- Email: [email protected]
Success of lung transplantation without surveillance bronchoscopy
CLINICAL LUNG AND HEART/LUNG TRANSPLANTATION
Success of Lung Transplantation Without Surveillance Bronchoscopy Vincent G. Valentine, MD, FCCP,a David E. Taylor, MD,a Gundeep S. Dhillon, MD,a Mark T. Knower, MD,b P. Michael McFadden, MD,a Denise M. Fuchs, RN,a and Stephen P. Kantrow, MDa Background: No current evidence demonstrates improved survival or decreased rate of bronchiolitis obliterans syndrome (BOS) despite regularly scheduled fiberoptic bronchoscopy (FOB) with transbronchial biopsy and bronchoalveolar lavage (TBB/BAL) after lung transplantation. Reduced lung function detected with spirometry or oximetry in symptomatic and asymptomatic lung allograft recipients (LARs) may be a more appropriate indication for bronchoscopic sampling. Hypothesis: Clinically indicated TBB/BAL without routine invasive surveillance sampling of the transplanted lung does not decrease survival or increase the rate of BOS in LARs. Methods: We reviewed 91 consecutive LARs transplanted at Ochsner Clinic between January 1995 and December 1999. Clinical indications for FOB with TBB/BAL include 10% decline in forced expiratory volume in 1 second below baseline; 20% decrease in forced expiratory flow rate between 25% and 75% of the forced vital capacity; or unexplained respiratory symptoms, signs, or fever. Along with demographic and clinical data, 1-year and 3-year survival rates for these 91 LARs were compared with 5,430 LARs from the International Society for Heart and Lung Transplantation (ISHLT) Registry transplanted during the same 60-month period. Ten of the 91 patients did not survive to hospital discharge after transplantation. We divided the remaining 81 LARs into 2 subsets: Group A patients (n ⫽ 43) underwent zero to 1 TBB/BAL and Group B patients (n ⫽ 38) required more than 1 procedure. Demographic data, rejection, infection, and incidence of BOS were compared between groups. Results: The 1-year and 3-year survival rates in the Ochsner LAR cohort were 85% and 73%, respectively, vs 72% and 57% in the ISHLT cohort p ⬍ 0.01. The relative risks of death in the Ochsner group at 1- and 3-years were 0.56 (0.35– 0.91) and 0.66 (0.48 – 0.92), respectively, p ⬍ 0.05. The median (range) follow-up was 910 days (60 – 1,886) for Group A and 961 days (105–1,883) for Group B, p ⫽ not significant. We observed twice as many patients with cystic fibrosis and twice as many pneumonia episodes in Group B. The rate of acute rejection in each group was not statistically From the aDepartment of Multi-Organ Transplant, Ochsner Medical Institutions, and Department of Pulmonary and Critical Care, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and bDivision of Pulmonary and Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Submitted May 17, 2001, revised June 20, 2001; accepted October 1, 2001.
Reprint requests: Vincent G. Valentine, MD, Lung Transplantation, 1514 Jefferson Highway, New Orleans, LA 70121. Telephone: 504-842-4922. Fax: 504-842-6228. Email: vvalentine@ ochsner.org Copyright © 2002 by the International Society for Heart and Lung Transplantation. 1053-2498/02/$–see front matter PII S1053-2498(01)00389-8
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different. The cumulative incidence of BOS was increased in Group B at 1 year and at 3 years (5% and 56%) when compared with Group A (3% and 13%), p ⬍ 0.01. Conclusion: Based on the findings from this observational, single-institution study, clinically indicated TBB/BAL without routine surveillance sampling of the lung allograft is unlikely to pose greater risk than does regularly scheduled bronchoscopy after lung transplantation. J Heart Lung Transplant 2002;21:319 –326.
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he utility of fiberoptic bronchoscopy (FOB) with transbronchial biopsy and bronchoalveolar lavage (TBB/BAL) in symptomatic lung allograft recipients (LARs) is undisputed. No unique symptoms, signs, or changes in lung function reliably distinguish early acute lung rejection (REJ) from infection or anastomotic complications. Therefore, FOB with airway examination and TBB/BAL is indicated and useful in determining the cause of pulmonary dysfunction in patients who have undergone lung transplantation. However, the role of regularly scheduled FOB with TBB/BAL in totally asymptomatic LARs remains unsettled. Opinions vary greatly among lung transplant programs on the technique, timing, and impact on outcome of surveillance bronchoscopic procedures in LARs. Because frequency and intensity of REJ episodes seem to be associated with development of bronchiolitis obliterans syndrome (BOS), many centers perform routinely scheduled TBB/BAL to detect clinically covert REJ. This strategy would allow intervention before the onset of signs, symptoms, or alterations in lung function related to REJ, and timely treatment may reduce the development of BOS. Similarly, one could argue that clinical examination, chest radiography, spirometry, and measures of gas exchange are non-specific and unreliable in identifying REJ, especially during the first few weeks after lung transplantation (LT). Therefore, surveillance TBB/BAL procedures seem warranted. However, regularly scheduled procedures add cost, risk, and when positive usually identify only lower grades of rejection, because Grade 3 or 4 REJ episodes are rarely asymptomatic. To complicate matters, the appropriate treatment of asymptomatic Grade 1 or 2 REJ is unresolved. Aggressive intervention, such as with a steroid pulse, poses the added risk of increased immunosuppression and greater likelihood of infection or other complications. Furthermore, any decision to intensify treatment typically necessitates follow-up TBB/ BAL to assess the therapeutic response, and consequently, asymptomatic LARs are likely to undergo 2 or more procedures.1
To date, no prospective studies demonstrate improvement in LAR survival or incidence of BOS with surveillance procedures. In fact, 2 centers that treat patients without routine FOB and TBB/BAL have observed no increased incidence of BOS2 or mortality2,3 with this strategy. Nonetheless, about 66% of centers that provide data to the International Society for Heart and Lung Transplantation (ISHLT) Registry perform surveillance TBB/BAL, as illustrated in a recent survey by Kukafka et al.4 The Ochsner Lung Transplant Program does not perform regularly scheduled procedures in asymptomatic LARs. Instead, our program uses a protocol for FOB and TBB/BAL sampling in response to clinical findings. We have retrospectively reviewed the Ochsner experience in comparison with pooled data from the ISHLT Registry to evaluate whether clinically indicated TBB/BAL without routine surveillance sampling of lung allografts has a negative impact on survival in LARs and on the rate of BOS.
METHODS Group Comparisons Between January 1995 and December 1999, a total of 91 consecutive patients underwent single (n ⫽ 36) or bilateral sequential (n ⫽ 55) LT at Ochsner Clinic. Pre-operative and post-operative variables were abstracted for analysis. The Oschner Clinic (OC) cohort was then compared with 5,430 patients transplanted contemporaneously as identified from the ISHLT Registry data, obtained with permission. Basic demographic data, underlying diseases, and survival curves were compared between the 2 groups. In addition, the OC cohort was retrospectively divided into 2 groups based on the number of fiberoptic procedures undertaken. Patients who underwent zero or 1 FOB with TBB/BAL were designated as Group A, whereas LARs requiring ⬎1 procedure comprised Group B. Cumulative incidences for development of BOS in the 2 groups were compared. Variables analyzed to detect differences between Groups A and B included the following: pre-operative diagnosis, donor/recipient demographics and thoracic dimensions, cytomegalovirus
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(CMV) mismatch, HLA mismatch, type of transplant, ischemic time, need for nitric oxide or cardiopulmonary bypass, time on ventilatory support, intensive care unit length of stay, hospital length of stay, bacterial or fungal pneumonia, treated episodes of acute rejection, CMV infection/pneumonia, and absence of infection.
