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(Circulation. 1995;91:1975-1980.)
© 1995 American Heart Association, Inc.

Articles

Natural History of Focal Moderate Cardiac Allograft Rejection

Is Treatment Warranted?

Gayle L. Winters, MD; Evan Loh, MD; Frederick J. Schoen, MD, PhD

From the Department of Pathology (G.L.W., F.J.S.) and Cardiovascular Division, Department of Medicine (E.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.

	Abstract

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Background The rate of progression and potential long-term consequences of isolated foci of moderate acute rejection (FMR) on endomyocardial biopsy (EMB) have not been defined; therefore, whether FMR necessitates augmented immunosuppression remains controversial.

Methods and Results At our institution, recipients with EMBs having FMR, defined as one or two isolated foci of cellular infiltrates with associated myocyte damage (International Society for Heart and Lung Transplantation [ISHLT] grade 2 and a subset of grade 3A), do not routinely receive intensified immunosuppression. Accordingly, to determine the outcome of untreated FMR, we reviewed 4398 EMBs (mean, 4.4 samples each) obtained after orthotopic heart transplantation in 208 consecutive recipients maintained on triple immunosuppressive therapy. The incidence of progression versus resolution of FMR, the time interval after transplantation when FMR was detected, and the relation of untreated FMR to recipient survival were analyzed. FMR categorized as one (n=312) or two (n=89) foci was present in 401 EMBs (9% of total) obtained 10 days to 7.5 years after transplantation from 149 recipients (72%). EMBs with FMR resolved without treatment in 341 of 401 (85%), and only 60 of 401 (15%) progressed to higher grade rejection. EMBs that progressed occurred 7.5±7.9 months (mean±SD) after transplantation compared with 14.0±16.5 months after transplantation for those that resolved (P<.005). Of the 60 EMBs that progressed, 55% occurred within the first 6 months, 78% within the first year, and 97% within the first 2 years after transplantation. EMBs with two foci of FMR were no more likely to progress than those with one focus. Thirty-nine recipients experienced one (n=25), two (n=9), three (n=3), or four (n=2) episodes of FMR that progressed. One or more episodes of FMR that did not progress occurred in 110 recipients. By Kaplan-Meier analysis, survival at 1 and 5 years was similar in recipients with and those without FMR progression.

Conclusions First, untreated FMR consisting of either one or two foci has a low rate of progression. Second, progression of FMR decreases with increasing postoperative interval and becomes rare after 2 years. Last, FMR progression did not identify recipients with decreased survival.

Key Words: biopsy • pathology • rejection • transplantation

	Introduction

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The histological diagnosis and grading of acute rejection on serial endomyocardial biopsies (EMBs) are used to guide the immunosuppressive therapy of heart transplant recipients, but the exact point in the spectrum of histological rejection that requires intensification of immunosuppression remains to be determined. According to the International Society for Heart and Lung Transplantation (ISHLT) working formulation,¹ moderate acute rejection is defined as lymphocytic inflammatory infiltrates with associated myocyte encroachment or damage. This infiltrate may be present as a single focus (ISHLT grade 2), a multifocal pattern (ISHLT grade 3A), or a diffuse process (ISHLT grade 3B). Less severe degrees of rejection (ISHLT grades 1A and 1B) have been shown to resolve without treatment in a high percentage of cases^{2 3 4 5} and, therefore, remain untreated in many heart transplant centers.

Controversy remains regarding the treatment of focal moderate rejection (FMR), defined as one or two foci of lymphocytic infiltrates with associated myocyte damage. The clinical response to biopsy findings of asymptomatic FMR includes no change in therapy, repeat biopsy earlier than scheduled, or augmentation of immunosuppresssion. Although some transplant centers have elected not to treat single, or even several, foci of moderate rejection to reduce the risks of immunosuppression-related side effects, the natural history of isolated foci of moderate rejection has not been defined. Moreover, the decision of whether to treat lower grades of acute rejection may have long-ranging implications since the possible relation between rejection episodes and late deterioration of allograft function remains an unresolved issue.

The purpose of this study was to determine the frequency with which isolated foci of moderate rejection progress to higher-grade rejection if not treated, to define the relation between the posttransplantation interval at which FMR occurs and progression to more severe rejection, and to examine the relation between untreated focal moderate acute rejection and recipient survival.

	Methods

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Study Population
Of the 208 consecutive orthotopic heart transplant recipients at Brigham and Women's Hospital during the 9-year period of February 1984 through January 1993, 149 (72%) had one or two foci of moderate acute rejection on at least one EMB.

