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Abstract
The field of interventional pulmonology has grown rapidly since first being defined as a subspecialty of pulmonary and critical care medicine in 2001. The interventional pulmonologist has expertise in minimally invasive diagnostic and therapeutic procedures involving airways, lungs, and pleura. In this review, we describe recent advances in the field as well as up-and-coming developments, chiefly from the perspective of medical practice in the United States. Recent advances include standardization of formalized training, new tools for the diagnosis and potential treatment of peripheral lung nodules (including but not limited to robotic bronchoscopy), increasingly well-defined bronchoscopic approaches to management of obstructive lung diseases, and minimally invasive techniques for maximizing patient-centered outcomes for those with malignant pleural effusion.
Interventional pulmonology (IP) is a relatively nascent but rapidly growing subspecialty in the United States, primarily focused on advanced diagnostic and therapeutic procedures involving the airways, lungs, and pleura (1, 2). In this review, we describe recent advances and upcoming developments in the field of IP, chiefly from the perspective of medical practice in the United States.
Since its initial description as a distinct subspecialty in 2001 (3), IP has continued to garner recognition and interest in the medical community, with high-quality research studies, best practice guidelines, and Food and Drug Administration (FDA) approvals continuing to push the breadth and depth of its scope in clinical practice (4–10). Though all pulmonologists learn about the evaluation and management of lung nodules and pleural disease, it has been shown that dedicated IP training increases this disease-specific knowledge base in addition to improving procedural skills (11, 12). Furthermore, the number of “advanced” procedures offered by general pulmonary and critical care fellowship programs do not meet recommendations by the American Thoracic Society (ATS) and American College of Chest Physicians (ACCP) (13–15), whereas IP fellowship programs far exceed those numbers (16). To assess the level of procedural proficiency, skills assessment tools have been validated that can distinguish novice, intermediate, and expert skill levels for a variety of procedures (17, 18).
Although IP is not currently recognized as a distinct specialty by the American Board of Medical Specialties, the American Association for Bronchology and Interventional Pulmonology (AABIP) has conducted annual certification examinations in IP since 2013. Starting in 2017, completion of 1 year of dedicated fellowship training in IP became a mandatory prerequisite for AABIP certification. That same year, the Association of Interventional Pulmonary Program Directors partnered with AABIP, ATS, ACCP, and Association of Pulmonary and Critical Care Medicine program directors to publish a consensus statement defining minimum training standards for IP fellowship programs (19). There are now 38 IP fellowship programs throughout the United States. Training guidelines for IP procedures have also been adopted in other countries, including Australia and Italy (20, 21).
Convex endobronchial ultrasound (EBUS), first described in 2004, provides a sonographic view that is parallel to the long axis of the bronchoscope and allows for real-time visualization during transbronchial needle aspiration (TBNA) of mediastinal and hilar lymph nodes and other lesions. This technique has largely replaced conventional TBNA (i.e., non–ultrasound-guided TBNA based on anatomical landmarks) and even mediastinoscopy as the “gold standard” for lung cancer staging (22, 23), with recently published ACCP guidelines offering evidence-based recommendations on technical aspects of the procedure (24). It is important to note that in cases of suspected lung cancer (e.g., a suspicious lung nodule seen in a patient with significant tobacco history), EBUS-TBNA has the potential to provide diagnosis and mediastinal staging at the same time instead of putting the patient through the added risks of a transbronchial biopsy (TBB) or computed tomography (CT)-guided transthoracic biopsy; the latter, if done first, may require a subsequent procedure (such as convex EBUS) to stage the mediastinum (25).
