Advances in interventional pulmonology.

Review

Advances in interventional pulmonology Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Korea University on 01/08/15 For personal use only.

Expert Rev. Respir. Med. 8(2), 191–208 (2014)

Jason Akulian1, David Feller-Kopman2, Hans Lee2 and Lonny Yarmus*2 1 University of North Carolina, Pulmonary and Critical Care, Chapel Hill, CA, USA 2 Johns Hopkins University, Pulmonary and Critical Care, Baltimore, MD, USA *Author for correspondence: [email protected]

Interventional pulmonology (IP) remains a rapidly expanding and evolving subspecialty focused on the diagnosis and treatment of complex diseases of the thorax. As the field continues to push the leading edge of medical technology, new procedures allow for novel minimally invasive approaches to old diseases including asthma, chronic obstructive pulmonary disease and metastatic or primary lung malignancy. In addition to technologic advances, IP has matured into a defined subspecialty, requiring formal training necessary to perform the advanced procedures. This need for advanced training has led to the need for standardization of training and the institution of a subspecialty board examination. In this review, we will discuss the dynamic field of IP as well as novel technologies being investigated or employed in the treatment of thoracic disease. KEYWORDS: asthma . cryoprobe . EBUS . emphysema . interventional pulmonology . lung cancer . lung nodule .

navigational bronchoscopy . pleural effusion

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rigid bronchoscopy

Interventional pulmonology (IP) is an evolving field that has rapidly matured in recent years. The field of IP has always held a strong focus on the diagnosis and treatment of common airway and pleural diseases. Well documented is IP’s ability to manage malignant and nonmalignant complex airway disease through rigid and flexible bronchoscopic intervention [1–4]. In addition, advanced diagnostic bronchoscopic techniques such as convex and radial endobronchial ultrasound (EBUS)-guided procedures have become increasingly commonplace. While these techniques and technologies were once cutting edge, technological innovation and improvements in patient care have continued to drive IP into different areas of pulmonary disease resulting in many of these procedures now considered standard of care. In this review of advances in IP, we will present new interventional approaches to old diseases, emerging technologic innovation and the maturation of the field of IP. Endobronchial ultrasound

EBUS, first clinically introduced in the early 1990s [5], in combination with transbronchial needle aspiration (TBNA) has become a mainstay of lung cancer staging [6]. Prior to the introduction of EBUS, conventional TBNA (cTBNA) was used to approach mediastinal and hilar adenopathy. Despite long-standing informahealthcare.com

10.1586/17476348.2014.880053

evidence that cTBNA can accurately diagnose and stage malignant and non-malignant disease, data suggest that few pulmonologists routinely use this modality to sample the hilum and mediastinum [7]. In 2004, a dedicated curvilinear EBUS bronchoscope was introduced, which combined the ultrasound elements of the radial probe with a bronchoscopic working channel, thus allowing real-time TBNA of mediastinal and hilar lesions (FIGURE 1) [8,9]. Since its introduction, EBUS-TBNA has been shown to allow for a safe and effective minimally invasive approach to lung cancer staging [10]. EBUS-TBNA has been shown to be equal or potentially superior to mediastinoscopy with regard to staging and tissue acquisition [11–13]. In addition, EBUS-TBNA has repeatedly demonstrated its ability to provide adequate material for advanced immunohistochemistry and molecular subtyping of lung cancer for the molecular characterization of lung cancer [14–20]. This is especially important as increasing numbers of molecular profile-specific chemotherapeutics become available. The first two EBUS bronchoscopes introduced have a 35˚ forward oblique view increasing the difficulty of scope manipulation within the airway. A newly introduced EBUS bronchoscope (Fujifilm, Japan, EB 530) provides a 120˚ field of view at 10˚ forward oblique (FIGURE 2). This adjustment in view allows for

2014 Informa UK Ltd

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Expert Review of Respiratory Medicine Downloaded from informahealthcare.com by Korea University on 01/08/15 For personal use only.

Review

Akulian, Feller-Kopman, Lee & Yarmus

Figure 1. Endobronchial ultrasound-guided transbronchial needle aspiration of a right hilar lymph node. Orange color represents Doppler flow of blood vessels within and around the lymph node. Arrow denotes the tip of the needle inserted into the lymph node.

airway visualization near to the 0˚ view seen with a standard flexible bronchoscope. This feature potentially benefits the bronchoscopist and patient as the scope then closely mimics a standard flexible bronchoscope with regard to airway examination and the performance of TBNA [21]. In addition, the bronchoscope has an additional 35˚ of flexion improving visualization and access of the proximal upper lobes. These attributes lend to the possibility that this scope could potentially act as a hybrid allowing for a full airway inspection and performance of procedures normally reserved for standard forward view bronchoscopes while giving the operator the luxury of EBUS. Evaluation & management of parenchymal lung lesions in patients unsuitable for surgery or with early-stage lung cancer

