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310 Interventional Pulmonary Medicine

during the first year after transplant. However, as infections can also occur late after transplant, most centers recommend prophylactic therapy be continued for life. ■ ■LONG-TERM MANAGEMENT OF LUNG TRANSPLANT RECIPIENTS While survival after lung transplantation continues to improve by era, the survival rates in this group are lower than in other solid-organ cohorts. Approximately 50% of lung transplant recipients will experi­ ence at least one episode of acute rejection in the first posttransplant year, and by 5 years posttransplant, approximately half will have devel­ oped chronic rejection. As a result, posttransplant immune suppression regimens may be more aggressive than in other solid-organ recipients, as described above. The immunosuppressive regimen must be bal­ anced against the potential toxicities that accrue with these medica­ tions over time. Acute cellular rejection in lung transplant recipients is most com­ mon in the first posttransplant year, with a decreased but not absent frequency thereafter. Infections can stimulate cellular rejection, most clearly demonstrated in the setting of CMV infection, but also noted after other infections. Most programs incorporate a schedule of routine surveillance bronchoscopy to assess for acute cellular rejection post­ transplant. Donor-derived cell-free DNA, which is produced in the setting of cell turnover and parenchymal injury, is increasingly being explored as a noninvasive method of detection of allograft dysfunction, most importantly in the setting of acute and chronic rejection. Acute cellular rejection manifests as a lymphocytic infiltrate involving the distal small vessels and capillaries and/or a lymphocytic bronchiolitis involving the distal airways of the lung. Acute cellular rejection, a risk factor for the development of CLAD, is treated with augmented immune suppression. Antibody-mediated rejection in its classic form is a neutrophilic vasculitis associated with the small vessels and capil­ laries of the lung, with associated deposition of by-products of the complement cascade, in the setting of allograft dysfunction and circu­ lating donor-specific HLA antibodies in the blood. The manifestations of antibody-mediated rejection in the lung allograft are less specific than in other organs. Further research is ongoing into the diagnostic and treatment considerations of this entity in lung transplantation. CLAD is an overarching description of the syndrome of long-term allograft rejection. The classic manifestation of CLAD is obliterative bronchiolitis, the development of fibrinous material within the distal airways that leads to small-airways obstruction. As transbronchial biopsies are insensitive for diagnosing obliterative bronchiolitis, a clini­ cal diagnostic designation of bronchiolitis obliterans syndrome can be made when specific PFT criteria are met and other causes of PFT decline are excluded. CLAD can also present as a restrictive phenotype, with imaging demonstrating upper lobe–predominant pleural thicken­ ing, small lung volumes, and interstitial changes on high-resolution computed tomography (CT). Numerous therapies for CLAD have been utilized, including azithromycin, montelukast, extracorporeal photo­ pheresis, alemtuzumab, and others, with varying degrees of success. Infection is a significant complication of lung transplantation, with persistent risk over the lifetime of the transplant recipient. As time progresses, the chance of opportunistic infection increases. The risk of bacterial infection and fungal infection remains, and can affect the lung parenchyma, airways and anastomotic sites, and other organs. Viral infections, such as CMV reactivation and infection, EBV-associated posttransplant lymphoproliferative disease, and other rarer infections, can also develop in the later posttransplant setting as well. Numerous longer-term medical complications can be seen in lung transplant recipients. Essential hypertension, diabetes mellitus, chronic renal insufficiency, and bone loss are some examples of chronic medi­ cal conditions observed following transplantation. A multidisciplinary approach to care that involves the patient’s primary care physician, local pulmonologist, and appropriate subspecialists, along with trans­ plant pharmacy, as well as social work and care coordination, is ben­ eficial in addressing the complex needs of lung transplant recipients over time. Predictors of short- and long-term outcomes after lung transplantation are outlined in Table 309-3.

