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(Circulation. 1996;94:1334-1338.)
© 1996 American Heart Association, Inc.
Articles |
Natural Course of Moderate Cardiac Allograft Rejection (International Society for Heart Transplantation Grade 2) Early and Late After Transplantation
the Division of Cardiology (H.P.B.-La R., G.S., F.F., W.K.) and the Department of Pathology (J.S.), University Hospital, Zurich, Switzerland.
Correspondence to Dr H.P. Brunner-La Rocca, Division of Cardiology, Department of Internal Medicine, University Hospital, Ramistrasse 100, CH-8091 Zurich, Switzerland.
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Abstract |
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Background The significance of International Society for Heart Transplantation (ISHT) grade 2 cardiac allograft rejection has been questioned, and the medical community is not in complete agreement as to its clinical management. We therefore retrospectively analyzed the follow-up of all available endomyocardial biopsy samples obtained from 161 transplant patients since introduction of the ISHT nomenclature at our institution.
Methods and Results Of 2868 biopsies performed 3 days to 8.9 years after transplantation, 420 biopsies had no follow-up or were preceded by intensified immunosuppression and were excluded from analysis. Of the remaining 2448 biopsies, 374 (15.3%) were repeat biopsies performed 7 to 10 days after prior ISHT 2 rejection without change of treatment. Of these, 70 (18.7%) had progressed to 
ISHT 3A, whereas 82 (21.9%) remained unchanged and 222 (59.4%) resolved. In contrast, follow-up of 2074 biopsies with lower-grade rejection showed graft rejection classified as ISHT 3A in 153 (7.4%), ISHT 2 in 240 (11.6%), and 
ISHT 1B in 1681 (81.1%) biopsy samples (P<.0001). In univariate analysis, the odds ratio (OR) of graft rejection ISHT 3A after ISHT 2 rejection was 2.89. Other univariate predictors of rejection ISHT 3A were time after transplantation (OR=0.96 per month, P<.0001), blood group type B (OR=1.62, P<.005), "Quilty" lesion on previous biopsy (OR=1.70, P<.005), number of HLA mismatches (OR=1.27 per mismatch, P<.005), female sex (OR=1.55, P<.05), and serum creatinine level (OR=0.93 per 10 µmol/L, P<.005). Young age of recipients was a risk factor during long-term (2 years) follow-up (P<.002), and lower cyclosporine level was a risk factor during the first month after transplantation (P<.01). In multivariate logistic regression analysis, ISHT 2 rejection on previous biopsy remained the strongest predictor of rejection ISHT 3A (OR=2.40, P<.0001).
Conclusions Several factors independently increase the risk of rejection classified as ISHT 3A. The strongest predictor of a grade of ISHT 3A was ISHT 2 rejection on the previous biopsy obtained 7 to 10 days earlier. Therefore, ISHT 2 graft rejection is of clinical significance, and short-term follow-up appears to be warranted even late after transplantation.
Key Words: transplantation • rejection • biopsy
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Introduction |
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Acute moderate cardiac allograft rejection (International Society for Heart Transplantation [ISHT] 2) is defined as one focus of lymphocytic infiltration associated with myocyte injury in endomyocardial biopsy.1
In recent years, the significance of ISHT 2 graft rejection has been questioned because progression to more severe rejection without specific therapy was found to be unusual2 3 4 5 and was rarely associated with clinical signs of hemodynamic compromise.6 It was also suggested that ISHT 2 graft rejection is representative of "Quilty" B lesions,7 which are defined as endocardial lymphocytic infiltrates without relation to acute rejection.8 The question therefore remains whether moderate graft rejection (ISHT 2) requires increased immunosuppression or early repeated biopsy.9
The policy at our institution has been to repeat the biopsy 7 to 10 days after ISHT 2 graft rejection with immunosuppression unchanged; this allowed us to study the short-term course of these lesions independent of any interference caused by therapy. Accordingly, we analyzed whether ISHT 2 graft rejection is an independent risk factor for the development of graft rejection ISHT 3A, whether there is a relation between the time after transplantation and progression to more severe graft rejection, and finally, whether other risk factors predict progression of graft rejection.
