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Pre-transplant corticosteroid use and outcome in lung transplantation
Pre-Transplant Corticosteroid Use and Outcome in Lung Transplantation Soon J. Park, MD,a Duc Q. Nguyen, MD,a Kay Savik, MS,a Marshall I. Hertz, MD,b and R. Morton Bolman III, MDa Background: The early experience of lung transplantation was plagued with airway anastomotic complications. The use of corticosteroids in the pre-transplant period has been implicated as a major contributing factor in bronchial dehiscence, and many patients have been denied transplantation on the basis of corticosteroid use. We conducted the current study to assess the risks associated with pre-transplant corticosteroid use. Methods: We analyzed records of 73 single- and bilateral-single lung transplant recipients who had chronic obstructive pulmonary disease or ␣1-antitrypsin deficiency as their underlying disease from 1986 to 1996. Twenty-six patients (steroid group) received daily corticosteroid therapy (prednisone, 1.5 to 40 mg/day) up to the time of transplantation, whereas 47 patients did not receive chronic corticosteroids and had no corticosteroid therapy within 3 months of transplantation (non-steroid group). Results: The demographic profiles of the 2 groups were comparable. We noted no statistical significances in length of hospital stay, duration of intensive care, and postoperative pulmonary function. The rates of cytomegalovirus infection, acute rejection, bronchiolitis obliterans syndrome, and survival were also similar. The non-steroid group seemed to have a higher rate of bronchial stenosis at 3 years (29% vs 6%, p ⫽ 0.03). Bronchial dehiscence did not occur in either study group. Conclusions: Pre-transplant use of corticosteroids does not adversely affect outcome following lung transplantation. J Heart Lung Transplant 2001;20:304–309.
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ung transplantation has become a viable treatment option for patients with end-stage lung disease; outcome following transplantation has been improving steadily. However, many problems such as inadequate airway healing, infection, rejection, From the Division of Cardiovascular and Thoracic Surgerya and Department of Pulmonary Medicine,b University of Minnesota Hospital and Clinic, Minneapolis, Minnesota. Submitted October 25, 1999; accepted October 26, 2000. Presented at the International Society for Heart and Lung Transplantation Seventeenth Annual Meeting and Scientific Sessions, April 2–5, 1997, London, England. Reprint requests: Soon J. Park, MD, Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Box 207, 420 Delaware Street S.E., Minneapolis, MN 55455. Telephone: 612-624-8130. Fax: 612-625-1683. E-mail: parkx021@maroon. tc.umn.edu. Copyright © 2001 by the International Society for Heart and Lung Transplantation. 1053-2498/01/$–see front matter PII S1053-2498(00)00316-8
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and subsequent development of obliterative bronchiolitis (OB) persist. Abundant experimental data have suggested that corticosteroids impair wound healing,1–3 and this has been a particularly concerning problem in the field of lung transplantation, in which early lung transplant failures were due to bronchial dehiscence. Patients on corticosteroids were often denied lung transplantation for fear of potential increased airway complications following transplantation. Yet many patients with advanced emphysema require corticosteroids to control bronchospastic components of their lung disease and are in desperate need of lung transplantation. Adverse effects of corticosteroid use on lung transplantation outcome are not well documented in the literature. The current study examines the issues related to the use of corticosteroids during the pre-transplant period.
The Journal of Heart and Lung Transplantation Volume 20, Number 3
PATIENTS AND METHODS We reviewed the University of Minnesota Lung Transplantation database from May 1986 to September 1996. Corticosteroid treatment during the pre-transplant period was strongly associated with the underlying lung disease. Patients with advanced emphysema, including ␣1-antitrypsin deficiency (␣1AT) and chronic obstructive pulmonary disease (COPD) comprised the majority. Therefore, we limited our study to 90 patients who underwent either single-lung (SL) or bilateral-single lung (BSL) transplantation for ␣1-AT or COPD. Eleven patients had poor documentation of corticosteroid use, and we excluded them from the study. Six additional patients were not included in the study because of ambiguous corticosteroid use; they were on chronic corticosteroid therapy but were weaned from corticosteroids several months before transplantation. Therefore, the remaining 73 patients comprised the study population. Twenty-six (36%) patients had been on daily corticosteroid therapy up to the time of transplantation (steroid group). The other 47 patients were not on chronic corticosteroids and had no corticosteroid therapy within 3 months of transplantation. They