Transplant Management of OC Candidates were listed after they fulfilled selection criteria as outlined in recently published international guidelines.5 Suitable donors were identified according to basic donor selection criteria published elsewhere.6 Sequential, rapid infusion of cold modified Euro-Collins crystalloid perfusate followed by an equal volume of the more viscid University of Wisconsin preservation solution was used for donor lung preservation.7,8 Induction immunosuppression with anti–T-lymphocyte globulin was given for 3 to 5 doses, limited by a white blood cell count below 4,000 or a platelet count below 50,000. Intravenous methylprednisolone was administered pre-operatively at a 5 mg/kg dose, followed by an intraoperative dose of 15 mg/kg, and 3 doses of 125 mg in the first post-operative day. Cyclosporine, azathioprine, and prednisone were used for maintenance immunosuppression. Within the first 6 months after transplantation, cyclosporine dosages were adjusted to maintain 12-hour trough serum levels between 250 and 300 ng/ml as measured by cyclosporine monoclonal whole blood immunofluorescence assay (Abbott Laboratories; North Chicago, IL). Sixmonth to 1-year target trough levels were between 200 and 250 ng/ml. Azathioprine was started at 2 mg/kg/day, and the dosage was reduced if the white blood cell count fell below 4,000. Prednisone was started at 0.6 mg/kg/day within the first post-operative week and reduced to 0.2 mg/kg/day by the 10th week. If lung function and clinical status remained stable at the end of the first post-operative year, attempts were made to gradually reduce and possibly discontinue prednisone. To date only 5 patients are durably free from prednisone therapy. Clarithromycin was given at 250 mg twice daily, to lessen the dosage and cost of cyclosporine, beginning around the fifth post-operative day.9 Episodes of REJ were treated with 15 mg/kg/day of intravenous methylprednisolone for 3 consecutive days followed by augmentation of prednisone and optimization of cyclosporine and azathioprine as detailed elsewhere.1,10 The need for antibiotic prophylaxis was determined by the recipient’s underlying disease and a
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gram stain of airway secretions from the donor. Cefazolin alone was given pre-operatively and intraoperatively to recipients without suppurative lung disease. Vancomycin was given to patients with a history of immediate allergic reactions to betalactams. Two anti-pseudomonal agents, including an aminoglycoside (usually tobramycin), were used peri-operatively in all recipients with suppurative lung disease, with the choice of agents based on the recipient’s most recent pre-transplant sputum culture. Antibiotic selections were modified based on culture results of donor airway secretions. Prophylaxis against opportunistic pathogens included the following regimen: trimethoprim/sulfamethoxazole (dapsone if sulfa allergic) for Pneumocysitis carinii; nystatin or clotrimazole for mucosal candidiasis; ganciclovir for either donor or recipient seropositivity for CMV; and acyclovir for those with donor and recipient CMV seronegativity. Lung allograft recipients with any CMV exposure (either donor or recipient CMV-positive status), received 10 mg/kg/ day intravenous ganciclovir, started on the fifth post-operative day. From the 21st post-operative day until the 50th day, a reduced dosage of 6 mg/kg was administered intravenously Monday through Friday. Ganciclovir was then reduced to three times weekly given intravenously until the 100th postoperative day, when oral ganciclovir was started at 1,000 mg/day, in divided doses and continued indefinitely. Concentrated immunoglobulin to CMV was given to all LARs on the 3rd, 14th, 28th, and 56th post-operative days. An LT critical pathway was followed beginning immediately before transplant until post-operative Day 10 as described elsewhere.8 Significant deviation from these guidelines was subject to audit. Outpatient follow-up was also standardized, with history and physical examination, hematologic profile, basic metabolic panel, and 12-hour trough cyclosporine level obtained at each clinic visit. Simple spirometry and rest/exercise pulse oximetry also were performed, according to American Thoracic Society guidelines, at each outpatient visit for surveillance of allograft function.11 Chest radiography was not routinely performed unless indicated by clinical circumstances, such as pulmonary signs/ symptoms or altered respiratory mechanics/gas exchange. As outlined in the Ochsner LT pathway, clinical criteria for FOB with TBB/BAL included (1) an asymptomatic 10% decline in the forced expiratory volume in 1 second (FEV1) compared with baseline; (2) an asymptomatic change in configuration of the
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TABLE I
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Characteristics of 91 study patients FVC
FEV1 Percent Predicted
Pre-operative Obstructive lung disease (n ⫽ 32) Suppurative lung disease (n ⫽ 31) Restrictive lung disease (n ⫽ 26) Body mass index (kg/m2) Creatinine clearance (ml/min) Total bilirubin (mg/dl) Post-operative Left lung ischemic time (minutes) Right lung ischemic time (minutes) Ventilator time (hours)* ICU LOS (days)* Hospital LOS (days)*
49.5 ⫾ 17.2 39.1 ⫾ 10.3 42.3 ⫾ 14.7
24.7 ⫾ 8.5 22.3 ⫾ 7.9 45.4 ⫾ 18.4
21.8 ⫾ 4.0 108.5 ⫾ 35.6 0.52 ⫾ 0.22 258.2 ⫾ 79.0 223.1 ⫾ 68.9 24 (0–1584) 4 (0–61) 14 (0–102)
*median (range). FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICU, intensive care unit; LOS, length of stay.
flow-volume loop with 20% reduction in the slope of the line between the forced expiratory flow rate at 25% and 75% (FEF25–75) of the forced vital capacity compared with baseline; or (3) unexplained dyspnea, non-productive cough, new auscultatory findings on lung examination, or fever. A BAL sample was obtained from the right middle lobe and lingula in bilateral LARs or the middle lobe/lingula of the allograft in single lung recipients.11 Eight to 12 TBB specimens were obtained from the lower, right middle, or lingular lobes, and specimens were processed as described elsewhere.10 Histopathologic interpretation of TBB specimens was based on the working formulation from the Lung Rejection Study Group.13 In accordance with recommendations of the International Study Group,14 BOS was defined as an irreversible decline in FEV1 of at least 20% from baseline. In the absence of rejection shown by TBB/BAL specimens, essentially all LARs with clinical indication for the procedure received antibiotics. Antibiotic therapy was modified according to results of cultures obtained from sampling the allograft.8,10
Statistical Analysis All data were expressed as mean ⫾ SD, median (range) or as percentages. Comparisons between groups were made by Mann-Whitney for continuous data or chi-square test for categorical data. Relative risks of death at 1, 2, and 3 years in the study cohort were calculated. Survival analysis and cumulative incidence of BOS were performed using KaplanMeier method. Survival and cumulative incidence of
BOS in Groups A and B were compared using log-rank test. All tests were 2-sided, and p ⬍ 0.05 was considered significant.
RESULTS Table I shows pre-operative and post-operative characteristics of the Ochsner group. Table II illustrates demographic characteristics and pre-transplantation diagnoses of OC and ISHLT groups. In addition to a larger proportion of females and African Americans, cystic fibrosis and idiopathic pulmonary fibrosis comprised a greater percentage of LARs in the OC cohort when compared with the
TABLE II
Demographics of the 2 cohorts ISHLT cohort n ⴝ 5,430
Study cohort n ⴝ 91
Age (years) 46.0 ⫾ 14.5 43.4 ⫾ 14.8 African Americans* 3.7% 12.1% Females* 47.5% 52.7% Bilateral lung transplantation* 46.9% 60.4% Pre-transplantation diagnosis† Emphysema 34.0% 34.1% Cystic fibrosis* 16.2% 31.9% Idiopathic pulmonary 15.2% 24.2% fibrosis* Other* 23.3% 9.8% *p ⬍ 0.05, †616 pre-transplantation diagnoses in ISHLT cohort are missing. ISHLT, International Society for Heart and Lung Transplantation.
