Abstract
This meeting report provides an overview of the highlights of the Bronchitis XI international symposium, held in June 2024 in Groningen, The Netherlands. The theme of this year’s symposium was “heterogeneity of lung disease in a changing environment,” and the symposium contained five different sessions focused on (i) heterogeneity of chronic lung disease, (ii) environmental changes with impact on lung disease, (iii) the aging lung, (iv) bronchitis, and (v) innovative therapy. The highlights from each of these sessions will be discussed separately, providing an overview of latest studies, new data, and enthralling discussions.
Introduction
In June 2024, the Groningen Research Institute of Asthma and COPD (GRIAC) hosted the 11th International Bronchitis Symposium in the University Medical Center Groningen (UMCG), The Netherlands. The Bronchitis symposium has a longstanding history in Groningen. Ever since the early 60s of the last century, the latest developments in the field of obstructive respiratory diseases have been discussed during the Bronchitis symposia. “The Dutch hypothesis,” that describes the overlap and similarities between bronchitis, emphysema, and asthma, was also developed during these early Bronchitis symposia. This year, over 150 scientists, students, and healthcare professionals from 15 different countries were participating. The topic of Bronchitis XI was heterogeneity of lung disease in a changing environment, which was addressed by five different sessions, i.e., heterogeneity of chronic lung disease, environmental changes with impact on lung disease, the aging lung, bronchitis, and innovative therapy. Important aspects that were discussed in these sessions were (epi)genetic mechanisms, environmental risk factors, disease endotypes, novel technologies, and innovative treatment strategies (Fig. 1). The sessions consisted of presentations of leading experts in the field followed by interactive discussions. The highlights of each session are discussed below.
Heterogeneity of Chronic Lung Disease
This session explored the complex nature of asthma and COPD from various perspectives. Experts presented advancements in artificial intelligence (AI)-driven imaging, small airway remodeling, exacerbation subtypes, endotyping, and genetics in asthma and COPD.
Bram van Ginneken (Nijmegen, The Netherlands) presented an overview of the development of AI in medical imaging and highlighted its current applications and future potential in obstructive lung diseases. He described Thirona’s lung quantification software LungQ (Thirona, Nijmegen, The Netherlands) as an example of an advanced AI system that can analyze lung conditions by measuring airway wall thickness and detecting bronchiectasis and mucus plugs. Next, recent studies on the application of AI to lung imaging were discussed, for example, deep neural networks for emphysema subtyping on computerized tomography (CT) scans [1] and a deep learning approach that can be used to estimate lobe-specific lung function from CT scans [2]. Finally, he highlighted the potential of photon-counting CT technology, demonstrated by Flohr et al. [3]. This technology offers high spatial resolution and improved tissue contrast, holding promise for enhancing image quality and reducing the radiation dose.
Tillie-Louise Hackett (Vancouver, Canada) addressed insights on spatial imaging of small airway remodeling in asthma and COPD. She highlighted findings from her group, which showed that applying stereology – a quantitative method analyzing the spatial structure of three-dimensional objects based on two-dimensional sections – to multi-resolution CT images allowed a comprehensive analysis of the human lung parenchyma [4]. Next, Tillie Hackett showed that up to 40% of the terminal and transitional bronchioles in asthma patients contained mucus plugs, where the mucus-plugged airways displayed airway remodeling and inflammatory infiltrates and the non-plugged airways did not [5]. Finally, during the discussion a suggestion was made to develop a single-cell atlas to elucidate the cellular composition of terminal bronchioles and airway mucus plugs [6].
Maarten van den Berge (Groningen, The Netherlands) discussed COPD exacerbations, emphasizing different subtypes and their implications for treatment decisions. He referred to a study by Muiser et al. [7] using the real-world NOVELTY dataset, showing that in patients with asthma and COPD, increased fractional exhaled nitric oxide (FeNO) is associated with a higher risk of exacerbations treated with oral corticosteroids but not those treated with antibiotics. In contrast, in patients with COPD without asthma, elevated FeNO levels were associated with a lower risk of all exacerbation types. These findings demonstrate that FeNO might not be a reliable biomarker for all exacerbations in the NOVELTY real-world study. In addition, Maarten van den Berge highlighted the challenge of accurately diagnosing COPD exacerbations. He mentioned the Rome proposal by Celli et al. [8], which updated the definitions and severity classifications of COPD exacerbations, stressing the importance of a comprehensive clinical assessment that includes potential respiratory and non-respiratory comorbidities.
