Chapter 22

Upcoming techniques

Daniela Gompelmann

Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg and Member of the German Center for Lung Research (DZL), Heidelberg, Germany.

Correspondence: Daniela Gompelmann, Pneumology and Critical Care Medicine, Thoraxklinik at University of Heidelberg, Röntgenstrasse 1, 69126 Heidelberg, Germany. E-mail: daniela.gompelmann@med.uni-heidelberg.de

Therapeutic bronchoscopy had been performed using a rigid bronchoscope in the late 1800s by Gustav Killian, the father of bronchoscopy. At that time, instruments for foreign body extraction, dilators and endobronchial stents were already available. After the advent of flexible bronchoscopes in the 1960s, bronchoscopy spread rapidly, thus presenting one of the most important diagnostic and therapeutic tools in the field of pneumology. Nowadays, interventional bronchoscopic procedures facilitate minimally invasive therapeutic approaches in various pulmonary diseases.

Recent developments in the field of interventional pulmonology include therapeutic options in pulmonary diseases such as COPD, chronic bronchitis, central airway obstruction (CAO) or solitary pulmonary nodules (SPNs). This chapter summarises the upcoming techniques in interventional pulmonology: targeted lung denervation (TLD) for patients with obstructive lung diseases, cryospray therapy for the treatment of chronic bronchitis, biodegradable stents for CAO, bronchoscopic transparenchymal nodule access (BTPNA) and various endoscopic therapeutic modalities for peripheral lung cancer. Furthermore, the development of robotic endoscopy systems is also discussed.

TLD for treatment of obstructive lung diseases

COPD is pathophysiologically characterised by chronic bronchitis, expiratory airflow limitation and emphysematous destruction of the lung parenchyma associated with hyperinflation. The main symptoms are productive cough, shortness of breath and limited exercise capacity reducing quality of life. So far, there is no curative treatment approach, so that the fundamental therapeutic strategies, including cessation of cigarette smoking, exercise training, pulmonary rehabilitation and pharmacological therapy, are aimed at preventing progression of COPD [1]. In appropriately selected patients with very advanced COPD, lung transplantation may be considered as a therapeutic, symptom-modifying treatment approach. Moreover, lung volume reduction techniques comprising lung volume reduction surgery and various therapeutic endoscopic approaches may reduce hyperinflation in adequately selected patients with the emphysema phenotype and a residual volume >175% predicted [2].

Patients with predominant chronic bronchitis without significant emphysema and hyperinflation will, however, not benefit from lung volume reduction techniques, as airflow obstruction is the leading cause of symptoms. Airflow limitation results from irreversible airway remodelling and reversible bronchoconstriction due to increased cholinergic parasympathetic innervation. It seems that vagal dysregulation in patients with COPD contributes to enhanced bronchial smooth muscle contraction and greater mucus secretion [3]. Therefore, antimuscarinic drugs that block acetylcholine binding to muscarinic receptors and thus lead to bronchodilation are recommended as first-line therapy for patients with COPD [1].

The idea of the anticholinergic therapeutic approach came historically from parasympathetic nerve disruption via surgical vagotomy in patients with obstructive lung diseases. This surgical approach certainly showed proof of principle, but revealed generally poor results given the underlying invasiveness of this surgical method [4].

A new treatment approach, i.e. TLD (Holaira, Minneapolis, MN, USA), provides minimally invasive radiofrequency ablative therapy targeting the parasympathomimetic innervation of the airways, leading to sustainable bronchodilation.

In order to perform TLD, a dedicated catheter (dNerva dual-cooled radiofrequency catheter; Holaira) designed to target tissue heating at depth is advanced bronchoscopically into the main bronchus. After positioning the catheter, the balloon at its distal tip is inflated so that the silver electrode on the balloon that delivers the radiofrequency has contact with the airway wall (figure 1). Furthermore, a contrast-filled balloon is inserted into the oesophagus so that the proximity from the electrode of the dNerva catheter to the oesophagus can be estimated under fluoroscopy (figure 2). Depending on the distance to the oesophagus, an adequate energy dose is chosen and delivered to ablate the parasympathetic pulmonary nerves along the main bronchi. During delivery of radiofrequency current, a coolant circulates through an outflow conduit on the balloon to protect the inner surface of the airway wall. Once the energy has been delivered in one position, the balloon is deflated and rotated to the next position so that the electrode is activated in four rotational positions to achieve complete circumferential treatment. TLD can be performed bilaterally in both main bronchi in one single procedure.

Figure 1. Bronchoscopic image. Positioning of the dNerva dual-cooled radiofrequency catheter (Holaira, Minneapolis, MN, USA) in the main bronchus. Reproduced with kind permission of D-J. Slebos (University Medical Center Groningen, Groningen, The Netherlands).

Figure 2. Fluoroscopic image. A contrast-filled balloon is inserted into the oesophagus so that the proximity of the electrode of the dNerva catheter (Holaira, Minneapolis, MN, USA) to the oesophagus can be estimated.