TABLE 309-3  Predictors of Survival After Lung Transplantation   1-YEAR SURVIVAL ≥10-YEAR SURVIVAL Donor factors HCV donor   Recipient factors Age <70 years Age 18–35 years Diagnosis other than pulmonary fibrosis, pulmonary hypertension, sarcoidosis, A1AT O2 requirement <5 L Interventional Pulmonary Medicine CHAPTER 310 CI >2 Outpatient at time of transplant Preserved recipient eGFR Total bilirubin <2 Donor/recipient factors Non–female-to-male transplant Higher levels of HLA matching Donor/recipient weight ratio

0.7 Operative factors Avoidance of unplanned conversion to cardiopulmonary bypass Bilateral lung transplant Decreased ischemic time Posttransplant factors PaO2/FIO2 >260 at 72 h Fewer hospitalizations for rejection Absent need for postoperative ECMO support Other factors Higher center volume Higher center volume Abbreviations: A1AT, α1 antitrypsin deficiency; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; Fio2, fraction of inspired oxygen; HCV, hepatitis C virus; HLA, human leukocyte antigen; Pao2, partial pressure of oxygen. ■ ■FURTHER READING Cypel M et al: Normothermic ex vivo lung perfusion in clinical lung transplantation. N Engl J Med 364:1431, 2011. Leard LE et al: Consensus document for the selection of lung trans­ plant candidates: An update from the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 40:1349, 2021. Lehr CJ et al: The impact of change in definition of increased-risk donors on survival after lung transplant. J Thorac Cardiovas Surg 160:572, 2020. OPTN Lung Transplantation Committee: Establish continu­ ous distribution of lungs. https://optn.transplant.hrsa.gov/media/ esjb4ztn/20211206-bp-lung-establish-cont-dist-lungs.pdf.   Accessed January 11, 2023. Schwartz S et al: Procedural mechanical support for lung transplanta­ tion. Curr Opin Organ Transplant 26:309, 2021. Lonny Yarmus, David Feller-Kopman

Interventional Pulmonary Medicine Interventional pulmonary medicine is a subspecialty of pulmonary and critical care medicine focusing on the evaluation and management of patients with thoracic malignancy, central airway obstruction, pleural disease, and advanced obstructive lung disease such as chronic obstruc­ tive pulmonary disease (COPD)/emphysema and asthma. Novel mini­ mally invasive interventions have drastically changed the way we care for patients. In this chapter, we will summarize recent developments and evolving technologies in interventional pulmonology (IP).

DIAGNOSTIC BRONCHOSCOPY With the introduction of the rigid bronchoscope by Gustav Killian in 1897, the mortality associated with foreign-body aspiration dropped from over 90% to less than 5%, as patients no longer had to suffer from airway obstruction and postobstructive pneumonia. Shigeto Ikeda developed the flexible bronchoscope in 1967, allowing access to the peripheral airways and lung parenchyma. In 2018, the first roboticassisted bronchoscopy platforms were introduced, providing a novel approach with the ability to reach further into the peripheral lung reliably with precise control. Bronchoscopy has remained an impor­ tant diagnostic and therapeutic procedure, and recent technology has significantly increased its utility.

