J Thorac Cardiovasc Surg 2006;131:204-208
© 2006 The American Association for Thoracic Surgery
Cardiothoracic Transplantation |
Role of open lung biopsy in lung transplant recipients in a single children's hospital: A 13-year experience
Cliff K. Choong, FRACS
a
,
Fabio J. Haddad, MD
a
,
Charles B. Huddleston, MD
a
,
Jennifer Bell, RN
a
,
Tracey J. Guthrie, BSN
a
,
Eric N. Mendeloff, MD
a
,
Pam Schuler, MD
b
,
Maite De La Morena, MD
b
,
Stuart C. Sweet, MD
b
,
*
a Division of Cardiothoracic Surgery, Washington University School of Medicine, St Louis Children's Hospital, St Louis, Mo
b Department of Surgery, and Division of Pediatric Allergy/Pulmonary Medicine, Washington University School of Medicine, St Louis Children's Hospital, St Louis, Mo.
Received for publication March 1, 2005; revisions received July 4, 2005; accepted for publication July 11, 2005.
* Address for reprints: Stuart C. Sweet, MD, 1 Children's Place, Children's Hospital, St Louis, MO 63110. (Email: cliff.choong{at}papworth.nhs.uk).
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Abstract
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BACKGROUND: There are few data in the literature regarding the utility of open lung biopsy for the assessment of graft dysfunction after pediatric lung transplantation. The aim of this study is to review our experience with diagnostic open lung biopsy in lung transplant recipients in a children's hospital.
METHODS: Records of lung transplant recipients from January 1990 through December 2002 were reviewed to identify the indications, outcomes, and complications of open lung biopsy.
RESULTS: Two hundred twenty-four patients (mean age, 9.9 ± 6.2 years; median age, 11 years; age range, 0.01-19.6 years) underwent 249 lung transplantations: 231 bilateral, 8 single, and 10 heart-lung transplantations. Mean follow-up was 3.4 years. One hundred three open lung biopsies were performed in 89 (40% of all recipients) patients. Thirteen recipients underwent open lung biopsy twice, and 1 recipient had 3 open lung biopsies. The indications for open lung biopsy were suspicion of bronchiolitis obliterans (n = 70), posttransplantation lymphoproliferative disorder (n = 15), infection (n = 8), and unexplained respiratory failure (n = 10). A new diagnosis was made in 49 biopsies (48%), 50 biopsies (49%) confirmed the preoperative clinical diagnosis, and 4 biopsies (3%) were nondiagnostic. Bronchiolitis obliterans was confirmed in 40 (57%) of 70 open lung biopsies, posttransplantation lymphoproliferative disorder was confirmed in 4 (27%) of 15 open lung biopsies, and infection was confirmed in 6 (75%) of 8 open lung biopsies. A change in therapy occurred in 69% of the cases as a result of the diagnosis made from open lung biopsy. There was no mortality as a direct result of open lung biopsy. Eleven major complications and 22 minor complications occurred in 103 procedures.
CONCLUSION: Open lung biopsy can be performed safely, and established or confirmed a diagnosis in 97% of the cases. A change in therapy occurred in 69% of the cases as a result of the diagnosis made from open lung biopsy. In our experience open lung biopsy appears to be a useful tool.
Abbreviations and Acronyms BAL = bronchoalveolar lavage; BLT = bilateral sequential lung transplantation; BO = bronchiolitis obliterans; HLT = heart-lung transplantation; OLB = open lung biopsy; PTLD = posttransplantation lymphoproliferative disorder; TBB = transbronchial biopsy
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Introduction
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Open lung biopsy (OLB) has been used as a diagnostic tool in the evaluation of pulmonary diseases in lung transplant recipients when other investigations have been nondiagnostic. However, there are few data in the literature regarding the utility of OLB in lung transplant recipients. The purpose of this report is to review our experience with the use of diagnostic OLB in lung transplant recipients in a single children's hospital.