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Survival comparison between the study group (patients managed without surveillance transbronchial biopsy and bronchoalveolar lavage) and the International Society for Heart and Lung Transplantation Registry.
FIGURE 1
ISHLT cohort. In contrast, pulmonary hypertension was observed in a larger percentage of ISHLT LARs. Also of note, the OC cohort had a higher rate of bilateral LT than did the ISHLT cohort (60% vs 47%). Eighty-one of 91 consecutive LARs survived to hospital discharge. Acute graft failure was the most common cause of early death, occurring in 5 patients. Four additional patients died within the first post-operative year despite hospital discharge after transplantation. Three of these deaths were caused by infection. Late mortality beyond the first postoperative year was primarily caused by BOS, with 14 of 19 late deaths secondary to BOS. Figure 1 demonstrates overall patient survival in the OC cohort as compared with the ISHLT cohort. Survival rates at 1, 2, and 3 years in the OC cohort were 85%, 76%, and 72%, respectively, vs 73%, 65%, and 57% in the ISHLT cohort p ⬍ 0.01. The relative risk (95% confidence interval) of death in the OC cohort at 1, 2, and 3 years was 0.56 (0.35– 0.91), 0.69 (0.48 – 0.99), and 0.66 (0.48 – 0.92) p ⬍ 0.05. When analyzed as a function of frequency of bronchoscopy, we retrospectively identified 43 patients who underwent ⱕ1 TBB/BAL (Group A). Nineteen LARs (23% of the OC cohort) never required TBB/BAL, and the other 24 required only 1 procedure. Three LARs requiring only 1 TBB/ BAL were diagnosed with REJ: 2 were Grade 2 and 1 was Grade 3. These patients received methylprednisolone pulse, 15 mg/kg/day for 3 days, with im-
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Cumulative incidence of BOS comparison between Groups A and B, in the study cohort. BOS, bronchiolitis obliterans syndrome; TBB/ BAL, transbronchial biopsy and bronchoalveolar lavage.
FIGURE 2
proved/normalized pulmonary mechanics such that no follow-up TBB/BAL was performed. Group B consisted of the remaining 38 patients (47% of the OC cohort) who underwent 233 TBB/ BAL procedures. In this group, pneumonia and bronchitis were identified in 30 LARs, whereas 5 patients were diagnosed with REJ: 2 were Grade 2 and 3 were Grade 3. One patient was treated for REJ identified by TBB/BAL on post-operative Days 137, 229, and 264. This patient also had onset of BOS on the 228th post-operative day and subsequently died on post-operative Day 569. Fifteen LARs in Group B required balloon dilation and/or airway stent placement for stenosis or kinking of the anastomosis. Airway dehiscence was identified in 3, and all survived beyond 1 year after surgical repair with an intercostal muscle wrap. Median (range) follow-up in Groups A and B were 910 days (60 – 1,886) and 961 days (105–1,883), respectively, p ⫽ not significant. Figure 2illustrates the cumulative incidence of BOS in Groups A and B. One-year and 3-year cumulative incidence of BOS for Group A was 3% and 13%, respectively, vs 5% and 56% for Group B, p ⬍ 0.01. Overall 1-year and 3-year cumulative incidence of BOS in the 81 OC patients was 4% and 34%. Recipient and donor demographics and other variables were analyzed to determine whether differences existed between Groups A and B to account for the striking difference in the incidence of BOS. Table III shows statistically significant differences between the 2 groups. We found twice as many patients with cystic fibrosis and twice as many
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Comparing significant variables between groups in study cohort
TABLE III
Group A n ⴝ 43
Group B n ⴝ 38
Age (p ⫽ 0.09)† 51.3 (11.8–65.3) 39.2 (17.6–70.9) Females* 29 (67%) 15 (39%) Hospital LOS (days)*† 13 (7–102) 16 (9–70) Cystic fibrosis* 8 (19%) 17 (45%) Acute lung rejection 3 (7%) 5 (13%) Pneumonia* 12 (28%) 24 (63%) Patients without infec25 (58%) 8 (21%) tion* *p ⬍ 0.05, †median (range). LOS, length of stay.
pneumonia episodes in Group B. In contrast, Group A contained twice as many women and 3 times more LARs with no diagnosis of infection. Hospital length of stay was slightly longer for Group B and achieved statistical significance. Acute rejection rates were similar in both groups. However, when evaluating the relation between REJ and BOS, we found the 1and 3-year cumulative incidence of BOS for LARs with REJ (n ⫽ 8) was 12% and 60% respectively vs 3% and 26% for patients (n ⫽ 73) with no REJ history, p ⬍ 0.05.
DISCUSSION Transbronchial biopsy is considered the gold standard for determining the cause of respiratory decompensation in LARs. When clinical derangements are apparent, the ability of FOB with TBB/ BAL to diagnose infection or rejection ranges between 69% and 83%.15,16 This procedure’s sensitivity and specificity for acute rejection has been reported to be high as 94% and 100% in symptomatic LARs,1 although the diagnostic yield appears to be highly variable between institutions. At least 5 adequate TBB specimens with ⬎100 air sacs are recommended, and a pathologist familiar with lung transplant pathology should interpret serial sections to adequately assess for REJ.13 Although REJ and infection appear readily treatable, infection in the early post-operative period is the leading cause of death in LT. In contrast, REJ rarely results in early death. Several institutions have demonstrated an association between increased frequency and severity of REJ episodes and subsequent development of BOS.17–22 Bronchiolitis obliterans syndrome remains the major late complication of LT, afflicting nearly 66% of LARs by the fifth post-operative year.23 Bronchiolitis obliterans
syndrome also is the leading cause of death in the late post-operative period after LT.24 Therefore, it seems intuitive that any measure to lessen or eliminate REJ should minimize BOS and thus improve survival. This intent provides the rationale for surveillance TBB/BAL to detect REJ even in asymptomatic LARs. The major programs to initially identify a possible link between REJ and BOS recommend surveillance TBB/BAL, with the exception of the Papworth group. After originally introducing TBB/BAL in 1984 for diagnosis of rejection and infection in heart–lung transplantation, these investigators later found no difference in incidence of BOS or patient survival in a retrospective comparison of their first 51 patients who underwent regularly scheduled procedures vs their subsequent 75 patients observed without surveillance.2 This 1997 study suggests that REJ may not cause BOS and supports the notion that surveillance TBB/BAL procedures may not alter the course of BOS or survival—a conclusion consistent with our observations. Moreover, several centers report a positivity rate for REJ in up to 39% of their surveillance procedures.16,25,26 This finding probably overestimates the actual percentage of asymptomatic and functionally stable patients with occult REJ, because some “surveillance” TBB/BALs were performed in LARs with treated REJ and were probably repeated in the same patient. Likewise, only 2 of 46 patients in an era before routine use of ganciclovir prophylaxis were identified to have REJ by surveillance TBB/ BAL in 1 of the original prospective studies.15 Thus, the value of TBB/BAL in diagnosing sub-clinical REJ in LARs without clinical respiratory findings or abnormal lung function has not been established prospectively in the context of the current standards for post-transplant care. For this reason, nearly 33% of lung transplantation programs listed in the United Network for Organ Sharing directory do not perform surveillance bronchoscopy.4 We formulated critical pathways in 1995 to standardize and optimize treatment without regularly scheduled TBB/ BALs and instead to emphasize clinical parameters and simple spirometry at each clinic visit.9 In the current study, we have reviewed our experience and compared it with the ISHLT Registry over the same 5-year period. Although the ISHLT group is not a homogeneous cohort, the large numbers of participating institutions and registered LARs provide a valuable source of pooled data that encompass many variations in LT practice, including patient mix, immunosuppression, and post-trans-
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plant surveillance. Given results from earlier member surveys, we estimated that more than 50% of the programs in the ISHLT group perform regularly scheduled TBB/BAL. A priori we assumed that unless our strategy of clinically driven TBB/BAL was unsafe, survival between the ISHLT and the OC cohorts should be similar. Given the larger percentage of higher risk patients with idiopathic pulmonary fibrosis and cystic fibrosis in the OC cohort, one might have anticipated a lower survival rate in our LAR population. Likewise, the ISHLT group had a greater number of high-risk patients with primary and secondary pulmonary hypertension. The larger proportion of bilateral lung transplants in the OC cohort also might have been expected to unfavorably alter the earlier portion of the survival curve. In fact, analysis shows that the 1-, 2-, and 3-year survival rates for the OC cohort are better than for the ISHLT cohort. Although a causal relation between REJ and BOS may exist, currently available treatment strategies do not necessarily alter the natural history of BOS. Aggressive treatment of asymptomatic REJ as identified by surveillance TBB/BAL may actually be harmful. To answer this question, we sub-divided our population into asymptomatic LARs who underwent zero to 1 TBB/BAL and those patients who required more frequent procedures as clinically indicated. The most striking finding was the low BOS incidence in asymptomatic patients (13% at 3 years in Group A). Despite this low incidence, we found an association between clinically evident REJ and BOS, as seen elsewhere.17–22 Group A also had half the number of pneumonia episodes and nearly 3 times as many LARs who were infection-free. By comparison, there were twice as many men and patients with cystic fibrosis in Group B, and these LARs underwent up to 10 times more TBB/BAL procedures. Survival in Group A patients was 76% at both 3.5 and 5 years after LT, whereas survival in Group B survival was much lower at the same time points (50% and 16% respectively). Although one might propose that TBB/BAL itself is potentially harmful, it seems more likely that either changes in clinical condition to justify bronchoscopy or interventions based on results of the procedure contribute to worsened outcome for symptomatic LARs. However, clinically apparent REJ episodes were identified much less frequently (10% of patients in the OC cohort) than in other published series. This observation suggests that clinically covert REJ episodes may have been missed by our non-surveillance strategy.