Rosa Faner (Barcelona, Spain) discussed the heterogeneity of asthma and COPD and emphasized the importance of endotyping, to facilitate more personalized treatments. She also presented findings from the real-world NOVELTY study, showing data from Augustí et al. [9], on common pulmonary, extrapulmonary, and behavioral treatable traits in patients with asthma, COPD, and asthma + COPD. The study showed that some treatable traits were specific to the diagnosis and severity of the disease, while others were not. Rosa Faner highlighted the necessity to integrating multi-omics data to identify clinically relevant endotypes, referring to a study by Olvera et al. [10] that used an innovative multilayer network approach to uncover molecularly distinct patient groups, even among clinically similar phenotypes. This suggests that distinct endotypes may be associated with specific clinical symptoms.
Michael Cho (Boston, USA) focused on the genetics of the susceptibility to develop asthma and COPD, emphasizing the importance of identifying genetic risk factors to gain a better understanding of disease pathogenesis and to identify potential drug targets and side effects. He showed that a deep learning model can be used on raw spirogram data to predict the onset of COPD, revealing new genome-wide genetic associations [11]. In addition, a study investigating the genetic variance associated with FEV1 and FVC identified more than 1,000 foci associated with lung function [12]. Despite significant progress that has been made in identifying genes associated with asthma and COPD in the past decades, Cho emphasized that caution is needed when interpreting identified genetic variants. The most significant variants are not necessarily the most relevant causal variants, and much remains to be understood about gene function and its precise contribution to disease pathogenesis.
Environmental Changes with Impact on Lung Disease
With the rapidly changing environment we are currently experiencing, it is key to understand the impact of both established and emerging environmental changes on lung disease. This session therefore focused on various aspects of the environment and their effects on the development and progression of lung diseases.
Giovanni Viegi (Pisa, Italy) opened this session by providing an extensive overview of studies linking climate change to the development of chronic lung diseases. According to the World Health Organization (WHO), climate change is expected to cause at least 250,000 additional deaths per year between 2030 and 2050 due to, among other things, malnutrition, malaria, air pollution, and heat stress. Recently, the 2024 Europe report of the Lancet Countdown on health and climate change provided a comprehensive overview of all aspects of climate change, from exposures and health effects to mitigation actions and economic consequences [13]. In the context of lung disease, climate change-associated air pollution and heat stress are the most relevant factors. Extreme weather and air pollution have, for example, been associated with increased risk of asthma morbidity and mortality [14, 15]. Especially children can be vulnerable to climate change, already in utero, which may result in increased prevalence of disease later in life [16]. In addition to association studies, mechanistic studies have demonstrated that air pollution and heat can negatively impact immune responses and barrier defense of our skin, gut, and lungs [17]. Giovanni Viegi emphasized that a holistic approach involving key stakeholders and adopting a common goal to improve public health is required to successfully halt climate change and associated air pollution. Specifically in respiratory research, it is crucial to quantify the impact of climate change and to elucidate underlying mechanisms, thereby including possible combined effects of multiple exposures (the so-called exposome).
