The Role of Transbronchial Lung Biopsy in the Treatment of Lung Transplant Recipients* An Analysis of 200 Consecutive Procedures E. P. Trulock, M.D., F.C.C.P.; Neil A. Ettinger; M.D., F.C.C.P.; Elizabeth M. Brunt, M.D.; Michael K. Pasque, M.D., F.G.C.P.; lArry R. Kaiset; M.D., F.C.C.P.; and]oel D. Cooper; M.D., F.G.C.P. Study Objective: The purposes of this study were as follows:
(1) to establish the positivity rate and complication rate of
transbronchial lung biopsies in the treatment of lung transplant recipients; (2) to determine the sensitivity of transbronchial lung biopsy specimens for the diagnosis of clinically suspected acute rejection and cytomegalovirus pneumonia; and (3) to examine the results of surveillance transbronchial lung biopsies in clinically and physiologically stable recipients. Design: Retrospective review and analysis of 203 consecutive procedures. Setting: Washington University Lung Transplantation Pr0gram, Washington University School of Medicine and Barnes Hospital, St. Louis, Mo. Patients: Fifty-five lung transplant recipients. Interventions: Biopsies were done with 2-mm fenestrated forceps using fluoroscopic guidance. Two hundred three bronchoscopies with transbronchial lung biopsy were performed for clinical indications (n = 88), routine surveillance (n=90), or follow-up of a previous biopsy (n=25). Biopsy specimens showing acute allograft rejection were classified according to the scheme recommended by the Lung Rejection Study Group. Measurements and Results: The positivity rate and complication rate were determined for the procedures. In procedures performed for clinical indications, the sensitivity for the diagnosis of acute rejection and cytomegalovirus pneu-
the last decade, both heart-lung and lung D uring transplantation became clinically successful and were extended to carefully selected patients with endstage lung disease, including primary pulmonary hypertension, Eisenmenger's syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, antitrypsin deficiency emphysema, and cystic fibrosis. One-year actuarial survival rates of . . . . 60 percent for heart-lung, . . . . 60 percent for single lung, and . . . . 45 percent for double lung transplantation have been reported. I
*From the Washin~ton University Lung Transplantation Group; Thoracic Section, Cardiothoracic Surgery Division, Department of Surgery; Respiratory and Critical Care Division, Department of Medicine; Surgical Patholo~ Division, Department of Pathology; Washin~ton University School of Medicine and Barnes Hospital, St. Louis. Manuscript received September 23; revision accepted January 21. Reprint requests: !Jr. Trulock, Respiratory and Critical Care Division, Washington University School of Medicine, 660 South Euclid, St. Louis 63110
monia was calculated by a decision-to-treat analysis. A specific histologic diagnosis was detected in 69 percent of the clinical procedures, 57 percent of the surveillance procedures, and 64 percent of the follow-up procedures. For clinical indications, the sensitivity of transbronchial lung biopsy was 72 percent for the diagnosis of acute rejection and 91 percent for the diagnosis of cytomegalovirus pneumonia. Surveillance biopsy specimens often showed clinically inapparent rejection or cytomegalovirus pneumonia. The overall complication rate was 8.9 percent; none of the complications were life threatening. Conclusions: Transbronchial lung biopsy is a useful and safe procedure in the treatment of lung transplant recipients. When performed for clinical indications, the procedure proved to be sensitive for the diagnosis of acute rejection and cytomegalovirus pneumonia. When performed for surveillance in clinically and physiologically stable recipients, the incidence of rejection and cytomegalovirus pneumonia was unexpectedly high; the potential clinical implications of these findings will require further study. (Chest 1992; 102:1049-54)
= =
= =
BLT bilateral lung transplant; CMV cytomegalovirus; D + serologically positive donor; DLT double lung transplant; GMS = Gomori methenamine silver; R - = serologically negative patients; SLT = single lung transplant
The major complications in long-term survivors of heart-lung transplantation have been infection and rejection. I Although fewer longitudinal follow-up data are available for isolated lung transplant recipients, similar problems have been encountered. I The role of transbronchial lung biopsy in the treatment of heartlung transplant recipients has been established,2-7 but only one study (to our knowledge) has been devoted to isolated lung transplant recipients. H
