Authors: Han Yang, Si Chen, Jiayuan Sun, Felix J.F. Herth
Categories: Review Article, Asthma, Bronchoscopic lung volume reduction, Chronic inflammatory airway disease, Chronic obstructive pulmonary disease, Emphysema, Targeted lung denervation
Source: Chinese Medical Journal Pulmonary and Critical Care Medicine
Authors: Han Yang, Si Chen, Jiayuan Sun, Felix J.F. Herth
Chronic inflammatory airway diseases, such as chronic bronchitis, chronic obstructive pulmonary disease, emphysema, and bronchial asthma, pose significant healthcare challenges. Interventional treatments offer promise as valuable complements to the optimal medical therapy recommended by the Global Initiative for Chronic Obstructive Lung Disease guideline and the Global Initiative for Asthma guideline. By directly accessing the airways, these minimally invasive procedures enable precise interventions. They encompass a wide range of techniques including bronchial thermoplasty and targeted lung denervation for both chronic obstructive pulmonary disease and severe asthma, bronchoscopic lung volume reduction (including the use of endobronchial valves, coils, and bronchoscopic thermal vapor ablation), airway bypass and peripheral stent placement for emphysema, bronchial rheoplasty and spray cryotherapy for chronic bronchitis, and other emerging methods. These interventional treatments aim to improve patients’ symptoms by reducing lung volume, alleviating hyperinflation, eliminating vagal innervation, disrupting hyperplastic goblet cells and thus reducing excessive mucus secretion, and weakening submucosal smooth muscles. This review highlights the potential advantages of interventional treatments for chronic inflammatory airway diseases and discusses relevant techniques tailored to specific disease subtypes. The overall aim is to assist interventional pulmonologists in selecting the most appropriate techniques for individual patients.
Chronic inflammatory airway disease is a group of common and burdensome chronic diseases, including chronic obstructive pulmonary disease (COPD), asthma, emphysema, and chronic bronchitis.^1^ Affected patients often experience characteristic symptoms of cough, expectoration, dyspnea, and wheezing, severely impacting their quality of life.^2^ Medications including bronchodilators, glucocorticoids, and expectorants are recommended as first-line treatments.^2^^,^^3^ Many patients experience long-lasting symptoms despite standard therapy such as optimal pharmacological treatment (according to the current Global Initiative for Chronic Obstructive Lung Disease [GOLD] guideline^2^ and Global Initiative for Asthma [GINA] guideline^3^), smoking cessation, influenza vaccination, monoclonal antibody therapy and treatment of common comorbidities. Poor patient adherence to treatment,^4^ adverse reactions,^5^ and suboptimal treatment efficacy in certain patients with advanced-stage disease^6^ can also pose challenges for both patients and clinicians. A review published in The Lancet^7^ highlights the scarcity of drug development for COPD compared with cardiovascular disease. No new drugs have entered the market for COPD since 2020,^7^ underscoring the urgent need for alternative treatment approaches to address the unmet needs of patients with COPD and other chronic inflammatory airway diseases.
The concept of identifying “treatable traits” (i.e., therapeutic targets identified by phenotype or endotype recognition) has prompted the development of multiple interventional treatment modalities during the last two decades.^8^ Bronchial thermoplasty (BT) has demonstrated favorable therapeutic outcomes and has been endorsed by the European Respiratory Society/American Thoracic Society and GINA guidelines as a treatment option for severe asthma^3^^,^^9^ based on the results of multiple clinical studies.10, 11, 12 Initially, BT primarily targeted airway smooth muscle.^13^ However, as research progresses, more evidence suggests that BT may also have beneficial effects on neuro-immune function and epithelial rejuvenation.^14^ Other techniques include reducing lung volume, attenuating excessive activity of the parasympathetic nervous system, and destroying hyperplastic goblet cells, thus reducing excessive mucus secretion. These techniques, which are based on the pathophysiology of specific diseases, offer patients more precise and targeted treatments. They therefore have the potential to be more effective and enhance patients’ quality of life.
In this review, we discuss all relevant interventional techniques for the treatment of COPD and asthma, the two major types of chronic inflammatory airway disease, and comprehensively elucidate the characteristics, indications, advantages, and limitations of these techniques.
Respiratory intervention techniques are extensively utilized in the management of patients with COPD. These techniques can be broadly classified into two categories based on the two phenotypes of COPD: emphysema and chronic bronchitis.^15^ In the following sections, we will discuss the relevant bronchoscopic techniques for these two phenotypes.