comprised the non-steroid group. The patients’ demographic profiles, pre-transplant Karnofsky score,4 length of hospital stay, length of intensive care unit stay, pulmonary function tests, cytomegalovirus (CMV) infections, acute rejection episodes, clinical evidence of OB, airway anastomosis-related complications, and survival rates were analyzed and compared between the 2 groups. Our operative technique for lung transplantation has been described previously.5 The bronchial anastomosis was performed either in a telescoping or an end-to-end manner using 4-0 prolene sutures. Until July 1991, the bronchial anastomoses were wrapped with omentum, but this technique was abandoned subsequently. Methylprednisolone (500 mg IV) was administered just before reperfusion of the transplanted lungs, and prednisone was continued at 0.5 mg/kg/day and eventually tapered to 10 mg per day over the next month. The remainder of the tripledrug immunosuppressive regimen included cyclosporine or tacrolimus and azathioprine or mycophenolate mofetil. The transplantation surgeons and pulmonologists followed all lung transplantation patients on a regular basis. Pulmonary function tests and bronchoscopy with endobronchial biopsy were performed on a scheduled basis, and additional studies were conducted when clinically indicated. We defined bronchial stenosis as the presence of
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granulation tissue or fibrosis that encroached into the airway lumen at the site of airway anastomosis as demonstrated on bronchoscopy. We based the diagnosis of bronchiolitis obliterans syndrome (BOS) on forced expiratory volume in 1 second (FEV1) deterioration on pulmonary function testing of greater than 20% from baseline (according to International Society for Heart and Lung Transplantation standards). We first assessed corticosteroid use by comparing those subjects who had not received any corticosteroids with those who had, regardless of dose. Bivariate comparisons between groups were assessed using a t-test for interval data and a chi-square test of association for categorical data or Fisher’s exact test, if resulting cell sizes were too small. A MannWhitney U test was used if the interval data were not normally distributed. Actuarial survival curves assessing time to the event of interest were constructed using the method of Kaplan-Meier. To control for the effect of variables that were significantly different between groups, we analyzed multivariate models assessing time to stenosis, survival, or time to BOS Grade 2, using proportional hazards regression. We considered 2 multivariate models, a full model with all variables entered and the model resulting from stepwise regression. We performed secondary analyses with the steroid group further broken down into those who had received an average prednisone dose of ⱖ 10 mg per day and those who had received less than 10 mg per day. To assess the presence of any dose-related effect on the outcomes of interest, we performed a sub-set analysis of the 2 steroid groups.
RESULTS For the entire study population, the mean age was 52 ⫾ 8 years. Forty-nine percent of the transplant recipients were male. For patients in the steroid group, the prednisone doses varied from 1.5 mg to 40 mg per day, with a mean of 12.4 mg per day. The average length of corticosteroid use before transplantation was 16.6 ⫾ 9.6 months (range, 3 to 36). Table I presents characteristics of the 2 study groups. The demographic profile is similar between the 2 groups, except that the steroid group had a higher percentage of non-Caucasians (11% vs 0%, p ⫽ 0.04). More patients in the steroid group had COPD as their underlying disease (81% vs 53%, p ⫽ 0.02). The time on the waiting list, length of hospital stay, duration of ICU care, and post-transplant follow-up interval were comparable. The proportion of SL vs BSL procedures and the ischemic times of
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TABLE I Characteristics of non-steroid vs steroid groups
Age at transplant (years) Gender: male Race: Caucasian Disease ␣1-AT COPD Time on waiting lists (days) Length of stay (days) ICU stay (days) Mean follow-up (months) Type of transplant SL BSL Ischemic time (minutes) SL FEV1 (liter/sec) @ 6 months SL BSL @ 24 months SL BSL Omental wrap Karnofsky scores (pre-transplant)
Non-steroid (n ⴝ 47)
Steroid (n ⴝ 26)
p
51.6 ⫾ 7.7 26 (55%) 47 (100%)
52.4 ⫾ 7.6 10 (39%) 23 (89%)
0.82 0.17 0.04†
22 (47%) 25 (53%) 229 ⫾ 169 23.4 ⫾ 15.5 7.5 ⫾ 7.2 53 ⫾ 31
5 (19%) 21 (81%) 267 ⫾ 147 25.2 ⫾ 38.2 5.3 ⫾ 5.6 43 ⫾ 26.5
0.02† 0.31 0.26 0.13 0.29
44 (94%) 3 (6%)
22 (85%) 4 (15%)
0.24
229 ⫾ 66
254 ⫾ 96
0.43
1.6 ⫾ 0.45 2.8 ⫾ 0.67
1.5 ⫾ 0.38 2.8 ⫾ 1.3
0.35 1.00
1.5 ⫾ 0.58 2.8 ⫾ 1.5 11/47 (23%) 4.7 ⫾ 0.64
1.3 ⫾ 0.42 3.2 ⫾ 1.4 0/26 (0%) 5.1 ⫾ 0.97
0.29 1.00 0.006* 0.03*
*Fisher’s exact test and Mann-Whitney U test. ␣1-AT, alpha 1-antitrypsin deficiency; BSL, bilateral single lung; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume at 1 second; ICU, intensive care unit; SL, single lung.