Transbronchial lung biopsy has been used extensively in the treatment of our lung transplant recipients. Our experience with this procedure has been analyzed. The purposes of this study were to confirm its value and saftey, to determine its sensitivity for the diagnosis of clinically suspected rejection and opportunistic infection, and to examine its role in surveillance. CHEST / 102 / 4 / OCTOBER, 1992
1049
METHODS Design
This study was a retrospective review and analysis of 203 bronchoscopies with transbronchial lung biopsies performed in 55 lung transplant recipients. lbtients
Between July 1, 1988 and February 13, 1991, 69 lung transplants were performed in 66 recipients. Three patients had retrcmsplantations, two for early graft failure and one for late chronic rejection. Potential recipients were selected according to predetermined criteria. 9 Single (SLT), double (DLT), and bilateral (BLT) lung transplants were performed as previously described. U).I2 Eight patients who died during the perioperative period and three longterm survivors did not undergo transbronchial lung biopsy during the study period. The remaining 55 recipients underwent one or more bronchoscopies with transbronchiallung biopsy and were the subjects of this analysis. The diagnosis and operations of these 55 patients are summarized in Table 1. Transbronchial Lung Biopsies
Bronchoscopy was done under topical anesthesia and intravenous sedation. An endotracheal tube was inserted over the bronchoscope for the procedure. Transbronchial lung biopsies were performed under fluoroscopic guidance with 2-mm fenestrated forceps. If a focal roentgenographic abnormality was present, the majority of biopsy specimens were taken from the involved region, but a few biopsy specimens were usually taken from roentgenographically uninvolved areas. If the infiltrate was relatively diffuse or if the roentgenogram was clear, biopsy specimens were taken from all easily accessible major bronchopulmonary segments ofthe allograft. In double or bilateral transplant recipients, biopsy specimens were taken from only one of the two lungs. The biopsy specimens were fixed in formaldehyde solution, and the number of biopsy specimens was recorded by the patholowst befc:>re processing. Biopsy specimens were serially sectioned and stained with hematoxylin-eosin. Gomori methenamine silver (G MS) and acid-fast stains were routinely done to screen for fungi; Pneumocystis carinii, and mycobacteria; immunoperoxidase stain for cytomegalovirus was done when indicated. If the clinical situation or the initial histologic findings su~ested bronchiolitis, connective tissue stains were included. The histologic diagnosis of acute rejection was based on the presence of a perivascular mononuclear infiltrate. The severity of acute rejection was graded according to the scheme recommended by the Lung Rejection Study Group of The International Society for Heart Transplantation 13 : grade AO = no significant abnormality; ~ade Al = minimal; grade A2 = mild; grade A3 = moderate; and ~ade A4 = severe.
Table 1- Pro}ik ofRecipients· Diagnosis
N
SLT
BLT
DLT
Chronic obstructive pulmonary disease Antitrypsin deficiency emphysema Cystic fibrosis Pulmonary fibrosis Primary pulmonary hypertension Eisenmenger"s syndrolne (atrial septal defect) Bronchiectasis Eosinophilic granuloma Lymphangioleiomyomatosis lhtals
16 16 6 6
11 4
3 12 6 1
2
5 2
2 1 1 55
5 5
Indications for Biopsy
The indication for each proc-edure was prospectively cate~orized as clinical, surveillance, or follow-up. The procedure was classified as "clinical" if it was prompted by a chan~e in the dinical or physiologic status of the patient. "Clinical" procedures were ~en erally done because of new symptoms (dyspnea, (.'()u~), signs (fever), physical findings (adventitious lung sounds), n>entgeno~aphic infiltrates, or declinin~ spirometric parameters (particularly FEV.). "Surveillance" procedures were performed for routine monitoring in clinically and physiolowcally stable recipients. A ri~id surveillance schedule was not followed in the whole group, but the customary protocol included a surveillance proc-edure at -3 to 4 weeks, -9 to 12 weeks, -6 months, and -1 year after transplantation. If a procedure had been performed for another indication around these times, the surveillance procedure was deferred. Procedures classified as "follow-up" were performed to reassess a histologic abnormality dis(.'Overed durin~ a previous "dinical" or ..surveillance" bronchoscopy. These procedures were done to evaluate the histologic response to therapy in patients with severe infection or rejection on the previous biopsy specimen or to reexamine the histologic features in patients who did not respond appropriately to therapy. "Follow-up" procedures were not routinely performed to document resolution of infection or rejection in mild and/or uncomplicated cases. Management