Multiple studies including meta-analyses illustrate that EBUS-TBNA has a pooled sensitivity of roughly 90% for staging of non–small cell lung cancer (26, 27). These statistics are comparable to a pooled sensitivity of 89% for video mediastinoscopy, which is considerably superior to that of conventional cervical mediastinoscopy (28). EBUS-TBNA also has a similarly high yield for intrathoracic lymph node metastases from extrathoracic malignancies, with a reported pooled sensitivity of 85% and specificity of 99% (29). However, EBUS has a more modest sensitivity of 55% (negative predictive value, 92%) for occult metastatic disease (i.e., in cases of pathologic N2 disease but radiographic N0 or N1 disease based on CT and/or positron emission tomography) (30). For pulmonary sarcoidosis, the sensitivity of EBUS-TBNA is 85%; in contrast, transbronchial lung biopsy plus endobronchial mucosal biopsy have a combined yield of only 35%. Combining all three modalities can slightly increase the yield further to 93% (31). In contrast, the yield of EBUS for diagnosing and subtyping lymphoma (particularly de novo lymphoma) is lower at approximately 70% with a considerable variation in estimates (32–34). EBUS is reported to have a lower sensitivity for Hodgkin’s lymphoma than for non-Hodgkin’s lymphoma, with at least part of the variability attributable to variations in local cytopathologic expertise. As a result, some centers are comfortable diagnosing both Hodgkin’s and non-Hodgkin’s lymphoma using TBNA specimens, whereas others prefer larger surgical samples for the diagnosis of Hodgkin’s lymphoma (34, 35).
Data indicate that performing concurrent endoscopic ultrasound-guided fine-needle aspiration via the esophagus improves diagnostic performance by a small but statistically significant margin, either using the standard gastrointestinal endoscope or simply using the EBUS bronchoscope in the esophagus (28, 36). A needle-based technique (either EBUS-TBNA, endoscopic ultrasound-guided fine- needle aspiration, or both) is now recommended as the first-line method for mediastinal staging of known or suspected lung cancer (28).
The ACCP clinical practice guideline for evaluation and management of lung cancer recommends the least invasive diagnostic procedure that would offer diagnosis and staging for patients with suspected cancer (37). As mentioned above, starting with convex EBUS in the bronchoscopic evaluation of a lung nodule offers the potential for achieving histopathologic diagnosis and mediastinal staging at the same time, with sampling of the nodule itself potentially becoming a “plan B” if mediastinal sampling does not readily indicate a definitive diagnosis per rapid on-site cytologic evaluation. Although standard flexible bronchoscopy is effective for the diagnosis of bronchoscopically visible endobronchial and central lesions (with an overall sensitivity of 88%), its diagnostic yield for peripheral lesions is much lower, with sensitivities of 34% and 63% for nodules less than 2 cm and greater than 2 cm, respectively (37). Technological advancements in peripheral bronchoscopy continue to be made with the goal of improving this yield.
Electromagnetic navigational bronchoscopy (ENB) is a technique best thought of as “GPS for the lungs” that uses an electromagnetic field to track instruments through the airways (38). “Virtual bronchoscopy” refers to an internal rendering of the airway from CT data to generate a virtual roadmap to the target lesion. Three systems currently available in the United States are SuperDimension (Medtronic), LungPoint (Bronchus Technologies, Inc.), and the SPiN System (Veran Medical Technologies). Each system uses slightly different technology, with LungPoint relying solely on virtual bronchoscopy without having an electromagnetic navigation component. LungPoint is the only system that permits “bronchoscopic transbronchial parenchymal nodule access” (i.e., direct tunneling through normal parenchyma) as opposed to navigation through smaller, more distal airways. To date, there have been no comparative efficacy trials between systems.
Though initial data suggested the diagnostic yield of ENB to be as high as 90%, especially when combined with radial endobronchial ultrasound (rEBUS), larger studies including meta-analyses and a recent multicenter registry of over 1,000 patients indicated overall yields around 70%, which can be as low as 38% when using ENB alone (10, 39–43). Operator experience (independent of lesion size and location) (44), presence of a “bronchus sign” on a CT scan (i.e., visible airway leading to the lesion), and addition of TBNA to other sampling tools have consistently been reported as predictors of higher diagnostic yield across multiple prospective studies (10, 39, 45, 46).