Lidwien Smit (Utrecht, The Netherlands) continued the session discussing correlations between air pollution and lung diseases. Despite improvements in air quality over the past few decades, air pollution still accounts for approximately 300,000 premature deaths annually in Europe. Although sufficient studies have demonstrated the impact of air pollution on (lung) health to justify immediate action, the speaker emphasized that studying air pollution is still highly relevant. New pollutants and sources continue to emerge; indoor air quality remains understudied compared to outdoor air and agricultural and energy transitions. Lidwien Smit discussed the Livestock Farming and Neighbouring Residents’ Health Study in the Netherlands that investigated the effect of agricultural air pollution on human health. The study measured and modeled exposures, linking these to respiratory health (zoonotic), infectious disease, and antimicrobial resistance. It was found that the prevalence of COPD, asthma, and allergies was lower in people living near livestock farms [18‒20]. However, the prevalence of COPD was higher among livestock farmers compared to control populations, and COPD patients living near farms experienced more respiratory symptoms and displayed increased usage of inhalable corticosteroids [18]. In addition, short-term ammonia exposure was shown to negatively impact lung function in a cross-sectional study in 2,500 adults and a panel study in 100 COPD patients [21, 22]. Additionally, Lidwien Smit highlighted that other diseases, such as COVID-19, are also affected by air pollution. Long-term exposure to air pollution was shown to increase the risk for SARS-CoV-2 infection and the risk of hospitalization with COVID-19. The source of the particulate matter was an important determinant in this process, with livestock-derived particulate matter (PM) showing the most detrimental effects [23]. Lidwien Smit concluded that an interdisciplinary approach is needed to further study and simultaneously mitigate air pollution and its detrimental effects on lung health.
Barbro Melgert (Groningen, The Netherlands) subsequently shed light on one of the emerging pollutants: microplastics. Microplastics are defined as pieces of plastic between 100 nm and 5 mm in size that can be produced deliberately or originate from abrasion of larger pieces of plastic. These microplastics have been detected in outdoor and especially indoor air, as well as in our lungs [24]. While other air pollutants and their relation to lung health have been studied extensively, the ambient exposure levels and possible respiratory health effects of microplastics are still understudied. Yet, in occupational exposure studies, microplastic exposure has been associated with the development of asthma, pulmonary fibrosis, and lung cancer [25]. Barbro Melgert discussed recent results from her group showing that the development of murine airway organoids was markedly inhibited by the presence of nylon (polyamide 6,6) microfibers. Interestingly, fully developed organoids were not affected by nylon exposure, indicating that nylon fibers are impeding organoid differentiation rather than inducing direct cytotoxicity. Follow-up experiments with nylon fiber-derived leachates showed a comparable detrimental effect on airway organoid outgrowth, indicating that chemicals leaching from the nylon fibers are responsible for the observed negative effect [26]. The search for the chemical culprit(s) is still ongoing as well-known chemical additives such as bisphenol A and benzophenone did not affect airway organoid formation. These findings suggest that developing and regenerating airways may be most at risk upon microplastic inhalation and that possible effects of leaching chemicals need to be taken into account when assessing the risk of ambient and occupational microplastic exposures.
Jakob Stokholm (Copenhagen, Denmark) emphasized the important role of the airway and gut microbiome in lung disease. He described how the environment can affect the microbiome by showing results from the COPSAC studies. COPSAC refers to the Copenhagen Prospective Studies on Asthma in Childhood, conducted by the Copenhagen Studies on Asthma in Childhood Research Center to investigate the contribution of early-life factors to the development of asthma and other allergic diseases in children. In these studies, longitudinal deep clinical phenotyping was performed in large cohorts, looking at interventions, environmental exposures, the microbiome, immune responses, genomics, metabolomics, and the prevalence of chronic inflammatory diseases. The presence of specific bacteria in the airway microbiome at 1 month of age was associated with the development of asthma later in life and was also predictive for duration of wheezing episodes and antibiotic efficiency in children with recurrent asthma-like symptoms [27, 28]. Impaired maturation of the gut microbiome within the first years of life was shown to increase the risk of asthma in childhood [29]. Urban living has been established as a risk factor for asthma and allergy but has also been shown to affect the airway and gut microbiome [30]. While microbiome studies mostly focus on bacteria, also the gut virome (mostly bacteriophages) could be related to the development of asthma. Interestingly, the bacteriome and virome showed to be independent and synergistic risk factors [30]. Jakob Stokholm concluded that there is ample evidence that the early-life microbiome in both the airway and in the gut is associated with the development of asthma later in life. Understanding perturbations and ineffective maturation processes of the microbiome in early life and possible effects of the environment may be key for future disease prevention.