The management of peripheral pulmonary nodules (PPN), often found incidentally on chest X-ray or computed tomography (CT), remains a difficult clinical scenario when encountered by specialty physicians. This issue continues to increase in importance with the National Lung Screening Trial showing a reduction in mortality associated with screening chest CT and an incidence of PPN seen in approximately 24% of patients screened [22]. This landmark study has been followed by a US Preventive services task force recommendation endorsing lowdose CT lung cancer screening in at-risk populations [23]. Utilization of mono- and bi-planar fluoroscopy during flexible bronchoscopy has been used in the evaluation of PPN but suffers from low localization rates and even lower diagnostic yields especially when targeting lesions in the outer third of the lung field [24,25]. The advent of advanced bronchoscopic modalities including the ultrathin bronchoscope and navigation bronchoscopy has led to improvements in localization rates and diagnostic yield when sampling PPN [26–28]. The use of electroand virtual navigation bronchoscopy (EVNB) first studied in 2005 then approved by the US FDA in 2008 have become 192

increasingly more common in the evaluation of PPN (FIGURE 3) [29,30]. In addition to the biopsy and diagnosis of peripheral lung lesions, EVNB is also being used to assist in the placement of fiducial markers for the guidance of stereotactic body radiation therapy (SBRT) and is now being evaluated as a technique to guide bronchoscopic ablative therapies in patients who are not surgical candidates. SBRT is used as a treatment in patients with parenchymal lung lesions not fit for or unwilling to undergo surgical resection [31]. A major limitation in the use of some SBRT systems is changes in lesion position during respiration that are overcome by a number of different techniques including breath hold, real-time tumor tracking, abdominal compression and fiducial marker targeting [32]. Fiducial markers, typically linear gold rods or coils can be placed via a transthoracic or an endobronchial approach (FIGURE 4). Transthoracic fiducial placement, while effective, carries with it a high incidence of pneumothorax not seen when using EVNB-guided bronchoscopic placement [33–35]. EVNB has been shown to be a safe, minimally invasive, feasible and effective modality for fiducial placement in early stage or inoperable lung cancer [36–38]. One limitation of linear fiducial placement has been with rates of marker displacement ranging from 10 to 30% [36,37]. This has led to the novel application of platinum coils as a potential replacement for gold beads. Schroeder et al. studied EVNBguided platinum coil placement reporting a significant decrease in the rate of fiducial migration when compared with linear markers, 1 versus 10–13% [39]. No data currently exist as to whether either marker holds an advantage during the targeting for SBRT. A new fiducial marker combining a linear gold rod with a distal nitinol coil has also recently been introduced (FIGURE 5). However, study as to whether this modification decreases migration rates or affects SBRT targeting has yet to be reported. Catheter-directed brachytherapy in the treatment of large airway malignancy has been well documented [40,41]. EVNBguided peripheral application of brachytherapy catheters has also been reported. Harms et al. first published a case report in which an EVNB-guided brachytherapy catheter was successfully placed and used in the right upper lobe of a non-surgical candidate with non-small cell lung cancer (NSCLC) [42]. This was followed in 2008, when Becker et al. reported the results of a feasibility and safety study in which 18 medically inoperable patients underwent successful EVNB-guided peripheral brachytherapy catheter placement. Of the 18 patients treated, 9 reportedly had complete remission with minimal side-effect profiles [43,44]. Since these reports, however, little has been published on this topic and larger prospective trials are needed. Radiofrequency tissue ablation (RFA) uses low frequency (460–480 kHz), long wavelength radio waves to generate thermal energy to achieve tissue coagulation and necrosis [45]. Used primarily as a percutaneous therapeutic technique, RFA has been shown to be effective in the treatment of pulmonary malignancy; however, high rates of pain, hemothorax, pneumothorax and reactive pleural effusion have been reported [44,46]. Expert Rev. Respir. Med. 8(2), (2014)


Advances in IP

One limitation of RFA has been coagulation of tissue around the site of energy delivery resulting in incomplete tissue necrosis and repeated catheter retrieval. A feasibility and safety study of an internally cooled RFA catheter deployed by CT-guided bronchoscopy treated 10 medically inoperable patients with stage 1 NSCLC, all of whom underwent successful RFA without complication [47]. Advances such as this make bronchoscopic RFA in combination with EVNB a potentially powerful tool in the treatment of peripheral lung lesions especially in those patients who are considered both inoperable and who demonstrate disease progression despite maximal doses of external radiotherapy.

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Advanced endobronchial & intraparenchymal imaging modalities

Improvements in bronchoscopic imaging of the large airways and parenchyma remains of great interest in the diagnosis and treatment of malignant and nonmalignant lung disease. Recent advances in bronchoscopic imaging have involved Figure 2. Fujifilm endobronchial ultrasound bronchoscope. (A) Left: ultrasound the use of differing wavelengths of light view. Right: white light view illustrating 10˚ forward view with TBNA needle extended. and the reflective characteristics of the (B) Fujifilm EBUS bronchoscope with balloon inflated. (C) Fujifilm EBUS bronchoscope airways themselves to highlight neovascuwith TBNA needle extended. larization, malignant and pre-malignant EBUS: Endobronchial ultrasound; TBNA: Transbronchial needle aspiration. endobronchial lesions [48]. Evaluation of Panels (B) and (C) provided courtesy of Fujifilm, Inc. these technologies has yielded mixed results; however, existing data may suggest a role for the detec- needle probes may be used to rapidly assess needle placement tion of pre-malignant airway lesions in high-risk patients [48–52]. before TBNA sample collection, the so-called ‘smart needle’ A major limitation of these technologies, however, is their use [58–60]. Further advancement within the field of OCT has been of direct visualization, thereby restricting its reliable use to the the development of polarization-sensitive OCT (PS-OCT). proximal airways. New bronchoscopic imaging modalities hold Polarization-sensitive OCT generates color images in which the promise of visualization to the level of the alveolus and light traveling through tissues undergoes a variable phase delay even beyond into the basement membrane and connective tis- dependent on organization of the parenchymal structures to light wave polarity. These measurable properties of light wave sue layers of the lung. Optical coherence tomography (OCT) is a non-invasive polarity and lung parenchymal interaction lead to a more imaging tool that rapidly generates high resolution cross- refined signal that is thought to be able to differentiate between sectional images of tissue with penetration depths approaching solid, air-filled or fibrotic structures [53]. While the first pub2–3 mm (FIGURE 6) [53]. It uses similar principles as ultrasound, lished use of OCT was in the measurement of endobronchial however, measures reflected light as opposed to sound waves. disease [61], there have since been reports evaluating normal OCT uses low coherence interferometry, in which light wave- lung parenchyma, airway dysplasia, carcinoma in situ, ex vivo lengths of the same frequency will undergo constructive inter- benign lesions and invasive malignancy [53,55,59,62]. Confocal laser fluorescence microendoscopy (CFM) utilizes ference, while those of a differing frequency will have destructive interference properties, the combination of which laser activation of injected fluorophores to create an in vivo leads to the generation of a pattern and ultimately an image image captured by a fiber optic bundle (FIGURE 7). In 2007, when measured at the near-infrared spectrum. Bronchoscopic Thiberville et al. reported the first bronchoscopic application of OCT catheters can be deployed through the working channel in vivo CFM on 29 patients at high risk for lung cancer [63]. of a flexible bronchoscope allowing in vivo evaluation of the This was followed in 2009 by CFM on a cohort of 41 healthy tracheobronchial tree [54–57]. Currently in development, OCT patients of whom 17 were active tobacco users. They reported informahealthcare.com