The induction immunosuppressive regimen (.'Onsisted of cyclosporine, azathioprine, and antilymphocyte ~Iobulin. Antilymphocyte globulin (-15 mglkglday) was administered for five to seven days in all except seven patients who received OKT3 monoclonal antibody instead. Maintenance immunosuppressive drugs were cyclosporine, azathioprine (-2 mWkglday), and prednisone. All patients received prophylaxis for P carinii pneumonia with trimethoprim-sulfamethoxasole or nebulized pentamidine (in sulfaallergic recipients). Acyclovir 200 mg twice daily was administered to all patients as prophylaxis for herpetic infection. Prophylaxis f(>r cytomegalovirus infection was attempted only in serologically negative recipients (R - ) ofdonor organ(s) from serologically positive donors (D +). Seven R -ID + patients were treated with ganciclovir and nonspecific immune globulin for the first two to three weeks after transplantation and then given high-dose acyclovir (800 mg four times daily); three other R -ID + patients were prescribed high-dose acyclovir from the outset. The clinical criteria for the diagnosis of acute allograft rejection are summarized in Table 2. Clinically or histologically dia~nosed
Table 2-Clinical Criteriafor the Diagnosis of Rejection Criteria
2
1 1 29
• • • •
2
24
2
·SLT = single lung transplant; BLT = bilateral lung transplant; DLT=double lung transplant.
1050
Cytomegalovinls (CMV) pneumonitis was identified hist()lo~ically by characteristic intracellular inclusions on the hematoxylin-eosin stain or by a positive immunoperoxidase stain. Pneumocystis carinii pneumonia was diagnosed pathologically hy pneumocysts on silver stain. Asperigillus pneumonia was confirmed by typical branching hyphae invading tissue on hematoxylin-eosin or silver stain and by the isolation of Aspergillus species in the cultures of bronchial washings or bronchoalveolar lavage fluid.
Temperature: Rise >O.5°C above baseline Oxy~enation: Fall> 10 mm Hg below ba~eline Roentgenogram: New or chanwng infiltrates Spirometry: Fall> 10-15 percent be I0\\' baseline AND
• Infection excluded • Response to treatment with rnethylprednisolone
Role of TBLB in Lung Transplant Recipients (Trulock et 81)
Table 3-1ndicatiomfor Bronchoscopy with Transbronchial BiopBy Indication
No. of Patients
Clinical Surveillance Follow-up
42
No. of Procedures 88
43 16
90
25
acute rejection was treated with high-dose methylprednisolone for three days. If the daily prednisone dose had been tapered. it was usually increased and retapered over the ensuinR 10 to 14 days. Cytomegalovirus pneumonitis was treated with ganciclovir. P carinii pneumonia was treated with trimethoprim-sulfamethoxasole. and aspergillosis was treated with amphotericin B.
Data Analysis For procedures performed for clinical indications. the sensitivity of transbronchial lung biopsy specimens for the diagnosis of acute rejection and CMV pneumonia was calculated using a decision-totreat analysis. The following formula was used: sensitivity = ([number with an abnormal result of biopsy]J[number treated)) x 100 percent. Defined by the decision-ta-treat. the denominator included not only all patients with an abnormal result of a biopsy. but also all patients with a normal result of a biopsy who were treated for clinically suspected rejection or CMV pneumonia. RESULTS
Two hundred three procedures were performed in 55 recipients. All except six recipients underwent more than one procedure, and the average number of procedures per recipient was 3.7. The number of procedures for each indication is presented in Table 3. Eighty-eight procedures were performed in 42 recipients for a clinical indication, 90 procedures were performed in 43 recipients for surveillance, and 25 procedures were performed in 16 recipients for followup. The results of the procedures are summarized in Table 4. Specific histologic features of rejection or infection were found in the biopsy specimens in 69 percent of the clinical procedures, 57 percent of the surveillance procedures, and 64 percent of the followup procedures. The number of biopsies had not been recorded for 19 clinical, 11 surveillance, and 6 followup procedures. The average number (± SD) of biopsy specimens per procedure was 10 ± 4, 9 ± 4, and 10 ± 4 for clinical, surveillance, and follow-up purposes, Table 4- Transbronchial Lung BiopBy Re8UU. Histology Specific Rejection CMV' Other No significant abnormality Nonspecific abnormality Positivity rate. % 'CMV = cytomegalovirus.