PART 7 Disorders of the Respiratory System ■ ■ENDOBRONCHIAL ULTRASOUND The diagnosis and staging of lung cancer remain one of the most important roles of advanced diagnostic bronchoscopy and IP. Convex endobronchial ultrasound (cEBUS) is a flexible bronchoscope com­ bined with ultrasound technology that allows for real-time visualiza­ tion during transbronchial needle aspiration (TBNA) of mediastinal and hilar lymph nodes and masses adjacent to the airways (Fig. 310-1). With a sensitivity of 90% and a specificity of 100%, cEBUS is the gold standard for lung cancer staging and can also provide sufficient tissue to perform molecular profiling to guide targeted therapies in lung cancer with adequacy rates for testing that exceed 95%. cEBUS is also extremely helpful in diagnosing mediastinal and hilar adenopathy due to sarcoidosis. The use of endobronchial ultrasound to diagnose lymphomas has historically been of limited utility owing to lack of tis­ sue architecture in needle aspirates. However, advances in cEBUS using a cryobiopsy technique in lieu of needle aspirate have shown promise in providing adequate tissue and histopathologic architecture from intranodal cryobiopsy. ■ ■PERIPHERAL BRONCHOSCOPY Evaluations of pulmonary nodules and lung masses are frequent indi­ cations for bronchoscopy as a way to achieve a minimally invasive diagnosis. Historically, the diagnostic yield of bronchoscopy to target peripheral pulmonary lesions was <60%. Multiple guidance platforms now allow for improved access in the periphery of the lung. Smaller or ultrathin bronchoscopes <4 mm in diameter can be combined with available imaging tools to improve target localization. Radial-probe endobronchial ultrasound utilizes a radial scanning ultra­ sound probe that is inserted through the bronchoscope and into the FIGURE 310-1  Endobronchial ultrasound transbronchial needle aspiration image of needle under ultrasound guidance sampling station 4L lymph node. AO, aorta; PA, pulmonary artery.

lung, producing a real-time image of the target lesion. Electromagnetic navigation bronchoscopy (ENB) involves image-guidance systems that manipulate thin-slice computed tomography (CT) images to create vir­ tual airway reconstructions used as guided maps during bronchoscopy. Robotic-assisted bronchoscopic platforms offer the enhanced articula­ tion and stability of a robotic arm, replacing the traditional flexible bronchoscope. Recent innovation has allowed for advances in intrapro­ cedural imaging. Mobile cone beam CT scanners in combination with advanced peripheral bronchoscopy allow for image confirmation of a biopsy within the lesion of interest. Studies are currently underway to explore further the utility of these systems for peripheral lesion biopsy and the impact of advanced imaging techniques. THERAPEUTIC BRONCHOSCOPY Therapeutic bronchoscopy is indicated for the relief of malignant and nonmalignant central airway obstruction, asthma, and emphysema. Active research is also focusing on the utility of bronchoscopy for the ablation of early-stage lung cancer, as well as the treatment of chronic bronchitis. ■ ■CENTRAL AIRWAY OBSTRUCTION Central airway obstruction (CAO) describes obstruction of the tra­ chea, main stem bronchi, bronchus intermedius, and/or lobar bronchi, and can present as intrinsic (endoluminal), extrinsic (extraluminal), or mixed (extraluminal tumor resulting in mass effect and endoluminal involvement) (Fig. 310-2). The differential diagnosis of CAO is shown in Table 310-1. Patients often initially present with cough and exertional dyspnea, but then progress with increasing severity of obstruction to dyspnea at rest, stridor, and respiratory failure. Patients may also have wheezing, hemoptysis, or symptoms of postobstructive infection. Rigid bronchos­ copy is the preferred tool to manage CAO in conjunction with ablative therapies, balloon bronchoplasty, and airway stenting to offer rapid symptomatic relief with immediate reductions in the level of required care. Therapeutic bronchoscopy for CAO has been shown to signifi­ cantly improve both quality of life and survival. ■ ■ABLATIVE THERAPIES FOR CAO Ablative therapy in the airway consists of both heat (laser, electrocau­ tery, and argon plasma coagulation) and cold (cryotherapy) modali­ ties. These techniques are most commonly used to destroy tumor and provide hemostasis. The cryoprobe can also be used for foreign-body removal. Other modalities, such as brachytherapy (BRT) and photody­ namic therapy (PDT), have a delayed therapeutic effect and are often not suitable for situations where immediate relief of airway obstruction is desired. ■ ■BRONCHOPLASTY Bronchoplasty (or bronchial dilation) can be achieved with the bar­ rel of the rigid bronchoscope or with balloons that can be passed via the rigid or flexible bronchoscope. Bronchoplasty is most commonly used for dilation of stenotic airways or disruption of webs related to nonmalignant causes of airway diseases. Although dilation generally leads to immediate relief of the stenosis, results can be short-lived, and hence, this technique is often combined with airway stenting. Compli­ cations are rare but can include airway tears if proper techniques are not followed. ■ ■AIRWAY STENTING After airway patency is achieved, airway stents can be utilized to pre­ vent recurrence of CAO. Reports of endoscopically implantable stents for the airways date back to 1914. Airway stents are commonly used to treat patients with CAO due to extrinsic compression from a variety of malignant and nonmalignant disorders. Stents are effective and lead to symptomatic relief in >90% of patients. A variety of airway stents are available, each with its own benefits and detriments; it is important to choose the right stent for the specific indication. Stent complications are not uncommon and include migration, mucostasis, infection, and the development of granulation tissue. First-generation biodegrad­ able stents, custom three-dimensional printed stents, and drug-coated

