(Chest. 2004;126:273-280.)
© 2004
American College of Chest Physicians
Role of Transbronchial Biopsies in Pediatric Lung Diseases*
Gary A. Visner, DO;
Albert Faro, MD and
Dani S. Zander, MD
* From the Department of Pediatrics (Drs. Visner and Faro), University of Florida, Gainesville, FL; and the Department of Pathology (Dr. Zander), University of Texas-Houston Medical School, Houston, TX.
Correspondence to: Gary A. Visner, DO, Associate Professor and Chief, University of Florida, Dept. of Pediatrics, Division of Pediatric Pulmonary Medicine, Box 100296, Gainesville, FL 32610; e-mail: visnega{at}peds.ufl.edu
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Abstract
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Study objective: To evaluate the role of transbronchial biopsies (TBBs) in pediatric lung diseases.
Design and methods: We reviewed the records of TBBs performed in pediatric patients at the University of Florida between July 1996 and August 2003. The sample adequacy, diagnostic utility, and procedural complications of the two types of bronchoscopy apparatuses used to collect the samples were assessed and compared.
Patients: A total of 429 TBB procedures were performed in 46 patients (age range, 2 months to 21 years) who had received a heart-lung or lung transplant and in 38 non-lung transplant patients (age range, 2 weeks to 18 years). For 86 procedures, the pediatric bronchoscope and forceps that fit in a 1.2-mm channel were used, and a small adult bronchoscope and 2.0-mm forceps were used for the remaining procedures.
Results: Adequate tissue samples were obtained in 85% of the procedures using a pediatric bronchoscope and in 97% using an adult bronchoscope. In the non-lung transplant patients, the biopsy findings were considered to be diagnostic in 58% of all procedures (adult bronchoscope, 64%; and pediatric bronchoscope, 50%), contributory in 21%, and noncontributory in 21%. In the lung transplant patients, treatable acute cellular rejection was diagnosed in 24% of the surveillance TBBs and in 47% of the TBBs performed as a result of clinical symptoms. Complications included five pneumothoraces and five episodes of excessive bleeding requiring the discontinuation of the procedure in three of the cases.
Conclusions: Adequate lung tissue for histologic diagnosis can be obtained safely and effectively from pediatric patients of all ages via flexible bronchoscopy with TBB. The performance of bronchoscopy should be considered based on clinical indications, rather than on the age or size of the patient, when a tissue diagnosis is needed. When feasible, the use of an adult bronchoscope is preferable due to the higher diagnostic yield.
Key Words: bronchoscopy • lung • pediatrics • transbronchial biopsy
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Introduction
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Since the 1970s, transbronchial biopsy (TBB) of the lung through a flexible fiberoptic bronchoscope has gained acceptance and has become the most common method of obtaining lung tissue from adults.1234 It requires the use of flexible biopsy forceps that fit through the suction or working channel of the bronchoscope. Until the past few years, this was restricted to adult-sized bronchoscopes. For this reason, TBB was limited to adults and older children. Younger children needing a pathologic diagnosis underwent open lung biopsy, video-assisted thorascopic surgery (VATS), or rigid bronchoscopy in the operating room under general anesthesia. In 1995, however, Mullins et al5 described a technique of attaching a plastic suction catheter to a neonatal bronchoscope (2.2 mm in diameter with no working channel). This was followed by the development of a small flexible biopsy forceps that could fit through the 1.2-mm working channel of the pediatric flexible fiberoptic bronchoscope. These advances led to a broadening of the patient group in whom bronchoscopy with TBB could be safely performed.
TBBs are performed to obtain a tissue diagnosis for a variety of conditions, such as tumors, chronic infiltrative diseases, and infections, and for lung transplant monitoring.123456 In adults, tissues obtained by TBB result in a pathologic diagnosis in > 50% of the patients.1234 With increased utilization of lung transplantation in the pediatric population, there is an increasing need for obtaining lung tissue from children in an efficient and less costly manner. At our institution, TBB has been the most common method of obtaining lung tissue in our pediatric lung transplant patients. Bronchoscopy with TBB also has become our first-line diagnostic procedure of choice in a large number of children with non-transplant-related lung diseases.
There have been few studies addressing the utility of bronchoscopy with TBB in the pediatric population. Several reports6789 have described results from biopsies obtained with an adult bronchoscope and biopsy forceps or a rigid bronchoscope, but little information exists regarding the utility of the small biopsy forceps for securing diagnostic material. This report presents a comparative assessment of the sample adequacy, diagnostic utility, and complication rate for bronchoscopy with TBB employing either the 2.0-mm or the 1.2-mm biopsy forceps in our pediatric population.