Emphysema is one of the most common structural lung abnormalities associated with COPD.^16^ In recent decades, significant advancements have been made in bronchoscopic interventions for the treatment of emphysema.^17^ Initially, lung volume reduction (LVR) was achieved through surgical procedures. However, with the emergence of bronchoscopic lung volume reduction (BLVR), patients have shown a preference for this technique, which they subjectively perceive as a less invasive procedure.^18^ The CELEB trial was a randomized controlled trial comparing the effects of surgical lung volume reduction surgery (LVRS) with endobronchial valves, and the results showed that both treatments had similar efficacy and safety in patients with intact fissures.^18^ BLVR encompasses techniques such as valves, coils, and vapor ablation (Fig. 1A), which are primarily aimed at reducing the volume of the target lung lobe to treat emphysema phenotypes, especially for patients with a residual volume (RV) of ≥175%. In addition to BLVR, other interventions designed to alleviate hyperinflation include airway bypass and peripheral stents (Fig. 1B). Several randomized controlled trials have assessed these various bronchoscopic treatment methods, leading to the inclusion of valves, coils, and vapor ablation in the GOLD treatment guideline^2^ (Table 1).Fig. 1Overview of the mechanisms in COPD interventional treatment (created with BioRender.com). (A) Bronchoscopic lung volume reduction (BLVR) techniques work by reducing the volume of the target lung lobe to treat emphysema phenotypes. (B) Several methods to alleviate hyperinflation. Airway bypass creates a direct connection between the lung parenchyma and the airway. Peripheral stents and bronchial thermoplasty (BT) aim to treat emphysema by alleviating airway obstruction. (C) Targeted lung denervation (TLD) techniques, including radiofrequency ablation and cryoablation, disrupt the parasympathetic neural innervation surrounding the main bronchi. (D) Several methods to alleviate goblet cell hyperplasia. Spray cryotherapy uses freezing, rheoplasty uses radiofrequency ablation, and Karakoca balloon uses mechanical action to improve excessive goblet cell proliferation (high mucus secretion) and mucus retention, and restore the mucociliary clearance function of the airways. Images of the devices are provided by our team or reproduced with permission from relevant companies. BTVA: Bronchoscopic thermal vapor ablation; COPD: Chronic obstructive pulmonary disease; EBV: Endobronchial valve; IBV: Spiration Valve System; PNEC: Pulmonary neuroendocrine cell.Fig 1Table 1Clinical trials of bronchoscopic lung volume reduction for emphysema.Table 1Study (year)Centers (n)Main inclusion criteriaGroup (N)OutcomesComplications reported as SAEFollow- up (months)FEV1 (%)FEV1 (ml)RV (ml)6MWT (m)SGRQmMRCCATFollow-up (months)Pneumothorax (%)Pneumonia (%)COPD exacerbation (%)Death (%)Valve migration or dislocation (%)Endobronchial Valve EBV (PulmonX Inc., Redwood City, CA, USA) VENT^20^ (2010)31Heterogenous; CV+/-; FEV1 15–45% pred; RV ≥150% pred.EBV (220)6+4.3*+34.5*–+9.3*-2.8*-0.1*–33790.910Usual care (101)-2.5-25.4–-10.7+0.6+0.2–0210– BeLieVeR-HIFi^28^ (2015)1Heterogenous; CV- (Chartis); FEV1 <50% pred; RV >150% pred.EBV (25)6+8.8+60*-260+25*-4.40†-238820820Sham (25)+2.9+30-80+3-3.60†030120– STELVIO^29^ (2015)1Heterogenous; CV- (Chartis); FEV1 <60% pred; RV >150% pred.EBV (34)3+20.9+161*-865*+60*-17.4*––61861239Usual care (34)+3.1+21-34-14-2.7––0360– LIVE^30^ (2016)144Not mentioned; CV-/+ (Chartis); FEV1 15–45% pred; RV >180% pred.EBV (343 and 321‡)6+11.9^§^+100^§^-420^§^––-0.49^§^-3.14^§^62.06.426.201.7 IMPACT^31^ (2016)8Homogenous; CV- (Chartis); FEV1 15–45% pred; RV >200% pred.EBV (43)3+13.8+100*-420*+22.6*-8.63*-0.39*-1.5325.6016.304.6Usual care (50)-3.5-20+50-17.3+1.010.18-0.702122– TRANSFORM^32^ (2017)17Heterogenous; CV- (Chartis); FEV1 15–45% pred; RV >180% pred.EBV (65)6+20.7+140*-660*+36.2*-7.2*-0.56*–120.04.64.61.5–Usual care (32)-8.6-90+10-0.7-0.70–0000– LIBERATE^22^ (2018)24Heterogenous; CV- (Chartis); FEV1 15–45% pred; RV >175% pred.EBV (128)12+17.2+104*-490*+13.0*-7.6*-0.5*–1.526.60.87.83.1–Usual care (62)-0.8-3+30-26.3-0.50.3–004.80– CELEB^18^ (2023)5Heterogenous; CV- (Chartis); FEV1 <60% pred; RV >170% pred.EBV (47)12+4.5––––-0.33†-1130.44.3–2.24.3LVRS (41)+1.1––––-0.65†-7–0–0–IBV (Olympus, Tokyo, Japan) REACH^33^ (2019)12Heterogenous; CV-; FEV1 ≤45% pred; RV ≥150% pred.IBV (66)6–+91-420+20.8-8.39*-0.73-2.1767.61.519.70–Usual care (33)–-24-50-15.6+2.11-0.36+1.940012.13– EMPROVE^23^ (2019)31Heterogenous; CV-; FEV1 <50% pred; RV >150% pred.IBV (113)6–+101-402*-4.4-8.1*-0.6*–612.48.916.80–Usual care (59)–-2-42-11.3+4.80–01.710.20–BTVA (InterVapor ® [Uptake Medical, Seattle, WA, USA]) STEP-UP^34^ (2016)13Heterogenous; CV-/+; FEV1 20–45% pred; RV >150% pred.BTVA (46)6+11.0*+130.8*^,^||-302.5*^,^||+30.5||-9.7*––6218242–Usual care (24)-3.70––0840– STEP-UP (CV+ subgroup)^39^(2016)13Heterogenous; CV+ (VIDA Diagnostics 2.1); FEV1 20–45% pred; RV >150% pred.BTVA (35)12+9.2*+65.0*-108.8+6.2-9.4––632393–Usual care (19)-5.4-46.7+111.1-4.8-1.0––0550–Coils (LVRC [PneumRx Inc, Mountain View, CA, USA]) RESET^43^ (2013)3Homogenous and Heterogenous; FEV1 ≤45% pred.Coils (23)3+14.2*–-510*+51*-8.10*-0.24–1155––Usual care (23)+3.6–-200-12+0.25-0.09–004–– REVOLENS^44^ (2016)10Homogenous and Heterogenous; FEV1 <50% pred; RV ≥220% pred.Coils (50)6+9*+60*-520*+18-11.1*-0.5*–12618268–Usual care (50)-3-30-150+3+2.3-0.1–24226– RENEW^45^ (2016)26Mostly Homogenous; FEV1 <45% pred; RV ≥225% pred¶.Coils (155)12+3.8*–-410*+10.3*-8.1*––129.720.027.76.5–Usual care (157)-2.5–-100-7.6+0.8––0.64.520.45.1–Airway bypass (Broncus Technologies, Mountain View, CA, USA) EASE^51^ (2011)38Homogenous; FEV1 <50% pred; RV >180% pred.Airway bypass (208)12-0.15-20-60-21-0.60-0.41–61.4–15.91.9–Sham (107)-1.10-40-1000-0.04-0.25–0.9–8.43.7–⁎Statistically significant difference between treatment and control group. ^†^ Medical research council scale (MRC) was used. ^‡^ 343 safety population, 321 efficacy population. ^§^Statistically significant difference between post-treatment and baseline. ^||^ Absolute difference between groups. ^¶^ Lowered to ≥175% pred after enrolment of 169 patients. BTVA: Bronchoscopic thermal vapor ablation; CAT: Chronic obstructive pulmonary disease assessment test; COPD: Chronic obstructive pulmonary disease; CV: Collateral ventilation; EBV: Endobronchial valve; FEV1: Forced expiratory volume in the first second of the maneuver; IBV: Intrabronchial valves; LVRC: Lung volume reduction coils; LVRS: Lung volume reduction surgery; mMRC: Modified medical research council scale; 6MWT: 6-min walk test; RV: Residual volume; SAE: Serious adverse event; SGRQ: St George's respiratory questionnaire.
An endobronchial valve is an implant that can be placed in the segmental bronchus of the target lung lobe using fiberoptic bronchoscopy. This valve allows unidirectional airflow, thus reducing the volume of the diseased lung region and enabling expansion and improved function of the healthy lung area.^19^ By aiding in restoration of the diaphragm to its proper position, valves enhance respiratory mechanics and improve patients’ exercise capacity and quality of life.
Currently, the only U.S. Food and Drug Administration (FDA)-approved device for BLVR is the endobronchial valve, which has the most extensive evidence supporting its effectiveness. The FDA-approved valves for BLVR include the Zephyr endobronchial valve (EBV, Pulmonx Corporation, Redwood City, CA, USA) and the Spiration Valve System (IBV, Olympus, Tokyo, Japan). The therapeutic efficacy of endobronchial valves is closely related to patient selection. In the 2010 VENT trial,^20^ researchers found a correlation between fissure completeness on high-resolution computed tomography (HRCT) and improvements in the postoperative forced expiratory volume in the first second (FEV1) and changes in lung lobe volume. Patients with complete interlobar fissures and less collateral ventilation showed better clinical responses to endobronchial valve treatment. Additionally, the heterogeneity of emphysema is an important predictor of a patient's response to treatment. Therefore, preoperative use of quantitative HRCT and the Chartis™ Pulmonary Assessment System (Pulmonx Corporation), which assesses collateral circulation, is crucial for patient selection.^21^
The LIBERATE trial,^22^ a multicenter randomized controlled trial focusing on heterogeneous emphysema, evaluated the effectiveness of the Zephyr endobronchial valve in patients with little to no collateral ventilation (CV). The results demonstrated clinically meaningful benefits of EBV in terms of lung function, exercise tolerance, and breathlessness. The EMPROVE trial,^23^ similar to the LIBERATE trial, focused on patients with heterogeneous emphysema characterized by complete fissures separating the target lung lobe from the adjacent lobes. However, the EMPROVE trial employed a different FDA-approved valve called IBV. The results showed statistically significant improvement in the mean FEV1 between the treatment and control groups. At 6 months, the treatment group exhibited a significant decrease in the target lobe volume, with 40% of the entire treatment cohort achieving complete lobar atelectasis; hyperinflation and breathlessness were also significantly reduced. Another study investigating the prognosis of endoscopic valve therapy concluded that patients can experience benefits for at least 5 years following the procedure.^24^ The study showed that these patients can also achieve long-term improvements in their quality of life, which is a significant outcome for individuals with end-stage COPD.^25^
One common complication of valve treatment is pneumothorax,^26^ which occurs at a rate of 4.2% to 26.6%.^27^ This complication is due to the decrease in lung volume of the treated lobe after valve placement, resulting in compensatory expansion of the remaining lobes and subsequent visceral pleural defects. Pneumothorax is typically an acute postoperative complication and can be managed by chest tube drainage, valve removal, or a “wait-and-see” approach, depending on the specific circumstances.^27^ Other complications include cough, pneumonia, hemoptysis, COPD exacerbation, valve migration, and granulation tissue hyperplasia. All of these complications can be managed effectively. Timely follow-up is crucial to identify and address potential complications.
