Introduction
Transbronchial lung biopsy (TBB) is a safe and effective tool useful for the diagnosis of a wide variety of diffuse and focal pulmonary diseases. TBB is regularly performed by 69 percent of practicing physicians documented in a survey of 1800 North American pulmonary and critical care physicians. This chapter describes the primary indications and contraindications to performing TBB during bronchoscopy, our approach to TBB, and methods to manage complications that may arise during or after the procedure.
Indications
Biopsy forceps commonly used for TBB via the flexible bronchoscope are generally on the order of 3 mm or smaller in any given dimension. Because of this restriction in size, tissue samples obtained via the transbronchial approach are generally 2–3 mm in any dimension. Despite the small size, TBB provides information regarding pathology that is located beyond the cartilaginous airways that may include elements of the small airways of the distal bronchial tree, the alveolar space, the vasculature, and lymphatic structures immediately surrounding the alveoli. Pulmonary diseases that require examination of larger pieces of lung tissue to assess heterogeneity or homogeneity of different regions of the involved lung (such as many of the idiopathic interstitial lung diseases) are generally not amenable to diagnosis by TBB, so consideration of video-assisted thoracoscopic lung biopsy should be pursued for patients in whom these diseases are a strong consideration. With these limitations in mind, TBB is useful for the diagnosis of a variety of interstitial, infectious, and malignant pulmonary diseases (Box 10.1).
Box 10.1 Indications for TBB
Sarcoidosis
Langerhans cell histiocytosis
Pulmonary alveolar proteinosis
Lipoid pneumonia
Eosinophilic pneumonia
Drug-induced pneumonitis
Pulmonary infiltrates in the immunocompromised host
Pulmonary nodule or mass
Lymphangitic malignancy
Interstitial Diseases
TBB has a high sensitivity for the diagnosis of sarcoidosis involving the lung. Even with Stage I disease, TBB may be positive in up to 50–85 percent of patients undergoing this procedure, although yields are greater with increasing radiographic abnormality of the lung parenchyma. To optimize sampling of tissue for sarcoidosis, a minimum of four biopsies has been suggested to be collected before termination of the procedure. TBB has a high yield in other interstitial lung diseases such as Langerhans cell histiocytosis, pulmonary alveolar proteinosis, lipoid pneumonia, eosinophilic pneumonia, and drug-induced pneumonitis.
Infectious Diseases
Diagnosis of infectious pulmonary disease in the immunocompromised host is a common indication for TBB. Sensitivity for infectious organisms ranges from 81 to 90 percent. Bronchoalveolar lavage (BAL) is often as efficacious as TBB in detecting infectious organisms in immunocompromised patients and use of TBB has been discouraged in the most recent BTS statement on bronchoscopy except when there is substantial suspicion for tuberculosis where it is still considered to be useful for diagnosis. Nevertheless, in most series there is a small number of patients in whom the diagnosis is made by TBB but missed with BAL. In addition, compared with BAL, TBB enhances diagnostic yield for noninfectious lung disease in immunocompromised patients (an increase in yield from 31 to 40.4 percent, respectively).
Infections with Pneumocystis jiroveci deserve special comment. BAL generally has excellent sensitivity for Pneumocystis infection in the patient with advanced HIV/AIDS, particularly when combined with immunofluorescent monoclonal antibody staining. However, the sensitivity of BAL in immunocompromised hosts without HIV/AIDS may be lower. Addition of TBB to the diagnosis of Pneumocystis pneumonia in patients with cancer, bone marrow transplantation, or pharmacologic immunosuppression increases the diagnostic sensitivity from 82 to 92 percent.
Neoplastic Diseases
TBB is commonly used for the diagnosis of suspicious pulmonary nodules and masses. Overall, the yield of TBB for peripheral lesions is 57 percent although the yield from a specific nodule is related to size, location, and number of pieces of tissue collected. Sensitivity increases with the size of the nodule in question, with a diagnosis obtained 34 percent of the time in nodules <2 cm and 63 percent in nodules >2 cm. The presence of an airway leading to the nodule on thoracic computed tomography scan (positive bronchus sign) increases yield from 25 to 63 percent. Diagnostic yield from pulmonary nodules increases with number of pieces of tissue collected. Popovich and colleagues examined the effect of repeated sampling of peripheral pulmonary nodules by TBB. The initial biopsy had a sensitivity of 45 percent, which increased to 70 percent by the sixth sample. In malignancies with a diffuse distribution (such as lymphangitic tumor), sensitivity of TBB is generally good.