the SL recipients did not significantly differ between groups. The FEV1 at 6 months and 2 years following transplantation showed no statistically significant differences between the 2 groups. All of the patients who had omental wraps were in the non-steroid group (0% vs 23%, p ⫽ 0.006). Patients in the steroid group had a significantly higher pre-transplant Karnofsky score of 5.1 (range, 3 to 8) compared with 4.7 (range, 3 to 6) in the non-steroid group, indicating a worse degree of debilitation at the time of transplant. Within the steroid group, the median dose of prednisone was 9.9 mg per day (range, 1.5 to 40); 52% of the patients received doses ⬍ 10 mg per day, and 48% received doses ⱖ 10 mg per day. To control for differences in race, underlying disease, omental wrap, and Karnofsky score between the steroid and non-steroid groups, we included these variables in multivariate assessments of survival, time to BOS Grade 2, and time to bronchial stenosis. Actuarial survival at 1 year was 89% for the non-steroid group and 77% for the steroid group
(p ⫽ 0.18, Figure 1). Overall survival also did not statistically differ (p ⫽ 0.47). The patients in the steroid group who received ⬍ 10 mg per day had 73% survival at 1 year, and those who received ⱖ 10 mg per day had 70% survival at 1 year (p ⫽ 0.74). In
FIGURE 1 Cumulative survival comparing steroid vs non-steroid groups. Log-rank chi-square ⫽ 0.51, p ⫽ 0.47.
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TABLE II Incidence of airway complications, CMV infection, and acute rejection Non-steroid
Steroid
79% 71% 71%
100% 100% 94%
0 (0%) 0.19 ⫾ 0.39 0.05 ⫾ 0.04
0 (0%) 0.09 ⫾ 0.08 0.08 ⫾ 0.13
Time free from bronchial stenosis 1 year 2 years 3 years Bronchial dehiscence CMV infection* Acute rejection†
p
0.03 0.44 0.93
*Number of positive cultures per patient month from bronchoalveolar lavage. †Episodes of acute rejection per patient month. Mann-Whitney U test. CMV, cytomegalovirus.
proportional hazards regression, COPD (rr ⫽ 0.38, 95% confidence interval [CI] ⫽ 0.16 to 0.93, p ⫽ 0.034) and the pre-transplant Karnofsky score (rr ⫽ 1.7, 95% CI ⫽ 1.0 to 2.8, p ⫽ 0.05) were significant predictors of survival, but corticosteroid use before transplant was not (rr ⫽ 1.4, 95% CI ⫽ 0.48 to 4.0, p ⫽ 0.55). In stepwise regression, only the pretransplant Karnofsky score significantly predicted survival (rr ⫽ 1.7, 95% CI ⫽ 1.05 to 2.6, p ⫽ 0.03). We also analyzed survival data according to era, from 1986 to 1991 vs 1991 to 1996, regardless of corticosteroid use status, to determine whether improvement of outcome could be observed over time. The 1-year survival in the 1986 to 1991 period was 91% compared with 84% for the 1991 to 1996 era (p ⫽ 0.15). Table II depicts airway complications. Time free from bronchial stenosis was evaluated in each group. In the non-steroid group, 71% remained free from stenosis at 3 years. In the steroid group, 94% remained free from stenosis during the same time period (p ⫽ 0.03). Those who received ⬍ 10 mg per day had an 86% rate of freedom from stenosis, and those who received ⱖ 10 mg per day had a 100% rate of freedom from stenosis at 3 years (p ⫽ 1.00). Two patients in the steroid group required additional interventions, one received stent placement and the other had laser ablation. Proportional hazards regression to assess the association between corticosteroid use, Karnofsky, COPD, omentum wrap, and race on time to stenosis resulted in a non-significant overall model. However, stepwise regression again identified corticosteroid use as a significant predictor of time to stenosis (rr ⫽ 0.22, 95% CI ⫽ 0.05 to 0.97, p ⫽ 0.045). Bronchial dehiscence did not occur in either group. Both groups developed BOS Grade 2 at compa-
rable rates, as shown in Figure 2. We observed no significant difference in time to BOS Grade 2 for the 2 dosing groups. Multivariate analysis of the above set of variables revealed no significant predictors of time to BOS Grade 2 in the full model or in stepwise regression. The rate of acute rejection and the rate of positive CMV cultures obtained from bronchoalveolar lavage fluid during bronchoscopy were similar between the 2 groups (Table 2).
DISCUSSION Airway anastomotic complication was a major cause of morbidity and mortality in the early experience of lung transplantation. An important factor implicated in causing a higher incidence of airway com-
FIGURE 2 Survival free from bronchiolitis obliterans
syndrome (BOS) Grade ⱖ2 comparing steroid vs nonsteroid groups. Log-rank chi-square ⫽ 0.22, p ⫽ 0.40.