In summary, the endobronchial valve is a respiratory intervention device used for the treatment of emphysema. Its effectiveness has been demonstrated in patients with FEV1 15% to 50% of predicted, RV >150% of predicted, and total lung capacity (TLC) >100% of predicted.28, 29, 30, 31, 32, 33
Bronchoscopic thermal vapor ablation (BTVA) (Uptake Medical Technology, Inc., Seattle, WA, USA) is a procedure primarily designed for the treatment of patients with severe upper lobe-predominant emphysema, regardless of the presence of interlobar collateral ventilation.^34^ By delivering heated water vapor to the targeted emphysematous segments, BTVA induces an inflammatory reaction within the treated pulmonary segments, resulting in fibrosis and shrinkage of the segment.^35^ This reaction leads to a reduction in both volume and mass within these segments,^36^ making BTVA a promising treatment option for intralobar heterogeneous emphysema. The feasibility of BTVA was initially clinically investigated in 11 patients with severe heterogeneous emphysema in 2009.^37^ Although the results of the study were ambiguous, the findings served as a valuable reference for subsequent research.
The 2018 STEP-UP study^34^ was an open-label randomized, controlled trial that established sequential bilateral treatment as the optimal treatment approach for BTVA. The results demonstrated that BTVA treatment directed toward more severely diseased lung lobes significantly improved lung function and quality of life at 6 months compared with standard medical management. In the BTVA group, approximately half of the patients achieved the minimal clinically important difference (MID) in FEV1 at 6 months, while two-thirds of the patients reached the MID for St. George's Respiratory Questionnaire (SGRQ) improvement.^36^ Although an increase in respiratory-related serious adverse events (SAEs) was observed immediately after treatment, most of these events were managed through routine care. Researchers initially proposed the notion that patients who develop lower respiratory adverse events in the early postoperative period might have better long-term outcomes.^38^ However, this proposition now seems paradoxical; evidence has since indicated that such adverse events are primarily due to the larger volume reduction in these patients.^36^^,^^38^
In the subsequent 12-month study,^39^ the treatment arm showed a 9.2% improvement in FEV1 compared with a 5.4% decrease in the control group. The treatment arm also exhibited an 8.4-point more improvement in the COPD-specific version of SGRQ (SGRQ-C) compared with the control arm. Both the aforementioned study^39^ and a retrospective analysis of a multicenter single-arm trial^40^ consistently demonstrated that lobar fissure integrity (FI) had minimal influence on BTVA-induced volume reduction. Administration of BTVA by sequential bilateral treatment is recommended because the clinical MID value is more easily achieved using this technique. Additionally, as the volume of a single treatment increases, the risk of complications also tends to rise. By opting for sequential bilateral treatment, overall safety is enhanced while maintaining treatment efficacy.^36^ Endobronchial valve placement can lead to difficulties in sputum clearance and colonization by pathogenic microorganisms. These issues are not encountered in BTVA, making it a preferable alternative. The use of BTVA for other lung lobes and tumors is being explored, although no data have yet been published.
Coils, specifically shape-memory nitinol coils, are deployed in the subsegmental airways to induce LVR and enhance lung recoil.^41^^,^^42^ These coils are inserted into the targeted lobe through a catheter inserted in a bronchoscope, and their deployment is guided by fluoroscopy. The coils compress the diseased lung tissue, restoring tissue tension and reducing air trapping. In each treatment session, typically under general anesthesia, 8 to 14 coils are placed, and additional target lobes can be addressed in subsequent procedures.^42^ Unlike valves, coils are considered non-blocking devices; this makes them effective even in patients with collateral ventilation.^42^
Numerous randomized controlled trials and single-arm studies have focused on LVR coils since 2013.43, 44, 45 A meta-analysis^46^ of 8 trials involving 680 patients showed that LVR coil treatment resulted in a significant improvement in FEV1 at the 6-month follow-up (0.07 L [95% CI: 0.03–0.10]), a significant reduction in RV at the 12-month follow-up (−0.36 L [95% CI: −0.64 to −0.08]), and a significant reduction in SGRQ total score at the 12-month follow-up (−9.8 points [95% CI: −15.0 to −4.7]). These findings indicate that LVR coil treatment can improve patients’ lung function and quality of life. Regarding SAEs,^46^ the treatment group had a significantly higher risk of pneumothorax, exacerbation of COPD, and pneumonia compared with the conventional care group. However, no significant difference in the risk of mortality was observed between the two groups.
The company that manufactured the LVR coil has ceased production.^47^ However, the effectiveness and safety of the Cinenses® LVR Reverser^48^ (Lifetech Scientific Co., Ltd., Shenzhen, China) are currently under investigation. This device reduces lung volume by bending the bronchi, but several improvements have been made to more effectively bend the airways, prevent granulation and injuries, and permit reloading in vivo. In preliminary animal experiments,^48^ no severe complications such as pneumothorax, abscesses, or respiratory tract bleeding occurred. CT scans also indicated a decreasing trend in lung volume in the treatment group at 1 and 3 months post-treatment. Currently, this device had progressed to the clinical trial stage, and we eagerly await further research outcomes.
Patients with emphysema not only undergo destruction of the alveolar walls and a decrease in the effective ventilation–perfusion ratio, but they also develop small airway narrowing, resulting in gas trapping and overinflation.^49^^,^^50^ Airway bypass is an interventional bronchoscopic technique employed to alleviate hyperinflation. It involves the creation of transbronchial passages in the lung to release trapped air, and these passages are supported by paclitaxel-coated stents to facilitate breathing mechanics.^51^ This concept originated from a hypothesis,^52^ suggesting that the creation of noncollapsing extra-anatomic stents connecting the lung parenchyma to large airways could enhance expiration and alleviate some of the adverse effects of dynamic hyperinflation. This provided a potential treatment option for emphysematous patients with significant hyperinflation and severe homogeneous pulmonary destruction. Subsequent research^53^ demonstrated the safe performance of airway bypass under Doppler guidance, avoiding peribronchial blood vessels.