The session was closed by Erik Melén (Stockholm, Sweden), providing an overview on how the environment can actually affect our susceptibility to obstructive lung disease through epigenetic changes. Especially children are vulnerable to air pollution, which can among other things be a consequence of more time spent outside, higher breathing rates, and narrower airways. In the BAMSE project, a prospective and longitudinal project to establish risk factors for asthma and other allergic diseases in childhood, Erik Melén and his team demonstrated significant plasticity in individual lung function from childhood to adulthood, as well as associations between improved air quality and lung development [31, 32]. Furthermore, Erik Melén discussed that these negative effects of exposure to air pollution can already originate in utero, as maternal smoking during pregnancy has been related to widespread DNA-methylation changes in the fetus, which may predispose the child to the development of disease later in life [33]. In conclusion, early-life exposures may have long-lasting effects, likely through epigenetic changes. This statement aligns with the common thread of this session on environmental changes with impact on lung disease: early intervention is crucial to prevent environment-related chronic respiratory diseases later in life.
The Aging Lung
The prevalence of chronic age-related diseases is rising with increased life expectancy. It is expected that by 2050, 20% of the population is 65 years of age or older [34]. Chronic age-related diseases are the main cause of death with 74% of deaths worldwide. This will result in a high burden on society and healthcare systems. Therefore, many studies are ongoing to understand the underlying mechanisms of chronic age-related diseases and to develop antiaging therapies. Lung aging has been recognized to play a role in the pathogenesis of chronic lung diseases as well, including COPD and idiopathic pulmonary fibrosis (IPF) [35‒38]. The speakers of this session elaborated on the underlying mechanisms of lung aging, including inflammatory processes, cellular senescence, epigenetics, and tissue regeneration.
Alexander Misharin (Chicago, USA) opened the session describing the interplay between aging, alveolar macrophages, and the alveolar environment. Alveolar macrophages play an important role in innate immunity and tissue homeostasis, including tissue repair after injury [39]. His group demonstrated that age-related changes in alveolar macrophages are not cell autonomous but are driven by the aging alveolar niche. In this study, alveolar macrophages were transferred from old to young mice and vice versa and subsequently single-cell RNA sequencing was performed. Importantly, it was observed that young alveolar macrophages in old mice acquired a similar transcriptomic profile as old naïve alveolar macrophages [40]. Misharin’s group also demonstrated that this effect was not dependent on circulating cells or growth factors but on the microenvironment. Next, Alexander Misharin presented data to show that monocyte-derived macrophages play a crucial role in tissue resolution after injury and that persistent pro-inflammatory macrophages drive lung fibrosis [41], highlighting the importance of macrophages in tissue homeostasis. Lastly, it was shown that alveolar macrophages also play an important role in a positive feedback loop with T cells that drives alveolar inflammation in COVID-19 pneumonia and that intervening with this feedback loop is a promising therapeutic strategy for severe COVID-19 pneumonia [42].
Maaike de Vries (Groningen, The Netherlands) continued the session on the relevance of epigenetic clocks in COPD. Epigenetic clocks can estimate the biological age of an individual based on DNA methylation. The first generation of epigenetic clocks were developed by Horvath and Hannum et al. [43, 44]. These clocks were developed only based on a combination of methylated CpG sites and chronical age. The second-generation epigenetic clocks additionally included health status and mortality risk. Moving further, the third generation of epigenetic clocks can predict the pace of aging. Maaike de Vries presented a study on accelerated aging, in which the association between accelerated aging estimated by the different generation of epigenetic clock and lung function and COPD was studied in blood samples of 1,622 subjects from the large Dutch Lifelines cohort study. Additionally, these findings were validated in COPD patients in the Spanish cohort from the group of Rosa Faner from Barcelona. One of the limitations of the current epigenetic clocks is that they are developed based on DNA-methylation profiles in blood. So, in the future it will be of relevance to develop lung-specific epigenetic clocks. During the discussion, it was mentioned that smoking has a major effect on DNA methylation, which partly drives biological aging and thus the epigenetic clocks.