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plications was corticosteroid use.6 We conducted the current study to evaluate the effects of corticosteroid use during the pre-transplant period on the subsequent outcome of patients following lung transplantation. Historically, the routine use of corticosteroids as a post-operative immunosuppression agent was delayed as long as possible because of its negative effects on bronchial anastomotic healing. Pre-operative corticosteroid therapy was considered an absolute contraindication to lung transplantation for the same reason. Many patients had been rejected by various transplant centers for fear of airway complications simply on the basis of their pre-transplant use of corticosteroids. However, evidence regarding the negative effects of corticosteroids on bronchial anastomotic healing is equivocal. Cooper et al3,7 demonstrated in a canine model that routine peri-operative corticosteroids had a negative impact on bronchial anastomotic healing, whereas others showed favorable effects with corticosteroid administration.8,9 A few clinical reports hinted at a possibility of normal bronchial healing despite corticosteroids.10,13 At our institution, many patients were referred for lung transplantation while on corticosteroids for end-stage emphysema. They were otherwise suitable candidates for lung transplantation. Diligent efforts were made to wean down corticosteroids as much as possible. Our initial experience with lung transplantation was favorable despite many anticipated adverse problems related to corticosteroids. As we gained more clinical experience, it seemed clear that a small to moderate dose of corticosteroids during the pre-transplant period did not adversely affect the outcome. In our study population, daily prednisone dosages ranged from 1.5 to 40 mg. Sub-group analyses comparing patients who received a higher daily dose (ⱖ 10 mg) with those who received a smaller dose (⬍ 10 mg) revealed no statistical differences in terms of survival outcome, time to BOS Grade 2, and time to bronchial stenosis. Ischemia of the donor bronchus was also implicated as an important factor in airway healing.14,15 This has resulted in various modifications in surgical techniques in an attempt to improve blood supply to the donor bronchus, including the use of an omental wrap16,17 and direct revascularization of a bronchial artery.18 These changes have not proven to be more efficacious than the currently practiced telescoping or end-to-end anastomotic technique.19 At our institution, the omental wrap was abandoned after July 1991. We noted no difference in the incidence
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of airway complications between the patients who received omental wrap and those who did not. In this study, bronchial dehiscence did not occur in either the steroid or non-steroid group. Other investigators reported low rates of airway anastomotic complications. Colquhoun et al13 reported a 6.6% incidence of airway dehiscence. In that series, 5 of 66 patients were on pre-transplant corticosteroids, and of those, 1 had a bronchial dehiscence. In our study, the incidence of bronchial stenosis was significantly higher in the non-steroid group. Pretransplant corticosteroid use may have a protective effect on bronchial stenosis by reducing the formation of granulation tissue at the site of airway anastomosis. The nature of the stenosis varied widely, but most of the patients from both groups had evidence of only mild narrowing at the anastomoses. Only 2 out of the 18 patients with bronchial stenoses required therapeutic interventions. In their report on 29 lung transplant patients, Scha¨fers et al found that the incidence of bronchial stenosis did not differ between patients with and without pretransplant corticosteroid use. In our study, patients who have COPD as their underlying disease and those who have lower pretransplant Karnofsky scores had improved survival outcome. Corticosteroid use in the pre-transplant period, on the other hand, was not a significant predictor of survival. The estimated survival rate was not statistically different between the 2 groups despite the fact that patients in the steroid group were more debilitated before transplantation, as reflected by their higher Karnofsky scores. Survival outcome was not statistically different when analyzed according to time periods (1986 to 1991 vs 1991 to 1996). We found no apparent causal relationship to corticosteroid use when we reviewed individual causes of death in our patient population. We examined several other variables, including the incidences of BOS and acute rejection, and we found no differences between the groups. Although several factors, including donor–recipient characteristics, immunosuppression protocols, and CMV prophylaxis, contribute to the risk of developing CMV infections, corticosteroid use did not increase the incidence of CMV infection.
CONCLUSIONS The use of corticosteroids during the pre-transplant period does not seem to increase adverse outcome following lung transplantation. The mortality associated with lung transplantation is not enhanced. The incidence of bronchial dehiscence remains low
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despite use of pre-transplant corticosteroids. Patients on pre-transplant corticosteroids may have a lower rate of bronchial stenosis. Pre-transplant corticosteroid use should not be considered a contraindication to lung transplantation.
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11.