The use of electromagnetic navigational transthoracic needle aspiration (ETTNA) in combination with ENB has recently been investigated. This procedure uses a sensor-tipped transthoracic needle that can be tracked in the same electromagnetic field as for ENB to provide electromagnetic navigation (in lieu of CT guidance) as the needle is advanced transthoracically toward the target. In a single-center, prospective pilot study examining the safety, feasibility, and diagnostic yield of combined ENB and ETTNA, 24 patients underwent EBUS for staging followed by ENB and ETTNA for sampling of a peripheral lesion. The diagnostic yield for ETTNA alone was 83% and increased to 87% when combined with ENB. With all three modalities combined, the diagnostic yield increased to 92% (47). A multicenter randomized study is currently underway to validate these results (All in One Study: A Prospective Trial of Electromagnetic Navigation for Biopsy of Pulmonary Nodules; NCT03338049) (48). ENB and ETTNA have also been demonstrated to be safe and feasible for the placement of fiducial markers to guide stereotactic body radiation therapy, as well as for dye marking to guide video-assisted or robotic-assisted thoracoscopic resection of lesions that may not be palpable by the surgeon, such as ground-glass nodules/carcinoma in situ (49, 50).
rEBUS, first described in 1992, was initially used to guide TBNA and assess early tumor invasion versus compression in the central airways. With the advent of convex EBUS allowing for real-time visualization during biopsy of central lesions, use of rEBUS is now largely confined to intraprocedural imaging of peripheral lesions that are outside the reach of the larger convex EBUS bronchoscope (51). A 2011 meta-analysis including 16 trials with 1,420 patients showed that bronchoscopy with rEBUS-assisted peripheral nodule sampling had a specificity of 100% and sensitivity of 73% for detection of lung cancer, though, once again, more recent data suggest that actual yields may be significantly lower (52, 53). The diagnostic yield with rEBUS increases with nodule size and the presence of a CT bronchus sign (54–56).
Unlike electromagnetic navigation, rEBUS does not assist with navigation to the lesion of interest. It does, however, offer “true” bronchoscopic visualization of the nodule/mass as opposed to a software rendering based on CT image data. Unfortunately, real-time imaging is not available during sampling; the ultrasound probe needs to be removed from the bronchoscope’s working channel before any sampling instrument is introduced. A prospective, multicenter pilot study was recently completed testing a prototype that permits peripheral sampling under real-time rEBUS visualization (L. Yarmus and colleagues, unpublished results) (iNod System Human Feasibility Assessment; NCT02832284). If future product development is successful, this will represent a major advancement in the field.
Cone-beam computed tomography (CBCT) has recently been investigated to guide bronchoscopic biopsy, and, like rEBUS, it can offer definitive localization of peripheral lung lesions (57). CBCT goes one step further than conventional rEBUS because it allows real-time visualization of the target lesion with the sampling tool in place (Figure 1).
Figure 1. Use of cone-beam computed tomography and augmented fluoroscopy (OncoSuite; Philips) as adjuncts to electromagnetic navigational bronchoscopy. Top left: Peripheral lung nodule in the left upper lobe. Top right: Augmented fluoroscopy suggesting that the sampling tool is within the lesion. Bottom: Cone-beam computed tomography confirming the presence of the sampling tool within the lesion. Biopsy revealed metastatic renal cell carcinoma. Reprinted with permission from Dr. Michael Pritchett.
[More] [Minimize]In a recent study of 75 consecutive patients (93 lesions sampled), CBCT was used at the start of bronchoscopy to identify the target and, using dedicated software, to create an overlay of the target on live fluoroscopic images; this approach, termed “augmented fluoroscopy,” improved fluoroscopic visualization of the lesion (58). Upon ENB navigation to the target, augmented fluoroscopy was employed to confirm successful localization. The median size of these lesions was 16 mm (range, 7–55 mm), whereas the diagnostic yield was a promising 83.7% (95% confidence interval, 74.8–89.9%). The mean effective radiation dose was 2 mSv per CBCT scan, and the average number of CBCT scans per patient was 1.5. Although early findings are yet to be corroborated through prospective studies, CBCT holds promise for improving the diagnostic performance of peripheral bronchoscopy.