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TABLE IV Indications for TBB/BAL in the Ochsner Lung Transplant Program Asymptomatic 10% decline in FEV1 from established baseline Asymptomatic 20% decline in FEF25–75 from established baseline* Unexplained dyspnea, non-productive cough, or fever New auscultatory findings on lung exam *A single, isolated reduction in the FEF25–75 was not an indication in asymptomatic single lung recipients. FEF25–75, forced expiratory flow rate at 25% and 75%; FEV1, forced expiratory volume in 1 second.
This retrospective study has the limitations of all observational studies including the inability to account for changes in practice patterns over time. However, our findings are unique in that the comparison group was a contemporaneous cohort, unlike the descriptive report by Tamm et al2 that was limited by the use of historical controls and changing clinical practices in LAR care. In addition, the current study was performed in a single center, and as such, factors unique to our institutional practice may prove beneficial to LARs not subjected to regularly scheduled TBB/BAL. Along with strict adherence to established critical pathways in LT at the Ochsner Clinic, other aspects of LAR treatment that might favorably influence outcome include induction immunosuppression with anti-thymocyte globulin; aggressive use of intravenous ganciclovir for 100 days for patients at risk followed by indefinite use of oral ganciclovir; administration of hyperimmune immunoglobulin directed against CMV; use of clarithromycin to minimize cyclosporine dose; and very slow taper of prednisone over more than a year. All of these factors may account for our extraordinarily low REJ rate. Although the large size of the ISHLT cohort is likely to incorporate many recent changes in LAR management, detailed reporting of these variations in practice is not currently available from the database to allow accurate comparison between the 2 cohorts. In the absence of a homogeneous comparison group, it is impossible to delineate the specific effects of different practices in immunosuppression or infection treatment from surveillance protocols in improving the survival of our LAR cohort. Finally, demographic differences between the ISHLT and the OC cohorts outlined in Table II make comparisons between LAR survival potentially unreliable. Differences in outcome probably reflect multiple factors including patient selection, immunosuppression, and post-LT care. Al-
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though performing surveillance TBB/BAL may have further improved outcome in the OC cohort, it seems unlikely that limiting bronchoscopy only to patients with clinical indications produced worse results. In summary, limiting TBB/BAL procedures to patients with clinical indications will likely contain costs and pose a lesser threat to LARs than regularly scheduled bronchoscopy and will not compromise survival or detection rate for BOS. Although we recognize the limitations inherent in the observational nature of this single-center study, we recommend FOB with TBB/BAL based on the clinical triggers illustrated in Table IV. Nonetheless, a prospective, multicenter, randomized trial is the only reliable way to determine definitively whether routine surveillance TBB/BAL procedures improve outcome in the care of patients after lung transplantation. REFERENCES 1. Trulock EP. Lung transplantation: state of the art. Am J Respir Crit Care Med 1997;155:789 –818. 2. Tamm M, Sharples LD, Higenbottam TW, Stewart S, Wallwork J. Bronchiolitis obliterans syndrome in heart-lung transplantation: surveillance biopsies. Am J Respir Crit Care Med 1997;155:1705–10. 3. Patel SR, Kirby TJ, McCarthy PM, et al. Lung transplantation: the Cleveland Clinic experience. Cleve Clin J Med 1993;60:303–19. 4. Kukafka DS, O’Brien GM, Furukawa S, Criner GJ. Surveillance bronchoscopy in lung transplant recipients. Chest 1997; 111:377–81. 5. Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR. International guidelines for the selection of lung transplant candidates. J Heart Lung Transplant 1998;17:703–9. 6. Frost AE. Donor criteria and evaluation. Clin Chest Med 1997;18:231–7. 7. Struber M, Ehlers KA, Nilsson FN, Miller VM, McGregor CG, Haverich A. Effects of lung preservation with EuroCollins and University of Wisconsin solutions on endothelium-dependent relaxation. Ann Thorac Surg 1997;63:1428 – 35. 8. Valentine VG, McFadden PM, Ochsner JL. Advances in lung transplantation. Ochsner J 1999;1:12–8. 9. Knower MT, Labella-Walker K, McFadden PM, Kantrow SP, Valentine VG. Clarithromycin for safe and cost-effective reduction of cyclosporine doses in lung allograft recipients. South Med J 2000;93:1087–92. 10. Valentine VG, Robbins RC, Berry GJ, et al. Actuarial survival of heart-lung and bilateral sequential lung transplant
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22. 23. 24. 25.