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Figure 3. Navigation bronchoscopy. (A) Broncus LungPoint navigation system virtual and computed tomography airway mapping. (B) Veran navigation virtual and computed tomography mapping. (C) Superdimension navigation.

a difference in the presence or absence of macrophages when comparing smokers with non-smokers [64]. Lane et al. reported on the histopathologic correlation between in vivo imaging and ex vivo transbronchial biopsy (TBBx) samples [65]. Since then CFM has been used to evaluate NSCLC of the large airways and its associated mucosal derangement, pulmonary alveolar microlithiasis, pulmonary alveolar proteinosis, amiodaroneinduced interstitial lung disease and chronic obstructive pulmonary disease (COPD) [66–70]. In addition, results of a data consistency analysis reported fair-to-good observational reliability of repetitive examination of the lung parenchyma in patients who underwent post-lung transplantation [71]. The 194

biggest limitation with these technologies has been the identification of an effective clinical use as the majority of data are purely descriptive. To date, no large diagnostic trials have been reported. Endocytoscopy (Olympus, Tokyo, Japan) is a recently introduced imaging technology that allows for in vivo imaging of mucosa to the cellular level. It incorporates either a probe- or scope-based platform with resolution as high as 1400-fold magnification of the imaged structure. Originally introduced for use within the gastrointestinal tract [72], a case series and pilot study were published on its use within the central airways, specifically in identification of small cell lung cancer and Expert Rev. Respir. Med. 8(2), (2014)

Advances in IP

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differentiation between normal and dysplastic/malignant airway cells, respectively [73,74]. These two reports offer an early view of a potentially powerful tool in the in vivo diagnosis of airway malignancy or dysplasia.


Cryotherapy & diagnostics

Cryotherapy is a safe and effective tool in the treatment of both benign and malignant central airway obstruction (CAO). The cryoprobe unit operates by releasing gas (NO or CO2) stored under high pressure into the tip of the cryoFigure 4. Gold coil and rod fiducial markers. probe (low pressure) which rapidly cools via adiabatic Figure provided courtesy of Superdimension/Covidien, Inc. expansion to -89˚C (FIGURE 8). This rapid cooling and the freeze-thaw cycle results in tissue destruction. In addition to extrinsic compression [1]. Airway stents are currently available in the treatment of CAO, cryotherapy is effective in the retrieval the self-expanding metallic (covered and uncovered) and silicone of mucous and blood airway casts as well as other organic varieties (FIGURE 10). Uncovered metallic stents have been given the foreign bodies. More recently, the cryoprobe has been studied FDA warning as a modality of last resort [78] in non-malignant as a method of TBBx. Cryoprobe transbronchial biopsies CAO due to their propensity for epithelialization, granulation, (CPBx) have been studied in interstitial lung disease, post- stent fracture and difficulty in removal. Metallic stents can be lung transplant surveillance and peripheral nodule sampling. deployed via either flexible or rigid bronchoscopy, whereas siliIn 2009, Babiak et al. reported the comparison of CPBx with cone stents can only be deployed via a rigid bronchoscope. The flexible forceps TBBx (FTBBx) in sampling 41 patients with effectiveness of airway stenting on relieving symptoms of CAO diffuse lung disease. CPBx resulted in significantly larger has been well documented and has shifted the treatment strategy biopsy samples, with minimal complications [75]. This work was followed-up in 2013 by Yarmus et al., who performed B A the first direct comparative trial of CPBx versus FTBBx in patients who had undergone post-lung transplantation (FIGURE 9). In this study, CPBx were shown to be a safe and effective tool in sampling of the transplanted lung parenchyma. Significantly larger biopsy specimens were obtained from CPBx with no difference in pneumothorax or bleeding seen [76]. Recently reported was a study of EBUS-guided CPBx in patients diagnosed with PPN. In this C D feasibility study, both CPBx and FTBBx of PPN were taken through a radial EBUS-navigated peripherally placed guide sheath. The reported diagnostic yield in lesions identified by EBUS and subsequently biopsied was 74.2%. Of 31 patients sampled with both modalities, 19 were diagnosed via both modalities, in another four cases only the CPBx yielded a diagnosis [77]. Further large prospective studies of CPBx are needed to establish it as a superior method of TBBx, however, current data are encouraging. Figure 5. Superlock Cobra fiducial marker. (A) The Superlock Cobra fiducial marker Novel airway stents

Airway stenting is the procedure of choice in patients presenting with CAO due to informahealthcare.com

loaded into the application catheter. (B) Partial deployment of the Superlock Cobra fiducial marker. (C) Full deployment of the Superlock Cobra fiducial marker. (D) Superlock Cobra fiducial marker. Figure provided courtesy of Superdimension/Covidien, Inc.