Morten Scheibye-Knudsen (Copenhagen, Denmark) presented a newly developed method to better detect senescent cells in vitro and in vivo. Cellular senescence, defined as irreversible cell cycle arrest, has been extensively described to contribute to aging and age-related diseases [45, 46]. As no specific single marker of senescent cells is available, Scheibye-Knudsen’s group developed a method to detect senescent cells using nuclear morphology [47]. Senescent cells display an altered nuclear morphology with an increase in size and irregularities in the nuclear envelope. His group used deep machine learning on thousands of nuclei from senescence-induced dermal fibroblasts in vitro. Their prediction model was validated with strong correlations with the common senescence markers in these fibroblasts and other cell types [47]. Next, the prediction model was evaluated on in vivo samples, where strong correlations between precited senescence scores and p21 and age in mice skin were found. In human dermis samples, a less strong, but significant, correlation with age was observed. Applying this newly developed method on breast cancer biopsies resulted in identification of increased risk ratios with high predicted senescence scores [48]. In the discussion, it became clear that his group is trying to train the prediction model using different senescent cell types to improve the senescence prediction, especially in vivo.
Mareike Lehmann (Marburg, Germany) presented the molecular mechanisms underlying impaired tissue regeneration in the aging lung, including inflammaging, stem cell exhaustion, and cellular senescence. Mareike Lehmann proposed that aging predisposed to chronic lung diseases by cell intrinsic factors, including progenitor cell function, and cell extrinsic factors, including inflammaging. Lehmann’s group demonstrated that fewer organoids were formed by alveolar type 2 (AT2) cells from old mice, which was driven by cellular senescence [49]. Higher levels of cellular senescence was demonstrated previously in airway and alveolar epithelial cells, fibroblasts, and endothelial cells from patients with chronic lung diseases, including IPF and COPD. Next, Mareike Lehmann presented that senescent fibroblasts impair the stem cell function as fewer murine organoids were formed with senescence-induced human fibroblasts [50]. Thus, by using different models, it was demonstrated that cellular senescence affects the progenitor cell function and thereby contributes to impaired tissue regeneration in lung aging.
The session was finished with a presentation from Jonathan Baker (London, UK) about the development of antiaging strategies in lung diseases, with a special focus on targeting cellular senescence. Jonathan Baker described that cellular senescence plays an important role in COPD, where data demonstrated higher levels of senescence in small airway epithelial cells (SAECs) from COPD patients compared to those from healthy controls, which was driven by oxidative stress [51]. The senescence-associated secretory phenotype (SASP) of the senescent cells may contribute to the inflammation in the lungs of COPD patients. To prevent senescence-driven inflammation in COPD, strategies to target senescent cells have been developed. These strategies include senolytics that eliminate senescent cells and senomorphics that reduce the effects of the SASP [52]. Jonathan Baker presented results of a study where SAECs were cultured at air-liquid interface and were treated with dasatinib and quercetin (D+Q), a combination of drugs that was found to be senolytic and currently is in clinical trials for kidney diseases and IPF [53, 54]. His group observed a reduction in p16 levels and SASP secretion and a restoration of epithelial barrier function in SAECs from COPD patients after D+Q treatment, indicating the potential of senescence-targeting strategies in COPD. At the moment, many studies are focusing on developing more specific senescence-targeting therapies, including targeting SA-β-gal, CAR T-cell therapy, targeting iron accumulation, and targeting the cGAS-STING pathway.
Bronchitis
In this session, Marcus Mall (Berlin, Germany) reviewed the effects of mucoid impaction in several lung diseases. Mucus plays an important role in the pathogenesis of a spectrum of muco-obstructive lung diseases, such as cystic fibrosis, COPD, asthma, and bronchiectasis. In case of cystic fibrosis, due to the CFTR-gene dysfunction, impaired mucociliary clearance leads to chronic infection and inflammation, subsequently causing bronchiectasis and progressive irreversible lung damage [55]. In patients with COPD and asthma, mucus plugging can also lead to inflammation and subsequent lung damage. Increased mucus production can be caused by abnormal ion or fluid transport or hypersecretion of mucins. Accumulation of mucus increases the osmotic pressure and slows mucociliary clearance. Furthermore, mucus is a nidus for airway infections [56]. Marcus Mall explained that the airway microbiota composition is different across muco-obstructive lung diseases and that mucus plugging can promote bacterial infections. Additionally, he discussed that hypoxia due to mucus plugging also triggers sterile neutrophil airway inflammation via IL-1 receptor signaling [57]. For example, knock out of the IL-1 receptor reduces neutrophilic inflammation and structural damage, in absence of infectious causes [58]. Furthermore, mucus triggers airway macrophage immune responses and dysfunction, which can also lead to disease progression [59]. Thus, there are multiple reasons why mucus plugging can contribute to disease progression, and mucus plugging can be a promising therapeutic target, which was further supported by the observation that the use of hypertonic saline and amiloride to reduce mucus plugging can alleviate inflammation [60]. Marcus Mall concluded his presentation by showing that preventive inhalation of hypertonic saline improves lung clearance in infants with CF (PRESIS study) and by mentioning that novel mucolytics are currently being developed.
