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(Chest. 1999;116:1273-1277.)
© 1999 American College of Chest Physicians

A Low Incidence of Posttransplant Lymphoproliferative Disorder in 109 Lung Transplant Recipients*

Stephanie M. Levine, MD, FCCP; Luis Angel, MD; Antonio Anzueto, MD; Irawan Susanto, MD, FCCP; Jay I. Peters, MD, FCCP; Edward Y. Sako, MD, PhD, FCCP and Charles L. Bryan, MD, FCCP

* From the Department of Medicine (Drs. Levine, Angel, Anzueto, Susanto, Peters, and Bryan), Division of Pulmonary Diseases/Critical Care Medicine, and Department of Surgery (Dr. Sako), Division of Cardiothoracic Surgery and Transplant, University of Texas Health Science Center at San Antonio; and the South Texas Veterans Health Care System, Audie L. Murphy Memorial Veterans Hospital Division, San Antonio, TX

Correspondence to: Stephanie M. Levine, MD, FCCP, South Texas Veterans Health Care System, Audie L. Murphy Memorial Veterans Hospital Division, Pulmonary Section (111E), 7400 Merton Minter Blvd., San Antonio, TX 78284; e-mail: levines{at}uthscsa.edu


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: The incidence of posttransplant lymphoproliferative disorder (PTLD) has been reported to range from 6.4 to 20% in lung transplant (LT) recipients. Postulated contributing factors include Epstein-Barr virus (EBV) infection and the use of immunosuppression, particularly muromonab-CD3 (OKT3)(Orthoclone OKT-3; Ortho Biotech; Raritan, NJ). We sought to examine these PTLD risk factors in 109 LT recipients at our institution who survived > 1 month.

Design: Retrospective review of EBV serology of all LT recipients at our institution. Our standard transplant protocol includes OKT3 for induction and refractory rejection, as well as lifelong acyclovir for herpes prophylaxis. We do not perform EBV donor-recipient matching.

Setting: A university-based LT center.

Results: We found that 5 of 109 patients were serologically negative for EBV prior to lung transplantation, and all of these patients converted following lung transplantation. The mean time to conversion was 151 days (range, 11 to 365 days). One fatal case of PTLD was documented in an EBV seroconverter (one of five patients) 12 weeks status posttransplantation for lymphangioleiomyomatosis. One nonfatal extrathoracic PTLD was documented in a seropositive patient (1 of 104 patients) 33 months posttransplantation.

Conclusions: We conclude the following: (1) PTLD in LT recipients may have a lower incidence (2 of 109 patients; 1.8%) than previously reported, despite an aggressive immunosuppressive regimen; and (2) the incidence of PTLD is higher in patients with primary EBV infection (20% vs 1%).

Key Words: Epstein-Barr virus • lung transplantation • posttransplant lymphoproliferative disorder


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
It is well recognized that solid organ transplantation with its inherent immunosuppression is complicated by an increased incidence of malignancy.1 2 This is particularly true for lymphoproliferative disorders. Large series of solid organ posttransplant lymphoproliferative disease (PTLD) cases have revealed that the majority of PTLDs are non-Hodgkin’s lymphomas, particularly of the B-cell origin, and can range from polyclonal benign B-cell hyperplasia to malignant, aggressive monoclonal B-cell lymphomas.

Several contributing factors to PTLD have been postulated, including Epstein-Barr virus (EBV) donor-recipient mismatch and EBV seroconversion.3 4 The vast amount of evidence suggests that EBV plays an important role in the pathogenesis of PTLD.3 4 5 6 7 8 In the setting of immunosuppression, T-cell surveillance is suppressed, allowing B cells infected with EBV to proliferate unabated, potentially resulting in the transformation to PTLD.6 7 8 It has also been suggested that the development of PTLD is more often associated with primary EBV infection than reactivation EBV infection.3 4 9

Many authors have speculated that immunosuppressive regimens can contribute significantly to the development of PTLD.1 10 Various specific immunosuppressive agents have been implicated, including cyclosporine and particularly muromonab-C3 (OKT3) (Orthoclone OKT-3; Ortho Biotech; Raritan, NY) as an induction immunosuppressive agent or as a treatment for rejection.10

Four recent studies of lung transplant (LT) recipients reported the incidences of PTLD to be 6.4%, 7.9% 10%, and 20%, respectively–almost two- to six-times higher than that reported in other solid organ transplant recipients.3 11 12 13