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recipients with obliterative bronchiolitis. J Heart Lung Transplant 1996;15:371–83. American Thoracic Society. Standardization of spirometry— 1987 update. Am Rev Resp Dis 1987;136:1285–96. 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 –61. Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant 1996;15:1–15. Cooper JD, Billingham ME, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993;12:713–6. Starnes VA, Theodore J, Oyer PE, et al. Evaluation of heart-lung transplant recipients with prospective, serial transbronchial biopsies and pulmonary function studies. J Thorac Cardiovasc Surg 1989;98:683–90. Trulock EP, Ettinger NA, Brunt EM, Pasque MK, Kaiser LR, Cooper JD. The role of transbronchial lung biopsy in the treatment of lung transplant recipients. An analysis of 200 consecutive procedures. Chest 1992;102:1049 –52. Scott JP, Higenbottam TW, Sharples L, et al. Risk factors for obliterative bronchiolitis in heart-lung transplant recipients. Transplantation 1991;51:813–7. Bando K, Paradis IL, Similo S, et al. Obliterative bronchiolitis after lung and heart-lung transplantation. An analysis of risk factors and management. J Thorac Cardiovasc Surg 1995;110:4 –13. Girgis RE, Tu I, Berry GJ, et al. Risk factors for the development of obliterative bronchiolitis after lung transplantation. J Heart Lung Transplant 1996;15:1200 –8. Heng D, Sharples LD, McNeil K, Stewart S, Wreghitt T, Wallwork J. Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors. J Heart Lung Transplant 1998;17:1255–63. Husain AN, Siddiqui MT, Holmes EW, et al. Analysis of risk factors for the development of bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 1999;159:829 –33. Boehler A, Estenne M. Obliterative bronchiolitis after lung transplantation. Curr Opin Pulm Med 2000;6:133–9. Arcasoy SM, Kotloff RM. Lung transplantation. N Engl J Med 1999;340:1081–90. Paradis I. Bronchiolitis obliterans: pathogenesis, prevention, and management. Am J Med Sci 1998;315:161–78. Becker FS, Martinez FJ, Brunsting LA, Deeb GM, Flint A, Lynch JP, III. Limitations of spirometry in detecting rejection after single-lung transplantation. Am J Respir Crit Care Med 1994;10:159 –66. 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;152:2037–43.
Success of Lung Transplantation Without Surveillance Bronchoscopy Vincent G. Valentine, MD, FCCP,a David E. Taylor, MD,a Gundeep S. Dhillon, MD,a Mark T. Knower, MD,b P. Michael McFadden, MD,a Denise M. Fuchs, RN,a and Stephen P. Kantrow, MDa Background: No current evidence demonstrates improved survival or decreased rate of bronchiolitis obliterans syndrome (BOS) despite regularly scheduled fiberoptic bronchoscopy (FOB) with transbronchial biopsy and bronchoalveolar lavage (TBB/BAL) after lung transplantation. Reduced lung function detected with spirometry or oximetry in symptomatic and asymptomatic lung allograft recipients (LARs) may be a more appropriate indication for bronchoscopic sampling. Hypothesis: Clinically indicated TBB/BAL without routine invasive surveillance sampling of the transplanted lung does not decrease survival or increase the rate of BOS in LARs. Methods: We reviewed 91 consecutive LARs transplanted at Ochsner Clinic between January 1995 and December 1999. Clinical indications for FOB with TBB/BAL include 10% decline in forced expiratory volume in 1 second below baseline; 20% decrease in forced expiratory flow rate between 25% and 75% of the forced vital capacity; or unexplained respiratory symptoms, signs, or fever. Along with demographic and clinical data, 1-year and 3-year survival rates for these 91 LARs were compared with 5,430 LARs from the International Society for Heart and Lung Transplantation (ISHLT) Registry transplanted during the same 60-month period. Ten of the 91 patients did not survive to hospital discharge after transplantation. We divided the remaining 81 LARs into 2 subsets: Group A patients (n ⫽ 43) underwent zero to 1 TBB/BAL and Group B patients (n ⫽ 38) required more than 1 procedure. Demographic data, rejection, infection, and incidence of BOS were compared between groups. Results: The 1-year and 3-year survival rates in the Ochsner LAR cohort were 85% and 73%, respectively, vs 72% and 57% in the ISHLT cohort p ⬍ 0.01. The relative risks of death in the Ochsner group at 1- and 3-years were 0.56 (0.35– 0.91) and 0.66 (0.48 – 0.92), respectively, p ⬍ 0.05. The median (range) follow-up was 910 days (60 – 1,886) for Group A and 961 days (105–1,883) for Group B, p ⫽ not significant. We observed twice as many patients with cystic fibrosis and twice as many pneumonia episodes in Group B. The rate of acute rejection in each group was not statistically From the aDepartment of Multi-Organ Transplant, Ochsner Medical Institutions, and Department of Pulmonary and Critical Care, Louisiana State University Health Sciences Center, New Orleans, Louisiana; and bDivision of Pulmonary and Critical Care Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Submitted May 17, 2001, revised June 20, 2001; accepted October 1, 2001.
Reprint requests: Vincent G. Valentine, MD, Lung Transplantation, 1514 Jefferson Highway, New Orleans, LA 70121. Telephone: 504-842-4922. Fax: 504-842-6228. Email: vvalentine@ ochsner.org Copyright © 2002 by the International Society for Heart and Lung Transplantation. 1053-2498/02/$–see front matter PII S1053-2498(01)00389-8
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different. The cumulative incidence of BOS was increased in Group B at 1 year and at 3 years (5% and 56%) when compared with Group A (3% and 13%), p ⬍ 0.01. Conclusion: Based on the findings from this observational, single-institution study, clinically indicated TBB/BAL without routine surveillance sampling of the lung allograft is unlikely to pose greater risk than does regularly scheduled bronchoscopy after lung transplantation. J Heart Lung Transplant 2002;21:319 –326.
T
he utility of fiberoptic bronchoscopy (FOB) with transbronchial biopsy and bronchoalveolar lavage (TBB/BAL) in symptomatic lung allograft recipients (LARs) is undisputed. No unique symptoms, signs, or changes in lung function reliably distinguish early acute lung rejection (REJ) from infection or anastomotic complications. Therefore, FOB with airway examination and TBB/BAL is indicated and useful in determining the cause of pulmonary dysfunction in patients who have undergone lung transplantation. However, the role of regularly scheduled FOB with TBB/BAL in totally asymptomatic LARs remains unsettled. Opinions vary greatly among lung transplant programs on the technique, timing, and impact on outcome of surveillance bronchoscopic procedures in LARs. Because frequency and intensity of REJ episodes seem to be associated with development of bronchiolitis obliterans syndrome (BOS), many centers perform routinely scheduled TBB/BAL to detect clinically covert REJ. This strategy would allow intervention before the onset of signs, symptoms, or alterations in lung function related to REJ, and timely treatment may reduce the development of BOS. Similarly, one could argue that clinical examination, chest radiography, spirometry, and measures of gas exchange are non-specific and unreliable in identifying REJ, especially during the first few weeks after lung transplantation (LT). Therefore, surveillance TBB/BAL procedures seem warranted. However, regularly scheduled procedures add cost, risk, and when positive usually identify only lower grades of rejection, because Grade 3 or 4 REJ episodes are rarely asymptomatic. To complicate matters, the appropriate treatment of asymptomatic Grade 1 or 2 REJ is unresolved. Aggressive intervention, such as with a steroid pulse, poses the added risk of increased immunosuppression and greater likelihood of infection or other complications. Furthermore, any decision to intensify treatment typically necessitates follow-up TBB/ BAL to assess the therapeutic response, and consequently, asymptomatic LARs are likely to undergo 2 or more procedures.1
To date, no prospective studies demonstrate improvement in LAR survival or incidence of BOS with surveillance procedures. In fact, 2 centers that treat patients without routine FOB and TBB/BAL have observed no increased incidence of BOS2 or mortality2,3 with this strategy. Nonetheless, about 66% of centers that provide data to the International Society for Heart and Lung Transplantation (ISHLT) Registry perform surveillance TBB/BAL, as illustrated in a recent survey by Kukafka et al.4 The Ochsner Lung Transplant Program does not perform regularly scheduled procedures in asymptomatic LARs. Instead, our program uses a protocol for FOB and TBB/BAL sampling in response to clinical findings. We have retrospectively reviewed the Ochsner experience in comparison with pooled data from the ISHLT Registry to evaluate whether clinically indicated TBB/BAL without routine surveillance sampling of lung allografts has a negative impact on survival in LARs and on the rate of BOS.