(N=90)
Follow-up (N=25)
34 23
35 14
9 7
2
25 69
16 57
HIstology
2 4
3 64
B
Non.pecllic
•
Spoclflc
...
E
Surveillance
3 22
15
~
Clinical (N=88)
5
respectively. The majority of the clinical procedures were performed during the first three posttransplantation months while the recipients remained near the center for observation and rehabilitation. Rejection was most frequent during the first month, and CMV pneumonia predominated during the second month. Procedures for clinical indications rarely yielded biopsy specimens without an abnormality (2188; 2 percent), but nonspecific histologic abnormalities were identified in 28 percent of the cases. Nonspecific biopsy specimens, particularly an alveolar damage pattern, were common during the first month and may have represented the histologic correlate of reimplantation lung injury. Other nonspecific interpretations were organizing pneumonia, interstitial pneumonitis, and chronic inflammation. The relationship between the number of biopsy specimens per procedure and the histologic result (specific vs nonspecific) is plotted in Figure 1. The proportion of specific histologic diagnoses did not increase in the procedures with more biopsy specimens. In the clinical procedures, the sensitivity of transbronchial lung biopsy for the detection of rejection was 72 percent. Among 47 episodes of histologically confirmed or clinically suspected rejection, 34 had abnormal results of biopsies, and 13 had nonspecific abnormalities. The histologic grade of acute rejection in 31 of these 34 abnormal biopsy results is shown in Table 5; one biopsy specimen was not graded, and two biopsy specimens showed chronic rejection. The sensitivity of transbronchial lung biopsy specimens for the diagnosis of CMV pneumonia was 91 percent. Among 23 episodes with this diagnosis, 21 had typical
:::0
5
Z
o
1·3
4·6
7·9
10·12
13·15
16·18
Number of Biopsies FIGl'RE 1. The distrihution of clinical procedures with specific and nonspecific histolowc results vs the number of hiopsy specimens per pro24 h after the procedure; all of these resolved with antibacterial antibiotic treatment. Postbronchoscopy Table 6-Complications a/Procedures ( ;omplication
N
Incidence, %
Excessive hleedin~ Pneumonia Hypoxemia Ventilatory decompensation Dysrhythlnia (SVT)* Pleurisy Pneum()thorax 1()tal
8 4
3.9 2.0
*SVT = supraventricular tachycardia.
1052
3 1 1 1
o
18
1.5
0.5 0.5 0.5 0.0 8.9
hypoxemia (5a0 2
(1) to establish the positivity rate and complication rate of
transbronchial lung biopsies in the treatment of lung transplant recipients; (2) to determine the sensitivity of transbronchial lung biopsy specimens for the diagnosis of clinically suspected acute rejection and cytomegalovirus pneumonia; and (3) to examine the results of surveillance transbronchial lung biopsies in clinically and physiologically stable recipients. Design: Retrospective review and analysis of 203 consecutive procedures. Setting: Washington University Lung Transplantation Pr0gram, Washington University School of Medicine and Barnes Hospital, St. Louis, Mo. Patients: Fifty-five lung transplant recipients. Interventions: Biopsies were done with 2-mm fenestrated forceps using fluoroscopic guidance. Two hundred three bronchoscopies with transbronchial lung biopsy were performed for clinical indications (n = 88), routine surveillance (n=90), or follow-up of a previous biopsy (n=25). Biopsy specimens showing acute allograft rejection were classified according to the scheme recommended by the Lung Rejection Study Group. Measurements and Results: The positivity rate and complication rate were determined for the procedures. In procedures performed for clinical indications, the sensitivity for the diagnosis of acute rejection and cytomegalovirus pneu-
the last decade, both heart-lung and lung D uring transplantation became clinically successful and were extended to carefully selected patients with endstage lung disease, including primary pulmonary hypertension, Eisenmenger's syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, antitrypsin deficiency emphysema, and cystic fibrosis. One-year actuarial survival rates of . . . . 60 percent for heart-lung, . . . . 60 percent for single lung, and . . . . 45 percent for double lung transplantation have been reported. I
*From the Washin~ton University Lung Transplantation Group; Thoracic Section, Cardiothoracic Surgery Division, Department of Surgery; Respiratory and Critical Care Division, Department of Medicine; Surgical Patholo~ Division, Department of Pathology; Washin~ton University School of Medicine and Barnes Hospital, St. Louis. Manuscript received September 23; revision accepted January 21. Reprint requests: !Jr. Trulock, Respiratory and Critical Care Division, Washington University School of Medicine, 660 South Euclid, St. Louis 63110
