymphocytic infiltrates and granuloma formation, causing bronchial obstruction [59][26]. In other words, in HP, there is a strong association with small airway abnormalities where patients often exhibit inflammation in the bronchioles, characterized by granuloma formation and lymphocytic infiltrates, leading to bronchial obstruction. Another condition highly connected with the small airways is cryptogenic organizing pneumonia (COP), of unknown etiology, while organizing pneumonia (OP) has a known etiology [60,61][27][28]. It obstructs or erases the small airways, leading to small airway obstruction, as indicated by spirometry and histopathology [62][29]. The disease is influenced by several factors, including preexisting factors and genetic variants [63][30]. It is thought to be caused by an initial insult in the lower airways, which leads to inflammation and tissue injury. The pathogenesis of COP is not yet fully understood, but the histopathological features show injured and inflamed small airways, leading to excessive fibroproliferation due to aberrant tissue repair. Many factors have been implicated in the development of COP, including an increased level of circulating CD4+ T-cells, CD 8+ T-cells, and Th-cells. It is also hypothesized that pulmonary antigens cause cytotoxic T-lymphocytes to target endothelial cells, leading to tissue fibrosis [62,63,64,65,66,67,68,69][29][30][31][32][33][34][35][36].

4. The Small Airways in Autoimmune Interstitial Lung Disease

Apart from the known ILDs, small airways are also linked to other respiratory diseases falling under different categories, including occupational disorders and connective tissue diseases. Connective tissue disease (CTD)-associated interstitial lung disease (CTD-ILD) is the most common pulmonary manifestation of CTD, affecting the airways, lung parenchyma, and pleura while also being related to increased morbidity and mortality [71,72,73,74][37][38][39][40]. However, the connection of small airways to CTD-ILD has not been researched enough. Autoimmune diseases are a group of at least 80 illnesses that share a common pathogenesis, which is an immune-mediated attack on the body’s organs [74][40]. The immune system is developed to protect hosts from infectious agents; however, it can lead to disease either by an inability of one or more of its components to respond protectively to a pathogen or by the failure to distinguish self from non-self, which is the basis for autoimmune diseases [75][41]. The etiology of autoimmune diseases is multifactorial, with genetic, environmental, hormonal, and immunological factors considered essential in their development. However, the onset of at least 50% of autoimmune disorders has been attributed to “unknown trigger factors” [76][42]. Some autoimmune diseases that can have pulmonary manifestations include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS). RA and SLE are among the most researched due to their prevalence and the significant impact they can have on multiple organ systems. Both have been shown to have connections to small airways. Rheumatoid arthritis (RA) is an autoimmune disease that has been recognized as a clinical entity for over two centuries [76][42]. It is the most frequent inflammatory arthropathy [77][43], characterized by chronic, systemic, and inflammatory manifestations that affect connective tissue [78,79,80,81][44][45][46][47]. The autoimmune disorder affects approximately 1% of the population worldwide [81,82][47][48]. Pulmonary involvement is one of the common causes of morbidity in patients with RA. ILD is the most common and severe manifestation of RA lung diseases associated with parenchymal rheumatoid nodules [83][49]. Bronchiectasis is also a common lung characteristic of RA with an estimated prevalence of 10 and 30%, depending on the population analyzed and the imaging methodology used for detection. However, RA directly affects all the compartments of the thorax, including the lung parenchyma, airways, pleura, and less common vessels [84][50]. The FEF25, FEF50, FEF75, and FEF25-75 measurements in 99 patients with RA, in the case–control study of Zohal MA et al., revealed that the abnormal results of PFTs in rheumatoid disease were higher than usual [85][51]. Respiratory system involvement occurs in 30–40% of RA patients, making it the second leading cause of death in patients with RA [86][52]. Older studies have confirmed the existence of a subgroup of non-smoking patients with RA who have isolated small airway obstruction, as indicated by FEV1, FVC, FEV1/FVC, FEF25–75, and diffusing capacity for carbon dioxide (DLCO) measurements [87][53], and imaging evidence of airway involvement [88][54]. SLE and SS are two chronic autoimmune inflammatory disorders that impact the lungs and can lead to serious morbidity and mortality [92][55]. While there is no cure for SLE, it can be managed effectively with medication. However, the mortality rate is still high, with renal disease, cardiovascular disease, and infection being the most common causes of death among patients [93][56]. The exact cause or underlying pathophysiological mechanisms that trigger the autoimmune response