Mixed Extrinsic Intrinsic C B A FIGURE 310-2  Types of central airway obstruction. stents are currently being evaluated, working toward a personalized medicine approach wherein stents are tailored to an individual’s airway anatomy and underlying disease. ■ ■ENDOBRONCHIAL INTRATUMORAL CHEMOTHERAPY Endobronchial intratumoral chemotherapy (EITC) is an intervention aimed at improving and/or maintaining airway patency in patients with malignant CAO, with the potential to eliminate the need for TABLE 310-1  Differential Diagnosis of Central Airway Obstruction MALIGNANT NONMALIGNANT Primary airway carcinoma Lymphadenopathy Bronchogenic Sarcoidosis Carcinoid adenoid cystic Infectious (i.e., tuberculosis, histoplasmosis) Mucoepidermoid Cartilage Metastatic carcinoma to the airway Relapsing polychondritis Bronchogenic Granulation tissue from endotracheal tubes Renal cell Tracheostomy tubes Breast Airway stents Thyroid Foreign bodies Colon Surgical anastomosis Sarcoma Granulomatosis with polyangiitis Melanoma Pseudotumor Laryngeal carcinoma Hamartomas Esophageal carcinoma Amyloid Mediastinal tumors Papillomatosis Thymus Hyperdynamic Thyroid Tracheomalacia Germ cell Bronchomalacia Lymphadenopathy Idiopathic Lymphoma Tuberculosis   Sarcoidosis   Other   Foreign-body goiter   Mucus plug   Blood clot

Interventional Pulmonary Medicine CHAPTER 310 airway stenting and its associated complications. Under bronchoscopic guidance, high-dose therapeutics can be safely injected directly into tumor to enhance response and limit systemic side effects. Multiple studies are ongoing to assess the efficacy of EITC. ■ ■ABLATIVE THERAPIES FOR EARLY-STAGE LUNG CANCER Bronchoscopic ablation of early-stage lung cancer has long been described as the “holy grail” of bronchoscopy due to the appeal of stag­ ing, diagnosing, and treating biopsy-proven early-stage lung cancer in one procedural setting. There is limited experience with bronchoscopic radiofrequency ablation (B-RFA) and microwave ablation (MWA) as a potential means to treat early-stage lung cancer. Ultimately, the efficacy of bronchoscopic ablation of early-stage nonoperable lung cancer must be proven in longitudinal studies demonstrating noninferiority in survival as compared to the current gold standard of stereotactic body radiation therapy (SBRT). To date, there are extremely limited safety and efficacy data for bronchoscopic ablation with multiple studies cur­ rently ongoing. Until there are adequate data to support the safe and effective use of this approach, bronchoscopic ablation is not recom­ mended for clinical use. ■ ■BRONCHOSCOPIC THERAPIES FOR ASTHMA Bronchial thermoplasty (BT) is a treatment for patients with severe persistent asthma who remain symptomatic despite maximal medi­ cal treatment that delivers radiofrequency energy to the airways to reduce their smooth muscle mass. A pivotal randomized clinical trial did not show a change in forced expiratory volume in 1 s (FEV1) or airway hyperresponsiveness but was able to demonstrate an improve­ ment in quality of life and reduction in exacerbation rates, visits to the emergency department, and days lost from school or work. At this time, the ideal asthma phenotypes and ideal candidates for this treat­ ment modality remain to be determined, and thus, the utility of this approach remains limited. ■ ■BRONCHOSCOPIC THERAPIES FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE The National Emphysema Treatment Trial (NETT), published in 2003, demonstrated that lung volume reduction (LVR) surgery for severe emphysema confers improved survival and exercise capacity in patients with upper lobe–predominant disease and poor exercise capacity. At the same time, it showed high perioperative morbidity and mortality. During the last decade, several bronchoscopic therapeutic modalities have been tested, including valves, coils, steam, stents, and foam, in