monia was calculated by a decision-to-treat analysis. A specific histologic diagnosis was detected in 69 percent of the clinical procedures, 57 percent of the surveillance procedures, and 64 percent of the follow-up procedures. For clinical indications, the sensitivity of transbronchial lung biopsy was 72 percent for the diagnosis of acute rejection and 91 percent for the diagnosis of cytomegalovirus pneumonia. Surveillance biopsy specimens often showed clinically inapparent rejection or cytomegalovirus pneumonia. The overall complication rate was 8.9 percent; none of the complications were life threatening. Conclusions: Transbronchial lung biopsy is a useful and safe procedure in the treatment of lung transplant recipients. When performed for clinical indications, the procedure proved to be sensitive for the diagnosis of acute rejection and cytomegalovirus pneumonia. When performed for surveillance in clinically and physiologically stable recipients, the incidence of rejection and cytomegalovirus pneumonia was unexpectedly high; the potential clinical implications of these findings will require further study. (Chest 1992; 102:1049-54)
= =
= =
BLT bilateral lung transplant; CMV cytomegalovirus; D + serologically positive donor; DLT double lung transplant; GMS = Gomori methenamine silver; R - = serologically negative patients; SLT = single lung transplant
The major complications in long-term survivors of heart-lung transplantation have been infection and rejection. I Although fewer longitudinal follow-up data are available for isolated lung transplant recipients, similar problems have been encountered. I The role of transbronchial lung biopsy in the treatment of heartlung transplant recipients has been established,2-7 but only one study (to our knowledge) has been devoted to isolated lung transplant recipients. H
Transbronchial lung biopsy has been used extensively in the treatment of our lung transplant recipients. Our experience with this procedure has been analyzed. The purposes of this study were to confirm its value and saftey, to determine its sensitivity for the diagnosis of clinically suspected rejection and opportunistic infection, and to examine its role in surveillance. CHEST / 102 / 4 / OCTOBER, 1992
1049
METHODS Design
This study was a retrospective review and analysis of 203 bronchoscopies with transbronchial lung biopsies performed in 55 lung transplant recipients. lbtients
Between July 1, 1988 and February 13, 1991, 69 lung transplants were performed in 66 recipients. Three patients had retrcmsplantations, two for early graft failure and one for late chronic rejection. Potential recipients were selected according to predetermined criteria. 9 Single (SLT), double (DLT), and bilateral (BLT) lung transplants were performed as previously described. U).I2 Eight patients who died during the perioperative period and three longterm survivors did not undergo transbronchial lung biopsy during the study period. The remaining 55 recipients underwent one or more bronchoscopies with transbronchiallung biopsy and were the subjects of this analysis. The diagnosis and operations of these 55 patients are summarized in Table 1. Transbronchial Lung Biopsies
Bronchoscopy was done under topical anesthesia and intravenous sedation. An endotracheal tube was inserted over the bronchoscope for the procedure. Transbronchial lung biopsies were performed under fluoroscopic guidance with 2-mm fenestrated forceps. If a focal roentgenographic abnormality was present, the majority of biopsy specimens were taken from the involved region, but a few biopsy specimens were usually taken from roentgenographically uninvolved areas. If the infiltrate was relatively diffuse or if the roentgenogram was clear, biopsy specimens were taken from all easily accessible major bronchopulmonary segments ofthe allograft. In double or bilateral transplant recipients, biopsy specimens were taken from only one of the two lungs. The biopsy specimens were fixed in formaldehyde solution, and the number of biopsy specimens was recorded by the patholowst befc:>re processing. Biopsy specimens were serially sectioned and stained with hematoxylin-eosin. Gomori methenamine silver (G MS) and acid-fast stains were routinely done to screen for fungi; Pneumocystis carinii, and mycobacteria; immunoperoxidase stain for cytomegalovirus was done when indicated. If the clinical situation or the initial histologic findings su~ested bronchiolitis, connective tissue stains were included. The histologic diagnosis of acute rejection was based on the presence of a perivascular mononuclear infiltrate. The severity of acute rejection was graded according to the scheme recommended by the Lung Rejection Study Group of The International Society for Heart Transplantation 13 : grade AO = no significant abnormality; ~ade Al = minimal; grade A2 = mild; grade A3 = moderate; and ~ade A4 = severe.