The purpose of this study is to evaluate the incidence and risk factors for PTLD, specifically the EBV status and immunosuppressive therapy, in our LT population.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We reviewed the records of 116 single (n = 95) and bilateral (n = 21) LT recipients at our institution from September 1989 to January 1998. Of these 116 LT recipients, 109 survived for > 1 month (86 survived for > 1 year), with a mean follow-up of 1,215 days (range, 40 to 3,600 days); they were the focus of this study. Lung transplantation was performed according to a previously established surgical protocol.14

Our immunosuppressive induction protocol includes the following: (1) cyclosporine, 5 mg/kg po preoperatively, 2 to 4 mg/h postoperatively, and then titrated to maintain serum levels at 250 to 350 ng/mL as measured by radioimmunoassay; (2) IV methylprednisone, 500 mg intraoperatively, followed by 125 mg IV every 12 h for 6 doses postoperatively, then a standard oral prednisone taper over a 3-month time period; (3) IV azathioprine, 2 to 2.5 mg/kg/d, and then po adjusted to maintain a WBC count > 4,000/mm3; and (4) IV OKT3, 5 mg/d for 7 to 10 days for induction (with dose adjusted to CD3 T-lymphocyte levels) for the first 10 and last 50 patients.

Our maintenance immunosuppressive protocol includes the following: (1) cyclosporine titrated to serum levels of 250 to 350 ng/mL as measured by radioimmunoassay; (2) prednisone, 5 mg/d po; and (3) azathioprine, 2 mg/kg/d po. For acute or chronic rejection, our standard protocol includes two courses of augmented corticosteroid therapy followed by a slow taper. For resistant acute or chronic rejection, our protocol consists of OKT3 or lymphocyte immune globulin. An additional 15 patients received OKT3 or antithymocyte globulin for refractory rejection at some point in time during their posttransplant course. Fifteen patients received both induction and salvage lympholytic treatment.

Our standard infection prophylaxis for this group of patients includes the following: (1) IV ganciclovir 14 days postoperatively in addition to cytomegalovirus immune globulin intravenous (human), 150 mg/kg on day 1 and 100 mg/kg on day 14; (2) trimethoprim-sulfamethoxazole double strength, one tablet po three times per week; (3) itraconazole, 200 mg po qd for 3 months (beginning with patient 60); and (4) acyclovir, 800 mg po tid for 3 months, then 400 mg po tid lifelong.

Our EBV protocol includes recipient EBV screening of IgM and IgG pretransplant, during transplant, weekly posttransplant until hospital discharge, then monthly or on return to clinic. EBV matching of donor and recipient is not performed at our institution.

We retrospectively reviewed pretransplant and posttransplant EBV serology in our LT recipients. Serology was available on all 109 patients. EBV serologic and diagnostic titers included IgG and IgM antibodies to viral capsid antigen (VCA; IgG-VCA; IgM-VCA), early antigen (IgG-early antigen), and to EBV nuclear antigen run by standard immunoflorescence assay.4 15 Values are expressed as the ratio of the optical density of the patient’s sample to that of the calibrator value. EBV seropositivity was defined as the presence of any antibody (>= 1.0). We defined EBV seroconversion (primary infection) as conversion from negative IgM and IgG (< 1.0) serology prior to transplantation to an IgM >= 1.0 by enzyme immunoassay and/or an IgG >= 1.0 by enzyme immunoassay anytime following transplantation.4 15 Diagnosis of PTLD was made on the basis of histologic evaluation according to previously established criteria.15 We then correlated our incidence of PTLDs with these EBV findings. Statistical analysis included Student’s t test with a p value of <= 0.05 considered to be significant.16


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
There were two cases of PTLD out of 109 LT patients for an incidence of 1.8%. One hundred four of 109 patients (95%) had positive EBV serology prior to lung transplantation. Five of 109 patients (5%) had negative EBV serology prior to transplantation. All five patients who were EBV negative prior to transplantation converted following lung transplantation (Table 1 ). The mean and median time to seroconversion was 151 days (range, 11 to 365 days).


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  		Table 1. Demographics of EBV Seroconverters*

 
Illustrative Case 1
A 40-year-woman with lymphangioleiomyomatosis underwent a right single lung transplant (SLT) with a standard induction immunosuppressive regimen including OKT3. The patient was EBV seronegative prior to SLT (IgM, 0.07; IgG, 0.83) and converted 2 weeks following SLT (IgG, 1.73). Twelve weeks post-SLT, she presented with the new onset of a right chylothorax. The thoracentesis cytology was negative. An enlarging, right lower lobe nodule was noted on chest roentgenogram at that time, and a percutaneous fine needle aspirate was suggestive of lymphoma. Because of the nondefinitive pathologic findings, she underwent thoracotomy, the nodule was resected, and pathology revealed diffuse necrosis without evidence of malignancy. The right chylothorax persisted. Despite a reduction in immunosuppression, she died 7 months following SLT. Autopsy revealed disseminated monomorphic monoclonal B-cell lymphoma involving both the transplant and native lungs. In addition, the liver, kidneys, and CNS were also infiltrated with tumor. In situ hybridization for EBV was positive in the lymphoid infiltrates.