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stenosis [79]. Furthermore, Zhu et al. reported the successful placement of bioabsorbable drug-eluting stents in the trachea of rabbits in whom mucosal injury and tracheal stenosis had been elicited [80]. In 2013, Chao et al. surgically implanted chemotherapy-eluting tracheal stents in 15 white rabbits. Tracheal and systemic drug levels were then measured which showed sustained tracheal levels while systemic (blood) levels remained minimal [81]. This early work illustrates an exciting potential advancement in the treatment of both benign and malignant airways disease and should be followed by further animal and subsequent human studies. Figure 6. Optical coherence tomography of the tracheal wall. Star denotes tracheal ring.

for malignant CAO to one of combined stenting and external beam radiation [1]. A new and exciting tool being developed for the treatment of both benign and malignant CAO is the bioabsorbable stent. In 2011, Lischke et al. reported the safety and feasibility of the placement of biodegradable stents in the management of five patients with post-transplant bronchial

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Bronchoscopic lung volume reduction

Lung volume reduction surgery has been shown to improve both the quality and duration of life in patients with upper lobe predominant emphysema and a low exercise capacity [82]. Despite this, the specificity of patients who would benefit in combination with the high peri- and post-operative complication rate of lung volume reduction surgery including a 90-day post-operative mortality of 5.2% has made it an infrequently performed procedure. This has led to the development of less invasive bronchoscopic therapies aimed at achieving a similar result. There are currently several bronchoscopic lung volume reduction (BLVR) systems being studied in an effort to show clinically meaningful benefit and gain the FDA approval. These systems include oneway airway valve placement, thermal, biologic and coil segmental/lobar ablation. The specifics of each therapeutic modality for BLVR are presented below with TABLE 1 summarizing the major points for each modality.

Figure 7. In vivo confocal fluorescence microscopic imaging of the alveolus in smokers. (A) Alveolar system filled with highly fluorescent alveolar macrophages. Axial view down the alveolar duct. (B) Alveolar duct, oblique view. Arrows: helical arrangement of the axial cables of the alveolar duct. (C) In vivo imaging of the alveolar walls, showing bubbles on the surface of the alveolar wall and alveolar entrance. (D) Fine details of the alveolar wall from the same patient as in (A). Reproduced with permission of [64].

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Endobronchial valves

Two one-way airway valves placed for the purpose of promoting segmental lung atelectasis currently exist. The Emphasys Zephyr Endobronchial valve (ZEBV) is a second-generation device that consists of a silicone ‘duck bill’ attached to a nitinol skeleton and is reported to have a lower airway resistance profile than previous models (FIGURE 11). In 2012, Herth et al. reported the results of a study in which ZEBV were placed in patients with advanced emphysema. Chest CT assessment of fissure integrity was performed prior to ZEBV placement and it was found that patients with complete fissures had significant improvements in forced expiratory volume in 1 s (FEV1) at 6 and 12 months when compared with medically managed controls. Expert Rev. Respir. Med. 8(2), (2014)


Advances in IP

No significant difference was seen in the rates of complications; however, a trend toward increased pneumothorax rate was noted in the ZEBV group [83]. The intrabronchial valve, (IBV, Spiration Inc., Redmond, WA, USA) uses a polymer membrane suspended from a nitinol framework shaped like an umbrella to act as a one-way valve, allowing secretions and air to flow proximally while occluding distal flow (FIGURE 12). In 2010, Sterman et al. reported the results of a pilot study in which 91 patients with severe upper lobe predominant emphysema and obstruction had IBV placed bilaterally. Post-procedure, significant improvements in St George Respiratory Questionnaire (SGRQ) scoring measurements from baseline and a shift of lung volume to untreated lobes was observed. The most common complication was the incidence of pneumothorax with one death from tension pneumothorax 4 days after valve placement [84]. This study was followed in 2012 by a multicenter trial which reported a significantly greater number patients who reported a >4 point increase in SGRQ and shift in lung volume to untreated lobes when comparing treated patients versus controls. No significant difference in adverse events was noted between treated patients and controls [85]. Of note, neither valve system has yet shown difference in 6-min walk test or SGRQ scoring. Further studies are required to ascertain the effectiveness of this technology and how best to apply it in patients with advanced COPD and both valves are currently being studied in large multicentered randomized controlled trials. One of the primary challenges in BLVR has been the issue of lobar collateral ventilation [3,86]. During the endobronchial Valve for Emphysema palliatioN Trial, it was noted that patients with complete lobar fissures responded better to the treatment than those with incomplete fissures [87]. This led to further study of collateral ventilation in BLVR [88] and the TM development of an endobronchial catheter (Chartis , Pulmonx Inc., Neuchatel, Switzerland) that measures lobar flow distal to proximal occlusion of the airway (FIGURE 13). Herth et al. studied the Chartis system, reporting an accuracy level of 75% in predicting those patients who would respond to airway valve placement. They showed that those predicted to respond had a significantly greater degree of lobar atelectasis and FEV1 improvement than those patients predicted not to respond to therapy [89]. The Chartis system is currently being studied in a large multicenter randomized trial in conjunction with the ZEBV. Ablative BLVR