Table 1- Pro}ik ofRecipients· Diagnosis
N
SLT
BLT
DLT
Chronic obstructive pulmonary disease Antitrypsin deficiency emphysema Cystic fibrosis Pulmonary fibrosis Primary pulmonary hypertension Eisenmenger"s syndrolne (atrial septal defect) Bronchiectasis Eosinophilic granuloma Lymphangioleiomyomatosis lhtals
16 16 6 6
11 4
3 12 6 1
2
5 2
2 1 1 55
5 5
Indications for Biopsy
The indication for each proc-edure was prospectively cate~orized as clinical, surveillance, or follow-up. The procedure was classified as "clinical" if it was prompted by a chan~e in the dinical or physiologic status of the patient. "Clinical" procedures were ~en erally done because of new symptoms (dyspnea, (.'()u~), signs (fever), physical findings (adventitious lung sounds), n>entgeno~aphic infiltrates, or declinin~ spirometric parameters (particularly FEV.). "Surveillance" procedures were performed for routine monitoring in clinically and physiolowcally stable recipients. A ri~id surveillance schedule was not followed in the whole group, but the customary protocol included a surveillance proc-edure at -3 to 4 weeks, -9 to 12 weeks, -6 months, and -1 year after transplantation. If a procedure had been performed for another indication around these times, the surveillance procedure was deferred. Procedures classified as "follow-up" were performed to reassess a histologic abnormality dis(.'Overed durin~ a previous "dinical" or ..surveillance" bronchoscopy. These procedures were done to evaluate the histologic response to therapy in patients with severe infection or rejection on the previous biopsy specimen or to reexamine the histologic features in patients who did not respond appropriately to therapy. "Follow-up" procedures were not routinely performed to document resolution of infection or rejection in mild and/or uncomplicated cases. Management
The induction immunosuppressive regimen (.'Onsisted of cyclosporine, azathioprine, and antilymphocyte ~Iobulin. Antilymphocyte globulin (-15 mglkglday) was administered for five to seven days in all except seven patients who received OKT3 monoclonal antibody instead. Maintenance immunosuppressive drugs were cyclosporine, azathioprine (-2 mWkglday), and prednisone. All patients received prophylaxis for P carinii pneumonia with trimethoprim-sulfamethoxasole or nebulized pentamidine (in sulfaallergic recipients). Acyclovir 200 mg twice daily was administered to all patients as prophylaxis for herpetic infection. Prophylaxis f(>r cytomegalovirus infection was attempted only in serologically negative recipients (R - ) ofdonor organ(s) from serologically positive donors (D +). Seven R -ID + patients were treated with ganciclovir and nonspecific immune globulin for the first two to three weeks after transplantation and then given high-dose acyclovir (800 mg four times daily); three other R -ID + patients were prescribed high-dose acyclovir from the outset. The clinical criteria for the diagnosis of acute allograft rejection are summarized in Table 2. Clinically or histologically dia~nosed
Table 2-Clinical Criteriafor the Diagnosis of Rejection Criteria
2
1 1 29
• • • •
2
24
2
·SLT = single lung transplant; BLT = bilateral lung transplant; DLT=double lung transplant.
1050
Cytomegalovinls (CMV) pneumonitis was identified hist()lo~ically by characteristic intracellular inclusions on the hematoxylin-eosin stain or by a positive immunoperoxidase stain. Pneumocystis carinii pneumonia was diagnosed pathologically hy pneumocysts on silver stain. Asperigillus pneumonia was confirmed by typical branching hyphae invading tissue on hematoxylin-eosin or silver stain and by the isolation of Aspergillus species in the cultures of bronchial washings or bronchoalveolar lavage fluid.
Temperature: Rise >O.5°C above baseline Oxy~enation: Fall> 10 mm Hg below ba~eline Roentgenogram: New or chanwng infiltrates Spirometry: Fall> 10-15 percent be I0\\' baseline AND
• Infection excluded • Response to treatment with rnethylprednisolone
Role of TBLB in Lung Transplant Recipients (Trulock et 81)
Table 3-1ndicatiomfor Bronchoscopy with Transbronchial BiopBy Indication
No. of Patients
Clinical Surveillance Follow-up
42
No. of Procedures 88
43 16
90
25
acute rejection was treated with high-dose methylprednisolone for three days. If the daily prednisone dose had been tapered. it was usually increased and retapered over the ensuinR 10 to 14 days. Cytomegalovirus pneumonitis was treated with ganciclovir. P carinii pneumonia was treated with trimethoprim-sulfamethoxasole. and aspergillosis was treated with amphotericin B.