The 2011 EASE trial^51^ was a multicenter, randomized, double-blind, sham-controlled study evaluating airway bypass. Patients who underwent airway bypass showed significant improvements in RV, RV/TLC, and FEV1 compared with the sham control group on the first day after the procedure. However, these acute benefits in pulmonary function declined at 1 month. Additionally, there were no significant differences in the percent change in RV per lobe at 6 months compared with the sham control group. This study suggested that the treatment efficacy was unsustainable because of airway bypass obstruction by mucus or granulation tissue, bypass displacement, or other factors. The above issues remain to be addressed to achieve long-term efficacy in upgraded versions of the airway bypass.^51^ Additionally, the study indicated that the combination of paclitaxel and silicone polymer was insufficient in maintaining stent patency. The EASE trial failed to demonstrate sustained long-term effects in patients with severe homogeneous emphysema. Furthermore, it revealed adverse events including pneumothorax, hemoptysis, COPD exacerbation, and infection.^51^^,^^54^
Peripheral airway stents are placed to alleviate airway obstruction. A multicenter prospective trial evaluating the Pulmair implantable artificial bronchus (IAB) (Pulmair Medical, San Diego, CA, USA) began in 2022 (ClinicalTrials.gov Identifier: NCT05087641). The IAB is indicated for bronchoscopic treatment of adults with COPD/emphysema, relieving hyperinflation and allowing bidirectional ventilation of the affected lobes. Preliminary results from this trial indicated improvements in FEV1, RV, 6-minute walk test, symptoms, and quality of life after 3 months of treatment.^55^ We eagerly anticipate the publication of further results from this clinical trial and are hopeful that it will provide benefits for patients with COPD.
BT was initially used to treat severe asthma. It employs a radiofrequency catheter to deliver energy to specific locations within the airway wall, targeting bronchial smooth muscle cells and ablating the thickened airway smooth muscle layer.^56^ This procedure is explained in more detail in the section on asthma treatment. BT has been found to reduce airway hyperresponsiveness and reverse airway remodeling,^57^ thus offering benefits to patients with COPD, especially for those with emphysema. A randomized pilot study^56^ published in 2018 explored the potential application of BT in COPD. The results suggested that compared with conventional medication, combined BT treatment showed superior outcomes in improving lung function and quality of life in patients with COPD. Furthermore, it significantly reduced the risk of COPD exacerbations without causing severe adverse events.^56^
Additional research has demonstrated that BT can decrease the number of pulmonary neuroendocrine cells, affect airway autonomic regulation, and downregulate airway neuronal excitability and nervous reflexes.58, 59, 60 These findings suggest potential therapeutic benefits for COPD.^56^
Chronic bronchitis (CB), another significant phenotype of COPD, is characterized by persistent cough and expectoration caused by airway inflammation, excessive mucus secretion, and ineffective clearance due to ciliary dysfunction.^61^ According to the classic definition, CB is diagnosed as a chronic cough and sputum production lasting at least 3 months per year for two consecutive years, without other underlying conditions that could explain these symptoms.^2^ The first two questions in the COPD Assessment Test (CAT) evaluate the severities of cough and sputum, respectively; the combination of their scores is a valid approach to CB diagnosis as recommended in previous studies.^15^^,^^62^^,^^63^ A longer duration of chronic mucus hypersecretion is associated with greater FEV1 decline.^64^ Additionally, increased parasympathetic nerve activity in patients with COPD leads to elevated acetylcholine levels, resulting in airway smooth muscle contraction and increased mucus production.^65^ Treatment options for these patients, including smoking cessation, physical measures, and drug therapy,^61^ have limited effectiveness because of the difficulty in reversing the already established structural changes. Among bronchoscopic interventions, targeted lung denervation (TLD) works by disrupting the pulmonary parasympathetic innervation (Fig. 1C). Other methods, such as spray cryotherapy (SCT), rheoplasty, and Karakoca resector balloon, target excessive mucus secretion by goblet cells in the first to fifth generations of the bronchial tree (up to the subsegmental bronchi) of chronic bronchitis (Fig. 1D).