METHODS Group Comparisons Between January 1995 and December 1999, a total of 91 consecutive patients underwent single (n ⫽ 36) or bilateral sequential (n ⫽ 55) LT at Ochsner Clinic. Pre-operative and post-operative variables were abstracted for analysis. The Oschner Clinic (OC) cohort was then compared with 5,430 patients transplanted contemporaneously as identified from the ISHLT Registry data, obtained with permission. Basic demographic data, underlying diseases, and survival curves were compared between the 2 groups. In addition, the OC cohort was retrospectively divided into 2 groups based on the number of fiberoptic procedures undertaken. Patients who underwent zero or 1 FOB with TBB/BAL were designated as Group A, whereas LARs requiring ⬎1 procedure comprised Group B. Cumulative incidences for development of BOS in the 2 groups were compared. Variables analyzed to detect differences between Groups A and B included the following: pre-operative diagnosis, donor/recipient demographics and thoracic dimensions, cytomegalovirus
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(CMV) mismatch, HLA mismatch, type of transplant, ischemic time, need for nitric oxide or cardiopulmonary bypass, time on ventilatory support, intensive care unit length of stay, hospital length of stay, bacterial or fungal pneumonia, treated episodes of acute rejection, CMV infection/pneumonia, and absence of infection.
Transplant Management of OC Candidates were listed after they fulfilled selection criteria as outlined in recently published international guidelines.5 Suitable donors were identified according to basic donor selection criteria published elsewhere.6 Sequential, rapid infusion of cold modified Euro-Collins crystalloid perfusate followed by an equal volume of the more viscid University of Wisconsin preservation solution was used for donor lung preservation.7,8 Induction immunosuppression with anti–T-lymphocyte globulin was given for 3 to 5 doses, limited by a white blood cell count below 4,000 or a platelet count below 50,000. Intravenous methylprednisolone was administered pre-operatively at a 5 mg/kg dose, followed by an intraoperative dose of 15 mg/kg, and 3 doses of 125 mg in the first post-operative day. Cyclosporine, azathioprine, and prednisone were used for maintenance immunosuppression. Within the first 6 months after transplantation, cyclosporine dosages were adjusted to maintain 12-hour trough serum levels between 250 and 300 ng/ml as measured by cyclosporine monoclonal whole blood immunofluorescence assay (Abbott Laboratories; North Chicago, IL). Sixmonth to 1-year target trough levels were between 200 and 250 ng/ml. Azathioprine was started at 2 mg/kg/day, and the dosage was reduced if the white blood cell count fell below 4,000. Prednisone was started at 0.6 mg/kg/day within the first post-operative week and reduced to 0.2 mg/kg/day by the 10th week. If lung function and clinical status remained stable at the end of the first post-operative year, attempts were made to gradually reduce and possibly discontinue prednisone. To date only 5 patients are durably free from prednisone therapy. Clarithromycin was given at 250 mg twice daily, to lessen the dosage and cost of cyclosporine, beginning around the fifth post-operative day.9 Episodes of REJ were treated with 15 mg/kg/day of intravenous methylprednisolone for 3 consecutive days followed by augmentation of prednisone and optimization of cyclosporine and azathioprine as detailed elsewhere.1,10 The need for antibiotic prophylaxis was determined by the recipient’s underlying disease and a
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gram stain of airway secretions from the donor. Cefazolin alone was given pre-operatively and intraoperatively to recipients without suppurative lung disease. Vancomycin was given to patients with a history of immediate allergic reactions to betalactams. Two anti-pseudomonal agents, including an aminoglycoside (usually tobramycin), were used peri-operatively in all recipients with suppurative lung disease, with the choice of agents based on the recipient’s most recent pre-transplant sputum culture. Antibiotic selections were modified based on culture results of donor airway secretions. Prophylaxis against opportunistic pathogens included the following regimen: trimethoprim/sulfamethoxazole (dapsone if sulfa allergic) for Pneumocysitis carinii; nystatin or clotrimazole for mucosal candidiasis; ganciclovir for either donor or recipient seropositivity for CMV; and acyclovir for those with donor and recipient CMV seronegativity. Lung allograft recipients with any CMV exposure (either donor or recipient CMV-positive status), received 10 mg/kg/ day intravenous ganciclovir, started on the fifth post-operative day. From the 21st post-operative day until the 50th day, a reduced dosage of 6 mg/kg was administered intravenously Monday through Friday. Ganciclovir was then reduced to three times weekly given intravenously until the 100th postoperative day, when oral ganciclovir was started at 1,000 mg/day, in divided doses and continued indefinitely. Concentrated immunoglobulin to CMV was given to all LARs on the 3rd, 14th, 28th, and 56th post-operative days. An LT critical pathway was followed beginning immediately before transplant until post-operative Day 10 as described elsewhere.8 Significant deviation from these guidelines was subject to audit. Outpatient follow-up was also standardized, with history and physical examination, hematologic profile, basic metabolic panel, and 12-hour trough cyclosporine level obtained at each clinic visit. Simple spirometry and rest/exercise pulse oximetry also were performed, according to American Thoracic Society guidelines, at each outpatient visit for surveillance of allograft function.11 Chest radiography was not routinely performed unless indicated by clinical circumstances, such as pulmonary signs/ symptoms or altered respiratory mechanics/gas exchange. As outlined in the Ochsner LT pathway, clinical criteria for FOB with TBB/BAL included (1) an asymptomatic 10% decline in the forced expiratory volume in 1 second (FEV1) compared with baseline; (2) an asymptomatic change in configuration of the
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TABLE I
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Characteristics of 91 study patients FVC
FEV1 Percent Predicted
Pre-operative Obstructive lung disease (n ⫽ 32) Suppurative lung disease (n ⫽ 31) Restrictive lung disease (n ⫽ 26) Body mass index (kg/m2) Creatinine clearance (ml/min) Total bilirubin (mg/dl) Post-operative Left lung ischemic time (minutes) Right lung ischemic time (minutes) Ventilator time (hours)* ICU LOS (days)* Hospital LOS (days)*
49.5 ⫾ 17.2 39.1 ⫾ 10.3 42.3 ⫾ 14.7
24.7 ⫾ 8.5 22.3 ⫾ 7.9 45.4 ⫾ 18.4
21.8 ⫾ 4.0 108.5 ⫾ 35.6 0.52 ⫾ 0.22 258.2 ⫾ 79.0 223.1 ⫾ 68.9 24 (0–1584) 4 (0–61) 14 (0–102)
*median (range). FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; ICU, intensive care unit; LOS, length of stay.
flow-volume loop with 20% reduction in the slope of the line between the forced expiratory flow rate at 25% and 75% (FEF25–75) of the forced vital capacity compared with baseline; or (3) unexplained dyspnea, non-productive cough, new auscultatory findings on lung examination, or fever. A BAL sample was obtained from the right middle lobe and lingula in bilateral LARs or the middle lobe/lingula of the allograft in single lung recipients.11 Eight to 12 TBB specimens were obtained from the lower, right middle, or lingular lobes, and specimens were processed as described elsewhere.10 Histopathologic interpretation of TBB specimens was based on the working formulation from the Lung Rejection Study Group.13 In accordance with recommendations of the International Study Group,14 BOS was defined as an irreversible decline in FEV1 of at least 20% from baseline. In the absence of rejection shown by TBB/BAL specimens, essentially all LARs with clinical indication for the procedure received antibiotics. Antibiotic therapy was modified according to results of cultures obtained from sampling the allograft.8,10
Statistical Analysis All data were expressed as mean ⫾ SD, median (range) or as percentages. Comparisons between groups were made by Mann-Whitney for continuous data or chi-square test for categorical data. Relative risks of death at 1, 2, and 3 years in the study cohort were calculated. Survival analysis and cumulative incidence of BOS were performed using KaplanMeier method. Survival and cumulative incidence of
BOS in Groups A and B were compared using log-rank test. All tests were 2-sided, and p ⬍ 0.05 was considered significant.