REFERENCES 1. Arunugan S, Nimmannits S, Enguis JIF. The effect of immunosuppression on wound healing. Surg Gynecol Obstet 1981;133:72– 4. 2. Aszodi A, Ponsky JL. Effects of corticosteroids on the healing bowel anastomosis. Am Surg 1984;50:546 – 8. 3. Lima O, Cooper JD, Peters WJ, et al. Effects of methylprednisolone and azathioprine on bronchial healing following lung autotransplantation. J Thorac Cardiovasc Surg 1981;82: 211–5. 4. Gross CR, Savik K, Bolman RM, et al. Long-term health status and quality of life outcomes of lung transplant recipients. Chest 1995;108:1587–93. 5. Shumway SJ. Operative techniques in lung transplantation. In: Shumway SJ, Shumway NE, eds. Thoracic transplantation, 1st ed. Boston: Blackwell Science, 1995, pp. 181– 6. 6. Patterson GA, Cooper JD. Status of lung transplantation. Surg Clin North Am 1988;68:545– 8. 7. Goldberg M, Lima O, Morgan E, et al. A comparison between cyclosporine A and methylprednisolone plus azathioprine on bronchial healing following canine lung autotransplantation. J Thorac Cardiovasc Surg 1983;85:821– 6. 8. Inui K, Scha¨fers HJ, Aoki M, et al. Bronchial circulation after experimental lung transplantation. J Thorac Cardiovasc Surg 1993;105:474 –9. 9. Pinsker KL, Veith FJ, Kamholz SL, Montefusco C, Emerson
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E, Hagstrom JWC. Influence of bronchial circulation and corticosteroid therapy on bronchial anastomotic healing. J Thorac Cardiovasc Surg 1984;87:439 – 44. Miller JD, DeHoyos A, Patterson GA. An evaluation of the role of omentopexy and of early perioperative corticosteroid administration in clinical lung transplantation. J Thorac Cardiovasc Surg 1993;105:247–52. Scha¨fers HJ, Wagner TOF, Dementzis S, et al. Preoperative corticosteroids: a contraindication to lung transplantation? Chest 1992;102:1522–5. Colquhoun IW, Gascoigne Ad, Au J, Corris PA, Hilton CJ, Dark JH. Airway complications after pulmonary transplantation. Ann Thorac Surg 1994;57:141–5. Novick RJ, Menkis AH, McKenzie FN, et al. The safety of low-dose prednisone before and immediately after heart-lung transplantation. Ann Thorac Surg 1991;51:642–5. Inui K, Wada H, Yokomise H, et al. Evaluation of a bronchial anastomosis by laser Doppler velocimetry. J Thorac Cardiovasc Surg 1990;99:614 –9. Pinsker KL, Veith FJ, Kamholz SL, Emeson EE, Norin A, Montefusco C. Bronchial anastomotic healing in canine lung allotransplants treated with cyclosporine. Transplantation 1985;40:143– 6. Lima O, Goldberg M, Peters WJ, Ayabe H, Townsend E, Cooper JD. Bronchial omentopexy in canine lung transplantation. J Thorac Cardiovasc Surg 1982;83:418 –31. Pasque MK, Cooper JD, Kaiser LR, Haydock DA, Triantafillou A, Trulouk EP. Improved technique for bilateral lung transplantation: rational and initial clinical experience. Ann Thorac Surg 1990;49:785–91. Couraud L, Baudet E, Martigne C, et al. Bronchial revascularization in double lung transplantation: a series of eight patients. Ann Thorac Surg 1992;53:88 –94. Calhoon JH, Grove FL, Gibbons WJ, et al. Single lung transplantation—alternative indications and technique. J Thorac Cardiovasc Surg 1991;101:816 –25.
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ung transplantation has become a viable treatment option for patients with end-stage lung disease; outcome following transplantation has been improving steadily. However, many problems such as inadequate airway healing, infection, rejection, From the Division of Cardiovascular and Thoracic Surgerya and Department of Pulmonary Medicine,b University of Minnesota Hospital and Clinic, Minneapolis, Minnesota. Submitted October 25, 1999; accepted October 26, 2000. Presented at the International Society for Heart and Lung Transplantation Seventeenth Annual Meeting and Scientific Sessions, April 2–5, 1997, London, England. Reprint requests: Soon J. Park, MD, Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Box 207, 420 Delaware Street S.E., Minneapolis, MN 55455. Telephone: 612-624-8130. Fax: 612-625-1683. E-mail: parkx021@maroon. tc.umn.edu. Copyright © 2001 by the International Society for Heart and Lung Transplantation. 1053-2498/01/$–see front matter PII S1053-2498(00)00316-8
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and subsequent development of obliterative bronchiolitis (OB) persist. Abundant experimental data have suggested that corticosteroids impair wound healing,1–3 and this has been a particularly concerning problem in the field of lung transplantation, in which early lung transplant failures were due to bronchial dehiscence. Patients on corticosteroids were often denied lung transplantation for fear of potential increased airway complications following transplantation. Yet many patients with advanced emphysema require corticosteroids to control bronchospastic components of their lung disease and are in desperate need of lung transplantation. Adverse effects of corticosteroid use on lung transplantation outcome are not well documented in the literature. The current study examines the issues related to the use of corticosteroids during the pre-transplant period.