Enhanced function of the parasympathetic nervous system has been implicated in the progression of COPD and has long been recognized as a critical target for reversible intervention in managing airway obstruction.^66^ Anticholinergic medications are widely used in the treatment of COPD. Surgical interventions have been proposed to directly interrupt the vagus nerve, reducing acetylcholine release at its source. As early as the 1950s, Jammes et al^67^ attempted lung denervation surgery in 19 patients with refractory bronchial asthma and demonstrated that the postoperative lung capacity increased from 2.36 to 2.79 L and the maximum voluntary ventilation increased from 43 to 50 L/min. Although the treatment efficacy of lung denervation is notable in many patients, this procedure has become infrequently utilized, possibly because of the occurrence of gastrointestinal complications, Horner's syndrome,^67^ and a lack of long-term follow-up. TLD emerged from the development of respiratory endoscopy techniques, primarily radiofrequency ablation and cryotherapy. Radiofrequency ablation involves the application of dual-cooled radiofrequency catheters to heat deep tissues,^68^ reducing mucosal damage through deep ablation and superficial cooling. The aim of TLD is to block vagus nerve in the left and right main bronchi, thereby reducing airway smooth muscle tone, attenuating pulmonary neural reflexes, and decreasing mucus secretion, thus potentially alleviating small airway obstruction and hyperinflation.^17^^,^^69^
Mayse et al^70^ in 2014 and Hummel et al^71^ in 2018 reported that TLD had sustained denervation effects and good safety. Population-based studies have also revealed a significant reduction in inflammatory factors in the alveolar compartment following TLD,^72^ suggesting its positive effect on airway inflammation. In several previous studies, including AIRFLOW-1, Sober et al^68^^,^^73^^,^^74^ not only established the optimal dosage and safety of TLD, but also demonstrated the proof of concept. Patients with a diagnosis of moderate to severe symptomatic COPD (FEV1 30–60% of predicted, mMRC score ≥2 or a CAT score ≥10) were enrolled. The team then conducted a further trial (AIRFLOW-2)^69^^,^^75^ in which they compared adverse events and clinical benefits between two optimal medical therapy with bronchoscopic sham procedure, and optimal medical therapy with TLD. This trial revealed a significant delay in the first occurrence of acute exacerbation chronic obstructive pulmonary disease (AECOPD) after TLD treatment as compared with the control group.^69^ Additionally, no significant differences in adverse events were observed throughout the 0- to 12.5-month study period.^75^ In 2020, Sober et al^76^ published the study protocol for AIRFLOW-3, a multicenter, randomized, full sham bronchoscopy-controlled, double-blind trial aiming to enroll 400 patients. The results of this study are currently awaiting disclosure. Furthermore, a subsequent study^77^ of AIRFLOW-1 showed that both FEV1 and FVC improved at 1 year relative to baseline with average increases of 60 mL (P =0.031) and 219 mL (P = 0.004) respectively, which might be related to the alleviation of hyperinflation by relaxing airway smooth muscle, decreasing mucus hypersecretion and relieving of airway obstruction. Of note, the change in FEV1 at 6 months relative to baseline was set as primary endpoint in an ongoing multicenter, randomized clinical study (NCT05799664) led by the West China Hospital utilizing the radiofrequency ablation device manufactured by Broncus Medical (San Jose, CA, USA).
The use of a novel low-temperature cryoballoon TLD system has been reported in China. A goat model demonstrated promising results characterized by minimal tissue damage, few device-related adverse reactions, and a short surgical time.^78^
During the past decade, SCT has been gradually applied in respiratory interventions. SCT involves the rapid release of a cryogenic agent through a spray catheter; this leads to the formation and aggregation of ice crystals within cells, ultimately resulting in organelle rupture and cell death.^79^ This method addresses the limitations of traditional cryoablation probes, such as a small contact area, slow onset of action, and a lengthy procedure time, making it applicable to a wide range of lesions. One of the most representative systems is the RejuvenAir® Metered Cryospray™ System developed by CSA Medical (Lexington, MA, USA). This system utilizes circular spraying of liquid nitrogen within the airways to rapidly freeze the epithelial cells of the airway wall while preserving the extracellular matrix.^80^ By ablating hyperplastic goblet cells and submucosal glands, it reduces mucus secretion and ensures rapid epithelial regeneration without scar formation. Two preliminary clinical trials (NCT02106143 and NCT02483052) focusing on use of the RejuvenAir® Metered Cryospray™ System in bronchial applications at the lung segment and lobe levels confirmed its safety, with no device-related SAEs. Subjects with a diagnosis of CB and COPD (symptomatic for ≥2 years, FEV1/FVC of <0.70, FEV1 30–80% of predicted, CAT score ≥ 10) were included. Histological evidence of goblet cell and submucosal gland ablation was obtained.^81^ Three larger-scale clinical trials have been underway since 2016 (NCT02483637, NCT03892694, and NCT03893370). In addition, an animal study from China suggests that SCT should be avoided in the right middle lobe because of its anatomically small lung volume and proximity to vital structures such as the sinoatrial node, vagus nerve, and sympathetic nerve, which could increase the risk of complications such as arrhythmia.^82^
Bronchial rheoplasty is a nonthermal pulsed electrical field-based procedure that induces cell death through electroporation, aiming to ablate the abnormal mucus-producing cells of the airway epithelium. This type of cell death does not compromise the tissue's architectural function, allowing for normal epithelial regeneration.^83^ Consequently, sputum retention is improved, mucociliary clearance is restored, and small airway obstruction is alleviated. The entire treatment process is divided into two sessions, with each session targeting one lung and a 1-month interval between sessions.
In 2020, a clinical trial^83^ focused on bronchial rheoplasty using the RheOx System (Gala Therapeutics, San Carlos, CA, USA) was published. The trial included patients who were diagnosed with CB and with a CAT score ≥10 (CAT1 and CAT2 sum to at least 7 points). This study revealed that bronchial rheoplasty resulted in an average decrease of 39% in the goblet cell hyperplasia score compared with baseline. Significant improvements were also observed in the CAT and SGRQ scores at 3, 6, and 12 months post-treatment. Importantly, no device- or procedure-related SAEs were observed. Further research and longer-term follow-up studies are warranted to validate and refine the outcomes of this technique.
The Karakoca resector balloon is a latex balloon enveloped by a mesh structure of polyurethane/Lycra (ENBIO MEDICAL, Istanbul, Turkey) fibers.^84^ Repeated inflation and deflation of the balloon mechanically disrupts hyperplastic goblet cells, providing a treatment approach for chronic bronchitis. In 2015, the first clinical study of the Karakoca resector balloon included 10 patients with stage IV COPD primarily manifesting as chronic bronchitis.^84^ This study provided preliminary evidence of improved lung function, symptom alleviation, and reduction in goblet cells.