Illustrative Case 2
A 56-year-old man with COPD underwent a right SLT with standard immunosuppression. The patient was EBV seropositive prior to SLT (IgG, 3.08), and IgG titers remained in this range throughout the posttransplant period. He had an uncomplicated post-SLT course without acute or chronic rejection. Thirty-three months following SLT, he presented with constipation and abdominal swelling, and was found to have a 7 x 7 x 7 n-cm colonic mass by abdominal CT. He underwent colonoscopy, during which time an apple core lesion of the colon was found. A biopsy revealed PTLD, and he underwent colonic resection and a reduction in immunosuppression. EBV serologies at the time of diagnosis were IgM (0.03) and IgG (2.96). Pathology of the resected specimen revealed monomorphic, monoclonal B-cell lymphoma that stained positive for EBV by in situ hybridization. He is free of disease 8 months following diagnosis.


   Discussion
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 Abstract
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 Materials and Methods
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References
 
Recent studies (Table 2 ) have reported incidence rates of PTLD in LT recipients from 6.4 to 20%.3 11 12 13 In contrast to the reported PTLD incidence rates in the literature, our center has noted only a 1.8% incidence of PTLD in 109 LT recipients at risk, accounting for 1% mortality in our patient population. Montone et al13 have reported the highest incidence of PTLD in LT recipients (9 of 45 patients; 20%). All patients in her series presented with early PTLD (within the first year posttransplant) in the allograft, with a median and average time to development of 12 days and 52 days, respectively (range, 6 to 264 days). All nine patients had biopsy evidence of EBV RNA and DNA by in situ hybridization. The investigators examined but found no clear statistical relationship between human leukocyte antigen status of donor and recipient and PTLD development, and cumulative immunosuppression drug levels were comparable in the groups with and without PTLD. PTLD was not the primary cause of death in any patient in the series by Montone et al.13


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  		Table 2. Literature Review of PTLD in LT Recipients*

 
The large majority of our patients (104 of 109 patients; 95%) had positive EBV serology prior to undergoing lung transplantation. This high incidence of EBV positivity is most likely a result of our primarily adult patient population and is comparable to that in the general population.3 Those centers that primarily perform lung transplantation for cystic fibrosis (a younger population) have a lower incidence of positive EBV serology pretransplant, since EBV is often acquired during adolescence and young adulthood.12 All five of our seronegative patients (100%) seroconverted for EBV. This rate of primary EBV conversion is comparable to rates reported in other solid organ transplant series.12 17 However, only one of five EBV seroconverters (20%) developed PTLD. This is in contrast to findings from a recent series of 94 LT recipients by Aris et al12 at the University of North Carolina, in which 5 of 12 seroconverters (42%) developed PTLD. The overall incidence of PTLD in this series was 6 of 94 cases (6.4%).12 All six patients developed PTLD in thoracic structures at initial presentation, and all occurred within the first posttransplant year. Two patients died of PTLD. Also in this study, 1 of 60 of the seropositive recipients (< 2%) developed PTLD. This is comparable to that noted in our study, where only one case of PTLD occurred in 104 seropositive LT recipients at risk. Our study, as do many other series, supports that patients who are EBV seronegative pretransplantation are much more likely to develop PTLD than seropositive LT recipients (1 of 5 patients [20%] vs 1 of 104 patients [1%]; p < 0.01).

The presentation of PTLD with primary graft involvement developing within the first year following transplantation and the association with primary EBV infection (as in our illustrative case 1) are quite consistent with those described by Walker et al,3 Yousem et al,5 Armitage et al,11 Aris et al,12 and Montone et al.13 In contrast, the patient described in illustrative case 2 had an atypical PTLD presentation in that he was seropositive prior to SLT and developed a late (> 1 year post-SLT) extrathoracic PTLD. It is possible that we may observe more cases of PTLD with longer follow-up; however, our study has one of the longest follow-up periods (mean, 1,215 days), and 86 of patients (79%) were followed for > 1 year. Although the numbers in our study are small, our data support the significant mortality associated with PTLD as reported by Walker et al,3 Armitage et al,11 and Aris et al,12 but not Montone et al.13 Our patient with early PTLD suffered a rapidly fatal course, while our patient with late PTLD is tumor free at 8 months following diagnosis.