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Methods |
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Study Population
In this retrospective study, we included all biopsy samples classified according to the working formulation of the ISHT from July 1991 to May 1995. Biopsies performed before July 1991 were graded according to the Texas classification10 and were therefore omitted in the present study to avoid misinterpretation. A total of 2868 endomyocardial biopsy samples from 161 heart transplantation patients (mean age at transplantation, 47.7±12.2 years; range, 11.3 to 65.2 years; 148 males, 13 females) who had at least two biopsies were analyzed (mean, 499±639 days after transplantation; median, 197 days; range, 3 days to 8.9 years). Transplantation had been performed because of dilated cardiomyopathy in 79 patients (49.1%), coronary artery disease in 63 (39.1%), congenital heart disease in 11 (6.8%), valvular heart disease in 6 (3.7%), and other reasons in 2 (1.2%). HLA histocompatibility mismatches of six factors between the donor and recipient were found in 38 patients (23.6%), of five in 65 (40.4%), of four in 42 (26.1%), of three in 14 (8.7%), of two in 1 (0.6%), and of one factor in 1 patient (0.6%). Fifty-three patients (32.9%) had blood group O, 88 (54.7%) had blood group A, 16 (9.9%) had blood group B, and 5 (3.1%) had blood group AB.
Management and Controls
All patients received induction therapy with rabbit anti-thymocyte globulin for the first 5 days after transplantation and standard triple-drug immunosuppression with cyclosporine, prednisone, and azathioprine. Biopsies were performed routinely according to the following schedule: weekly for the first 8 weeks, every 10 days for the following month, biweekly for the next 3 months, and then monthly until 1 year after transplantation. In the second year, biopsies were performed every other month for 6 months and then every 3 months, and from the third year on, every 6 months. Graft rejection of ISHT 2 or episodes of higher degrees of rejection that required increased immunosuppressive therapy were followed up by a biopsy 7 to 10 days later and were classified as "resolved" if no or only mild graft rejection (ISHT 0, 1A, or 1B) was diagnosed, "persistent" if one focus of aggressive infiltrate (ISHT 2) was diagnosed, or "progressive" if moderate or severe graft rejection (ISHT 3A, 3B, or 4) was diagnosed.
Histological grading was performed according to the ISHT working formulation1 on the basis of at least four specimens.
Statistical Analysis
Data are presented as frequencies (percentage) or as mean±SD. Group comparisons were performed by use of 
2 analysis, Student's t test, or Mann-Whitney U test as appropriate. If possible, an odds ratio (OR) and 95% CIs were calculated. In addition to univariate analysis, the influence of drug dosages, monoclonal blood level of cyclosporine, serum creatinine level, number of HLA mismatches, age, and time after transplantation were entered into a multivariate logistic regression analysis to determine which of these factors independently predicted progression to subsequent graft rejection ISHT 3A. A value of P<.05 was considered statistically significant. All calculations were performed with use of a commercially available statistical package (SPSS for Windows 6.0).
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Results |
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Univariate Predictors of Graft Rejection
ISHT 3AWe analyzed 2868 endomyocardial biopsies. Of these, 162 biopsies had no follow-up and 258 showed acute graft rejection treated by intensified immunosuppression and were excluded from analysis. Of the remaining 2448 biopsies, 374 (15.3%) were subsequent biopsies after ISHT 2 graft rejection. Of these, 70 (18.7%) progressed to more severe grades of rejection, whereas 82 (21.9%) remained unchanged and 222 (59.4%) resolved. In contrast, of the 2074 biopsies with lower grades of graft rejection (
ISHT 1B), the subsequent biopsy showed graft rejection ISHT 3A in only 153 patients (7.4%), ISHT 2 in 240 (11.6%), and mild or no graft rejection (ISHT 1B) in 1681 (81.1%) (2=89.7; P<.0001; Fig 1
). The OR of graft rejection ISHT 3A 7 to 10 days after ISHT 2 graft rejection was 2.89 compared with the follow-up after mild or no rejection (P<.0001). This OR was highest at month 2 and in the second year after transplantation and was lowest at month 5. In the third and subsequent years after transplantation, there was only a tendency toward an increased risk (Table 1).
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Time after transplantation was inversely related to graft rejection ISHT 3A; the OR per month after transplantation was 0.96 (95% CI, 0.95 to 0.98; P<.0001). Although the risk of graft rejection ISHT 3A decreased during late follow-up, it did not disappear even years after transplantation. The corresponding data during the second year after transplantation showed 19 episodes of graft rejection ISHT 3A (6.2% of 308 biopsies), and during the third and subsequent years, 22 such episodes occurred (3.6% of 616 biopsies) (Fig 2).