A subsequent investigation^85^ of 188 patients with stage III–IV COPD and chronic bronchitis findings on CT showed continuous improvement in FEV1, the modified Borg dyspnea score, peripheral oxygen saturation, and the 6-minute walk test at 1 week and 1 month post-procedure (P < 0.001 for each). No exacerbations were reported in the 3-month postoperative follow-up period. Safety evaluations indicated no intraoperative, perioperative, or postoperative complications in any patients. Although the results of these two studies are encouraging, further evidence from larger multicenter controlled trials is needed to confirm the efficacy and safety of the Karakoca resector balloon.
Asthma is a chronic inflammatory airway disorder characterized by airway hyperresponsiveness and remodeling.^86^ Considering these features, the following sections will explore the application of two techniques, BT and TLD, with the aim of highlighting their potential benefits and implications in the treatment of asthma.
As mentioned above, BT is an endoscopic procedure that delivers controlled thermal energy to the airway wall, primarily targeting airway remodeling and resulting in prolonged reduction in airway smooth muscle mass.^13^ The aim of this treatment is to improve symptoms and quality of life in patients with asthma. The entire process is typically divided into multiple sessions, with each session targeting different lung lobes.
The GINA guideline^3^ indicate that BT can be considered for some adult patients with severe asthma, mainly based on the 2007 AIR and RISA trials but also on the 2010 AIR2 trial. These three clinical studies10, 11, 12 consistently showed that BT results in a significant reduction in severe exacerbations and emergency healthcare utilization along with improvements in patients’ quality of life and symptom scores (Table 2). A study^87^ involving patients with severe refractory asthma who received treatment with BT or biologicals showed that the BT group achieved positive results comparable to those in the biologicals group in terms of hospitalization, exacerbation, and oral corticosteroid use, despite patients in the BT group having worse baseline data in these areas. Regarding the safety of BT, the most common adverse event in the short term after the procedure is airway irritations, leading to worsened asthma symptoms (wheezing, chest discomfort, cough, and chest pain) and upper respiratory tract infections.^12^ However, these adverse events are generally temporary.^12^ A 10-year follow-up study^88^ on the three above-mentioned randomized controlled trials showed that the proportion of severe exacerbations remained consistent at 1, 5, and 10 years post-treatment. Quality of life and lung function tests showed similar results across these time points. Among 89 participants who underwent BT, 7% exhibited bronchial dilation after treatment, and the safety profile was acceptable.Table 2Clinical trials of bronchoscopic interventions for asthma.Table 2Study (year)Number of centersGroup (N)Main inclusion criteriaFollow-up timeOutcomesAdverse events and safetyBronchial thermoplasty AIR^10^(2007)11(4 countries)BT group (56)Usual care group (56)(1) Moderate–severe asthma;(2) FEV1 60 to 85% pred.12 monthsMean rate of mild exacerbations change from baseline was significantly lower in the BT group compared to the usual care group at 3 months and at 12 months. No significant difference in number of severe exacerbations was observed.Significant improvements in morning PEF, AQLQ, ACQ and percentage of symptom free days within the BT group compared with the control group were detected.Greater response was observed among those who required higher maintenance ICS (>1000 μg/day beclomethasone or equivalent).Increase in adverse respiratory events peri-procedure in BT group, with majority occurring within a day and resolved within an average of 7 days.Hospitalizations for adverse respiratory events peri-procedure were more frequent in the BT group.The proportions of subjects with adverse respiratory events during the post-treatment period were similar in the two groups. RISA^11^ (2007)8(3 countries)BT group (15)Usual care group (17)(1) Severe asthma;(2) FEV1 ≥ 50% pred.12 monthsSignificant improvements in rescue medication use, prebronchodilator FEV1% predicted, and ACQ scores among the BT group compared to the control group at 22 weeks.Improvements in rescue medication use and ACQ scores remained significantly different from the control group at 52 weeks.Seven hospitalizations for respiratory symptoms occurred in 4 of 15 BT subjects during the treatment period. Five hospitalizations were within 3 days of treatment. Two subjects had segmental collapse involving the most recently treated lobe; 1 required bronchoscopy and aspiration of a mucus plug.There were no hospitalizations during the treatment period in the 17 control subjects.The rates of hospitalizations were similar in both groups in the posttreatment period. AIR2^12^(2010)30(6 countries)BT group (196)Sham group (101)(1) Severe asthma;(2) FEV1 ≥60% pred.12 monthsImprovement from baseline in the integrated AQLQ score was superior in the BT group (1.35±1.10) compared with sham (1.16±1.23).79% of BT and 64% of sham subjects achieved changes in AQLQ of 0.5 or greater.During the treatment period (up to 6 weeks post-BT), there was a six percent increase in hospitalizations among BT subjects.During the posttreatment period (6–52 weeks after BT), the BT group experienced fewer severe exacerbations, emergency department visits, and days missed from work/school compared with the sham group.During treatment, the BT group reported more respiratory adverse events (85% of subjects) than the sham group (76% of subjects).The most common events consisted of typical airway irritations such as worsening asthma symptoms (wheezing, chest discomfort, cough, and chest pain), and upper respiratory tract infections. The majority of respiratory adverse events occurred within 1 day of the bronchoscopy and resolved within 7 days.During the posttreatment period, fewer adverse respiratory events were reported in the BT group (70% of subjects vs. 80% in the sham group).Targeted lung denervation BCD^97^(2024)1(1 country)BCD group (15)(1) Severe asthma;(2) FEV1 ≥30% pred.12 monthsAt the month 1 follow-up, mean (SD) changes from baseline in ACQ-7 and ACT were -1.19 (0.68) and 3.18 (2.44), respectively, showing statistically significant improvements. Similarly, at the month 12 follow-up, they were -1.35 (0.93) and 6.18 (4.14), with significant improvements as well.There were no statistically significant changes in FEV1% and FEV1/FVC at month 1, 3, 6, 9, and 12 after the procedure compared with baseline.Technical feasibility was 96.7%, with successful catheter deployment and full circumferential denervation in 29–30 procedures among all enrolled patients.No device-related and 2 procedure-related SAEs were reported through 12-month follow-up.The most frequent AEs were increased cough, chest discomfort, dyspnea, and mucus production.ACQ: Asthma control questionnaire; ACT: Asthma Control Test; AEs: Adverse events; AQLQ: Asthma quality of life questionnaire; BCD: Bronchial cryo-denervation; BT: Bronchial thermoplasty; FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; ICS: Inhaled corticosteroid; PEF: Peak expiratory flow; SD: Standard deviation.