The year 2018 saw important advances in the growing sphere of robotic bronchoscopy, with one robotic bronchoscopic system receiving FDA approval for commercial use and a second manufacturer following suit in early 2019 (59). A pilot study on 15 patients in Costa Rica demonstrated its safety and feasibility with a zero percent rate of major bleeding or pneumothorax (biopsies having been performed in 93% of patients) (60). The concept is that a thinner, more flexible, and more easily steerable bronchoscope could go farther into the airways than a conventional one, including into areas that would ordinarily be out of the bronchoscopist’s reach (Figure 2). Although a paucity of data currently makes it unsuitable for use outside the investigational setting, the technology carries promise and is bound to generate considerable interest and research in coming years.
Figure 2. Robotic bronchoscopy potentially offers increased maneuverability throughout peripheral airways as demonstrated in this plastic model. Reprinted with permission from Reference 105.
[More] [Minimize]In 2012, a large meta-analysis of more than 3,000 cases found that the diagnostic yield of all advanced bronchoscopic techniques, including rEBUS and ENB for peripheral lung nodules (malignant or nonmalignant), was roughly 70% (95% confidence interval, 67.1–72.9%), with a low risk of pneumothorax (1.5%) that compares favorably with the 15–20% rate associated with transthoracic needle aspiration (37, 42, 61). However, analysis of prospectively gathered, multicenter registry data indicates a considerably lower diagnostic yield of only 39% for EMN, whereas a 2017 meta-analysis puts the diagnostic yield for rEBUS at 57% (10, 62). Several factors may explain this discrepancy in yields. First, it is plausible that in the “real world,” many providers reserve EMN for difficult-to-access lesions (e.g., smaller, more peripheral lesions without a CT bronchus sign) rather than using it for all cases in which EMN could have been employed, thereby introducing a selection bias. That being said, as a retrospective study of consecutive rEBUS cases illustrated, diagnostic yield can be as low as 59% even when the rate of successful navigation and localization is as high as 95% (54). One reason for this “diagnostic drop” may be the lack of real-time visualization during sampling. In this context, augmented fluoroscopy/CBCT and real-time rEBUS-guided sampling carry genuine promise. Another issue may be the inherent limitations of existing software to correctly map the airways, as well as limitations in sampling tools, making it difficult to sample a lesion owing to its location with respect to the airway. It is possible that the robot’s improved dexterity in the periphery of the lung will provide incremental value; however, more studies need to be performed to confirm or refute this notion. Finally, another reason for the diagnostic drop with EMN may be that a lesion seen on a prior CT scan may have resolved by the day of bronchoscopy. A recent study involving same-day CT scans (which is part of the procedural routine involving one of the commercially available ENB platforms) found that this occurred in approximately 7% of the cases (63).
In addition to standard bronchoscopic sampling techniques, including bronchoalveolar lavage, brushing, and TBB, cryobiopsy has emerged as a potentially attractive sampling technique for interstitial lung disease. It has brought with it the promise to obtain larger pieces of lung tissue with intact parenchymal architecture and a higher yield than TBB (with a recent meta-analysis of 27 studies demonstrating a yield of 72.9%), together with a lower complication rate than surgical lung biopsy (64). However, concerns persist about the optimal procedural technique and safety profile. Pneumothorax and significant bleeding are reported to range from 9% to 10% and from 14% to 20%, respectively. Furthermore, it remains to be demonstrated whether the diagnostic yield varies with underlying etiology (e.g., idiopathic pulmonary fibrosis vs. hypersensitivity pneumonitis). In 2018, an international conference on transbronchial cryobiopsy published an expert statement on its safety and utility including a call for the standardization of this procedure. Its promise notwithstanding, cryobiopsy in its current form is not quite ready for routine use outside the research setting (65). Recent idiopathic pulmonary fibrosis guidelines do not recommend for or against cryobiopsy in the evaluation of patients with a CT pattern compatible with “probable usual interstitial pneumonia,” “indeterminate for usual interstitial pneumonia,” or “alternative diagnosis,” and they emphasize the importance of a multidisciplinary “tumor board”–type discussion guiding individualized management (66).