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Age at transplantation was not a predictor of graft rejection ISHT 3A. However, during the third and subsequent years after transplantation, those patients who suffered from graft rejection ISHT 3A were on average 9.8 years younger than those with only mild or no rejection (mean age, 32.4±16.8 versus 42.3±13.2 years; 95% CI, 2.3 to 17.4; P<.002).
Quilty effect was described in 442 biopsies (15.4%), of which 344 (77.8%) were type A and 98 (22.2%) type B. There was a strong correlation when graft rejection according to ISHT classification and Quilty lesions were compared (Table 2). The next biopsy after presence of Quilty A or B lesions was demonstrated showed an increased risk of graft rejection ISHT 3A (13.5% versus 8.4% compared with biopsies without Quilty lesion on previous biopsy; OR=1.70; 95% CI, 1.20 to 2.40; P<.005).
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The number of mismatches was related to the severity of graft rejection; the OR per mismatch for the appearance of graft rejection ISHT 3A was 1.27 (95% CI, 1.09 to 1.49; P<.005).
The mean dose of prednisone used during the study was 18.9±14.2 mg (median, 15 mg), that of azathioprine was 84.9±30.9 mg (median, 75 mg), and that of cyclosporine was 274.7±129.8 mg (median, 260 mg). The mean trough blood level of cyclosporine (monoclonal) was 188.7±66.3 µg/L (median, 182 µg/L). On average, blood levels of cyclosporine were lower in patients with graft rejection ISHT 3A (183.2±61.4 versus 192.3±65.9 µg/L; P=.07 by Mann-Whitney U test), and this difference was statistically significant in the first month after transplantation (164.3±59.2 versus 199.7±59.2 µg/L; P<.01). A significant positive relation between the occurrence of graft rejection ISHT 3A and the dose of prednisone and azathioprine was observed, but this relation disappeared after the introduction of time after transplantation as a covariable. This mirrors the effort to reduce the degree of immunosuppression late after transplantation.
Serum creatinine level (mean, 116.2±37.0 µmol/L; median, 109.0 µmol/L) was lower in graft rejection ISHT 3A (109.9±36.4 versus 117.7±35.9 µmol/L; P<.002 by Mann-Whitney U test) but was not correlated to blood level and correlated only very weakly to the dose of cyclosporine (r=.10; P<.001). Women had a slightly higher risk of graft rejection ISHT 3A (12.9% versus 8.7%; P<.05) as did patients with blood group type B (13.0% versus 8.4%; P<.005). Finally, our results failed to show a relation between cytomegalovirus infection and graft rejection.
Multivariate Predictors of Graft Rejection ISHT 3A
To determine which factors independently predicted graft rejection ISHT 3A, a multivariate logistic regression analysis was performed that included all parameters that showed a significant association with graft rejection ISHT 3A in univariate analysis. The results are shown in Table 3. ISHT 2 graft rejection remained an independent, significant predictor of graft rejection ISHT 3A on repeat biopsy 7 to 10 days later (OR=2.40; 95% CI, 1.69 to 3.42; P<.0001) and showed a similar pattern after transplantation as it did in univariate analysis (Table 1
). The influence of serum cyclosporine level was again strongest during the first month after transplantation (OR=0.92 per 10 ng/mL; 95% CI, 0.86 to 0.98; P<.01), although it remained an independent risk factor even late after transplantation. On the other hand, age primarily influenced the risk of rejection more than 2 years after transplantation (OR=0.94 per year; 95% CI, 0.91 to 0.98; P<.005). Overall, the two strongest predictors were time after transplantation (inversely correlated) and ISHT 2 graft rejection on previous biopsy.
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Discussion |
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In the present analysis, ISHT 2 rejection and time after transplantation emerged as the most important independent predictors of subsequent graft rejection
ISHT 3A. Although a strong, inverse correlation between graft rejection and time after transplantation has been described repeatedly,11 12 13 the finding of a strong, positive predictive value of ISHT 2 rejection is contrary to some previous reports.2 3 5 This discrepancy is not readily explained but may reflect differences in the use of repeat biopsies after ISHT 2 rejection. Because all ISHT 2 rejection episodes were followed up in this series by a control biopsy 7 to 10 days later without change of therapy, our data presumably are more representative of the short-term consequences of ISHT 2 lesions compared with other reports2 5 that did not follow this strict schedule of reassessment.
