Ann Thorac Surg 2008;86:198-203. doi:10.1016/j.athoracsur.2008.03.075
© 2008 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Role of Clinically Indicated Transbronchial Lung Biopsies in the Management of Pediatric Post–Lung Transplant Patients
Christina L. Greene, BS,
Brian Reemtsen, MD,
Anastasios Polimenakos, MD,
Monica Horn, RN,
Winfield Wells, MD*
Department of Cardiothoracic Surgery, Childrens Hospital Los Angeles, Los Angeles, California
Accepted for publication March 28, 2008.
* Address correspondence to Dr Wells, Childrens Hospital Los Angeles, Department of Cardiothoracic Surgery, 4650 Sunset Blvd, No 66, Los Angeles, CA 90027-6062 (Email: wwells{at}chla.usc.edu).
Presented at the Poster Session of the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.
 |
Abstract
|
|---|
Background: Although transbronchial biopsy (TBB) is the definitive method for diagnosing graft dysfunction after pediatric lung transplantation, concern over procedural complications has limited its use. We reviewed our institutional experience with clinically indicated TBB to determine its safety and efficacy with emphasis on how biopsy findings altered management.
Methods: A retrospective chart review was done of 61 pediatric lung transplantation patients undergoing 179 TBB procedures. Data were collected on pre-TBB symptoms, pulmonary function testing, and imaging studies. The prebiopsy diagnosis was noted and compared with the findings from TBB to see how frequently treatment changed after biopsy.
Results: Age at TBB ranged from 2 months to 20 years, with an average of 3 biopsies per patient. There was no procedure-related mortality. The incidence of complications was 9% and included important bleeding with spontaneous resolution in 6% and pneumothorax in 3%. The usual indication for TBB was a change in the chest roentgenogram, frequently accompanied by a decrease in flows on spirometry. The TBB specimens were adequate for pathologic analysis 92% of the time, and a specific pathologic diagnosis could be made in 54% of cases. The findings from TBB altered the clinical management of the patient 64% of the time.
Conclusions: In pediatric lung transplant recipients presenting with graft dysfunction, TBB is a low-risk diagnostic procedure that yields clinically useful information in a majority of cases. In our experience, the findings from TBB altered medical treatment in 64% of patients. Treatment was most often changed in the group diagnosed with rejection as the probable cause of graft dysfunction.
|
Introduction
|
|---|
Early recognition and targeted therapy of complications after lung transplantation are critical to long-term survival. Bronchoscopy with transbronchial biopsy (TBB) is the most accurate method for diagnosing potential problems, but in the pediatric population there has been a reluctance to use this technique because of concern over procedure-related complications and questionable efficacy of TBB in securing a clinically useful diagnosis.
In our institution, TBB has been utilized to help guide treatment of patients presenting with posttransplant graft dysfunction thought to be related to rejection or infection or both. Because there is little published information on the outcomes of clinically indicated TBB in the pediatric lung transplant population, we have reviewed our experience with an emphasis on how frequently the findings from TBB altered the management of the patient.
|
Material and Methods
|
|---|
A retrospective chart review was carried out to identify pediatric (less than 21 years old) lung transplant recipients undergoing subsequent clinically indicated bronchoscopy with TBB for allograft dysfunction. Surveillance biopsy has not been used in our institution. Charts were reviewed for demographics, indication for transplantation, and the transplant operative course. At the time of each clinically indicated TBB procedure, information regarding the symptoms at presentation, preprocedure testing, and the working or clinical diagnosis of the present illness were sought. Details regarding the TBB procedure and any related complications were recorded. Finally, culture and histopathologic reports were studied to determine if TBB helped in defining the pathologic process, how frequently the working diagnosis was confirmed or modified by the TBB findings, and how often there was a change in management based on the biopsy findings.
For the purposes of this study, a change in patient management was defined as follows: (1) changing from antimicrobial therapy for suspected infection to treating for rejection or vice versa; (2) starting therapy for infection or rejection when there was no treatment before TBB; and (3) changing the type of antimicrobial therapy based on findings from the TBB.
Procedure for Bronchoscopy and TBB
Patients were given a general anesthesia and intubated with the largest endotracheal tube feasible (to allow unimpeded passage of the fiberoptic bronchoscope). After visualization of the airways, including a thorough inspection of each of the bronchial anastomosis, bilateral deep bronchoalveolar lavage specimens were obtained. Then under fluoroscopic guidance, transbronchial biopsy specimens were obtained from each allograft. The intent was to take three satisfactory biopsy specimens from different peripheral sites on each side. The adequacy of biopsy specimens was determined by the surgeon upon inspection of the tissue for size and gross appearance. In general, a tan spongy specimen suggestive of lung parenchyma was sought, as opposed to a whitish, more dense tissue that was usually indicative of bronchial wall. In some instances, this goal was impeded by brisk and persistent bleeding after obtaining a specimen. Under such circumstances, no further biopsies were done on that side.