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Materials and Methods
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A review of records from Shands Hospital at the University of Florida, from July 1996 to August 2003, was conducted to identify children, infants, and adolescents who had undergone bronchoscopy with TBB. Information was obtained about the type of bronchoscope and forceps used. The equipment available included the following: (1) pediatric bronchoscopes with a 3.6-mm outer diameter (model 3C30; Olympus; Tokyo, Japan) and a 2.8-mm outer diameter (model XP40; Olympus) with biopsy forceps that fit through the 1.2-mm channel (model FC-56D-1; Olympus) and have a smooth oval cup with a volume of 0.5 µL; and (2) adult bronchoscopes with a 4.9-mm outer diameter (BF-P40; Olympus) and 5.2-mm outer diameter (model BF-P240; Olympus) and biopsy forceps (model FB-19C-1; Olympus; or Radial Jaw 1266; Microvasive; Waterton, MA) that fit through the 2.0-mm channel and have a cup volume of 2.0 µL.
Nearly all of the procedures were performed with the patient under conscious sedation, most commonly with topical lidocaine, and a combination of midazolam and fentanyl. Twelve procedures were performed under general anesthesia, and 13 were performed while patients were receiving positive-pressure ventilator support.
TBBs were performed under fluoroscopic control, and the samples were obtained from one lung to reduce the likelihood of bilateral pneumothoraces. Biopsy sites were selected based on the location of radiographic abnormalities. For focal or patchy processes, sampling was directed to affected areas. If diffuse infiltrates were present or no significant abnormalities were observed, multiple locations within one lung were biopsied. Following BAL, attempts were made to obtain at least five tissue fragments for pathologic evaluation. The tissue for pathologic evaluation was placed on gelfoam and then immersed in a 10% neutral buffered formalin solution. After fixation, samples were routinely processed and embedded in paraffin. Five-micrometer sections were cut at three levels in the block and were stained with a standard hematoxylin-eosin stain. Additional histochemical and immunohistochemical staining was performed if indicated based on a review of the original slides, and consideration of the clinical and radiographic information.
A sample adequacy assessment was based on the presence or absence of tissue from the appropriate anatomic location (ie, bronchus and/or alveolar parenchyma). If a bronchial disorder was suspected and the biopsy included bronchial tissue, the biopsy was considered to be adequate. On the other hand, if a parenchymal (alveolar) disease process was expected and the biopsy included bronchial mucosa but no alveoli, the biopsy was considered to be less than optimal (LTO). For lung transplant recipients, a sample was considered to be adequate if it contained a minimum of five alveolar tissue fragments, or if a specific diagnosis (ie, treatable grade of acute cellular rejection [ACR] or infection) was evident in a smaller sample. The diagnostic utility of the biopsy specimens was evaluated by two of the authors (G.A.V. and D.S.Z.), and the biopsies were classified as diagnostic, contributory, or noncontributory. The procedural complication rates also were assessed for each type of bronchoscopy apparatus.
The Fisher exact test was used to compare differences between the groups, such as adequate and LTO samples between the pediatric and adult bronchoscopes for obtaining TBB specimens, and ACR rates in the lung transplant patients.
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Results
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In a 7-year period at the University of Florida, 429 TBB specimens were obtained from 46 patients who had undergone lung or heart/lung transplantation and from 38 non-lung transplant pediatric patients with suspected lung diseases. All of the biopsies were performed in order to collect lung tissue for histologic diagnosis, and, in some cases, cultures. Children without transplanted lungs ranged in age from 2 weeks to 18 years (mean, 8.7 years), and their weights ranged from 2.4 to 110 kg. Eighty-six of the TBB samples were collected with biopsy forceps having a 0.5-µL cup volume through a pediatric flexible fiberoptic bronchoscope, and the other TBB samples were acquired using biopsy forceps with a 2.0-µL cup volume that fit through a 2.0-mm channel (ie, an adult bronchoscope). Table 1
summarizes the numbers and ages of the patients undergoing TBB with each type of bronchoscope and forceps.
Sample adequacy data for the TBBs are shown in Table 2
. Most of the TBB procedures (95%) yielded adequate tissue, but sample adequacy rates for the adult-sized apparatus (97%) and the pediatric bronchoscope/forceps (85%) were significantly different (p < 0.001). In the lung transplant patients, TBBs produced adequate samples in 84% and 97% of patients, respectively, using the pediatric and adult bronchoscopes, and clinical decisions were based on this information. Adequate sampling rates in non-lung transplant patients were similar (approximately 90%) [Table 2]. Although the numbers of diagnostic TBBs were higher in the nontransplant group who underwent TBBs with the adult apparatus, the numbers of samples yielding clinically helpful information (ie, diagnostic plus contributory samples) were similar (p > 0.05) [Table 3
]. Table 4
(small forceps) and Table 5
(large forceps) provide details about the non-lung transplant patients, including clinical and radiographic presentation, biopsy results, clinicopathologic diagnosis, and outcome.