The Journal of Heart and Lung Transplantation Volume 20, Number 3
PATIENTS AND METHODS We reviewed the University of Minnesota Lung Transplantation database from May 1986 to September 1996. Corticosteroid treatment during the pre-transplant period was strongly associated with the underlying lung disease. Patients with advanced emphysema, including ␣1-antitrypsin deficiency (␣1AT) and chronic obstructive pulmonary disease (COPD) comprised the majority. Therefore, we limited our study to 90 patients who underwent either single-lung (SL) or bilateral-single lung (BSL) transplantation for ␣1-AT or COPD. Eleven patients had poor documentation of corticosteroid use, and we excluded them from the study. Six additional patients were not included in the study because of ambiguous corticosteroid use; they were on chronic corticosteroid therapy but were weaned from corticosteroids several months before transplantation. Therefore, the remaining 73 patients comprised the study population. Twenty-six (36%) patients had been on daily corticosteroid therapy up to the time of transplantation (steroid group). The other 47 patients were not on chronic corticosteroids and had no corticosteroid therapy within 3 months of transplantation. They comprised the non-steroid group. The patients’ demographic profiles, pre-transplant Karnofsky score,4 length of hospital stay, length of intensive care unit stay, pulmonary function tests, cytomegalovirus (CMV) infections, acute rejection episodes, clinical evidence of OB, airway anastomosis-related complications, and survival rates were analyzed and compared between the 2 groups. Our operative technique for lung transplantation has been described previously.5 The bronchial anastomosis was performed either in a telescoping or an end-to-end manner using 4-0 prolene sutures. Until July 1991, the bronchial anastomoses were wrapped with omentum, but this technique was abandoned subsequently. Methylprednisolone (500 mg IV) was administered just before reperfusion of the transplanted lungs, and prednisone was continued at 0.5 mg/kg/day and eventually tapered to 10 mg per day over the next month. The remainder of the tripledrug immunosuppressive regimen included cyclosporine or tacrolimus and azathioprine or mycophenolate mofetil. The transplantation surgeons and pulmonologists followed all lung transplantation patients on a regular basis. Pulmonary function tests and bronchoscopy with endobronchial biopsy were performed on a scheduled basis, and additional studies were conducted when clinically indicated. We defined bronchial stenosis as the presence of
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granulation tissue or fibrosis that encroached into the airway lumen at the site of airway anastomosis as demonstrated on bronchoscopy. We based the diagnosis of bronchiolitis obliterans syndrome (BOS) on forced expiratory volume in 1 second (FEV1) deterioration on pulmonary function testing of greater than 20% from baseline (according to International Society for Heart and Lung Transplantation standards). We first assessed corticosteroid use by comparing those subjects who had not received any corticosteroids with those who had, regardless of dose. Bivariate comparisons between groups were assessed using a t-test for interval data and a chi-square test of association for categorical data or Fisher’s exact test, if resulting cell sizes were too small. A MannWhitney U test was used if the interval data were not normally distributed. Actuarial survival curves assessing time to the event of interest were constructed using the method of Kaplan-Meier. To control for the effect of variables that were significantly different between groups, we analyzed multivariate models assessing time to stenosis, survival, or time to BOS Grade 2, using proportional hazards regression. We considered 2 multivariate models, a full model with all variables entered and the model resulting from stepwise regression. We performed secondary analyses with the steroid group further broken down into those who had received an average prednisone dose of ⱖ 10 mg per day and those who had received less than 10 mg per day. To assess the presence of any dose-related effect on the outcomes of interest, we performed a sub-set analysis of the 2 steroid groups.
RESULTS For the entire study population, the mean age was 52 ⫾ 8 years. Forty-nine percent of the transplant recipients were male. For patients in the steroid group, the prednisone doses varied from 1.5 mg to 40 mg per day, with a mean of 12.4 mg per day. The average length of corticosteroid use before transplantation was 16.6 ⫾ 9.6 months (range, 3 to 36). Table I presents characteristics of the 2 study groups. The demographic profile is similar between the 2 groups, except that the steroid group had a higher percentage of non-Caucasians (11% vs 0%, p ⫽ 0.04). More patients in the steroid group had COPD as their underlying disease (81% vs 53%, p ⫽ 0.02). The time on the waiting list, length of hospital stay, duration of ICU care, and post-transplant follow-up interval were comparable. The proportion of SL vs BSL procedures and the ischemic times of
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TABLE I Characteristics of non-steroid vs steroid groups
Age at transplant (years) Gender: male Race: Caucasian Disease ␣1-AT COPD Time on waiting lists (days) Length of stay (days) ICU stay (days) Mean follow-up (months) Type of transplant SL BSL Ischemic time (minutes) SL FEV1 (liter/sec) @ 6 months SL BSL @ 24 months SL BSL Omental wrap Karnofsky scores (pre-transplant)
Non-steroid (n ⴝ 47)
Steroid (n ⴝ 26)
p
51.6 ⫾ 7.7 26 (55%) 47 (100%)
52.4 ⫾ 7.6 10 (39%) 23 (89%)
0.82 0.17 0.04†
22 (47%) 25 (53%) 229 ⫾ 169 23.4 ⫾ 15.5 7.5 ⫾ 7.2 53 ⫾ 31
5 (19%) 21 (81%) 267 ⫾ 147 25.2 ⫾ 38.2 5.3 ⫾ 5.6 43 ⫾ 26.5
0.02† 0.31 0.26 0.13 0.29
44 (94%) 3 (6%)
22 (85%) 4 (15%)
0.24
229 ⫾ 66
254 ⫾ 96
0.43
1.6 ⫾ 0.45 2.8 ⫾ 0.67
1.5 ⫾ 0.38 2.8 ⫾ 1.3
0.35 1.00
1.5 ⫾ 0.58 2.8 ⫾ 1.5 11/47 (23%) 4.7 ⫾ 0.64
1.3 ⫾ 0.42 3.2 ⫾ 1.4 0/26 (0%) 5.1 ⫾ 0.97
0.29 1.00 0.006* 0.03*
*Fisher’s exact test and Mann-Whitney U test. ␣1-AT, alpha 1-antitrypsin deficiency; BSL, bilateral single lung; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume at 1 second; ICU, intensive care unit; SL, single lung.