Central airway obstruction (CAO), defined as obstruction of the trachea or mainstem bronchi, can be have both malignant and nonmalignant etiologies. Although the clinical presentation of CAO can be subacute, it often presents in an urgent or emergent setting with significant morbidity and mortality if left untreated. Therapeutic bronchoscopy can often offer rapid symptomatic relief, and it has been associated with both improved quality of life and increased survival (67). Therapeutic modalities include mechanical tumor debulking using the rigid bronchoscope itself (i.e., a “core out”), mechanical forceps, and/or a microdebrider; placement of airway stents made of either silicone or a metallic alloy (the latter often externally covered by a film of silicone or polyurethane); thermal ablative therapies such as laser, electrocautery, argon plasma coagulation, and cryotherapy; and nonthermal ablative therapies such as brachytherapy and photodynamic therapy. Therapeutic bronchoscopy for CAO has been shown to significantly improve both quality of life and survival (68–70). In a study of 102 patients with malignant CAO, therapeutic bronchoscopy was shown to significantly improve dyspnea and healing-related quality of life as well as long-term quality-adjusted survival (71). Likewise, recent data suggest improved survival when airway stenting is used in conjunction with external beam radiation therapy as opposed to external beam radiation therapy alone (72).
Ost and colleagues analyzed prospective observational data from the ACCP quality improvement registry evaluation and education (AQuIRE) program (spanning 15 centers with 1,115 procedures on 947 patients) to evaluate outcomes of therapeutic bronchoscopy for malignant CAO (69). There was considerable institutional variability in terms of choice of anesthesia, ventilation strategy, use of the rigid bronchoscope, and stent placement. The overall complication rate was 3.9%, and the 30-day mortality rate was 14.8%. Factors associated with a higher rate of complications included urgent/emergent procedures, American Society of Anesthesiologists (ASA) score greater than 3, repeat bronchoscopy, and the use of moderate sedation as compared with general anesthesia. ASA score greater than 3, Zubrod score greater than 1, intrinsic obstruction, mixed obstruction (i.e., intrinsic obstruction plus extrinsic compression), and stent placement were associated with a higher risk of 30-day mortality (69).
The AQuIRE registry data also demonstrated an overall technical success rate of 93%. Clinical factors associated with higher technical success were presence of an endobronchial lesion (as opposed to purely extrinsic compression) and stent placement (Figure 3). Conversely, clinical factors associated with failed procedural outcome were ASA score greater than 3, renal failure, primary lung cancer, left mainstem disease, and tracheoesophageal fistula. Forty-eight percent of all patients who underwent therapeutic bronchoscopy achieved improvement in dyspnea, with higher rates of improvement among those with more severe baseline symptoms and more central obstruction (nonlobar vs. lobar). These data underscore the obvious need to critically ascertain the likelihood of and expected degree of any potential benefit from a bronchoscopic intervention in addition to performing a thorough risk assessment.
Figure 3. Therapeutic bronchoscopy for malignant central airway obstruction. (A) Left mainstem endobronchial obstruction coupled with extrinsic compression by extramural tumor. (B) Successful rigid bronchoscopic debulking of the endobronchial tumor followed by placement of a self-expanding, covered metallic stent to counteract extrinsic compression. (C) Radiographs of the chest before and after bronchoscopic intervention.
[More] [Minimize]Nonmalignant causes of CAO for which bronchoscopic intervention can offer symptomatic relief include excessive dynamic airway collapse/tracheobronchomalacia (for which airway stenting can prevent expiratory airway collapse), tracheal and subglottic stenosis (for which bronchoscopy can be used for airway dilation, stenting, and/or injection of antimitotic agents for patients not wanting or not qualifying for surgery), and inflammatory conditions such as relapsing polychondritis that can present with airway stenosis and/or malacia. Post–lung transplant airways can also develop stenosis and malacia in addition to anastomotic dehiscence, which is potentially treatable with bronchoscopically applied fibrin glue or airway stenting.
The past decade has been marked by a steadily increasing interest in the employment of bronchoscopic modalities for the treatment of early-stage lung cancer (73). With the support of airway navigation and nodule localization tools described earlier, peripheral bronchoscopy has the potential not only to sample a peripherally located malignant lesion but also to deliver in situ therapy such as local/intratumoral chemotherapy, gene therapy, or focal tumor ablation using radiofrequency or microwave energy (74). In addition, the bronchoscope can place radiopaque or dye-based markers within or near a lesion to facilitate subsequent radiotherapy or surgery. EBUS-guided injection of immunotherapy also has the potential to offer safe and effective treatment for locoregional disease (75). Currently, however, these therapies remain largely investigational.