For comparative analysis, patients were placed into one of three subgroups based on the pre-TBB working clinical diagnosis: group 1 included patients with a pre-TBB diagnosis of infection; group 2 consisted of patients diagnosed with rejection before biopsy; and group 3 was made up of patients with an uncertain diagnosis of rejection versus infection.
|
Results
|
|---|
Demographics
There were 85 patients who underwent bilateral lung transplantation in our institution between 1993 and 2006. Among these 85 were 61 (72%) who had at least one TBB. The median age at transplant for this group of 61 patients was 15 years (range, 2 months to 20 years). Figure 1
shows the age distribution of this population. There was nearly equal distribution between girls and boys (32 versus 29), and most were Caucasian or Hispanic (76% and 18%, respectively). The most common indication for transplantation was cystic fibrosis (46 of 61, or 75%). Table 1
summarizes the indications for transplant for the entire series.
View larger version (10K):
[in this window]
[in a new window]
|
Fig 1. Number of transbronchial biopsies (TBBs) according to time after transplant in 6-month intervals.
|
|
Transplant Procedure
All 61 patients had bilateral lung transplantation utilizing cardiopulmonary bypass. Living donor allografts were used in 39 transplant patients (64%). The technique for living donor lobar transplantation has been previously described from our institution by Starnes and colleagues [1]. The ischemic time for living donor versus cadaveric allografts was significantly different (78 versus 177 minutes; p = < 0.05).
Clinical Presentation Before TBB
Patients presenting with graft dysfunction were first evaluated clinically and, based on the examiners' initial impressions, were given a working or clinical diagnosis for the present illness. Factors that influenced the working diagnosis were subjective such as a history from the family of shortness of breath, cough with sputum production, decreased activity, or "appearing ill." Objective findings from the physical examination such as fever, abnormal breath sounds, or decreased oxygen saturations also influenced the clinical impression. Further objective information came from chest roentgenogram and pulmonary function testing.
As depicted in Table 2, the majority (68%) of patients were sent for TBB with an indeterminate clinical diagnosis of rejection versus infection; 16% were suspected of having rejection and 15% were thought to have infection.
The most common findings leading to referral for TBB varied according to the prebiopsy clinical impression, as would be expected. Among those suspected of having infection an infiltrate on chest film (62%), fever (50%), and respiratory symptoms such as cough, sputum production, wheezing and shortness of breath were most common. Patients with a prebiopsy working diagnosis of rejection were referred most commonly because of abnormal pulmonary function testing (46%) or infiltrate on chest x-ray film (32%). The largest group of patients was referred with an indeterminate diagnosis of rejection versus infection. In this group, the findings before TBB were nearly evenly divided between infiltrate on chest roentgenogram (50%), decrease in PFTs (35%), and decrease in oxygen saturation (38%). Table 3
summarizes the preoperative clinical findings for each of the three groups by number of TBBs.
Bronchoscopy and TBB
The majority of TBBs were performed within 1 year of transplant, with 41% occurring within 6 months. The median interval between transplant and TBB was 5.5 months (range, 3 days to 16 years).
In all, 170 TBB procedures were analyzed. There were 39 living donor transplant patients with 107 TBB procedures, for an average of 3 per patient. This was equal to the incidence of TBB among the 22 cadaveric recipients in whom 63 TBBs were done.
Histopathologic results from the TBB were generally available within 12 hours of the procedure and in 92% of cases (157 of 170) the tissue submitted was deemed adequate for diagnosis.
There was no TBB procedure-related mortality. Complications included noteworthy bleeding that occurred in 9 of the 170 TBB procedures (5%). In all 9 instances, the bleeding resolved spontaneously aided by transbronchial topical measures. Pneumothorax was seen on 6 occasions (3%) and resolved with tube thoracostomy.
Histologic Diagnosis from TBB
When considering the findings from the 170 TBB episodes, the pathologist had sufficient tissue to make a diagnosis in 157 TBBs (92%). There was evidence of both rejection and infection, in 39% (n = 61). Rejection was diagnosed in 37% (n = 58), and infection in 15% (n = 24). The remaining 14% of findings were spread among less common diagnosis such as bronchiolitis obliterans, interstitial fibrosis, hemosiderosis, and diffuse alveolar damage. Table 4
summarizes the histologic findings for all of the patients.