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Table 4.. Clinical, Radiographic, and Pathologic Information for Patients Evaluated With the Pediatric Bronchoscope and Smaller Biopsy Forceps*
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Table 5.. Clinical, Radiographic, and Pathologic Information for Patients Evaluated With Adult Bronchoscope and Larger Biopsy Forceps*
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TBB procedures for the lung transplant patients were performed for surveillance (25%), ACR treatment follow-up (38%), and for pulmonary symptoms (eg, a decrease in lung function, fever, tachypnea, hypoxia, or cough) [37%]. A treatable grade of ACR (ie, working formulation grades A2 to A4)10 was diagnosed in 24% of the surveillance TBB specimens (Table 6
). Interestingly, only 5% of the surveillance TBB specimens obtained in younger children (ie, performed with pediatric forceps) revealed ACR vs 29% of the TBB specimens obtained with the adult apparatus (p = 0.03). ACR was found more frequently in specimens obtained with nonsurveillance TBB procedures compared to surveillance procedures (with adult bronchoscope, p = 0.001; with pediatric bronchoscope, p = 0.006). There was no significant difference in ACR rates from nonsurveillance procedures performed with the adult and pediatric biopsy forceps. Symptomatic children were more likely to have ACR (younger children using pediatric forceps, 27%; older children using adult forceps, 49%), as were children with a previous diagnosis of ACR. After receiving ACR therapy, histologic evidence of persistent ACR was found in 42% and 54%, respectively, of the younger and older patients. Twenty TBBs were performed with the adult forceps in patients who previously had undergone TBB using the pediatric forceps. None of the nine surveillance biopsies showed ACR, and 4 of 11 of the nonsurveillance TBBs (36%) showed ACR, which is similar to the rate of ACR found in these same children with the smaller forceps (38%).
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Table 6.. TBBs Showing ACR (grades A2 to A4) in Procedures Performed for Surveillance, Follow-up of ACR Therapy, or Symptoms
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Postprocedural complications included pneumothorax, excessive bleeding of > 150 mL or that required a transfusion, and postprocedural septicemia. The overall complication rate was approximately 2%, and was similar between TBBs using the pediatric and adult forceps (Table 7
). The complication rate in the non-lung transplant group was approximately 8%. All complications occurred in patients who underwent biopsies performed using the adult forceps. However, this was not statistically different from the complication rate of TBBs performed using the pediatric forceps (p = 0.26). There were five pneumothoraces among all patients, with three in posttransplant patients, one who had undergone TBB using the pediatric forceps, and two who had undergone TBB using the adult forceps. Two pneumothoraces occurred in two of the three patients with cystic fibrosis who underwent TBBs, and both of these patients required chest tube placement. One excessive bleeding episode occurred in a patient with chemotherapy-induced thrombocytopenia, despite platelet transfusion prior to and during bronchoscopy. Four episodes of excessive bleeding developed in lung transplant patients with cystic fibrosis. There were no episodes of excessive bleeding with the pediatric bronchoscope/forceps. Two lung transplant patients were readmitted to the hospital within 48 h of undergoing the procedure for sepsis due to the same organism cultured from their BAL fluid (group A Streptococcus, one patient; and Candida albicans, one patient).
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Discussion
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This study compares the efficacy and complication rates of the pediatric bronchoscope/forceps and adult bronchoscope/forceps. Previous studies6789 in adults and older children have shown the utility of TBBs for the diagnosis of lung diseases, but there are no reports addressing the relative efficacy of the smaller biopsy forceps and pediatric bronchoscope vs the adult-sized apparatus for obtaining lung tissue for diagnosis. Although both types of equipment obtained adequate amounts of tissue for diagnosis in the majority of our patients, the use of the adult apparatus resulted in a higher frequency of adequate and diagnostic samples than the smaller equipment.