RESULTS Table I shows pre-operative and post-operative characteristics of the Ochsner group. Table II illustrates demographic characteristics and pre-transplantation diagnoses of OC and ISHLT groups. In addition to a larger proportion of females and African Americans, cystic fibrosis and idiopathic pulmonary fibrosis comprised a greater percentage of LARs in the OC cohort when compared with the
TABLE II
Demographics of the 2 cohorts ISHLT cohort n ⴝ 5,430
Study cohort n ⴝ 91
Age (years) 46.0 ⫾ 14.5 43.4 ⫾ 14.8 African Americans* 3.7% 12.1% Females* 47.5% 52.7% Bilateral lung transplantation* 46.9% 60.4% Pre-transplantation diagnosis† Emphysema 34.0% 34.1% Cystic fibrosis* 16.2% 31.9% Idiopathic pulmonary 15.2% 24.2% fibrosis* Other* 23.3% 9.8% *p ⬍ 0.05, †616 pre-transplantation diagnoses in ISHLT cohort are missing. ISHLT, International Society for Heart and Lung Transplantation.
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Survival comparison between the study group (patients managed without surveillance transbronchial biopsy and bronchoalveolar lavage) and the International Society for Heart and Lung Transplantation Registry.
FIGURE 1
ISHLT cohort. In contrast, pulmonary hypertension was observed in a larger percentage of ISHLT LARs. Also of note, the OC cohort had a higher rate of bilateral LT than did the ISHLT cohort (60% vs 47%). Eighty-one of 91 consecutive LARs survived to hospital discharge. Acute graft failure was the most common cause of early death, occurring in 5 patients. Four additional patients died within the first post-operative year despite hospital discharge after transplantation. Three of these deaths were caused by infection. Late mortality beyond the first postoperative year was primarily caused by BOS, with 14 of 19 late deaths secondary to BOS. Figure 1 demonstrates overall patient survival in the OC cohort as compared with the ISHLT cohort. Survival rates at 1, 2, and 3 years in the OC cohort were 85%, 76%, and 72%, respectively, vs 73%, 65%, and 57% in the ISHLT cohort p ⬍ 0.01. The relative risk (95% confidence interval) of death in the OC cohort at 1, 2, and 3 years was 0.56 (0.35– 0.91), 0.69 (0.48 – 0.99), and 0.66 (0.48 – 0.92) p ⬍ 0.05. When analyzed as a function of frequency of bronchoscopy, we retrospectively identified 43 patients who underwent ⱕ1 TBB/BAL (Group A). Nineteen LARs (23% of the OC cohort) never required TBB/BAL, and the other 24 required only 1 procedure. Three LARs requiring only 1 TBB/ BAL were diagnosed with REJ: 2 were Grade 2 and 1 was Grade 3. These patients received methylprednisolone pulse, 15 mg/kg/day for 3 days, with im-
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Cumulative incidence of BOS comparison between Groups A and B, in the study cohort. BOS, bronchiolitis obliterans syndrome; TBB/ BAL, transbronchial biopsy and bronchoalveolar lavage.
FIGURE 2
proved/normalized pulmonary mechanics such that no follow-up TBB/BAL was performed. Group B consisted of the remaining 38 patients (47% of the OC cohort) who underwent 233 TBB/ BAL procedures. In this group, pneumonia and bronchitis were identified in 30 LARs, whereas 5 patients were diagnosed with REJ: 2 were Grade 2 and 3 were Grade 3. One patient was treated for REJ identified by TBB/BAL on post-operative Days 137, 229, and 264. This patient also had onset of BOS on the 228th post-operative day and subsequently died on post-operative Day 569. Fifteen LARs in Group B required balloon dilation and/or airway stent placement for stenosis or kinking of the anastomosis. Airway dehiscence was identified in 3, and all survived beyond 1 year after surgical repair with an intercostal muscle wrap. Median (range) follow-up in Groups A and B were 910 days (60 – 1,886) and 961 days (105–1,883), respectively, p ⫽ not significant. Figure 2illustrates the cumulative incidence of BOS in Groups A and B. One-year and 3-year cumulative incidence of BOS for Group A was 3% and 13%, respectively, vs 5% and 56% for Group B, p ⬍ 0.01. Overall 1-year and 3-year cumulative incidence of BOS in the 81 OC patients was 4% and 34%. Recipient and donor demographics and other variables were analyzed to determine whether differences existed between Groups A and B to account for the striking difference in the incidence of BOS. Table III shows statistically significant differences between the 2 groups. We found twice as many patients with cystic fibrosis and twice as many
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Comparing significant variables between groups in study cohort
TABLE III
Group A n ⴝ 43
Group B n ⴝ 38
Age (p ⫽ 0.09)† 51.3 (11.8–65.3) 39.2 (17.6–70.9) Females* 29 (67%) 15 (39%) Hospital LOS (days)*† 13 (7–102) 16 (9–70) Cystic fibrosis* 8 (19%) 17 (45%) Acute lung rejection 3 (7%) 5 (13%) Pneumonia* 12 (28%) 24 (63%) Patients without infec25 (58%) 8 (21%) tion* *p ⬍ 0.05, †median (range). LOS, length of stay.
pneumonia episodes in Group B. In contrast, Group A contained twice as many women and 3 times more LARs with no diagnosis of infection. Hospital length of stay was slightly longer for Group B and achieved statistical significance. Acute rejection rates were similar in both groups. However, when evaluating the relation between REJ and BOS, we found the 1and 3-year cumulative incidence of BOS for LARs with REJ (n ⫽ 8) was 12% and 60% respectively vs 3% and 26% for patients (n ⫽ 73) with no REJ history, p ⬍ 0.05.