The available literature reveals that immunosuppression in those LT patients developing PTLD did not differ significantly from the remainder of the LT population. Similarly, neither of the two patients we described had had prior documented episodes of rejection, nor had they received augmentation of immunosuppression during the posttransplant course, although OKT3 was included in the induction regimen in both patients.

Previous studies suggest a strong association between EBV and the development of PTLD.17 18 19 20 Following solid organ transplantation and subsequent immunosuppression, reactivation of EBV infection in seropositive recipients, and to a more important extent, newly acquired primary EBV infection in seronegative recipients, either from an EBV-positive donor and/or EBV-containing blood products, can result. Subsequently, EBV can cause a polyclonal B-cell proliferation. In those individuals who are nonimmunosuppressed, B-cell proliferation is moderated by T-cell responses. Since immunosuppressive therapy impairs these controlling responses, EBV-induced polyclonal B-cell proliferation remains unchecked, allowing rapid proliferation and the potential for chromosomal translocation, resulting in monoclonal B-cell malignancy.17 18 19 Some authors have postulated that those patients acquiring primary EBV infection experience higher levels of oropharyngeal EBV shedding; in various studies, this seems to correlate with a higher risk of PTLD.21 Recently, the presence of latent membrane protein 1, the protein that facilitates the transformation of EBV-infected human B lymphocytes into malignant cells, has been documented to play a pathogenic role in PTLD.20

Our report describes a significantly lower PTLD incidence and mortality (1.8% and 1%, respectively) in a series of 109 LT recipients. We and others have speculated that perhaps the initial use of ganciclovir followed by prolonged acyclovir use may prevent the development of PTLD.21 22 23 Although the majority of LT programs use IV ganciclovir in the immediate posttransplant period (primarily for cytomegalovirus prophylaxis), in our program, following the conversion to oral medications, we use both a higher dosage of acyclovir and maintain this regimen for a longer duration (800 mg po tid for 3 months, and 400 mg po tid thereafter) than many other transplant programs (Table 2) .

Beneficial effects of acyclovir and ganciclovir have been reported for treatment of established PTLD.7 24 Antiviral agents such as acyclovir exert their antiviral effect on the lytic but not the latent phase of EBV infection.21 Acyclovir serves to eliminate oropharyngeal EBV shedding. However, following discontinuation of the drug, there is a rapid return to pretreatment levels of EBV shedding.21 Therefore, investigators have found that although oropharyngeal shedding was eliminated in patients on acyclovir therapy, the number of EBV-infected latent B cells in the peripheral blood did not change.25 Perhaps the role of acyclovir therapy could be limited because of this transient effect. Preiksaitis et al21 postulate that prophylactic antiviral therapy initiated at the time of transplantation may prevent the initial increases seen in EBV organisms, and thus acyclovir prophylaxis for EBV infection may be more effective in eliminating PTLD than preemptive or therapeutic treatment when EBV levels are high. We are currently recommending that, at the minimum, all EBV-negative LT recipients remain on lifelong acyclovir. Extrapolation of these recommendations to other solid organ recipients and seropositive patients will require further multicenter studies.

Other centers have taken the approach of performing EBV donor-recipient matching, ie, an EBV-negative recipient would only receive an organ from an EBV-negative donor, or even a more extreme approach of not considering EBV-negative patients for transplantation.3 At our institution, due to the limited donor resources, we have not undertaken this practice. In addition, the incidence of PTLD in our patient population would not support the practice of EBV seromatching or considering EBV seronegativity to be a contraindication to transplantation.

In conclusion, the 1.8% incidence of PTLD in our LT population, despite an aggressive immunosuppressive regimen, is significantly lower than that reported in the literature. Our study supports the hypothesis that primary EBV seroconversion may be an important contributing factor to the development of PTLD. Therefore, we further speculate that the low incidence of PTLD reported in this study may be due to prolonged acyclovir prophylaxis and its probable effect in preventing an initial rise in EBV organisms.


   Footnotes
 
Abbreviations: EBV = Epstein-Barr virus; LT = lung transplant; OKT3 = muromonab-CD3; PTLD = posttransplant lymphoproliferative disorder; SLT = single lung transplant; VCA = viral capsid antigen

Presented as an abstract at the 1995 International Conference of the American Thoracic Society, Seattle, WA, May 20–24, 1995.

Received for publication January 25, 1999. Accepted for publication May 11, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Penn, I (1990) Cancer complicating organ transplantation. N Engl J Med 323,1767-1769[ISI][Medline]
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