Bronchoscopic thermal vapor ablation (BTVA, InterVapor, Uptake Medical, Seattle, WA, USA) is a novel technology in which targeted heated water vapor or steam is applied to emphysematous lung in order to cause irreversible inflammation and fibrosis. Snell et al. published the first feasibility and safety study when ‘low-dose’ BTVA (5 cal/g lung tissue) was applied unilaterally in 11 patients with severe heterogeneous emphysema. They reported a significant improvement in diffusing capacity for carbon monoxide and improvement informahealthcare.com

Review

Figure 8. Cryoprobe (left) versus conventional forceps (right).

in SGRQ scoring. Complications included COPD exacerbation and probable bacterial pneumonia [90]. This was followed by a study of 44 patients with upper lobe predominant emphysema who were treated unilaterally with BTVA. Significant improvements were seen in 6-min walk distance (6MWT) and modified Medical Research Council Score (mMRC). The safety profile closely mirrored the previous pilot study [91]. Gompelmann et al. attempted to correlate lung fissure integrity and efficacy of BTVA. Forty-four patients with severe heterogeneous emphysema underwent chest CT followed by ‘high-dose’ (10 cal/g lung tissue) upper lobe single lung BTVA. The findings at a 6-month follow-up showed significant improvements in FEV1, forced vital capacity (FVC), residual volume (RV), mMRC, SGRQ score and 6MWT. In addition, fissure integrity was found to have little or no influence on BTVA therapeutic outcomes [92]. One-year follow-up of this cohort reported sustained significant improvements from baseline in FEV1, RV, mMRC, SGRQ and BODE index seen at 6 months were seen again, albeit lower, at 12 months. Further subgroup analysis of patients based on GOLD staging (3 and 4) and emphysema heterogeneity index showed similar findings at 6- and 12-month follow-up. Thirty-nine serious adverse events were reported in 23 patients, the most common being COPD exacerbation. One death was reported at 67 days secondary to end-stage lung disease and a second death was reported at 350 days post-treatment following thoracic surgical complications [93]. Polymer-based BLVR

The bronchoscopic instillation of polymers into emphysematous lung is another novel approach to the treatment of severe emphysema. Initial use of biologic agents [94] has given way to a synthetic polymer (emphysema lung sealant [ELS]), applied via a catheter to subsegmental airways. The synthetic foam polymerizes into a glue that obstructs the 197

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management [95]. Magnussen et al. followed this study with an evaluation of the effect of fissure integrity on ELS administration, in which chest CT imaging and unilateral ELS was performed on 28 patients with upper lobe predominant heterogeneous emphysema. Lobar fissure integrity was then assessed and correlated with physiologic data. Significant improvements from baseline were observed for all measures (FEV1, FVC, RV, TLC, dyspnea scoring, 6MWT) when corrected for multiple comparisons. Fissure integrity was found to have little or no impact on the physiologic changes seen [96]. Finally, in 2012, Kramer et al. published their findings at 3-, 6- and 12-months from a study in which 20 patients underwent bilateral ELS application. Of interest, the cohort was split evenly between patients with heterogeneous upper lobe predominant and homogeneous emphysema. Significant improvements in FEV1, FVC, RV, RV/TLC, diffusing capacity for carbon monoxide and dyspnea score were noted at 12 months. Ten adverse events in nine patients were reported during the study, including one procedurally related death. The two major limitations of the study were a lack of correcting for multiple comparisons and subgroup analysis of the different emphysema architectural types [97]. Although the polymer is available in Europe, a recent multicentered trial in the USA closed due to lack of funding (Aeris Therapeutics Inc., Woburn, MA, USA). Coil BLVR

Figure 9. Cryoprobe transbronchial biopsy in patients who had undergone post-lung transplantation. (A) Forceps TBBx (left) versus Cryoprobe TBBx (right). (B) Microscopic image of forceps TBBx showing crush artifact and hemorrhage. (C) Microscopic image of cryoprobe TBBx showing open alveolar, lack of crush artifact or hemorrhage. TBBx: Transbronchial biopsy. Reproduced with permission of [76].

target airways leading to distal lung atelectasis. In 2011, Herth et al. reported their findings from a study in which 25 patients with severe heterogeneous emphysema (GOLD stage 3 and 4) had unilateral ELS applied. At 24 week follow-up, significant improvements in FEV1, FVC, % RV/total lung capacity ratio (TLC) and SGRQ scores were observed; however, after correction for multiple comparisons only change in FVC remained statistically significant. On subgroup analysis, improvements were found in only in the GOLD stage 3 cohort prompting the authors to hypothesize that GOLD stage 4 patients likely have a greater degree of lung tissue destruction which would require additional volume reduction to achieve results similar to GOLD stage 3 patients. All patients reported ‘flu-like’ symptoms and 10 patients had COPD exacerbations requiring medical 198

Coil BLVR is another device aimed at overcoming lung collateral ventilation in the treatment of severe emphysema. The coil is a straightened nitinol wire which when deployed into the subsegmental airways is designed to refold into a predesigned configuration. Once deployed and refolded, it acts by retracting the lung and causing atelectasis. A pilot study published in 2010 in which coils were placed in 11 patients with both hetero- and homogeneous emphysema showed that the technique was well tolerated and a feasible method of BLVR [98]. This study was followed in 2012 by a prospective cohort study in which 16 patients with severe upper lobe heterogeneous emphysema had 28 coils placed. Four patients were treated in one lung, while the rest underwent bilateral coil placement. A median of 10 coils were placed per lung. Six-month follow-up showed significant improvements in FEV1, FVC, SGRQ score and 6MWT from baseline. Adverse events possibly related to the device or procedure, defined by having occurred 4 point increase in SGRQ, lobar volume shift