The data also show that the risk of progression to more severe rejection is highest, ie, 
40%, during the first few months after transplantation. Although the risk is lower later after transplantation, it nevertheless remains elevated. Accordingly, our data argue against the view that ISHT 2 rejection is a benign finding that rarely progresses to more severe rejection that requires additional therapy.2 3 7
The present data also shed more light on the controversy regarding the significance of Quilty-type lesions. Although the pathogenesis and significance of Quilty lesions remain unclear, some investigators have suggested that Quilty lesions may predict14 or represent graft rejection,14 15 whereas others16 have suggested that they are of little clinical significance and require neither increased immunosuppression nor short-term follow-up. In the present analysis, Quilty lesions were an independent predictor of subsequent higher-grade graft rejection (ISHT 3A), although the predictive value was less than that of the presence of ISHT 2 rejection. Moreover, we did not routinely perform follow-up biopsies in cases of isolated Quilty lesions; accordingly, the true importance of Quilty lesions cannot be accurately assessed from our data. However, our data disagree with the contention that ISHT 2 rejection may represent subendocardial portions of Quilty lesions7 for the following reasons. If this were true, Quilty B lesions should have been observed mainly in rejection classified as ISHT 2 or lower. However, Quilty B lesions were found predominantly in cases of higher degrees of cellular rejection (ISHT 3A), whereas Quilty A lesions mainly occurred in mild to moderate rejection. Furthermore, the frequency of Quilty lesions in our population was comparable to that seen in other surveys. Regarding Quilty B lesions and ISHT 2 rejection, a much higher proportion of Quilty B lesions would have to be assumed in our population (more than 15% of all biopsies) than previously reported.14 17 18
In addition to being a strong predictor of graft rejection ISHT 3A in univariate analysis, the presence of ISHT 2 rejection remained a powerful predictor in multivariate analysis into which all significant univariate parameters were entered. Multivariate analysis also showed that a low cyclosporine blood level, the number of HLA mismatches,12 19 20 21 22 blood group type B,23 age,12 19 and Quilty lesion on previous biopsy independently predicted graft rejection ISHT 3A. In contrast to other factors, cytomegalovirus seroconversion,24 sex,12 20 25 serum creatinine level,26 or dosage of immunosuppressive therapy26 27 28 did not independently influence the risk of graft rejection ISHT 3A. Although the majority of these differences cannot be explained easily, it is conceivable that the influence of serum creatinine reflects the negative impact of elevated cyclosporine levels in patients with a more difficult course regarding rejection and therefore that the association is lost when cyclosporine levels are entered into the equation.
The issue of the influence of cyclosporine levels on the incidence of graft rejection has been controversial in the past. Cyclosporine levels were found to have no or limited predictive value for graft rejection,29 30 31 but a reduction of cyclosporine levels was also found to increase the risk of graft rejection even late after transplantation.27 32 Our data indicate that its importance is greatest during the first month after transplantation when the incidence of graft rejection is also highest. Afterward, cyclosporine level remained an independent predictor of graft rejection, although its predictive value was much weaker.
Although not the main purpose of this investigation, it is interesting to note that graft rejection ISHT 3A was observed in our population up to 6 years after transplantation. Although the risk of graft rejection ISHT 3A is low during that period compared with the early postoperative period, this observation provides an argument for the performance of routine biopsies to detect moderate to severe graft rejections even late after transplantation because such episodes might still prove fatal.33
Our observation that ISHT 2 rejection progressed to higher-grade rejection in up to 20% of patients does not necessarily mean that these mild forms of rejection should be treated. However, it is possible that repeated episodes of mild to moderate graft rejection may impair the allograft and decrease the chance of survival.34 Prospective studies would be required to resolve the issue of whether the potential benefit of intensified immunosuppression for such episodes would outweigh the risks inherent in such a strategy.
The most important limitation of the present study is its retrospective design, and it might be argued that other important predictors of graft rejection were not examined in the present evaluation. However, the data were collected in a prospective manner, and all biopsy samples were examined by the same team of pathologists, which excluded a major source of bias. In addition, we avoided reclassification of biopsies performed before the introduction of the ISHT classification and thereby prevented further bias.
In conclusion, our data show that the strongest independent predictor of graft rejection ISHT 3A was prior ISHT 2 rejection 7 to 10 days earlier. Hence, ISHT 2 graft rejection is of clinical significance, and even if routine intensified immunosuppressive therapy is not mandatory, short-term follow-up seems to be warranted.
Received December 18, 1995; revision received March 27, 1996; accepted April 2, 1996.
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