Patient Characteristics and Immunosuppression Protocol
The mean age of the study population was 46±12 years (mean±SD; range, 14 to 63 years). There were 112 males and 37 females. Indications for transplantation were ischemic heart disease in 60, idiopathic dilated cardiomyopathy in 76, valvular heart disease in 8, and other in 5 patients. Maintenance immunosuppression consisted of cyclosporine and prednisone before 1988, and triple-drug immunosuppression consisting of cyclosporine, azathioprine, and prednisone beginning in 1988. Recipients received no lymphocytolytic induction therapy. Patient demographics and immunosuppression protocols were similar between the study group and in the total recipient population.

EMBs
After heart transplantation, EMBs were routinely performed according to the following schedule: first posttransplantation year, weekly for 4 weeks, biweekly for 4 weeks, monthly for 6 months, and then every other month to 1 year; second posttransplantation year, every 3 months for 6 months, then every 6 months; and third and subsequent posttransplantation years, every 6 months. Additional unscheduled biopsies may have been performed due to an adverse change in the recipient's clinical condition or new findings on objective testing.

Processing of the biopsies consisted of fixation in 10% neutral buffered formalin followed by paraffin embedding, sectioning at 4-µm thickness, and staining with hematoxylin and eosin. Special stains (most frequently, Masson's trichrome) and other studies (such as immunohistochemistry) were done when indicated based on morphological findings.

The number of myocardial tissue samples evaluated per biopsy ranged from 3 to 10 with a mean of 4.4 samples per biopsy evaluation. Biopsies consisting of two or fewer myocardial samples were considered insufficient for accurate grading.

Biopsy Interpretation and Treatment of Rejection
EMB samples were assigned a histological grade of rejection according to the ISHLT working formulation.¹ Grade 2 rejection, defined as one focus of lymphocytic infiltrate with associated myocyte encroachment or damage, is not routinely treated in this transplant program. ISHLT grade 3A, containing three or more foci of lymphocytic infiltrate with myocyte damage, is routinely treated with augmented immunosuppression. Because EMBs with two foci were not routinely treated with augmented immunosuppression, those biopsies were given a separate designation and therefore retrievable for this study (Fig 1). In the context of this study, focal moderate rejection (FMR) refers to those biopsies with either one or two foci of lymphocytic infiltrate with associated myocyte damage that were not treated with increased immunosuppression. All biopsies obtained before 1991 were retrospectively graded according to the ISHLT working formulation with the above-stated modification for the purpose of this study.

View larger version (221K): [in this window] [in a new window]   Figure 1. Photomicrographs of endomyocardial biopsies with focal moderate rejection (FMR) characterized by one focus, International Society for Heart and Lung Transplantation (ISHLT) grade 2 (A), or two foci, a subset of ISHLT grade 3A (B) of lymphocytic infiltration with associated myocyte damage. FMR was not treated with intensified immunosuppression. Compare with focus of perivascular lymphocytic infiltrate without associated myocyte damage, ISHLT grade 1A (C), which also is not treated. Biopsies containing multifocal (three or more) lymphocytic infiltrates, grade 3A (D), with associated myocyte damage (inset) are uniformly treated. A through C and inset, hematoxylin and eosin x400; D, hematoxylin and eosin, x100.

Definition of Outcomes
"Resolution" was defined as histological findings of one or two foci of moderate rejection on one or more consecutive biopsies that were followed by a biopsy negative for rejection with no intervening episodes of more severe rejection. "Progression" was defined as histological findings of one or two foci of moderate rejection on one or more consecutive biopsies that were followed by a biopsy with grade 3A or greater rejection.

Statistical Analysis
Data are presented as mean±SD. Group comparisons were performed using t test and ² analyses where appropriate. Kaplan-Meier curves were used to evaluate survival. A value of P<.05 was considered to be statistically significant.

	Results

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Of 4398 EMBs obtained 10 days to 7.5 years after heart transplantation, 401 (9%) contained one (n=312) or two (n=89) foci of moderate acute rejection. Of these, 341 (85%) resolved, whereas only 60 (15%) progressed to more severe grades of rejection. Similar results were obtained when one or two foci of moderate rejection were considered separately (Fig 2). Of the 60 EMBs that progressed, 45 progressed from one focus and 15 progressed from two foci (Fig 3). The most common pattern of progression from either one or two foci was to grade 3A. A higher percentage of biopsies with two foci than one focus progressed to grade 3B rejection, but the difference was not statistically significant. No EMBs with FMR progressed directly to severe rejection (ISHLT grade 4).