Primary end points

Heterogeneous Upper lung

Emphysema distribution

[84]

HRQoL Improvement* acceptable safety proportional shift of lobar volume to untreated lobes

Reduction in upper lobe volume* Improvements in FEV1, FVC, DLCO, RV, RV/TLC observed 1 procedurally related death

Safe with COPD exacerbation and pneumonia, Improvement in: DLCO* and SGRQ*

Herth – improvements seen at 12 months less than at 6 but still significant above baseline Snell – improvements in: FEV1*, SGRQ*, 6MWT* mMRC* Safe, COPD exacerbation most common Gompelmann – lobar fissure integrity, no influence on outcomes

[97]

[90]

[91–93]

[87]

[83]

Improvement in dSGRQ*, cycle ergometry*, dFEV1, 6MWT

Mean improvement in FEV1* Median d6MWT from baseline* More frequent exacerbations of COPD, pneumonia and hemoptysis

[85]

Ref.

Shift in volume* 8 vs 0 responders* No difference in mean SGRQ

Results

*Statistical significance (p < 0.05). 6MWT: 6-min walk test; DLCO: diffusing capacity for carbon monoxide; FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; HRQoL: Health-related quality of life; mMRC: Modified Medical Research Council; RCT: Randomized controlled trial; RV/TLC: Residual volume/Total lung capacity ratio; SGRQ: St. George’s Respiratory Questionnaire.

Kramer et al. (2012)

Single-arm, prospective

Feasibility and safety

Snell et al. (2009)

Polymer

Open-label, single-arm, safety

Snell et al. (2012) Gompelmann et al. (2012) Herth et al. (2012)

Ablative

RCT

Type of study

Ninane et al. (2012)

Endobronchial valves

Study (year)

Table 1. Summary of bronchoscopic lung volume reduction studies.


Review Akulian, Feller-Kopman, Lee & Yarmus

Expert Rev. Respir. Med. 8(2), (2014)

[98]

No severe adverse events, no pneumothorax. Efficacy appeared better in heterogeneous than homogeneous disease Heterogeneous Homogeneous Safety and feasibility pilot Herth et al. (2010)

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DSGRQ Heterogeneous 16 Prospective cohort Slebos et al. (2012)

Coil

*Statistical significance (p < 0.05). 6MWT: 6-min walk test; DLCO: diffusing capacity for carbon monoxide; FEV1: Forced expiratory volume in 1 s; FVC: Forced vital capacity; HRQoL: Health-related quality of life; mMRC: Modified Medical Research Council; RCT: Randomized controlled trial; RV/TLC: Residual volume/Total lung capacity ratio; SGRQ: St. George’s Respiratory Questionnaire.

[99]

Improvement in SGRQ*, FEV1*, FVC*, RV* and 6MWT* observed

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Safety and feasibility

[95]

Safe, %D in RV/TLC* at 24 weeks. Also showed improvements in FEV1, FVC, DLCO, 6MWT, SGRQ Heterogeneous Open-label, dose escalation study Herth et al. (2011)

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RV/TLC ratio Safety

[96]

Fissure integrity, no influence on outcomes. Improvements in FEV1, FVC, DLCO, 6MWT, SGRQ observed Heterogeneous Open-label Magnussen et al. (2012)

Polymer (cont.)

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Effect of fissure integrity of physiologic changes

Results Primary end points Emphysema distribution Subjects (n) Type of study Study (year)

Table 1. Summary of bronchoscopic lung volume reduction studies (cont.).


Ref.

Advances in IP

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department visits, hospitalizations and stability of pre- and post-bronchodilator FEV1 [106,108]. Approved by the FDA in 2010, BT continues to face significant hurdles including a lack of consistent insurance reimbursement, recognition and generalizability to patients with severe asthma. Further studies are needed to more fully identify those patients most likely to benefit from this treatment as well as its short- and long-term safety in those patients with more severe symptoms than those included in previous trials prior to BT being included in guideline management. Management of malignant pleural effusion

Recent advances in malignant pleural disease has been primarily focused on the use of tunneled pleural catheters (TPCs) in the management of dyspnea, hospital length of stay (LOS), quality of life (QoL) and cost–effectiveness of the procedure. The catheter is a 15 French fenestrated drain that is inserted into the pleural space and then tunneled subcutaneously to reduce the risk of infectious complications (FIGURE 15). The majority of these procedures can be done in an outpatient setting. Since their introduction, TPCs have become increasingly ubiquitous with the palliative management of malignant pleural disease. This technology continues to be rigorously studied as providers search for less invasive management options than classic surgical intervention. Shown to be safe and effective in the treatment of MPEs [109,110], the study of TPCs has turned toward comparisons with invasive surgical techniques and chemical pleurodesis. In a study aimed at developing a method of ‘rapid’ pleurodesis for the management of MPE, thoracoscopy, talc pleurodesis and TPC placement were performed simultaneously followed by aggressive outpatient TPC drainage. Compared with TPC spontaneous pleurodesis rates of 40–60% and a historical LOS of 5 days following talc poudrage, pleurodesis and LOS were found to be 92% and a median of 1.79 days in the ‘rapid pleurodesis’ cohort, respectively. This pilot study was not powered nor randomized to assess a statistical difference between modalities and prospective randomized trials are needed [111]. Hunt et al. retrospectively reviewed 109 patients who underwent thoracoscopy and talc poudrage versus TPC placement for symptomatic MPE. Patients undergoing TPC placement had significantly shorter LOS and lower rates of reintervention [112]. In a propensity matched retrospective study comparing TPC with thoracoscopy and talc poudrage, Freeman et al. reported that patients undergoing TPC placement for MPE had significantly shorter LOS, interval to systemic therapy and lower rates of operative morbidity [113]. Two recent prospective studies of MPE treatment comparing TPC and talc pleurodesis, via slurry or poudrage, reported significantly shorter LOS, improvements in dyspnea, QoL and fewer episodes of pleural reintervention [114,115]. Puri et al. published a cost–effectiveness study of the treatment of MPE that used decision analysis to compare repeated 201

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patients enrolled, measures at 14 weeks were improved but did not reach statistical significance [117].