DISCUSSION Transbronchial biopsy is considered the gold standard for determining the cause of respiratory decompensation in LARs. When clinical derangements are apparent, the ability of FOB with TBB/ BAL to diagnose infection or rejection ranges between 69% and 83%.15,16 This procedure’s sensitivity and specificity for acute rejection has been reported to be high as 94% and 100% in symptomatic LARs,1 although the diagnostic yield appears to be highly variable between institutions. At least 5 adequate TBB specimens with ⬎100 air sacs are recommended, and a pathologist familiar with lung transplant pathology should interpret serial sections to adequately assess for REJ.13 Although REJ and infection appear readily treatable, infection in the early post-operative period is the leading cause of death in LT. In contrast, REJ rarely results in early death. Several institutions have demonstrated an association between increased frequency and severity of REJ episodes and subsequent development of BOS.17–22 Bronchiolitis obliterans syndrome remains the major late complication of LT, afflicting nearly 66% of LARs by the fifth post-operative year.23 Bronchiolitis obliterans
syndrome also is the leading cause of death in the late post-operative period after LT.24 Therefore, it seems intuitive that any measure to lessen or eliminate REJ should minimize BOS and thus improve survival. This intent provides the rationale for surveillance TBB/BAL to detect REJ even in asymptomatic LARs. The major programs to initially identify a possible link between REJ and BOS recommend surveillance TBB/BAL, with the exception of the Papworth group. After originally introducing TBB/BAL in 1984 for diagnosis of rejection and infection in heart–lung transplantation, these investigators later found no difference in incidence of BOS or patient survival in a retrospective comparison of their first 51 patients who underwent regularly scheduled procedures vs their subsequent 75 patients observed without surveillance.2 This 1997 study suggests that REJ may not cause BOS and supports the notion that surveillance TBB/BAL procedures may not alter the course of BOS or survival—a conclusion consistent with our observations. Moreover, several centers report a positivity rate for REJ in up to 39% of their surveillance procedures.16,25,26 This finding probably overestimates the actual percentage of asymptomatic and functionally stable patients with occult REJ, because some “surveillance” TBB/BALs were performed in LARs with treated REJ and were probably repeated in the same patient. Likewise, only 2 of 46 patients in an era before routine use of ganciclovir prophylaxis were identified to have REJ by surveillance TBB/ BAL in 1 of the original prospective studies.15 Thus, the value of TBB/BAL in diagnosing sub-clinical REJ in LARs without clinical respiratory findings or abnormal lung function has not been established prospectively in the context of the current standards for post-transplant care. For this reason, nearly 33% of lung transplantation programs listed in the United Network for Organ Sharing directory do not perform surveillance bronchoscopy.4 We formulated critical pathways in 1995 to standardize and optimize treatment without regularly scheduled TBB/ BALs and instead to emphasize clinical parameters and simple spirometry at each clinic visit.9 In the current study, we have reviewed our experience and compared it with the ISHLT Registry over the same 5-year period. Although the ISHLT group is not a homogeneous cohort, the large numbers of participating institutions and registered LARs provide a valuable source of pooled data that encompass many variations in LT practice, including patient mix, immunosuppression, and post-trans-
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plant surveillance. Given results from earlier member surveys, we estimated that more than 50% of the programs in the ISHLT group perform regularly scheduled TBB/BAL. A priori we assumed that unless our strategy of clinically driven TBB/BAL was unsafe, survival between the ISHLT and the OC cohorts should be similar. Given the larger percentage of higher risk patients with idiopathic pulmonary fibrosis and cystic fibrosis in the OC cohort, one might have anticipated a lower survival rate in our LAR population. Likewise, the ISHLT group had a greater number of high-risk patients with primary and secondary pulmonary hypertension. The larger proportion of bilateral lung transplants in the OC cohort also might have been expected to unfavorably alter the earlier portion of the survival curve. In fact, analysis shows that the 1-, 2-, and 3-year survival rates for the OC cohort are better than for the ISHLT cohort. Although a causal relation between REJ and BOS may exist, currently available treatment strategies do not necessarily alter the natural history of BOS. Aggressive treatment of asymptomatic REJ as identified by surveillance TBB/BAL may actually be harmful. To answer this question, we sub-divided our population into asymptomatic LARs who underwent zero to 1 TBB/BAL and those patients who required more frequent procedures as clinically indicated. The most striking finding was the low BOS incidence in asymptomatic patients (13% at 3 years in Group A). Despite this low incidence, we found an association between clinically evident REJ and BOS, as seen elsewhere.17–22 Group A also had half the number of pneumonia episodes and nearly 3 times as many LARs who were infection-free. By comparison, there were twice as many men and patients with cystic fibrosis in Group B, and these LARs underwent up to 10 times more TBB/BAL procedures. Survival in Group A patients was 76% at both 3.5 and 5 years after LT, whereas survival in Group B survival was much lower at the same time points (50% and 16% respectively). Although one might propose that TBB/BAL itself is potentially harmful, it seems more likely that either changes in clinical condition to justify bronchoscopy or interventions based on results of the procedure contribute to worsened outcome for symptomatic LARs. However, clinically apparent REJ episodes were identified much less frequently (10% of patients in the OC cohort) than in other published series. This observation suggests that clinically covert REJ episodes may have been missed by our non-surveillance strategy.
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TABLE IV Indications for TBB/BAL in the Ochsner Lung Transplant Program Asymptomatic 10% decline in FEV1 from established baseline Asymptomatic 20% decline in FEF25–75 from established baseline* Unexplained dyspnea, non-productive cough, or fever New auscultatory findings on lung exam *A single, isolated reduction in the FEF25–75 was not an indication in asymptomatic single lung recipients. FEF25–75, forced expiratory flow rate at 25% and 75%; FEV1, forced expiratory volume in 1 second.
This retrospective study has the limitations of all observational studies including the inability to account for changes in practice patterns over time. However, our findings are unique in that the comparison group was a contemporaneous cohort, unlike the descriptive report by Tamm et al2 that was limited by the use of historical controls and changing clinical practices in LAR care. In addition, the current study was performed in a single center, and as such, factors unique to our institutional practice may prove beneficial to LARs not subjected to regularly scheduled TBB/BAL. Along with strict adherence to established critical pathways in LT at the Ochsner Clinic, other aspects of LAR treatment that might favorably influence outcome include induction immunosuppression with anti-thymocyte globulin; aggressive use of intravenous ganciclovir for 100 days for patients at risk followed by indefinite use of oral ganciclovir; administration of hyperimmune immunoglobulin directed against CMV; use of clarithromycin to minimize cyclosporine dose; and very slow taper of prednisone over more than a year. All of these factors may account for our extraordinarily low REJ rate. Although the large size of the ISHLT cohort is likely to incorporate many recent changes in LAR management, detailed reporting of these variations in practice is not currently available from the database to allow accurate comparison between the 2 cohorts. In the absence of a homogeneous comparison group, it is impossible to delineate the specific effects of different practices in immunosuppression or infection treatment from surveillance protocols in improving the survival of our LAR cohort. Finally, demographic differences between the ISHLT and the OC cohorts outlined in Table II make comparisons between LAR survival potentially unreliable. Differences in outcome probably reflect multiple factors including patient selection, immunosuppression, and post-LT care. Al-
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though performing surveillance TBB/BAL may have further improved outcome in the OC cohort, it seems unlikely that limiting bronchoscopy only to patients with clinical indications produced worse results. In summary, limiting TBB/BAL procedures to patients with clinical indications will likely contain costs and pose a lesser threat to LARs than regularly scheduled bronchoscopy and will not compromise survival or detection rate for BOS. Although we recognize the limitations inherent in the observational nature of this single-center study, we recommend FOB with TBB/BAL based on the clinical triggers illustrated in Table IV. Nonetheless, a prospective, multicenter, randomized trial is the only reliable way to determine definitively whether routine surveillance TBB/BAL procedures improve outcome in the care of patients after lung transplantation. REFERENCES 1. Trulock EP. Lung transplantation: state of the art. Am J Respir Crit Care Med 1997;155:789 –818. 2. Tamm M, Sharples LD, Higenbottam TW, Stewart S, Wallwork J. Bronchiolitis obliterans syndrome in heart-lung transplantation: surveillance biopsies. Am J Respir Crit Care Med 1997;155:1705–10. 3. Patel SR, Kirby TJ, McCarthy PM, et al. Lung transplantation: the Cleveland Clinic experience. Cleve Clin J Med 1993;60:303–19. 4. Kukafka DS, O’Brien GM, Furukawa S, Criner GJ. Surveillance bronchoscopy in lung transplant recipients. Chest 1997; 111:377–81. 5. Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR. International guidelines for the selection of lung transplant candidates. J Heart Lung Transplant 1998;17:703–9. 6. Frost AE. Donor criteria and evaluation. Clin Chest Med 1997;18:231–7. 7. Struber M, Ehlers KA, Nilsson FN, Miller VM, McGregor CG, Haverich A. Effects of lung preservation with EuroCollins and University of Wisconsin solutions on endothelium-dependent relaxation. Ann Thorac Surg 1997;63:1428 – 35. 8. Valentine VG, McFadden PM, Ochsner JL. Advances in lung transplantation. Ochsner J 1999;1:12–8. 9. Knower MT, Labella-Walker K, McFadden PM, Kantrow SP, Valentine VG. Clarithromycin for safe and cost-effective reduction of cyclosporine doses in lung allograft recipients. South Med J 2000;93:1087–92. 10. Valentine VG, Robbins RC, Berry GJ, et al. Actuarial survival of heart-lung and bilateral sequential lung transplant
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