the SL recipients did not significantly differ between groups. The FEV1 at 6 months and 2 years following transplantation showed no statistically significant differences between the 2 groups. All of the patients who had omental wraps were in the non-steroid group (0% vs 23%, p ⫽ 0.006). Patients in the steroid group had a significantly higher pre-transplant Karnofsky score of 5.1 (range, 3 to 8) compared with 4.7 (range, 3 to 6) in the non-steroid group, indicating a worse degree of debilitation at the time of transplant. Within the steroid group, the median dose of prednisone was 9.9 mg per day (range, 1.5 to 40); 52% of the patients received doses ⬍ 10 mg per day, and 48% received doses ⱖ 10 mg per day. To control for differences in race, underlying disease, omental wrap, and Karnofsky score between the steroid and non-steroid groups, we included these variables in multivariate assessments of survival, time to BOS Grade 2, and time to bronchial stenosis. Actuarial survival at 1 year was 89% for the non-steroid group and 77% for the steroid group
(p ⫽ 0.18, Figure 1). Overall survival also did not statistically differ (p ⫽ 0.47). The patients in the steroid group who received ⬍ 10 mg per day had 73% survival at 1 year, and those who received ⱖ 10 mg per day had 70% survival at 1 year (p ⫽ 0.74). In
FIGURE 1 Cumulative survival comparing steroid vs non-steroid groups. Log-rank chi-square ⫽ 0.51, p ⫽ 0.47.
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TABLE II Incidence of airway complications, CMV infection, and acute rejection Non-steroid
Steroid
79% 71% 71%
100% 100% 94%
0 (0%) 0.19 ⫾ 0.39 0.05 ⫾ 0.04
0 (0%) 0.09 ⫾ 0.08 0.08 ⫾ 0.13
Time free from bronchial stenosis 1 year 2 years 3 years Bronchial dehiscence CMV infection* Acute rejection†
p
0.03 0.44 0.93
*Number of positive cultures per patient month from bronchoalveolar lavage. †Episodes of acute rejection per patient month. Mann-Whitney U test. CMV, cytomegalovirus.
proportional hazards regression, COPD (rr ⫽ 0.38, 95% confidence interval [CI] ⫽ 0.16 to 0.93, p ⫽ 0.034) and the pre-transplant Karnofsky score (rr ⫽ 1.7, 95% CI ⫽ 1.0 to 2.8, p ⫽ 0.05) were significant predictors of survival, but corticosteroid use before transplant was not (rr ⫽ 1.4, 95% CI ⫽ 0.48 to 4.0, p ⫽ 0.55). In stepwise regression, only the pretransplant Karnofsky score significantly predicted survival (rr ⫽ 1.7, 95% CI ⫽ 1.05 to 2.6, p ⫽ 0.03). We also analyzed survival data according to era, from 1986 to 1991 vs 1991 to 1996, regardless of corticosteroid use status, to determine whether improvement of outcome could be observed over time. The 1-year survival in the 1986 to 1991 period was 91% compared with 84% for the 1991 to 1996 era (p ⫽ 0.15). Table II depicts airway complications. Time free from bronchial stenosis was evaluated in each group. In the non-steroid group, 71% remained free from stenosis at 3 years. In the steroid group, 94% remained free from stenosis during the same time period (p ⫽ 0.03). Those who received ⬍ 10 mg per day had an 86% rate of freedom from stenosis, and those who received ⱖ 10 mg per day had a 100% rate of freedom from stenosis at 3 years (p ⫽ 1.00). Two patients in the steroid group required additional interventions, one received stent placement and the other had laser ablation. Proportional hazards regression to assess the association between corticosteroid use, Karnofsky, COPD, omentum wrap, and race on time to stenosis resulted in a non-significant overall model. However, stepwise regression again identified corticosteroid use as a significant predictor of time to stenosis (rr ⫽ 0.22, 95% CI ⫽ 0.05 to 0.97, p ⫽ 0.045). Bronchial dehiscence did not occur in either group. Both groups developed BOS Grade 2 at compa-
rable rates, as shown in Figure 2. We observed no significant difference in time to BOS Grade 2 for the 2 dosing groups. Multivariate analysis of the above set of variables revealed no significant predictors of time to BOS Grade 2 in the full model or in stepwise regression. The rate of acute rejection and the rate of positive CMV cultures obtained from bronchoalveolar lavage fluid during bronchoscopy were similar between the 2 groups (Table 2).