Lung Transplant Surveillance
TBB is the primary diagnostic procedure in evaluating the presence of allograft rejection in patients after lung transplantation. Although surveillance strategies differ among various institutions, most institutions perform some form of TBB-based surveillance as well as diagnostic biopsies during periods of declining lung function in transplant recipients. Sensitivity of TBB for allograft rejection has been reported to be as high as 94 percent when ten or more pieces of tissue are collected, although most institutions do not regularly collect this many samples during surveillance bronchoscopies.
Contraindications
Contraindications for TBB are similar to those for bronchoscopy in general. Absolute contraindications are few and include inability to provide informed consent, status asthmaticus, severe hypoxemia, and unstable cardiovascular conditions. Pulmonologists’ perceptions of relative contraindications to TBB were examined during a survey of 158 North American respiratory physicians. Physicians’ opinions were obtained regarding the safety of TBB in the presence of thrombocytopenia, pulmonary hypertension, uremia, hypoxemia, and management of anticoagulant and antiplatelet medications.
Thrombocytopenia
Approximately 70 percent of the surveyed physicians felt that a platelet count of 50,000 was adequate to perform TBB safely. Few data are available regarding bleeding complications from TBB in the thrombocytopenic patient. One series examined 24 patients with platelet count <60,000 and an average count of 30,000. Twenty of the 24 patients received prophylactic platelet transfusion prior to TBB with an incidence of significant bleeding in four patients, one of whom expired and theremaining were self-limited. Our practice has been to use a minimum platelet value of 50,000 when TBB is planned during the bronchoscopy. We have not experienced any life-threatening bleeding events related to thrombocytopenia in our practice using this criterion.
Pulmonary Hypertension
A single prospective study is available regarding TBB and pulmonary hypertension. This study examined 37 heart transplant recipients who had measurements of pulmonary pressures obtained within 72 hours of bronchoscopy. Moderate bleeding (defined as 25–100 mL of blood) was encountered in 15 percent of the 20 patients with MPAP >16 mm Hg, whereas no significant bleeding occurred in the remaining patients. No incidence of major hemorrhage occurred in any. Current recommendations from the British Thoracic Society (BTS) suggest that caution should be observed in performance of TBB in patients with elevated pulmonary arterial pressures. We have not established a pulmonary pressure at which TBB is contraindicated within our practice, and we assess each patient individually regarding the overall clinical scenario before we commit to performing TBB.
Uremia
The presence of uremia adversely affects platelet function, resulting in abnormal platelet aggregation and prolonged bleeding times and potentially increasing the risk of significant hemorrhage in patients undergoing TBB. No studies that have rigorously examined the effect of uremia on bleeding complications in TBB currently exist. Some authors have suggested that the use of recombinant arginine vasopressin may decrease the extent of bleeding in uremic patients, although examination of the surgical literature has shown mixed results. The current practice at our institution is to give recombinant arginine vasopressin at a dose of 0.3 μg/kg intravenously to all lung transplant recipients with creatinine >2.5 mg/dL 30 minutes prior to bronchoscopy. Non-lung transplant patients generally do not receive arginine vasopressin, and we have not encountered noticeably increased rates of bleeding in these patients.
Hypoxemia
No level of oxygen supplementation is currently recognized to be an absolute contraindication to TBB, although 37 percent of surveyed pulmonologists indicated that an inspired oxygen requirement of >60 percent fraction of inspired oxygen (FiO2) was a contraindication to TBB, whereas 36 percent of the respondents found no specific O2 requirement a contraindication. The BTS recommends supplying supplemental O2 to keep blood oxygen saturations >90 percent to minimize the risk of cardiac arrhythmias during and following bronchoscopy. Generally, we consider electively intubating patients for bronchoscopy when oxygen supplementation is >5 L/min via nasal cannula prior to performing TBB.