Medical thoracoscopy

Single port medical thoracoscopy is used in diagnosis and treatment of pleural disease by the interventional pulmonologist. Increasingly, medical thoracoscopy has gone from supplanting closed pleural biopsy in the diagnosis of malignant and infectious diseases [1,118] to including such interventions as talc poudrage in the setting of pneumothorax and MPE and in the treatment of complex parapneumonic effusion and empyema. In addition, semi-rigid thoracoscopes have been shown to have similar diagnostic yields to rigid thoracoscopes despite smaller biopsy size [119,120]. Pneumothorax Figure 11. One-way endobronchial valve – ZephyrTM valve. Figure provided courtesy of Pulmonx corp.

thoracentesis, TPC, bedside talc slurry and talc poudrage. They reported that when comparing pleurodesis strategies for patients with short expected survival time (3 months), TPC was the preferred treatment strategy due to decreased cost and improved efficacy. They went on to report that for patients with longer expected survival times (12 months) that bedside pleurodesis was more cost effective [116]. Sabur and colleagues published the first study specifically examining the effect of TPCs on QoL in patients with MPE. They reported that TPCs were associated with significant improvements in global health status, QoL and dyspnea at 2-week follow-up from pre-procedure baseline. Due to the death of 45% of the

The treatment of primary spontaneous pneumothorax (PSP) via semi-rigid or rigid medical thoracoscopy with talc poudrage has gained increasing acceptance as a therapeutic modality in those patients with persistent air leaks or recurrent pneumothorax, with a reported 93% durable success rate and potential cost savings when compared with standard chest tube drainage [121,122]. However, surgical intervention utilizing single lung ventilation and mechanical versus talc pleurodesis remains the ‘gold standard’ for treatment of this disease process. In an elegant study, Noppen et al. performed a comparison of white light medical thoracoscopy with thoracoscopy utilizing fluorescein-enhanced autofluorescence to assess pleural integrity in patients with PSP compared with controls. In those patients with PSP, autofluorescence showed abnormalities of the pleura in those areas that appeared normal under white light, suggesting that significant parenchymal abnormalities outside of readily visible blebs and bullae were present and likely responsible for the recurrent nature of the disease [123]. Empyema

In the USA and UK, invasive surgical intervention for complex parapneumonic effusion and empyema not responding to medical therapy remains the provenance of the thoracic surgeon. Three non-randomized non-comparator case series have recently reported high ‘success rates’ and low or no complications in patients undergoing medical thoracoscopy for pleural infection [124]. These case series present data that indicate a potential role for medical thoracoscopy in the treatment of these diseases; however, prospective randomized data are required before the applicability of medical thoracoscopy to pleural infections can be recommended. Interventional pulmonology in the pediatric population

Figure 12. One-way intrabronchial valve – Spiration valve. Figure provided courtesy of Spiration, Inc.

202

Little data exist on the application of IP procedures in the pediatric population. Long thought to be the provenance of pediatric surgeons and pulmonologists, a recent study describes the adult IP experience in the pediatric population at a major academic hospital. Gilbert et al. reported 22 cases Expert Rev. Respir. Med. 8(2), (2014)

Advances in IP

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C

Figure 13. Chartis console and pressure tracings. (A) Chartis system. (B) Flow and pressure tracings prior to balloon occlusion. (C) Decreasing flow and pressure tracings post-balloon occlusion. Figures provided courtesy of Pulmonx Corp.

of advanced diagnostic bronchoscopy, 17 cases of therapeutic rigid bronchoscopy and 15 pleural procedures performed on pediatric patients. The diagnostic bronchoscopy cases included the use of EBUS in 12 patients, 10 convex EBUSTBNA and 2 radial EBUS followed by TBBx. The mean age in these cases was 15.6 years. Of the EBUS-TBNA cases, a diagnosis was obtained in 8/12 (66.7%) and adequate sampling was observed in 11/12 cases (91.7%). Patients who underwent therapeutic bronchoscopy had a mean age of 14.9 years with 16/17 cases involving rigid bronchoscopy for either CAO or hemoptysis. Endobronchial stenting was performed in nine cases with stent removal in four. All pleural procedures were performed under ultrasound guidance and included six cases of tube thoracostomy and nine thoracentesis. No deaths or complications were reported and all patients were extubated after the procedure [125]. This was followed by a multicenter retrospective review at six academic medical centers of the feasibility of EBUS being performed in the pediatric population. Twenty-one patients underwent EBUS-TBNA with eight undergoing further surgical sampling. EBUS-TBNA yielded adequate material as defined as a diagnosis or the presence of lymphocytes, in 20 of 21 patients. Ten of the cases yield definitive diagnostic material and of the other 11 patients, 8 underwent further surgical sampling which led to the diagnosis of infection, lymphoma and hamartoma. No complications were reported and no patients required transfer to a higher level of care [126]. These studies illustrate that with a multidisciplinary approach, advanced diagnostic and therapeutic pulmonary procedures can be performed safely in the pediatric population. Further study is clearly required to aid in informahealthcare.com

the pre-procedural selection of those patients who would benefit most from these types of intervention. Interventional pulmonary certification & training

IP is a rapidly expanding subspecialty field whose growth has been driven by new diagnostic and therapeutic technology. With these technologic advances have come increasingly complex procedures that require high levels of skill and experience. The need for the development of these skills and experience has also led to an increasing number of IP subspecialty fellowships. With this maturation of the field have come a number of observations and needs. A study examining procedural volumes and IP fellowship structure found procedural volumes to be similar among IP programs but significantly higher than both the American College of Chest Physician and American Thoracic Society/European Thoracic

Figure 14. AlairTM bronchial thermoplasty catheter. Figure provided courtesy of BostonScientific.