TLD is currently under clinical investigation and is not yet commercially available. The first-in-human study published in 2015 demonstrated the safety and feasibility of TLD in patients with moderate to severe COPD [5]. In this prospective multicentre trial, TLD was performed at 20 W in 12 patients or 15 W in 10 patients in two endoscopic procedures that were well tolerated in all subjects. One year following intervention, patients treated with 20 W experienced a mild, but not statistically significant improvement in lung function parameters and exercise tests, but a significant improvement in heath-related quality of life measured by the St George’s Respiratory Questionnaire. These improvements tended to be larger than those observed in patients treated with 15 W. Furthermore, early data suggested that the combination of anticholinergic drugs and TLD might result in an increase in FEV₁ over that seen with an antimuscarinic drug alone. Within the first month following intervention, seven severe adverse events occurred, including COPD exacerbation, anaphylactic drug reaction, coronary artery bypass, chest pain and gastroparesis. Bronchial perforation was observed in two patients, and bronchial stenosis and bronchial ulceration were observed in one patient each.

Further trials are necessary to support the preliminary encouraging results and to show the safety of this new technology. Two prospective randomised controlled trials, the “Targeted Lung Denervation for Patients With Moderate to Severe COPD” trials known as AIRFLOW-1 and AIRFLOW-2, are currently ongoing in Europe (ClinicalTrials.gov: identifier NCT02058459). As TLD focuses on reversible bronchodilation, it may also present a treatment approach for patients with uncontrolled asthma, but this has to be evaluated in a pilot trial (ClinicalTrials.gov: identifier NCT02872298).

Liquid nitrogen metered cryospray for treatment of chronic bronchitis

Chronic bronchitis is defined as the presence of cough and sputum production for at least 3 months in 2 consecutive years. Mucus hypersecretion is pathophysiologically caused by chronic inflammation of the bronchial lining, submucosal mucus-producing gland hypertrophy and goblet cell hyperplasia [6]. The excess mucus in the bronchi may result in airway obstruction leading to impaired ventilation, and thus to dyspnoea and limited exercise capacity. Furthermore, mucociliary clearance is compromised, which enhances bacterial colonisation and exacerbations. There is no curative treatment at present; the current therapeutic options focus on promoting mucus clearance and symptom relief.

The RejuvenAir system (CSA Medical, Lexington, MA, USA) provides a new bronchoscopic treatment approach that addresses chronic bronchitis by destroying the mucus-producing glands and goblet cells by delivery of liquid nitrogen as a metered cryospray (MCS) (figure 3).

Figure 3. Bronchoscopic images. Cryospray therapy in the right main bronchus. Reproduced with kind permission of D-J. Slebos (University Medical Center Groningen, Groningen, The Netherlands).

Initially, cryospray therapy was developed for the treatment of oesophageal malignancies, particularly for the eradication of low-grade and high-grade dysplasia in Barrett’s oesophagus [7, 8]. Cryospray therapy provides a noncontact cryogenic effect on tissues. By spraying liquid nitrogen through a catheter, the target mucosa is frozen and cellular apoptosis due to intracellular ice crystallisation of the cryosensitive tissue is achieved. The boiling point of nitrogen liquid (–196°C) is very low, leading to a rapid flash-freezing on the tissue. Due to the uniform and planar distribution of the liquid nitrogen, a relatively large area is addressed despite irregular surfaces. When using cryospray therapy in the gastrointestinal tract, the nitrogen gas that is produced by the phase transformation of the liquid nitrogen droplets is evacuated by an additional suction tube.

In bronchoscopic procedures, however, no additional suction tube can be placed due to lack of space, so that the expansion of nitrogen gas may result in barotrauma or pneumothorax. Therefore, sufficient venting of nitrogen gas using a rigid bronchoscope or an endotracheal tube with the cuff deflated and disconnected from the ventilator is crucial. In 2010, KRIMSKY et al. [9] reported the first three cases where cryospray therapy was used successfully for the treatment of glottic or subglottic stenosis. After encouraging results in the initial trials and after modifying the device for the liquid nitrogen delivery, the cryospray device (G2 TruFreeze system; CSA Medical) received US Food and Drug Administration approval. Since then, different trials have been performed demonstrating the feasibility, safety and efficacy of cryospray therapy in patients with malignant or benign airway obstructions [10, 11, 12]. In the first trial using the new-generation device, the authors reported successful cryospray therapy in three patients with CAO due to lung cancer and in one patient with benign post-intubation tracheal stenosis [10]. In another trial published in 2016, 12 patients with malignant CAO and 10 patients with benign CAO underwent cryospray therapy [12]. An improvement in grade of stenosis after treatment was observed in 86.4% of the patients. No intraprocedural death occurred; the rate of procedure-related morbidity was 1.5%.

The RejuvenAir system is the latest development in the field of cryospray therapy. This system consists of a catheter and console with pressure and temperature controls that enable the delivery of liquid nitrogen in a circumferential pattern to meet a predetermined level of cooling for each MCS delivered. The amount of liquid nitrogen is adjusted so that each airway is treated by a standardised amount of nitrogen based on airway size, leading to a 10 mm circular cryoablation with a depth between 0.1 and 0.5 mm. It is hypothesised that the rapid freezing of the epithelial layer of the airway walls will destroy the mucus-producing goblet cells while preserving the extracellular matrix, thereby enabling the regrowth of healthy cells. The RejuvenAir system is currently under clinical investigation and is not commercially available.

The first description of the feasibility and safety of liquid nitrogen MCS therapy was by SLEBOS et al. [13

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