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Patients and Methods
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Patients
Between January 1990 and December 2002, 224 patients underwent 249 lung transplantations at the St Louis Children's Hospital. Two hundred thirty-one were bilateral sequential lung transplantations (BLTs), 8 were single-lung transplantations, and 10 were heart-lung transplantations (HLTs). The median age at the time of transplantation was 11 years, and the mean age was 9.9 ± 6.2 years (age range, 0.01-19.6 years). Indications, outcomes, and complications of OLB were obtained by means of a retrospective review of information prospectively collected in a computer database and from medical records. This study was reviewed and approved by the Washington University School of Medicine Human Studies Committee.
Operative Technique
Transplantation
The techniques have been well described elsewhere.
1,2
BLT was performed through a bilateral anterolateral transsternal (clamshell) thoracotomy incision through the fourth intercostal space. Single-lung transplantation was performed through an anterolateral thoracotomy extended across the sternum into the contralateral chest. HLT was performed through a median sternotomy. The majority of the operations were performed with the use of cardiopulmonary bypass because the airways in children are too small to safely accommodate the double-lumen endotracheal tubes that are necessary for single-lung ventilation.
OLB
OLB was performed after achievement of general anesthesia through a minianterolateral thoracotomy. The side (right or left) chosen in patients who had BLT or HLT is guided by the presence and severity of radiologic abnormalities. A lung specimen is removed and sent off for microbiologic and histologic analysis. Biopsies from 2 different locations were performed if 2 abnormal areas with clear differences were seen in the lung on preoperative imaging or during intraoperative inspection. The wound is routinely closed in layers. A chest tube is normally not inserted unless there is evidence of significant air leakage from the biopsy sites or from lung areas where adhesions have been divided during thoracotomy and exposure.
Transplant Management
Routine postoperative management has been described previously.
3
All patients received triple-drug immunosuppression (typically prednisone, cyclosporine [INN: ciclosporin], and azathioprine) and had routine scheduled surveillance to guide the maintenance of immunosuppressive therapy. Surveillance included pulmonary function measurements with standard techniques
4,5
and flexible bronchoscopy with biopsies and bronchoalveolar lavage (BAL).
6,7
These were performed at 2 weeks, 1 month, 2 months, 3 months, and every 3 months thereafter, as well as at any time that a change in clinical status occurred for which rejection was a plausible explanation.
3,6,7
OLB was performed when a patient had a clinical suspicion of pulmonary disease that was not confirmed by the above-mentioned investigations. These included patients in 4 groups: (1) patients with a clinical suspicion of bronchiolitis obliterans (BO) on the basis of a decrease in pulmonary function measurements without a clear diagnosis or explanation; (2) patients with a clinical suspicion of posttransplantation lymphoproliferative disorder (PTLD) on the basis of detectable lung nodules on chest radiography, computed tomography, or both; (3) patients with a clinical suspicion of infection, including clinical features consistent with a pulmonary infection and infiltrates seen on chest radiographs, but without a confirmatory diagnosis on the basis of the above-mentioned investigations; and (4) patients with unexplained respiratory failure associated with sudden clinical deterioration without an obvious cause and not fitting into groups 1 to 3.
Statistics
Descriptive statistics were used to describe the patients' characteristics and outcomes. Normally distributed continuous data are expressed as means ± standard deviations throughout. Medians with ranges are used when continuous data are not normally distributed. Categoric data are expressed as counts and proportions. The 
2 or Fisher exact test was used to analyze the categoric data. Kaplan-Meier (product-limit) graphs were used to demonstrate survival over time and freedom from BO. Survival and event-free survival comparisons between groups of patients were completed by using the Mantel-Haenszel log-rank test. All data analysis was performed with SPSS software (SPSS 11.0 for Windows; SPSS Inc, Chicago, Ill).
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Results
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One hundred three OLBs were performed in 89 patients (47 male patients; mean age, 12.3 ± 6.1 years) during a mean follow-up of 3.4 years. Thirteen recipients underwent OLB twice, and 1 recipient had 3 OLBs. The median period between lung transplantation and OLB was 14.9 months (range, 1 day to 8.13 years; mean, 25.8 ± 25.6 months). The indications and results of OLB are shown in Table 1. A new diagnosis was made in 48% of the cases. The new diagnoses made in the 27 (39%) patients with a clinical suspicion of BO were infective pneumonia (n = 8), pneumonitis (n = 13), BO with organizing pneumonia (n = 4), hemorrhagic infarction (n = 1), and Kaposi sarcoma (n = 1). The new diagnoses made in the 10 (67%) patients with clinical suspicion of PTLD were BO (n = 5), infective pneumonia (n = 2), pneumonitis (n = 2), and thrombotic emboli (n = 1). The 2 (25%) new diagnoses in patients with clinical suspicion of infection were BO and pneumonitis. The diagnoses found after OLB for unexplained respiratory failure were BO and infective pneumonia (n = 2), infective pneumonia only (n = 1), pneumonitis (n = 4), diffuse alveolar damage (n = 2), and BO with organizing pneumonia (n = 1).