View larger version (18K): [in this window] [in a new window]   Figure 2. Bar graph of outcome of untreated focal moderate rejection. P<.005 resolution vs progression.

View larger version (19K): [in this window] [in a new window]   Figure 3. Bar graph of progression to grade 3 rejection from one and two foci of focal moderate rejection (FMR). P=.50 progression to grade 3B from two foci vs one focus.

The outcome of FMR depended on the interval after transplantation (Fig 4). EMBs with FMR that progressed occurred 7.5±7.9 months (mean±SD) after transplantation compared with a posttransplantation interval of 14.0±16.5 months for EMBs with FMR that resolved (P<.005). All except one biopsy that progressed occurred within the first 2 posttransplantation years; all biopsies that progressed to grade 3B occurred within the first 6 months. Therefore, of the 60 biopsies that progressed, 55% occurred within the first 6 months, 78% within the first year, and 97% within 2 years after transplantation (Fig 5).

View larger version (26K): [in this window] [in a new window]   Figure 4. Plot of relation between posttransplantation interval and outcome. Each point represents a biopsy plotted according to whether it progressed or resolved and the time after transplantation that it was obtained. Note the change in scale from 36 to 48 months and the cumulative grouping of all biopsies obtained after 4 years. Biopsies that progressed were obtained a mean of 7.5 months after transplantation compared with a mean posttransplantation interval of 14 months for those that resolved. P<.005.

View larger version (19K): [in this window] [in a new window]   Figure 5. Bar graph of relation between posttransplantation interval and progression (n=60 endomyocardial biopsies).

FMR progression did not identify recipients with decreased survival. Recipients were divided into two groups according to the outcome of untreated FMR. Progression occurred in 39 recipients who experienced one (n=25), two (n=9), three (n=3), or four (n=2) episodes. The remaining 110 recipients had one or more episodes of FMR that did not progress. Survival of the two groups was identical at 1 and 5 years by Kaplan-Meier analysis (Fig 6).

View larger version (23K): [in this window] [in a new window]   Figure 6. Kaplan-Meier survival curve for recipients with one or more biopsies with focal moderate rejection (FMR) that progressed compared with recipients with FMR that resolved. P=.78.

	Discussion

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The major findings of the present study were that FMR has a low rate of progression, FMR detected during the early posttransplantation period is more likely to progress to more severe rejection, and outcome of FMR does not predict survival.

FMR Has a Low Rate of Progression
Immunosuppressive protocols and the threshold for treatment of histological rejection vary markedly among heart transplant centers.⁶ The point at which immunosuppression is intensified ranges from mild to subclasses of moderate rejection, with many programs using the presence of any myocyte injury as a threshold for treatment.

Although moderate (ISHLT grades 3A and 3B) and severe (ISHLT grade 4) rejection are treated with intensified immunosuppression in most transplant centers, there is much less agreement concerning at what point lower-grade rejection should first be treated.⁷ At some transplant centers, immunosuppression is intensified in the presence of mild rejection (ISHLT grade IB), whereas at other centers, focal moderate rejection (ISHLT grade 2) and some multifocal moderate rejection (ISHLT grade 3A) episodes are untreated. These treatment decisions are based, in part, on the specific immunosuppressive regimens used and prior experience with rejection in individual transplant centers and underscores the importance of close communication between the pathologist who is interpreting the biopsies and the clinician who is responsible for management of immunosuppression. Avoiding treatment of lower-grade rejection prevents unnecessary exposure of patients to the adverse effects of immunosuppression for levels of rejection that may resolve spontaneously.

Pathologists are frequently faced with the difficult decision of whether myocyte damage accompanies the inflammatory infiltrates since the finding of myocyte damage may increase the grade of rejection and result in augmented immunosuppression. In the present study, 9% of EMBs contained isolated foci of moderate rejection, 85% of which resolved without treatment regardless of whether there was one (ISHLT grade 2) or two foci of moderate rejection present. Based on frequency of progression, the results of the present study support not treating histological findings of one or two foci of moderate rejection. In addition, the practice of equating two foci with more advanced rejection may deserve reconsideration in grading schemes.