in these diseases remain largely unknown, although researchers have suggested the role of gene susceptibility. It is believed that a combination of susceptibility genes, the absence of protective genes, and epigenetics may all contribute to the development of these conditions [92,93,94][55][56][57]. Data from older studies indicate a very high prevalence of pulmonary function abnormalities in SLE patients [95][58], obstructive airway disease, and the rapid deterioration of the respiratory function determined by low PFTs, i.e., FVC, DLCO, and FEV1/FVC ratio [96][59], or by using, in addition to PFTs, chest X-rays, thoracic CT scans, ventilation–perfusion (VQ) scanning, and plethysmography with TLC measurement, while also identifying other pulmonary features such as pleural disease, pulmonary nodules, pulmonary cysts, and OP [96,97][59][60]. SS is a connective tissue disease that affects the exocrine glands, leading to their dysfunction and eventual destruction. This disease frequently affects the small airways, as indicated by spirometry and chest HRCT imaging, and is associated with mild to severe respiratory symptoms [105,107][61][62]. Lung involvement in SS is well characterized and is observed during the disease, although pleura involvement is more commonly seen in SLE patients. On the other hand, primary SS (pSS) typically involves the airways [108,109,110][63][64][65]. ILD involvement and the coexistence of small airway lesions in pSS-interstitial lung disease has been revealed through several studies of pSS patients using spirometry and total lung capacity, as well as diffuse lung capacity that were impaired [111,112][66][67]. In a cross-sectional study aimed at estimating the prevalence of chronic respiratory symptoms in pSS, 114 consecutive patients were investigated with PFTs and chest HRCT on inspiratory and expiratory phases. The study found that the most commonly recognized pulmonary disorder among symptomatic pSS patients (one-fifth of the study group) was SAD, followed by xerotrachea and interstitial lung disease [113][68]. Sarcoidosis is a systemic inflammatory granulomatous disease of unknown etiology that affects 2 to 160 people per 100,000 worldwide and can involve any organ [120][69]. It is considered an autoimmune disease, with growing research suggesting similar patterns of cellular immune dysregulation seen in other autoimmune diseases like RA. Recent large-scale population studies show that sarcoidosis frequently co-presents with other autoimmune diseases [121][70]. However, the pathophysiology of the disease remains poorly understood, and known autoantibodies or useful serologic markers for the diagnosis and monitoring of autoimmune disease activity are lacking [122][71]. Sarcoidosis is closely linked to environmental factors, especially occupational exposures such as silica, pesticides, and mold or mildew, which are associated with increased odds of pulmonary sarcoidosis [123][72]. Its etiology remains undetermined, characterized by variable clinical presentations and disease course [124][73].  Sarcoidosis is one of the few ILDs that can affect the entire length of the respiratory tract, from the nose to the terminal bronchioles, and it causes a broad spectrum of airway dysfunction [124][73]. Peripheral airway obstruction may be caused by the formation of granulomas in a perilymphatic distribution along the bronchovascular bundles [124,125][73][74]. Older studies suggest that functional abnormalities in small airways may occur early in sarcoidosis [126][75]. Patients with pulmonary sarcoidosis who have obstructive airway disease may also have regional air trapping, which indicates SAD and can be visualized on expiratory HRCT and newer imaging modalities [124,125][73][74].

5. Conclusions

In conclusion, SAD significantly contributes to lung function decline in various fibrotic respiratory conditions. Diagnosing SAD can be challenging, as no specific clinical findings exist. However, a combination of methods can be used to assess the quiet zone of the lungs. SAD worsens the prognosis, and several treatments focusing on SAD (such as bronchodilators, inhaled corticosteroids, and immunomodulatory therapies) can help to improve symptoms and slow the disease’s progression. It is important to note that the small airways are a complex and dynamic system with still not fully understood mechanisms. The heterogeneous nature of SAD in fibrotic diseases certainly does not make treating and diagnosing it any easier. Therefore, treatment and diagnosis must be tailored to the individual patient with a personalized and holistic approach, impacting disease progression. Environmental factors such as smoking can contribute to and exacerbate SAD. Patients with SAD can live a long and active life with the necessary changes in their lifestyle, like quitting smoking and exercising regularly. There is a need for more research regarding the impact of SAD in fibrotic respiratory diseases with advancements in imaging instruments and treatment plans, as well as longitudinal studies to observe disease progression and its impact on patients’ lives.

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