Of the 103 OLBs performed, a change in therapy occurred in 69% of the cases (Table 2). The majority of patients with a new diagnosis after OLB had a change in therapy. Among the 40 patients with a confirmed diagnosis of BO, 28 had a change of therapy in the form of either a change in the type or dosage of immunosuppressive therapy or removal of unwarranted concomitant therapy, such as antibacterial or antiviral medications. Among the 4 patients with confirmed PTLD, all patients had a change in therapy in the form of commencement of chemotherapy or a decrease in immunosuppressive therapy. Among the 6 patients with a confirmed diagnosis of infection, 5 patients had a change in therapy in the form of either a change in the type or dose of the antibacterial or antiviral medications. Six of the patients with unexplained respiratory failure had a change in management. No change in therapy was instituted among the patients with a nondiagnostic result. Overall, a change in therapy occurred after OLB in 66%, 80%, 88%, and 60% of the cases with a preoperative suspicion of BO, PTLD, infection, and unexplained respiratory failure, respectively. For those undergoing OLB for clinical suspicion of BO, there was no survival difference between patients who had a confirmed diagnosis and those who had a new diagnosis after OLB for clinical suspicion of BO (Figure 1).
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Figure 1. Kaplan-Meier survival in patients with clinical suspicion of bronchiolitis obliterans (BO), comparing patients with open lung biopsy–confirmed BO versus those with other diagnoses.
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There was no mortality as a direct result of OLB. Eleven major and 22 minor complications occurred as a result of OLB procedures (Table 3).
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Discussion
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As the success of lung transplantation increased over the last 2 decades, an increase in the number and spectrum of pulmonary complications has also been recognized.
8
The care of lung transplant recipients presents many diagnostic and therapeutic challenges. Long-term survivors of lung transplantation continue to be plagued by a high rate of complications, especially infections and chronic rejection. The most common difficulty in the care of these patients is differentiating not only between these 2 most common disease classes, rejection or infection, but also among the different types of disease within each class: acute or chronic rejection and bacterial, viral, fungal, mycobacterial, or parasitic infection. These complications often require a quick and safe procedure to establish a diagnosis. History, physical examination, pulmonary function tests, and chest radiographs are inadequate in differentiating among the many pulmonary problems that can occur in transplant recipients. Although spirometry has a sensitivity of 75% to 86% in detecting lung rejection or infection, it cannot differentiate between these 2 broad disease categories.
9
Other groups have reported even poorer sensitivities on spirometric tests, ranging as low as 31%.
10
Chest radiographs are also nonspecific and generally unhelpful in distinguishing among various disease processes.
The preferred route for investigation of pulmonary complication in lung transplant recipients is bronchoscopy. Transbronchial biopsy (TBB), used in the surveillance of these patients or in the case of acute clinical deterioration, has been shown to be useful in the detection of occult rejection or infection, especially when combined with BAL.
11-13
However, clinical settings arise in which symptoms and noninvasive studies, pulmonary function tests, and chest radiographs suggest lung pathology but bronchoscopy with TBB and BAL fails to establish a diagnosis. In addition, rapid deterioration of a patient's condition might demand a faster mode of investigation to establish a diagnosis than could be reliably provided by minimally invasive procedures. In these cases OLB might be necessary. OLB, although clearly more invasive than most diagnostic modalities, can provide useful information in a deteriorating patient because more tissue is provided to the pathologist. Conversely, TBB specimens are small fragments of randomly sampled lung and often are not truly representative of the entire allograft. We have routinely used OLB when all other investigations have been nondiagnostic and have decided to review the OLB results in our children's hospital program over a 13-year period.