Histological criteria that would allow prediction of whether FMR will progress or resolve are not readily apparent. It is possible that some isolated foci of lymphocytic infiltrates with associated myocyte damage may represent processes other than rejection (ie, early postoperative healing ischemic injury⁸ or a Quilty B⁹ lesion without apparent connection to the endocardium). These lesions would not be expected to progress to higher grades of rejection. However, heightened awareness and better definition of histological criteria will allow increasing ability to diagnose and separate these lesions from foci of rejection.

It seems reasonable that as severity of rejection increases, a critical level is reached that will not resolve without augmentation of immunosuppression. However, the pathobiological determinants of this process and the exact amount or characteristics of the infiltrate that should serve as the threshold for treatment have yet to be defined. Understandably, there is a reluctance to conduct randomized trials on higher grades of rejection since some patients would not receive standard immunosuppressive therapy. In our patient population using the described immunosuppressive regimen, the present study at least provides support for our approach of not intensifying immunosuppression in patients with histological findings of FMR.

FMR Detected During the Early Posttransplantation Period Is More Likely to Progress to More Severe Rejection
The majority of rejection episodes occur within the first 6 months after heart transplantation.^{10 11} Mild rejection that occurs within the first 3 posttransplantation months or is associated with allograft dysfunction has been shown to have increased frequency of progression to more severe rejection and may warrant closer follow-up in these settings.^{3 4} Similarly, the greater percentage of biopsies with FMR that progressed occurred during the early posttransplantation period. The likelihood of progression decreased as the posttransplantation interval increased so that only 3% of biopsies with FMR that progressed occurred after the second posttransplantation year. In addition, although progression to grade 3A was evenly divided between 6 months and >6 months after transplantation, all 7 EMBs with FMR that progressed to grade 3B rejection were obtained in the first 6 posttransplantation months. These findings suggest that untreated FMR occurring during the first 6 posttransplantation months merits at least increased surveillance.

Does Untreated FMR Affect Long-term Survival?
In the present study, recipients with FMR that progressed did not have decreased 1- and 5-year survival rates compared with recipients with FMR that did not progress. Although the results of the present study indicate no deleterious short-term effect or adverse survival from untreated FMR, the possibility that rejection contributes to long-term allograft dysfunction remains an unresolved but important consideration.

Two important etiologies of long-term allograft dysfunction are graft coronary disease (GCD) and impaired cardiac function secondary to myocardial fibrosis. Manifest as diffuse, concentric intimal thickening of uncertain pathogenesis,^{12 13 14} GCD accounts for as many as 60% of late deaths in cardiac allograft recipients.¹⁵ Several lines of evidence suggest that GCD is caused by ongoing immune injury against the vascular components of the allograft.^{16 17 18} However, attempts to correlate the incidence and/or severity of cellular rejection with the later development of GCD in the clinical setting have produced inconsistent results.^{19 20 21 22 23 24 25} When cause of death in our study population was examined, we could not demonstrate a statistically significant relation between FMR and death from GCD. Impaired diastolic function in the transplanted heart has been associated with myocardial fibrosis,^{26 27} which may result from a number of insults to the myocardium, including repeated rejection episodes. The key to successful prevention or early therapeutic intervention will likely involve a better understanding of the pathogenic mechanisms that cause or contribute to late graft failure. The relation of rejection episodes, whether treated or untreated, to processes resulting in allograft failure deserves further study.

Conclusion
Eighty-five percent of EMBs with one or two foci of moderate rejection resolve without treatment; therefore, routine intensification of immunosuppression is not warranted. In the present study, we were not able to detect any difference in the natural history of one focus compared with two foci of moderate rejection so that the clinical response to these two histological findings should be similar. FMR occurring early in the posttransplantation course is more likely to progress to more severe rejection and deserves closer follow-up. Treatment parameters, however, should be reconsidered if further studies confirm a contribution of rejection below current treatment thresholds to long-term allograft dysfunction.

	Acknowledgments

 
This work was supported in part by grant HL-43364 from the National Heart, Lung, and Blood Institute. We thank the members of the Brigham and Women's Hospital Cardiac Transplant Service for their efforts in the clinical management of the patients studied, Dr Richard Mitchell for his contributions in endomyocardial biopsy interpretation and transplant autopsies, and Dr Alex Kartashov for aiding us in statistical analysis.

	Footnotes

 
Reprint requests to Gayle L. Winters, MD, Department of Pathology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.

Dr Loh's present address is Heart Failure and Cardiac Transplantation Program, Hospital of the University of Pennsylvania (Philadelphia).

Received August 1, 1994; revision received November 1, 1994; accepted November 13, 1994.

	References

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