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Figure 15. Tunneled pleural catheter. (A) PleurxTM . (B) Rocket IPC. Figure (A) provided courtesy of CareFusion, Inc. Figure (B) provided courtesy of Rocket Medical plc.

Society guideline recommendations [127–129]. This study highlights the need for subspecialty training in IP, similar to other specialties requiring advanced technical skill [130]. In 2010, IP entered the National Residency Matching Program and the American Association of Bronchology and Interventional Pulmonology began the development of a specialty-specific didactic training curriculum to pair with the ‘hands-on’ experience. This was followed by a study reporting the validation of an in-service examination in which IP faculty, IP fellows finishing their training, incoming IP fellows and graduating pulmonary critical care fellows were administered a validated multiple choice exam. A statistically significant graduated improvement in mean score was observed with increasing level of IP training [131]. The findings from this study and the realized need for standardized training in the rapidly maturing field of IP has led to the institution of an IP subspecialty board certification examination first being administered in December 2013.

Expert commentary

As the field of IP continues to grow and new technologies become available, the paradigm of disease management continues to change. Diseases previously thought to only be manageable through medical or invasive surgical means are now being diagnosed and treated via minimally invasive approaches. With the introduction of new technologies, IP practitioners and collaborating physicians alike must now work together through rigorous study to find the best clinical setting for application. The primary challenge facing IP is the recognition of what the field can provide by other services. The nature of IP places it squarely in a unique position between the fields of medicine and surgery. This position allows for increased communication between services leading to improvements in patient care. IP facilitates a multidisciplinary environment of thoracic disease management that continues to improve patient care. Five-year view

The evolving and maturing nature of the field of IP, including new technologies, new applications of old technologies and further standardization of training in advanced bronchoscopic techniques, has a future that continues to appear bright. Over the next 5 years, we may see fundamental changes in the way in which we approach patients with asthma, COPD, metastatic and primary lung malignancies and patient’s with interstitial lung disease. .

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Conclusion

The growth of IP over the last 5 years has been nothing short of astounding. This has been driven by increasingly complex technology and its accompanying treatment algorithms. Diseases previously thought to be only treatable through medical or surgical means are having their paradigms drastically altered leading to improved patient care and fostering an environment of increasingly multidisciplinary management. Though many of these new technologies show promise, prospective randomized trials are required to rigorously assess their safety and clinical efficacy. These novel technologies have required increasing mastery of basic and advanced pulmonary interventions and their associated complications. This required mastery has led to a maturation of the field into one that has recognized a need for standardized practice and training of future practitioners. 204

. .

Bronchoscopes will continue to evolve in terms of ergonomics, ultrasound imaging, microscopic distal lung parenchymal and transmural imaging; Continued improvements in navigation technology will enable not only improved sampling of small peripheral lesion, it will allow for the application of ablative technologies in non-operable patients; Cryoprobe diagnosis and therapy will increasingly be used for biopsy and ablation of parenchymal lesions and may be shown to be superior to transbronchial forceps biopsy in the setting of lesions eccentric to the airway or in patients with interstitial lung disease; Bronchoscopic lung volume reduction and bronchial thermoplasty will become a commonplace in the treatment of patients with heterogeneous upper lobe predominant emphysema and asthma respectively; TPCs will become the mainstay of palliation in patients with MPEs; IP will become an Accreditation Council for Graduate Medical Education recognized subspecialty with its own annually proctored board examination.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.


Advances in IP

Review

Key issues .

Endobronchial ultrasound-transbronchial needle aspiration has been shown to allow for a safe and effective minimally invasive approach to lung cancer staging and tissue acquisition of molecular analysis. New endobronchial ultrasound bronchoscopes are being introduced which more closely mimic conventional bronchoscopes in their performance profiles.

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New navigation bronchoscopy modalities are allowing for improved peripheral lung lesion sampling and may pave the way for bronchoscopically deployed ablative technologies.

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Advanced bronchoscopic imaging modalities such as optical coherence tomography and confocal laser fluorescence microendoscopy


hold the potential to revolutionize lesion identification and visualization of lung parenchymal disease. .

Cryoprobe biopsy is being studied as a means to improve transbronchial biopsy yield.

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Novel bioabsorbable and drug-eluting airway stents may provide new ways of drug delivery and decrease stent complications.

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Multiple modalities of bronchoscopic lung volume reduction are being studied and appear to show potential efficacy in the treatment of heterogeneous emphysema.

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Bronchial thermoplasty has been shown to have durable demonstrable effect in difficult-to-control asthma. Its primary obstacles to overcome remain recognition in the medical community and reimbursement from insurance companies.

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Tunneled pleural catheter placement continues to encroach upon more invasive surgical techniques in the palliative management of malignant pleural effusion.

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Interventional pulmonology continues to evolve and mature prompting recognition of the need for standardized training and creation of a board certification.

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Interventional pulmonology.

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The future of interventional pulmonology.

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