The next presenter in this session was Fernando Martinez (New York, USA), who presented an overview on the trajectory of lung function in several lung diseases. He explained that there are several factors that influence the intrauterine growth, which might lead to impaired lung function. For example, preterm birth is a risk factor for chronic and lifelong pulmonary disease and there are structural and functional respiratory limitations in preterm survivors during mid-childhood [61]. Intrauterine growth retardation gives spirometric restriction in adult life. In persons with a restrictive spirometric baseline pattern, there is a slightly higher risk of cardiovascular disease. Moreover, there are also maternal factors, such as nutritional deficits (e.g., in case of excessive vomiting or anemia) that predict the development of spirometric restriction in adult life [62]. There are other genetic factors that are being studied and associated with decline in lung function, such as the alpha-1-antitrypsin levels, where lower levels are associated with lower FEV1. Martinez hypothesized that the balance between proteases and antiproteases may play a critical role in the determining trajectories of lung function and the timing of the decline in lung function in adult life.
Pallav Shah (London, UK) presented an overview of the bronchoscopic treatment options for bronchitis patients [62]. He explained that with metered cryospray treatment using liquid nitrogen, the endobronchial tissue rapidly freezes, cryo-ablating the abnormal epithelial surface overgrown with mucin-producing goblet cells. This facilitates regrowth of normal bronchial epithelial cells that will facilitate removal of mucins, subsequently reducing chronic inflammation. It was shown that this treatment is safe, with no severe adverse events and with an improvement in quality-of-life scores (SGRQ, CAT, cough questionnaire) [63]. Another treatment Pallav Shah discussed is bronchial rheoplasty, in which pulses of electrical energy cause apoptosis of epithelial cells, but extracellular matrix is preserved. This should lead to regeneration of normalized epithelium. Current evidence, open label and feasibility studies, show that there is a reduction in goblet cell hyperplasia scoring and an increase in airway volume [64]. Furthermore, there was a significant improvement in CAT and SGRQ scores, with the positive effect lasting for several years. The last treatment discussed by Pallav Shah is targeted lung denervation, in which radiofrequency is used to ablate the parasympathetic innervation of the lungs using a balloon with an electrode. The first randomized controlled trial showed a significantly lower risk of hospitalization due to COPD exacerbations, while the lung function and quality of life remained stable [65]. In conclusion, several new and exciting treatment options for patients with bronchitis have been developed recently and in the coming years we should expect data on randomized clinical trials.
Innovative Therapy
This session focused on innovative therapies in obstructive lung diseases, with presentations about the use of biologicals in asthma and COPD, the treatable traits approach, cell-based therapies for lung diseases, and novel medical devices for the treatment of emphysema. Gerard Koppelman (Groningen, The Netherlands) addressed the heterogeneity of asthma and its implications for targeted treatment with biologicals. He explained that genetic differences contribute to the clinical variability observed in asthma, and a review of genome-wide association studies led to the identification of 128 distinct single-nucleotide polymorphisms linked to asthma [66], with 38 of these single-nucleotide polymorphisms being associated with the regulation of blood eosinophilic count [67]. Furthermore, he explained that childhood-onset asthma exhibits a unique genetic profile, with specific genes not found in adult-onset asthma [68]. These genetic patterns can be utilized in targeted treatment of asthma with biologicals. Gerard Koppelman highlighted the treatment with mepolizumab (anti-IL-5), demonstrating greater reductions in the rates of exacerbations as baseline blood eosinophil counts increased, according to a secondary analysis of the DREAM and MENSA studies [69]. Furthermore, in the MUPPITS-2 study, nasal transcriptomic modular analysis was conducted to elucidate the mechanisms underlying mepolizumab’s response. This analysis revealed that nasal genes related to type 2 inflammation remained associated with exacerbations in the placebo group but lost this association in the mepolizumab-treated group. Additionally, the expression of this nasal gene module was more effective in predicting exacerbations and treatment response compared to previously studied biomarkers [70]. Finally, Gerard Koppelman discussed a study by El-Huseini et al. [71] introducing a gene signature to predict the presence of active IL-6+ sIL-6Rα signaling in asthma patients. This signature was found to be enhanced in asthma patients with low eosinophil counts, suggesting it could serve as a potential treatment target for olamkicept.