Clinical Diagnosis Versus TBB Diagnosis
Initial clinical assessments (working diagnoses) were compared with final histologic findings from TBB. When allograft dysfunction was thought clinically to be due to infection (n = 25), this diagnosis was confirmed in only 20%. Histology from TBB showed rejection in 32%, and evidence of rejection and infection was present in 28%.
When the clinical working diagnosis was rejection (n = 26), this diagnosis was confirmed by TBB in 58% of cases. Histology showed rejection in 15%, and in 23% the biopsy showed both rejection and infection.
The largest group had an uncertain clinical diagnosis of rejection versus infection (n = 106), and in this population the most frequent finding from TBB was also rejection versus infection, showing both of these problems (44%). However, the next most common diagnosis was rejection (33%).
Table 5
summarizes the initial clinical assessment compared with the final histologic diagnosis after TBB.
Pre-TBB Versus Post-TBB Treatment
An analysis of how the findings from TBB changed patient management has been carried out. The patients have again been grouped according to the prebiopsy clinical diagnosis.
Suspected infection (n = 26)
When the pre-TBB clinical diagnosis was infection, the majority of patients were found to have rejection (32%, n = 8) or an indeterminate biopsy with evidence of both infection and rejection (28%, n = 7). Thus, the findings from the TBB changed the management in more than half of this patient cohort. The majority (71%) of those with an indeterminate biopsy received antimicrobial therapy. Table 6
summarizes the different treatments received for each histologic diagnosis in those with suspected infection.
Suspected rejection (n = 28)
Patients with a working diagnosis of rejection were shown to have this diagnosis by TBB in the majority of cases (58%, n = 15). However, the biopsy findings changed therapy in those with indeterminate findings of rejection versus infection and when infection was seen (17% and 75%). The majority (83%) of patients with an indeterminate histologic diagnosis received neither treatment for infection nor rejection as a result of the TBB. Thus, in 42% of patients with a clinical diagnosis of rejection, treatment was modified on the basis of TBB findings. Table 7
summarizes the different treatments received for each histologic diagnosis, in those with suspected rejection.
Rejection versus infection (n = 116)
The largest cohort of patients had an uncertain clinical diagnosis of rejection versus infection before going for TBB, and in more than half these cases the biopsy was helpful in directing treatment. When the finding from the TBB was nondiagnostic for infection or rejection (45%, n = 47), half the patients were observed without new treatment; and most of the remaining patients were continued on treatment for probable infection. Table 8
summarizes the different treatments received for each histologic diagnosis in those with suspected rejection versus infection.
In the aggregate, the findings from TBB were found to have altered treatment of the patient in 64% of cases.
|
Comment
|
|---|
To date, the pediatric lung transplant program at our institution has performed 85 bilateral lung transplants, 53 of which were living donor. In the majority of the patients, the indication for transplant was either cystic fibrosis or pulmonary hypertension. Since the inception of the program, 170 TBBs have been performed in 60 patients. These biopsies were performed in a nonsurveillance manner, and were prompted by patient symptoms. With this retrospective review, we have sought to determine the efficacy, safety, and clinical significance of TBB in the post–lung transplant patient. Although bronchoalveolar lavage was performed at the time of TBB, findings from the lavage fluid have not been included in this report. It is our intention to carry out a separate analysis of the efficacy of bronchoalveolar lavage in a future study.
The ability to effectively biopsy children after transplant was first described by Visner and colleagues [2] from the University of Florida. Although this paper focused on the technical aspect of biopsy, the data suggested that this procedure was successful in obtaining tissue for pathologic diagnosis in 85% of patients and was relatively safe with a serious complication rate of only 2%. Our data have echoed this finding with 92% of biopsy specimens deemed sufficient for pathologic diagnosis. We have determined that 92% of the specimens received were examined and read by the pathologist in less than 12 hours. This portion of the experience seems critical when using this invasive procedure to guide immunosuppressive or antibiotic therapy. The importance of timely biopsy and pathology support cannot be overstated.
When performing an invasive procedure the issue of safety remains paramount. Studies from Visner and colleagues [2] and Benden and associates [3] have demonstrated a low complication rate, 4% and 3.2% in their respective studies. We have observed a similar low complication rate (8%), and have had no TBB-related mortality. The main two complications, namely, bleeding and pnuemothorax, can be life threatening to the posttransplant patient. And although the complication rate is low, the indication for biopsy must be clear before the procedure is initiated. The complication of pnuemothorax can mean months in the hospital for a posttransplant patient due to the immunomodulation effect of poor wound healing. The majority of our population are living donor transplants. During TBB on living donor post–lung transplant patients, we have noted large airways, with the biopsy forceps nearly reaching the chest wall in order to biopsy. We believe that this situation may in fact lead to a higher pnuemothorax rate in these select patients.