Anticoagulant and Antiplatelet Agents
Use of anticoagulants and antiplatelet agents is common among patients referred for bronchoscopy. No randomized trials exist regarding the use of warfarin in the setting of TBB. The BTS recommended holding warfarin for three days prior to bronchoscopy, or providing supplemental vitamin K prior to the procedure. Current recommendations suggest that an international normalized ratio of 1.5 is a safe level for most surgical procedures. Patients anticoagulated with heparin should have this medication held for 6 hours prior to bronchoscopy and may be restarted 12 hours following the procedure. O’Donnell and colleagues addressed the use of enoxaparin as a bridge for warfarin in patients scheduled for elective surgery. Ninety-four patients received a final dose of twice-daily enoxaparin at least 12 hours prior to surgery and were found to have persistently elevated anti-Xa levels at the time of surgery. Based on these findings, it is our policy to stop therapeutically dosed enoxaparin for 24 hours prior to performing TBB, whereas enoxaparin dosed for deep vein thrombosis prophylaxis is not administered on the morning of the procedure.
Aspirin use was previously considered to be a contraindication to TBB; however, a large multicenter study has shown no difference in bleeding following TBB in 285 patients taking aspirin at the time of bronchoscopy compared with 932 patients not on aspirin.Consequently, we do not have patients hold aspirin prior to TBB.
In a follow-up study examining the effect of the antiplatelet medication clopidogrel on incidence of bleeding during TBB, significant bleeding was increased to 89 percent compared with 3.4 percent in the control group. In a small number of patients taking both aspirin and clopidogrel, the incidence of significant bleeding was 100 percent following TBB. Given the relatively long half-life of clopidogrel, our current practice is to have patients discontinue clopidogrel a minimum of 5 days prior to undergoing bronchoscopy with TBB.
Several direct oral anticoagulants (DOACs) have been approved for use in patients with atrial fibrillation and deep vein thrombosis. These agents have bleeding risk profiles similar to warfarin and other conventional anticoagulants, however, laboratory monitoring of the effects of DOACs can be difficult since many of the necessary assays are not universally available. No specific data exist regarding use of these medications in the setting of TBB, although most expert organizations agree the drugs should not be taken 24 to 48 hours prior to invasive procedures. Drug metabolism may be altered by renal and hepatic dysfunction and so the agents should be avoided for up to 5 days in patients with impaired metabolism of DOACs, or in patients with increased risk of bleeding during TBB.
Procedural Considerations
TBB
TBB is most commonly performed via flexible bronchoscopy using conscious sedation. Careful study of a prebronchoscopy CT scan is useful in determining the best pulmonary segment to access for biopsy. In diffuse pulmonary disease, use of fluoroscopy is not necessary, although the risk of significant pneumothorax may be reduced. In focal disease that is visible on chest X-ray, use of fluoroscopy during the procedure may significantly increase the diagnostic yield of the study.
After a careful airway examination is performed, the pulmonary segment of interest is intubated with the tip of the bronchoscope, and the pulmonary forceps are passed through the working channel of the bronchoscope. As the forceps are visualized entering the pulmonary subsegment, the fluoroscopy unit may be activated to visualize the forceps as they enter the distal segments of the lung (Figure 10.1). To biopsy the lung periphery, the forceps should be gently advanced in the closed position until resistance is encountered (Figure 10.2). Next, the forceps are withdrawn approximately 1 cm, and the command is given to open the forceps jaws. The forceps are then advanced halfway to the area where resistance was encountered, and the forceps jaws are closed. With the fluoroscopy unit still activated, the forceps are retracted with firm, continuous pressure to allow the biopsy specimen to be removed from the surrounding lung parenchyma. The lung parenchyma should be watched on the fluoroscopy monitor for retraction during the collection of the biopsy sample (Figure 10.1). If there is excessive resistance, or extensive retraction of the lung parenchyma during sampling, the forceps should be opened to release the lung tissue, and the biopsy procedure should be restarted. After a sample is obtained, the forceps are removed from the working channel of the bronchoscope, and the biopsy is placed in formalin.