patients with severe emphysema to mimic the physiologic effects of surgical lung volume reduction (SLVR) in a less invasive fashion.

■ ■BRONCHOSCOPIC LUNG VOLUME REDUCTION Bronchoscopic lung volume reduction (BLVR) via valve placement involves placement of one-way valves in airways leading to areas of the lung with significant emphysema, allowing air and mucus to exit but blocking air entry to achieve lobar collapse. Several clinical trials on BLVR with valves have demonstrated improvements in lung function and overall improvement in quality of life and exercise tolerance. The overall safety profile of these valve systems compares favorably with SLVR with a lower rate of perioperative morbidity and mortality. PART 7 Disorders of the Respiratory System ■ ■PLEURAL INTERVENTIONS Thoracic ultrasound has become invaluable in the evaluation of patients with pleural effusion and pneumothorax. Medical thoracos­ copy (also called pleuroscopy) is a minimally invasive technique most commonly used to evaluate recurrent exudative pleural effusions and is associated with a diagnostic yield of >95%. Indwelling pleural catheters (IPCs) have gained tremendous popu­ larity and have been declared by evidence-based guidelines to be as acceptable as chemical pleurodesis for the management of symptom­ atic malignant pleural effusions. When comparing IPC and pleurodesis via talc slurry, two multicentered, open-label, randomized controlled trials demonstrated IPC effectively relieved dyspnea, decreased the duration of hospital stay, and lessened the need for future procedures. A recent study in patients without significant lung entrapment has shown that the outpatient administration of talc through an indwell­ ing pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. Pleural infection (empyema or complex parapneumonic effusion) is commonly encountered in clinical practice. The mainstay of therapy

typically consisted of antibiotics, drainage of the infected pleural space with tube thoracostomy, and possible need for surgical decortication. The landmark Multicenter Intrapleural Sepsis Trial (MIST2) dem­ onstrated that intrapleural sequential administration of recombinant tissue plasminogen activator (rtPA) and DNase resulted in significant radiographic and clinical improvements and allowed >90% of patients to avoid surgery. Randomized controlled trials are currently underway comparing intrapleural administration of rtPA and DNase to surgical decortication. ■ ■PNEUMOTHORAX AND PERSISTENT AIR LEAK Persistent air leak is defined as a nonresolving pneumothorax with an air leak lasting more than 5–7 days. For over a decade, the U.S. Food and Drug Administration has maintained a humanitarian device exemption for compassionate use of the Spiration Valve System for management of persistent air leak following lobectomy, segmentec­ tomy, or LVR surgery, although the device has also been used “off label” for the treatment of persistent air leak due to primary and secondary spontaneous pneumothoraces. SUMMARY IP provides diagnostic and therapeutic options that span the spectrum of benign and malignant airway and pleural disorders. The constant innovations in diagnostic and treatment modalities have continued to help push the boundaries of pulmonary medicine. ■ ■FURTHER READING Roberts ME et al: British Thoracic Society Guideline for pleural disease. Thorax 78:114, 2023. Wahidi MM et al: State of the art: Interventional pulmonology. Chest 157:734, 2020.