DISCUSSION Airway anastomotic complication was a major cause of morbidity and mortality in the early experience of lung transplantation. An important factor implicated in causing a higher incidence of airway com-
FIGURE 2 Survival free from bronchiolitis obliterans
syndrome (BOS) Grade ⱖ2 comparing steroid vs nonsteroid groups. Log-rank chi-square ⫽ 0.22, p ⫽ 0.40.
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plications was corticosteroid use.6 We conducted the current study to evaluate the effects of corticosteroid use during the pre-transplant period on the subsequent outcome of patients following lung transplantation. Historically, the routine use of corticosteroids as a post-operative immunosuppression agent was delayed as long as possible because of its negative effects on bronchial anastomotic healing. Pre-operative corticosteroid therapy was considered an absolute contraindication to lung transplantation for the same reason. Many patients had been rejected by various transplant centers for fear of airway complications simply on the basis of their pre-transplant use of corticosteroids. However, evidence regarding the negative effects of corticosteroids on bronchial anastomotic healing is equivocal. Cooper et al3,7 demonstrated in a canine model that routine peri-operative corticosteroids had a negative impact on bronchial anastomotic healing, whereas others showed favorable effects with corticosteroid administration.8,9 A few clinical reports hinted at a possibility of normal bronchial healing despite corticosteroids.10,13 At our institution, many patients were referred for lung transplantation while on corticosteroids for end-stage emphysema. They were otherwise suitable candidates for lung transplantation. Diligent efforts were made to wean down corticosteroids as much as possible. Our initial experience with lung transplantation was favorable despite many anticipated adverse problems related to corticosteroids. As we gained more clinical experience, it seemed clear that a small to moderate dose of corticosteroids during the pre-transplant period did not adversely affect the outcome. In our study population, daily prednisone dosages ranged from 1.5 to 40 mg. Sub-group analyses comparing patients who received a higher daily dose (ⱖ 10 mg) with those who received a smaller dose (⬍ 10 mg) revealed no statistical differences in terms of survival outcome, time to BOS Grade 2, and time to bronchial stenosis. Ischemia of the donor bronchus was also implicated as an important factor in airway healing.14,15 This has resulted in various modifications in surgical techniques in an attempt to improve blood supply to the donor bronchus, including the use of an omental wrap16,17 and direct revascularization of a bronchial artery.18 These changes have not proven to be more efficacious than the currently practiced telescoping or end-to-end anastomotic technique.19 At our institution, the omental wrap was abandoned after July 1991. We noted no difference in the incidence
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of airway complications between the patients who received omental wrap and those who did not. In this study, bronchial dehiscence did not occur in either the steroid or non-steroid group. Other investigators reported low rates of airway anastomotic complications. Colquhoun et al13 reported a 6.6% incidence of airway dehiscence. In that series, 5 of 66 patients were on pre-transplant corticosteroids, and of those, 1 had a bronchial dehiscence. In our study, the incidence of bronchial stenosis was significantly higher in the non-steroid group. Pretransplant corticosteroid use may have a protective effect on bronchial stenosis by reducing the formation of granulation tissue at the site of airway anastomosis. The nature of the stenosis varied widely, but most of the patients from both groups had evidence of only mild narrowing at the anastomoses. Only 2 out of the 18 patients with bronchial stenoses required therapeutic interventions. In their report on 29 lung transplant patients, Scha¨fers et al found that the incidence of bronchial stenosis did not differ between patients with and without pretransplant corticosteroid use. In our study, patients who have COPD as their underlying disease and those who have lower pretransplant Karnofsky scores had improved survival outcome. Corticosteroid use in the pre-transplant period, on the other hand, was not a significant predictor of survival. The estimated survival rate was not statistically different between the 2 groups despite the fact that patients in the steroid group were more debilitated before transplantation, as reflected by their higher Karnofsky scores. Survival outcome was not statistically different when analyzed according to time periods (1986 to 1991 vs 1991 to 1996). We found no apparent causal relationship to corticosteroid use when we reviewed individual causes of death in our patient population. We examined several other variables, including the incidences of BOS and acute rejection, and we found no differences between the groups. Although several factors, including donor–recipient characteristics, immunosuppression protocols, and CMV prophylaxis, contribute to the risk of developing CMV infections, corticosteroid use did not increase the incidence of CMV infection.
CONCLUSIONS The use of corticosteroids during the pre-transplant period does not seem to increase adverse outcome following lung transplantation. The mortality associated with lung transplantation is not enhanced. The incidence of bronchial dehiscence remains low
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despite use of pre-transplant corticosteroids. Patients on pre-transplant corticosteroids may have a lower rate of bronchial stenosis. Pre-transplant corticosteroid use should not be considered a contraindication to lung transplantation.
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11.
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