The Alair Bronchial Thermoplasty System (Boston Scientific) delivers radiofrequency energy to the airway wall with the intent of ablating smooth muscle and improving asthma control. Earlier studies demonstrating safety and potential efficacy of bronchial thermoplasty led to the AIR2 (Asthma Intervention Research 2) randomized, double-blind, sham-controlled trial, which demonstrated reduction in severe asthma exacerbations, emergency department visits, and hospitalizations among patients with “severe” asthma (76). Interestingly, improvement in Asthma Quality of Life Questionaire scores was seen in the placebo arm, too, although it was more marked in the treatment arm. Subsequently, the open-label PAS2 study (Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma) also demonstrated a similar safety profile; similar reductions in exacerbations, hospitalizations, and emergency department visits; and potentially durability of these effects (77, 78). It is important to note, though, that the AIR2 and PAS2 findings may not be applicable to patients with more severe airflow obstruction. In this regard, both studies excluded patients with prebronchodilator forced expiratory volume in 1 second (FEV1) values less than 60%; the mean prebronchodilator FEV1 for each study population was 79.63 ± 13.10% in PAS2 and 77.83 ± 15.65% in AIR2, whereas the mean post-bronchodilator FEV1 was greater than 80% in both cohorts (77). The ideal asthma phenotypes and ideal candidates for this treatment modality remain to be determined.
The NETT study (National Emphysema Treatment Trial), published in 2003, demonstrated that surgical lung volume reduction (LVR) for severe emphysema confers improved survival and exercise capacity in patients with upper lobe–predominant disease and poor exercise capacity (79). At the same time, it showed high perioperative morbidity and mortality. With the goals of providing a less invasive way to achieve similar outcomes, bronchoscopic approaches to LVR have included valves, coils, steam, stents, and foam. In 2017, a Europe-based expert panel report on bronchoscopic LVR suggested that current evidence only supported use of surgical LVR and bronchial valves outside the investigational setting (80). Of all the bronchoscopic modalities, one-way bronchial valves are currently the only FDA-approved modality available in the United States.
Two different designs available for bronchoscopic LVR are the Zephyr endobronchial valve (Pulmonx) and the Spiration Valve System (Olympus Corporation of the Americas). Studies directly comparing the two valves do not exist. The Zephyr endobronchial valve trial (VENT [Endobronchial Valve for Emphysema Palliation Trial]) showed little benefit in terms of lung function or patient symptoms together with an increase in adverse events, leading to initial FDA rejection of this technology (81). An early pilot study using the Spiration Valve System in patients with severe, bilateral heterogeneous emphysema demonstrated some improvement in health-related quality of life but no benefit in pulmonary function (82). Subsequent studies were designed to selectively enroll patients without evidence of interlobar collateral ventilation, which would counteract the ability of one-way valves to achieve lobar volume reduction. In 2018, 12-month follow-up results of two important trials were published, showing clinically meaningful improvements in pulmonary function as well as symptom scores. The LIBERATE (Pulmonx Endobronchial Valves Used in Treatment of Emphysema) trial used the Zephyr valve in conjunction with the Chartis System for endoscopically detecting collateral ventilation, whereas the EMPROVE (Evaluation of the Spiration Valve System for Emphysema to Improve Lung Function) trial used the Spiration valve in conjunction with high-resolution CT to exclude patients with an incomplete lobar fissure (6, 83). On the basis of findings of these trials, the FDA recently approved both of these valves for bronchoscopic LVR. The Zephyr valve was approved for LVR in cases of homogeneous emphysema as well, based on the IMPACT (Informing the Pathway of COPD Treatment) trial demonstrating improvement in lung function, exercise tolerance, and quality of life in patients with homogeneous disease (84). The overall safety profile of both of these valve systems compares favorably with surgical LVR with a much lower rate of perioperative morbidity and mortality. The most significant adverse event is life-threatening pneumothorax, particularly in the first three days of the procedure. As such, it is currently recommended to observe these patients in the hospital after bronchoscopy. Though this can increase the costs of the procedure, it is likely significantly less expensive than surgical LVR, and future studies are sure to investigate cost-effectiveness. It is important to note that unlike surgical LVR, bronchoscopic LVR has not demonstrated a mortality benefit to date. On the basis of current evidence, patients with advanced emphysema should undergo a systematic, stepwise evaluation to ensure appropriate triage to bronchoscopic LVR versus surgical LVR versus lung transplant (85). Our suggested approach is illustrated in the form of a clinical decision algorithm (Figure 4).