There are few data evaluating the usefulness of OLB in lung transplant recipients.
14-18
Paradis and coauthors
14
reported their experience with 10 OLBs that were performed after TBB in which the clinical situation was uncertain. The OLB revealed new information in 3 instances. Magee and associates
15
reported their experience of OLBs performed through thoracoscopy in 5 lung transplant recipients after TBB had failed to establish a diagnosis. They found that this approach was effective with little morbidity. The Loyola group reported their series of 18 OLBs in 16 transplant recipients and revealed a variety of diagnoses.
16
However, they did not report whether the biopsies resulted in treatment changes, although the information obtained would likely result in therapy interventions in the majority of the cases.
Chaparro and colleagues
18
reported the experience of the Toronto Lung Transplant Program in which 32 of 144 recipients underwent 38 OLBs over a 10-year period. Eleven OLBs were performed early (
45 days postoperative), with persistent parenchymal infiltrates as the indication. The remaining 27 OLBs were performed late (>45 days). Progressive radiologic disease with clinical findings or progressive loss of pulmonary function was the predominant indication in the late group. The group found that a new diagnosis that changed therapy was made in only 1 of 11 early OLBs but in 8 of 27 late OLBs. Eleven of the cases confirmed the suspected diagnosis, but treatment did not change as a result of the biopsy findings. An additional 2 biopsies suggested a diagnosis but likewise did not affect therapy. The nonspecific OLB findings were 42%, and these did not result in treatment changes. They concluded that OLB is of little value in the perioperative period but yields useful information in approximately 30% of patients when performed late.
Weill and coworkers
17
from the University of Alabama reported their experience of 48 OLBs performed in 42 of 202 patients who underwent lung transplantation between 1989 and 2000. A new clinically unsuspected diagnosis was made in 29% of all OLBs, and all of these resulted in therapy changes. Sixty-seven percent of all OLBs confirmed their clinical suspicions, and new therapy was initiated in 30 of these patients. Their nondiagnostic yield was 4% and did not result in any therapy change. Complications occurred in only 3 patients, all of whom had air leak for more than 7 days. The study found that the data obtained from OLBs was uniformly distributed according to time after transplantation in terms of new and confirmatory diagnosis that resulted in therapy changes, which is in contrast to the findings by Chaparro and colleagues.
18
Weill and coworkers
17
concluded that OLB was useful and should be considered when the diagnosis is uncertain in clinically deteriorating patients.
In our experience a new diagnosis was found in 48% of the cases after OLB, and the majority of these patients had a change in therapy. The results of OLB further confirmed a suspected diagnosis in 49% of the cases. This confirmatory information has been found to be useful because although it might not result in a better outcome, it confirms the use of ongoing therapy and helps to prevent the use of "shotgun," expensive, and nonindicated presumptive therapy because of uncertainty about the diagnosis. Toxic medications can be avoided that might have been used had empiric treatment been needlessly initiated. Most, if not all, of the medications used to treat acute and chronic rejections, as well as infections, are associated with significant side effects. Furthermore, the enhanced immunosuppressive regimens used to treat persistent acute rejection and chronic rejection increase the risk to the patient for opportunistic infections and PTLD, which can lead to significant morbidity and mortality. It is possible to avoid these regimens if an exact diagnosis can be made. The confirmatory information after the OLB in our patients resulted in a change of management in the majority of these patients. However, it is not possible to determine whether the same therapies would have been eventually given even without OLB. In our experience the nondiagnostic yield of OLB was low at 3%. Another limitation of this study is that it is a retrospective review and has limitations inherent to all retrospective studies. The major complication rate of 11% after OLB among our patients was comparable with the rate of 12% reported by Chaparro and colleagues.
18
No patient died as a direct result of OLB among our study population.
In summary, we have found that despite the availability of various useful investigative tools, such as radiology, pulmonary function studies, bronchoscopy, TBB, and BAL, it was not possible to diagnose pulmonary processes in 40% of our recipients. Although we will continue to use TBB and BAL as the primary means for diagnosis of pulmonary complications in lung transplant recipients, when these approaches fail, we find that diagnostic OLB plays an important role in establishing diagnosis and guiding therapy.
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References
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Abstract
Introduction