Data Analysis For procedures performed for clinical indications. the sensitivity of transbronchial lung biopsy specimens for the diagnosis of acute rejection and CMV pneumonia was calculated using a decision-totreat analysis. The following formula was used: sensitivity = ([number with an abnormal result of biopsy]J[number treated)) x 100 percent. Defined by the decision-ta-treat. the denominator included not only all patients with an abnormal result of a biopsy. but also all patients with a normal result of a biopsy who were treated for clinically suspected rejection or CMV pneumonia. RESULTS
Two hundred three procedures were performed in 55 recipients. All except six recipients underwent more than one procedure, and the average number of procedures per recipient was 3.7. The number of procedures for each indication is presented in Table 3. Eighty-eight procedures were performed in 42 recipients for a clinical indication, 90 procedures were performed in 43 recipients for surveillance, and 25 procedures were performed in 16 recipients for followup. The results of the procedures are summarized in Table 4. Specific histologic features of rejection or infection were found in the biopsy specimens in 69 percent of the clinical procedures, 57 percent of the surveillance procedures, and 64 percent of the followup procedures. The number of biopsies had not been recorded for 19 clinical, 11 surveillance, and 6 followup procedures. The average number (± SD) of biopsy specimens per procedure was 10 ± 4, 9 ± 4, and 10 ± 4 for clinical, surveillance, and follow-up purposes, Table 4- Transbronchial Lung BiopBy Re8UU. Histology Specific Rejection CMV' Other No significant abnormality Nonspecific abnormality Positivity rate. % 'CMV = cytomegalovirus.
(N=90)
Follow-up (N=25)
34 23
35 14
9 7
2
25 69
16 57
HIstology
2 4
3 64
B
Non.pecllic
•
Spoclflc
...
E
Surveillance
3 22
15
~
Clinical (N=88)
5
respectively. The majority of the clinical procedures were performed during the first three posttransplantation months while the recipients remained near the center for observation and rehabilitation. Rejection was most frequent during the first month, and CMV pneumonia predominated during the second month. Procedures for clinical indications rarely yielded biopsy specimens without an abnormality (2188; 2 percent), but nonspecific histologic abnormalities were identified in 28 percent of the cases. Nonspecific biopsy specimens, particularly an alveolar damage pattern, were common during the first month and may have represented the histologic correlate of reimplantation lung injury. Other nonspecific interpretations were organizing pneumonia, interstitial pneumonitis, and chronic inflammation. The relationship between the number of biopsy specimens per procedure and the histologic result (specific vs nonspecific) is plotted in Figure 1. The proportion of specific histologic diagnoses did not increase in the procedures with more biopsy specimens. In the clinical procedures, the sensitivity of transbronchial lung biopsy for the detection of rejection was 72 percent. Among 47 episodes of histologically confirmed or clinically suspected rejection, 34 had abnormal results of biopsies, and 13 had nonspecific abnormalities. The histologic grade of acute rejection in 31 of these 34 abnormal biopsy results is shown in Table 5; one biopsy specimen was not graded, and two biopsy specimens showed chronic rejection. The sensitivity of transbronchial lung biopsy specimens for the diagnosis of CMV pneumonia was 91 percent. Among 23 episodes with this diagnosis, 21 had typical
:::0
5
Z
o
1·3
4·6
7·9
10·12
13·15
16·18
Number of Biopsies FIGl'RE 1. The distrihution of clinical procedures with specific and nonspecific histolowc results vs the number of hiopsy specimens per pro24 h after the procedure; all of these resolved with antibacterial antibiotic treatment. Postbronchoscopy Table 6-Complications a/Procedures ( ;omplication
N
Incidence, %
Excessive hleedin~ Pneumonia Hypoxemia Ventilatory decompensation Dysrhythlnia (SVT)* Pleurisy Pneum()thorax 1()tal
8 4
3.9 2.0
*SVT = supraventricular tachycardia.
1052
3 1 1 1
o
18
1.5
0.5 0.5 0.5 0.0 8.9
hypoxemia (5a0 2