Figure 4. Clinical decision algorithm for patients with advanced emphysema. BLVR = bronchoscopic lung volume reduction; CT = computed tomography; CV = collateral ventilation; LVR = lung volume reduction; LVRS = lung volume reduction surgery; multi-D = multidisciplinary.
[More] [Minimize]Targeted lung denervation is a novel therapy that involves bronchoscopic ablation of peribronchial parasympathetic nerves to achieve permanent bronchodilation. Unlike bronchoscopic LVR, which focuses exclusively on patients with emphysema, targeted lung denervation is potentially applicable more broadly to all patients with chronic obstructive pulmonary disease. A 2018 safety and feasibility study on 15 patients with moderate to severe chronic obstructive pulmonary disease (post-bronchodilator FEV1 30–60% of predicted) demonstrated no deaths or adverse effects related to targeted lung denervation and a 40% mean improvement in FEV1 at 1 year (86).
Clinical practice guidelines published by the British Thoracic Society refer to medical thoracoscopy and video-assisted thoracoscopic surgery (VATS) as equivalent to each other in the management algorithm for undiagnosed pleural effusion (87). Medical thoracoscopy, which is typically performed by an interventional pulmonologist, does not require general anesthesia or single-lung ventilation and can instead be accomplished under local anesthesia with moderate sedation. Data on 51 consecutive patients undergoing medical thoracoscopy at the Mayo Clinic, chiefly for further evaluation of an undiagnosed lymphocytic exudate (86.3% of cases), demonstrated the technique to be safe, with no deaths or cases of significant hemodynamic or respiratory compromise reported. Malignancy was the most common histologic diagnosis (47.1%), followed closely by nonspecific pleuritis (45.1%) (88). Retrospectively analyzed data on patients with an undiagnosed pleural exudate at a tertiary care center in Canada demonstrated that medical thoracoscopy has a diagnostic and safety profile similar to that of VATS but carries distinct advantages, including shorter length of stay and lower procedural costs (89). In appropriately selected patients at experienced centers, medical thoracoscopy may therefore be considered preferable to VATS as the initial test of choice.
In 2018, the ATS, Society of Thoracic Surgeons, and Society of Thoracic Radiology jointly published clinical practice guidelines for management of malignant pleural effusion (7). For the first time, it was suggested that both chemical pleurodesis (using either talc slurry or thoracoscopic talc poudrage) and indwelling pleural catheters (IPCs) might be acceptable for definitive management of symptomatic malignant pleural effusions in patients with full lung expansion. TIME2 (Therapeutic Intervention in Malignant Effusion Trial 2) was a multicenter randomized trial that showed equivalent efficacy profiles for both options with no significant difference in quality of life at 6 weeks or 6 months (90). Pleurodesis was associated with an increased rate of subsequent procedures, whereas patients with IPCs experienced greater numbers of nonserious adverse events (chiefly cellulitis). Multiple cost-effectiveness analyses based on the TIME2 trial suggest that IPC is more cost-effective, although that appears to change with increasing life expectancy and with dependence on nursing support for drainage and dressing care (as opposed to dependence on a trained family member) (91, 92). Increasingly, IPC has also found favor in the management of symptomatic, recurrent, nonmalignant pleural effusions (such as those from congestive heart failure or hepatic hydrothorax) that are resistant to medical measures (e.g., diuresis) (93, 94).