Regarding the mechanism of BT for treating asthma, studies have shown a reduction of airway smooth muscle mass after BT treatment; however, the treatment response was not associated with this reduction.^89^ As a result, many additional studies have proposed potential mechanisms of BT for the treatment of asthma. First, BT can reverse airway remodeling by reducing collagen deposition and reticular basement membrane thickness in the submucosal layer.^90^^,^^91^ Additionally, it can modify bronchial epithelial cells, reducing secretion of heat shock protein 60 and subsequent expression of protein arginine methyltransferase 1, thereby suppressing airway remodeling.^92^ BT also lowers the concentrations of cytokines and chemokines in bronchoalveolar lavage fluid; these include transforming growth factor β1, the main mediator of inflammation, and chemokine (C-C motif) ligand 5 (CCL5), which induces eosinophil aggregation.^93^ Moreover, BT exhibits a denervation effect as evidenced by a statistically significant reduction of nerve fibers in the submucosa and airway smooth muscle.^60^ Furthermore, BT may enhance host immune responses, thereby attenuating exacerbations and symptoms in individuals who respond to BT.^94^ Finally, BT even impacts the metabolism of bronchial epithelial cells in patients with asthma, leading to a significant increase in the expression of oxidative phosphorylation genes and a decrease in fatty acid metabolism genes, indicating a shift toward a more normal metabolic profile in bronchial epithelial cells.^95^ Liao et al^14^ provided a thorough summary of these mechanisms in their review article.
As mentioned earlier in the context of COPD treatment, TLD exerts its therapeutic effects by disrupting the parasympathetic innervation in the lungs. In patients with severe asthma, cholinergic tone is elevated, resulting in bronchoconstriction and increased airway hyperresponsiveness.^96^ Anticholinergic medications have been proven effective in the treatment of these symptoms. Therefore, targeting the parasympathetic innervation in the lungs may be advantageous for patients with severe uncontrolled asthma.
Although TLD has mainly been studied in patients with COPD, it may also have benefits in the field of asthma treatment. A report^96^ in 2022 described the first two patients with asthma worldwide to undergo TLD treatment. Data were collected for 12 months following TLD administration, and no unexpected SAEs occurred during this period. Both patients experienced improvements in their cough symptoms. One patient's rescue medication use significantly decreased, while the other's did not change. However, no significant changes were observed in spirometry, lung volume, or health status. Additionally, a recent pilot study on Bronchial Cryo-Denervation (BCD) in 15 patients with severe asthma was published in 2024. The study results showed that following treatment, pulmonary function remained unchanged; however, significant improvements in the Asthma Control Questionnaire-7 scores and Asthma Control Test scores from baseline were noted as early as the first month of follow-up, with consistent trends observed throughout the 12-month follow-up. Furthermore, no device-related SAEs occurred, and the two procedure-related SAEs that occurred had no sequelae.^97^
A recent review^14^ consolidated the latest advancements and potential mechanisms of interventional pulmonology techniques in treating refractory asthma. Interplay between the immune and nervous systems occurs to various extents, with the vagus nerve influencing respiratory inflammation and asthma symptoms through complex regulatory interactions. Neuro-immune changes occur before and after intervention. In addition to reducing bronchial smooth muscle, BT also affects nerves and neuroendocrine cells.^98^ TLD, which directly targets the efferent fibers of the vagus nerve, may also influence afferent fibers.^14^^,^^99^ In conclusion, the therapeutic mechanisms of these interventions are related to blockade of neuro-immune crosstalk.
This review presents an overview of various interventional treatment modalities for chronic inflammatory airway diseases. These modalities include BLVR and airway bypass for emphysema; TLD, bronchial rheoplasty, and SCT for chronic bronchitis; and BT for asthma, among others. The field of respiratory interventions has undergone rapid advancements in recent years, with ongoing developments of additional techniques beyond the scope of this article. These techniques aim to alleviate respiratory difficulties, improve cough and sputum production, and enhance functional outcomes, offering valuable insights and options for managing chronic inflammatory airway diseases. Considering the substantial impact of chronic inflammatory airway diseases on a large number of patients, the field of respiratory interventions holds significant potential for investment returns. Current research focuses more on demonstrating efficacy than on elucidating the underlying mechanisms of treatment. We expect that in the future, single-cell biology, spatial transcriptomics, and proteomics will be used to compare changes before and after interventions, revealing mechanisms that may aid in identifying treatable traits and patient selection. This will provide more comprehensive information and references for patients with chronic inflammatory airway diseases.
This work was supported by the 10.13039/501100003399Science and Technology Commission of Shanghai Municipality (Nos. 22S31901300 and 23440790103), and Shanghai Innovative Medical Device Application Demonstration Project 2023 (No. 23SHS02600).
The authors have no conflicts of interest to declare.