At our institution we perform TBBs on the basis of clinical presentation and specific symptoms. We have chosen not to employ a surveillance biopsy as advocated by Benden and coworkers [3] from Great Ormond Street Hospital. They have determined that a significant number of subclinical rejection and infection episodes can be detected if the patients are serially biopsied every 3 months for the first year. We believe there may be significant downsides to this approach. First, the relevance of these subclinical events is not clear. This group has not been able to show a survival benefit from this surveillance procedure. In our series, 25 patients have avoided biopsy all together. This fact coupled with a low, but significant, complication rate may have caused significant disability in the asymptomatic patient. We believe that close follow-up, noninvasive testing, and aggressive TBB for symptoms can affectively monitor posttransplant patient without subjecting them to unnecessary risk.
Our most significant finding was the clinical modification influenced by TBB in our patient population: 64% of the time, the biopsy findings altered patient management with the modulation of antirejection or antibiotic therapy. Another example of efficacy is that 83% of patients with expected rejection, not substantiated by biopsy, received no specific alteration in treatment. One critical conundrum that can appear is the lack of differentiation of rejection versus infection by clinical grounds or TBB. In our experience, we have chosen to treat empirically with antibiotics in 50% or no specific treatment, only close observation, in 50%. We have a lower threshold to treat with antibiotics than change immunosupression therapy in our posttransplant patients.
We believe that TBB is a safe, efficacious, invasive diagnostic tool that will modulate therapy when applied to symptomatic patients after pediatric lung transplantation. We believe that aggressive timely biopsy with pathology support can negate the need for surveillance TBB. It is possible that a randomized study could determine if any method may hold a survival benefit [4–15].
|
References
|
|---|
- Starnes B, et al. Living-donor lobar lung transplantation experience: intermediate results J Thorac Cardiovasc Surg 1996;112:1284-1291.[Abstract/Free Full Text]
- Visner G, Faro A, Zander D. Role of transbronchial biopsies in pediatric lung diseases Chest 2004;126:273-280.[Medline]
- Benden C, Harpur-Sinclair O, Ranasinghe AS, et al. Surveillance bronchoscopy in children during the first year after lung transplantation: is it worth it? Thorax 2007;62:57-61.[Abstract/Free Full Text]
- Valentine V, Taylor D, Dhillon G, et al. Success of lung transplantation without surveillance bronchoscopy J Heart Lung Transplant 2002;21:319-326.[Medline]
- Hopkins P, et al. Prospective analysis of 1,235 transbronchial lung biopsies in lung transplant recipients J Heart Lung Transplant 2002;21:1062-1067.[Medline]
- Aboyoun, Benden C, Harpur-Sinclair O, Ranasinghe A, et al. Diagnostic value of follow-up transbronchial lung biopsy after lung rejection Am J Respir Crit Care Med 2001;164:460-463.[Abstract/Free Full Text]
- Faro A, Visner G. The use of multiple transbronchial biopsies as the standard approach to evaluate lung allograft rejection Pediatr Transplant 2004;8:322-328.[Medline]
- Baz M, et al. Diagnostic yield of bronchoscopies after isolated lung transplantation Chest 1996;110:84-88.[Medline]
- Boehler A, Vogt P, Zollinger A, Weder W, Speich R. Prospective study of the value of transbronchial lung biopsy after lung transplantation Eur Respir J 1996;9:658-662.[Abstract]
- Guilinger RA, Paradis IL, Dauber JH, et al. The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients Am J Respir Crit Care Med 1995;152:2037-2043.[Abstract]
- Sibley RK, Berry GJ, Tazelaar HD, et al. The role of transbronchial biopsies in the management of lung transplant recipients J Heart Lung Transplant 1993;12:308-324.[Medline]
- Girgis RE, Reichenspurner H, Robbins RC, Reitz BA, Theodore J. The utility of annual surveillance bronchoscopy in heart-lung transplant recipients Transplantation 1995;60:1458-1461.[Medline]
- Trulock EP, Ettinger NA, Brunt EM, et al. The role of transbronchial lung biopsy in the treatment of lung transplant recipients. An analysis of 200 consecutive procedures. Chest 1992;102:1049-1054.[Medline]
- Kurland G, Noyes BE, Jaffe R, et al. Brochoalveolar lavage and transbronchial biopsy in children following heart-lung and lung transplantation Chest 1993;104:1043-1048.[Medline]
- Scott JP, Fradet G, Smyth RL, et al. Prospective study of transbronchial biopsies in the management of heart-lung and single lung transplant patients J Heart Lung Transplant 1991;10:626-637.[Medline]
Top
Abstract
Introduction