In terms of optimizing management after IPC placement, the ASAP (Impact of Aggressive versus Standard Drainage Regimen Using a Long-Term Indwelling Pleural Catheter) trial demonstrated that daily drainage of the IPC led to earlier and more frequent pleurodesis than every-other-day drainage (95). The AMPLE-2 (Australasian Malignant Pleural Effusion 2) trial comparing daily versus symptom-guided IPC drainage similarly found higher pleurodesis rates in the former group together with improved patient-reported quality-of-life measures (96). The IPC-PLUS randomized trial tested the impact of combining strategies by instilling talc slurry 10 days after IPC placement after excluding patients with nonexpandable lung and found that the intervention group had double the rate of successful pleurodesis (permitting catheter removal) at both 35 days and 70 days, although it is noteworthy that the baseline pleurodesis rates reported in this study were substantially lower than those in prior publications (9). Finally, a recent study aims to assess the impact of IPCs coated with silver nitrate on pleurodesis rates and on time to pleurodesis (SWIFT trial [Safety and Effectiveness of a New Pleural Catheter for Symptomatic, Recurrent, MPEs Versus Approved Pleural Catheter]; NCT02649894), with preliminary data showing a median time to pleurodesis of 4 days (97).
The mortality associated with pleural infection is significant, approaching 40% at 1 year for those with hospital-acquired infection (98). Although the debate over whether to pursue tube thoracostomy versus surgery as the initial intervention for pleural infection has carried on for decades, the MIST-2 randomized trial (Multicenter Intrapleural Sepsis Trial 2) demonstrating the ability of intrapleural recombinant tissue plasminogen activator and DNase to reduce rates of surgical referral has made tube thoracostomy an attractive initial consideration for many patients (99). Concerns about higher bleeding rates with the use of fibrinolytic therapy prompted a pilot trial assessing the safety and efficacy of saline pleural irrigation three times daily, which similarly found decreased rates of surgical referral (100). Neither of these approaches has demonstrated improvement in mortality, and both may lead to longer lengths of stay. The expert consensus currently recommends a multidisciplinary and individualized approach that involves careful risk stratification for each patient, such as via the validated RAPID score, with which patients can be stratified into high-, medium-, and low-mortality cohorts based on renal function, age, purulence, infection source, and dietary factors (101, 102).
Persistent air leak is defined as a nonresolving pneumothorax with an air leak lasting more than 5–7 days (103). For over a decade, the FDA has maintained a humanitarian device exemption for compassionate use of the Spiration valve for management of persistent air leak after lobectomy, segmentectomy, or LVR surgery, although it has also been used “off label” for the treatment of persistent air leak due to primary and secondary spontaneous pneumothoraces. The rationale for temporary placement of one or more one-way valves is to decrease airflow through the fistula, allowing the visceral pleura to heal, before removing the valve(s) at 6 weeks. In some cases, bronchopleural fistulas can also be treated with other bronchoscopic approaches, such as placement of a stent or application of tissue glue to cover a visible airway wall defect (104).
The field of IP continues to evolve rapidly from the era of small case series and single-center experiences to the current conduct of multicenter, prospective trials focused on rigorous evaluation of procedural safety and efficacy and meaningful patient outcomes. Advanced bronchoscopic imaging techniques, such as ENB, EBUS (radial and convex), and novel uses of real-time fluoroscopy and CBCT, continue to transform the approach to lung nodules and the evaluation of mediastinal/hilar adenopathy. Robotic bronchoscopy and real-time imaging are emerging as potentially useful adjuncts or alternatives to conventional bronchoscopy for the diagnosis and potentially treatment of difficult-to-access peripheral lung lesions. There continue to be early but promising advances in therapeutic bronchoscopic modalities for the treatment of early-stage peripheral lung cancer, including intralesional chemotherapy, gene therapy, and immunotherapy. Emerging data on bronchoscopic approaches to management of airway diseases such as asthma and emphysema have opened new vistas for the interventional pulmonologist. Finally, several recent randomized clinical trials have provided new insights into optimal treatment of patients with pleural diseases.
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* D.F.-K. is an Associate Editor of AnnalsATS. His participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.
CME will be available for this article at www.atsjournals.org.
Author disclosures are available with the text of this article at www.atsjournals.org.