In adult lung transplant recipients, TBB is believed to be the procedure of choice for the evaluation of rejection and infection, which are the two major categories of posttransplant complications.1112 Similar to previous reports,11121314 we found ACR of grade A2 or higher in 27% of the pediatric TBB procedures and in 47% of the adult TBB procedures with adequate tissue in which samples were obtained for surveillance, clinical change, or follow-up ACR therapy. Although the higher rate of ACR in the samples obtained with the adult bronchoscope raises the concern of sampling error for the samples obtained with the smaller apparatus, same-patient comparisons do not support the existence of sampling error. Rather, the results suggest that younger patients who underwent TBBs with the pediatric equipment had a lower ACR rate than did the older children and adolescents, most of whom underwent TBBs with the adult apparatus. The higher rate in the older group is most likely due to issues of noncompliance in our teenage transplant recipients and to the fact that younger children, most notably infants, have a lower rate of ACR.15
The overall diagnostic yield of approximately 60% for the TBB in non-lung transplant children, using both the small and large biopsy forceps, compares favorably with data from adults, in whom the diagnostic rate usually exceeds 50% but varies depending on the disease process.12341617 For example, the diagnostic yield for hypersensitivity pneumonitis was > 90%, while that for idiopathic pulmonary fibrosis was < 50%.1617 An additional 20% of the procedures yielded information that was important for patient management. These TBBs were classified as contributory and influenced patient management, because they did not reveal specific infections or neoplasia and, therefore, patients could be treated empirically with corticosteroids or antibiotics, or were not treated, as was deemed appropriate. For example, in patient 1, findings were consistent with chronic aspiration, and the patient improved with surgery for gastroesophageal reflux. Patient 9 had findings suggestive of alveolar proteinosis and interstitial pneumonia, which was also found on examination of the explant following transplantation. The TBB information, in combination with the infant’s clinical and radiographic findings, was sufficient to list the child for transplantation without requiring an open lung biopsy. The TBB information from patient 27 showed necrotizing granulomas, most likely secondary to infection, although the results of stains for organisms were negative, and the patient improved with a prolonged course of therapy with antibiotics.
By improving sample adequacy rates, we could have potentially improved the diagnostic yield from the TBBs. The criteria for sample adequacy, however, have not been definitively established. For this study, we used the criteria that the samples had to have tissue from the region of interest to be considered adequate, and, for the vast majority of samples, there was enough tissue for the pathologist to provide a pathologic diagnosis. There are several reports91819 regarding adequate sample size for the evaluation of lung allografts in which as few as five specimens containing alveolar tissue may be adequate for an interpretation. In nontransplant patients, Descombes et al16 suggested that at least five or six specimens should be obtained for a good diagnostic yield. We attempted to obtain at least five or six specimens from each procedure, and most often more since not every sampling produced representative lung tissue. Some samples yielded blood, fibrinous material, or mucus. Nonetheless, we were successful in procuring adequate amounts of tissue in most patients, regardless of which apparatus was used.
In most of our patients, TBB was well-tolerated and was not accompanied by complications. The two major complications of bronchoscopy with TBB are excessive bleeding and pneumothorax, and the estimated complication rate is approximately 5%.2021 The overall complication rate in our experience was approximately 2%. In our patient population, the highest complication rate was associated with TBB performed in non-lung transplant patients. Two pneumothoraces occurred in non-lung transplant patients with cystic fibrosis, and both of these children required the placement of a chest tube. Hyperinflation is a relative contraindication for TBB, and this is frequently a problem for patients with cystic fibrosis. In light of this experience, we are now hesitant to perform TBBs in patients with cystic fibrosis and usually consider either open lung or VATS biopsies as the first option. Only one major bleeding complication occurred in a non-lung transplant patient with thrombocytopenia, despite the transfusion of platelets before and during the procedure. There were four major bleeding episodes in TBB procedures in lung transplant recipients with cystic fibrosis. These patients were all receiving supplemental vitamin K and had no clinical or laboratory evidence of coagulopathy.
Another potential adverse event following bronchoscopy is infection, although the risk is estimated to be very low (ie, 0.08%).22 However, the rate of postprocedural bacteremia has been reported to be as high as 6.5% following bronchoscopy.23 Lung transplant patients receive long-term immunosuppressive therapy and may be more prone to infectious complications. Two lung transplant recipients were readmitted to the hospital within 48 h of the procedure with the same organisms found in the BAL fluid and blood. Whether the bronchoscopy and TBB procedure triggered the septicemia or served merely to provide earlier evidence of the present of the infection is unclear.
In conclusion, we believe that flexible bronchoscopy with TBB represents a safe and effective method for obtaining lung tissue for histologic examination in the pediatric population. Our results indicate that the larger biopsy forceps and the small adult bronchoscope with the 2.0-mm working channel can be used safely and can provide slightly better diagnostic yield than the smaller pediatric equipment, but use of the smaller biopsy forceps also results in adequate tissue sampling in the majority of procedures. We believe that the decision to perform a TBB should not be made based on the age or size of the patient but, rather, on the indications for the procedure. As with a patient of any age, if adequate tissue is not obtained and there is further need for tissue sampling, then use of a more invasive method such as VATS or open lung biopsy should be con-sidered.
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Footnotes
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Abbreviations: ACR = acute cellular rejection; LTO = less than optimal; TBB = transbronchial biopsy; VATS = video-assisted thoracic surgery
Received for publication September 29, 2003.
Accepted for publication January 12, 2004.
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Abstract
Introduction