Guy Brusselle (Ghent, Belgium) discussed the current status of biological treatments in COPD and explained that COPD exacerbations can be categorized into biological clusters, including bacterial infection, viral infection or eosinophil-predominant clusters [72]. This classification suggests that the underlying mechanisms driving each type of exacerbation are distinct and may benefit from more targeted interventions. However, unlike asthma, for now there are currently no biologicals available for the treatment of COPD patients. The results from several trials were discussed. In the METREO study, which included patients with a blood eosinophil count of ≥150 per cubic millimeter, treatment with mepolizumab (anti-IL-5) resulted only in a slight reduction of exacerbations of 15% and in no improvement in quality of life [73]. In the TERRANOVA study, no reduction in exacerbation rate following treatment with benralizumab (anti-IL-5R) was observed [74]. Next, two studies that investigated dupilumab (anti-IL4Rα) were discussed. In the BOREAS trial, treatment with dupilumab resulted in a 30% reduction in exacerbation rate and an improvement in quality of life [75]. In the NOTUS trial, dupilumab was again found to significantly reduce exacerbations, and interestingly, cardiovascular events were also reduced [76]. Dupilumab is the first biological that has shown efficacy in the treatment of COPD with type 2 inflammation. Guy Brusselle concluded his talk by addressing tezepelumab (anti-TLSP) and showed that in the COURSE study, tezepelumab reduced the annualized rate of exacerbations by 17% but this reduction was not statistically significant. Greater reductions in exacerbations were seen in patients with blood eosinophil counts of more than 150 per cubic millimeter [77].
Frits Franssen (Maastricht, The Netherlands) touched upon the treatable traits approach to achieve personalized medicine in obstructive lung diseases. He explained that to effectively treat COPD and asthma, not only the pulmonary aspects need to be considered but also the extrapulmonary factors contributing to the overall disease burden. Treatable traits can stem from either phenotypic recognition or underlying causal pathways, identified through validated biomarkers. These traits must be clinically relevant, measurable, identifiable, and treatable. Challenges regarding the treatable traits approach were discussed. First, traits are not isolated features of disease, as highlighted by a study that identified clusters of comorbidities in patients with COPD [78]. Secondly, focusing solely on traits does not enhance our understanding of the underlying disease pathophysiology. Additionally, identifying traits requires an extensive diagnostic trajectory, given the potentially limitless number of treatable traits, as demonstrated in the NOVELTY study [9]. This process can be time-consuming and may not always be cost-effective. Pulmonary rehabilitation (PR) offers one approach to manage treatable traits by addressing multiple factors in a personalized manner. PR has demonstrated efficacy in improving various aspects such as exercise tolerance, quality of life, body composition, and psychological symptoms [9, 79, 80]. Finally, a randomized controlled trial was highlighted, which combined bronchoscopic lung volume reduction treatment (BLVR) with PR. However, this combined approach showed no additional benefit compared to BLVR alone [81].