Figure 10.1 Sequence of fluoroscopic images showing TBB from the right lung. Extension of the closed biopsy forceps to the periphery of the lung (A). Forceps opened and advanced to collect tissue (B). Forceps closed and partially withdrawn to collect the tissue sample (C). Note the subtle retraction of the underlying lung parenchyma by the forceps as the tissue sample is collected.
Figure 10.2 Artists representation of forceps in the distal bronchus. The jaws of the forceps produces and invagination of the bronchial wall resulting in sampling of both bronchial mucosa and alveolar tissue.
Two schools of thought exist as to how best to manage the airway after a biopsy sample is collected. The wedge technique may be employed, where the tip of the bronchoscope is lodged firmly (wedge position) in the airway subsegment that was sampled to monitor for bleeding. It is thought that leaving the bronchoscope wedged permits control of potential bleeding by continuous suctioning to remove extravasated blood, thereby preventing soiling of the remainder of the lung. Continuous suctioning also allows the operator to assess the quantity of bleeding present, and collapsing the distal airways produces a tamponade effect. When bleeding has slowed, the tip of the bronchoscope may be withdrawn from the wedge position to allow observation of the bleeding segment and, if necessary, to facilitate repeating the wedge maneuver if the bleeding continues to be significant. The disadvantage of the wedge maneuver is that the bronchoscopist is not able to either visualize the airways due to blood obscuring the optics of the bronchoscope or assess the effectiveness of the wedge in isolating the bleeding subsegment. In the alternative strategy, the tip of the bronchoscope is withdrawn from the subsegment of interest so that the bronchoscopist can watch for welling up of blood from the distal lung. Blood is suctioned with a back-and-forth motion to clear the airway and maintain vision. This suctioning permits a more global assessment of the extent of bleeding and potential seepage of blood into the other portions of the lung. There are currently no data to support the superiority of either approach. Our practice is to have novice bronchoscopists maintain the bronchoscope in the wedge position after each biopsy and use the observational technique after they have acquired more experience with the bronchoscope. Additional discussion of the management of bleeding complications will be presented later.
Optimizing Biopsy Yield
Forceps Biopsy
Several studies have examined how best to enhance biopsy yield in terms of number of samples to be collected and characteristics of the collected specimens. As described earlier, the number of tissue pieces needed to optimize sensitivity is dependent on the underlying disease. Most studies report a range of 4–10 pieces of tissue to optimize sampling sensitivity and the BTS guidelines on flexible bronchoscopy recommend five to six samples in patients with diffuse lung disease and seven to eight samples in patients with focal lung disease. Our practice is to obtain a minimum of six tissue pieces of a minimum size of 1–2 mm in the long axis for patients with either focal or diffuse lung disease.
Several studies have examined the optimal size of biopsy forceps for performing TBB and no clear difference has been established regarding size of tissue samples or diagnostic sensitivity between large and small forceps. Our practice is to use medium sized alligator style forceps (Figure 10.3) for all of our TBBs because they do not entirely occlude the working channel of the bronchoscope while the forceps are extended, thereby permitting continued use of the working channel for suctioning. Larger forceps show no clear advantage in biopsy quality, but do preclude effective suctioning while they are deployed.
Figure 10.3 Three types of forceps available for use with the flexible bronchoscope. Right to left: small forceps with teeth; large, smooth-cupped forceps with center spike; and large forceps with teeth. The forceps fitted with a center spike are more commonly used for performing endobronchial biopsies.
Adjunctive Techniques for TBB
Two recent technologic advances have shown the ability to improve diagnostic yield for transbronchial lung biopsy in peripheral lesions. The first, radial probe endobronchial ultrasound (radial EBUS) consists of a 1.4-mm-diameter catheter with a 20 MHz ultrasound probe on the tip capable of being placed through the working channel of the bronchoscope into the lung periphery. Use of this device permits real-time confirmation that the probe is being extended into or adjacent to a lung nodule of interest to enhance biopsy yield (Figure 10.5). Use of a plastic outer sheath over the radial EBUS probe permits removal of the probe and insertion of sampling tools such as biopsy forceps to be guided to the same location.