Daniel Weiss (Vermont, USA) provided an overview of the current status of cell-based therapies for COPD. The goal of cell-based therapy in COPD is to restore emphysematous tissue into structurally and preferably also functionally normal lung tissue. Various types of cell-based therapies are currently under investigation, with this presentation Daniel Weiss focused mainly on mesenchymal stromal cell (MSC)-based therapy. MSCs can be extracted from multiple adult human tissues, including bone marrow, adipose tissue, umbilical cord, and lungs, expanded in culture, and then administered systemically or directly intratracheally. Once in the lung, MSCs are hypothesized to respond to the inflammatory environment by releasing soluble mediators and by interacting with pulmonary epithelial or vascular endothelial cells in a paracrine manner, including the secretion of growth factors, anti-inflammatory mediators, and even intact mitochondria [82]. Although MSCs are currently not approved for lung diseases, numerous publications in pre-clinical models have led to clinical studies in respiratory diseases. A double-blind, phase II randomized controlled trial evaluating systemic MSC administration in patients with COPD was highlighted. No toxicity or serious adverse events related to MSC administration were observed but also no clinical improvements [83]. However, a post hoc analysis stratified by elevated baseline C-reactive protein did show improvement in pulmonary function and exercise capacity following MSC administration [84]. Daniel Weiss explained that this, coupled with the immunomodulatory properties of MSCs, highlights the potential of MSC-based cell therapy in disease phenotypes characterized by inflammation. This is supported by several clinical studies, investigating the potential of MSC therapy in acute respiratory distress syndrome, showing beneficial outcomes [85‒87]. In the discussion, the need for better understanding the optimal composition of the MSC secretome, MSC source, route of administration, and particularly strategies to lengthen MSC retention in the lungs was stressed in order to improve its performance in COPD.
Dirk-Jan Slebos (Groningen, The Netherlands) shed a light on novel medical devices for the treatment of emphysema patients. BLVR with endobronchial valves has been adopted as a treatment modality for patients with severe emphysema [88]. However, due to extensive selection criteria, only 20% of referred patients are eligible for endobrachial valve treatment, emphasizing the need for additional therapeutic options [89]. Dirk-Jan Slebos explained that one reason for ineligibility is the presence of collateral ventilation due to incomplete fissures. This problem is addressed by the CONVERT trial investigating whether AeriSeal foam can be used to close the fissure gap (NCT04559464). Another reason for ineligibility is a homogeneous distribution of emphysema. An alternative treatment option for this emphysema phenotype is endobronchial coil treatment, which has shown positive clinical outcomes in the past [90, 91]. However, the manufacturer (Boston Scientific) stopped producing these devices, and attempts by other manufacturers to develop a new coil have failed thus far. Currently, the original coil is being recreated, potentially making it a future therapeutic option. Another potential future therapy is endobronchial thermal liquid ablation, which is currently investigated in the REDUCE study (ACTRN12622001327774) in Australia. According to Dirk-Jan Slebos, the most promising field might be treatments aimed at releasing trapped air. The EASE trial, conducted 10 years ago, investigated the effect of creating airway bypasses using stents, but this only resulted in short-term improvements [92]. Currently, an implantable artificial bronchus (IAB-1) that supports the airways in order to reduce air trapping is under investigation (NCT05087641) [93].
Concluding Remarks
This highlights article offers a snapshot of the cutting-edge data discussed at the 11th Bronchitis symposium. The event was marked by high-quality speakers, lively discussions, and a compelling social program, contributing to its tremendous success. Key takeaways from this symposium include the recognition of multiple factors influencing the onset and progression of chronic lung diseases. It is important to consider patient heterogeneity when exploring potential future treatments. Additionally, environmental factors throughout life significantly impact the susceptibility to and progression of lung diseases. Future treatment strategies may focus on reducing accelerated aging, endotype-targeted biologicals, or exploring novel bronchoscopic approaches to relief symptoms and increase the quality of life of patients with obstructive respiratory diseases.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The study was not supported by any sponsor or funder.
Author Contributions
Conceptualization: S.D.P. and D.-J.S.; supervision: I.H.H., M.N.H., D.-J.S., M.V., and C.-A.B.; writing – original draft: S.D.P., E.A.M.D.H., T.D.K., P.J.M.K., G.F.V., R.R.W., and S.M.; and writing – review and editing: S.D.P., E.A.M.D.H., I.H.H., M.N.H., T.D.K., P.J.M.K., D.-J.S., G.F.V., M.V., R.R.W., C.-A.B., and S.M.