Lymphoproliferative disorder early after cardiac transplantation

most all patientswith acutePE. Dyspneaor tachypneaor pleuritic pain or radiographic evidenceof atelectasisor a parenchymal abnormality occurred in 99% of patients. All Inatients with PE had dvsnnea or tachvnnea or uleud I II ritic pain or deepvenousthrombosisor atelectasis/parenchymal abnormality or a Pa02 <80 mm Hg. Thesedata indicate that among; -- patients in whom PE was identified, only a small percentagedid not have a number of important manifestations.Thesemanifestationsare not specific for PE, and their presencedoesnot necessarilywarrant initiation of an investigation for PE. However, the recognition of these manifestations assistsin identifying patients in whom ventilation/perfusion scansor angiography, or both, may be necessary.

TABLE I Combinations of Clinical Findings in Patients with

Dyspnea or tachypnea* Dyspnea, tachypnea or pleuritic pain Dyspnea, tachypnea, pleuritic pain or DVT Dyspnea, tachypnea, pleuritic pain, or x-ray atelectasidparenchymal Dyspnea, tachypnea, pleuritic pain, DVT or x-ray atelectasislparenchymal Dyspnea, tachypnea, pleuritic pain, DVT, x-ray atelectasis/parenchymal or Pa02 < 80 mm Hg *Tachypnea = respiratory rate 220 beatslmin. DVl = signs of deep venous thmmbosis; Pa02 = partial arterial blood.

(91)

347/383 3711383 3731383 379/383

(97) (97) (99)

381/383

(99)

280/280

(100)

pressure of oxygen in

were identified among patients who participated in the Urokinase Pulmonary Embolism trial,3 and this experiencewas expandedupon in the PIOPED study through the identification of additional useful combinations.l Although such combinations are not specific for PE, thev are extremely sensitive in identifying the population in whom PE should be considered.In the presentstudy we tested combinations of clinical characteristicsamong all patients with acutePE, irrespectiveof prior cardiopuhnonary disease.Several combinations were present in alI

Lymphoproliferative

,

w

l. Stein PD, Terrin ML, Hales CA, PalevskyHI, SaltzmanHA, ThompsonBT, Weg JG. Clinical, laboratory, roentgenographicand electrocardiographictindings in patients with acute pulmonary embolismand no pre-existing cardiac or pulmonary disease.Chest 1991;100:598-603. 2. The PIOPED Investigators.Value of the ventilation/perfusion scan in acute pulmonary embolism:resultsof the ProspectiveInvestigation of Pulmonary Emholism Diagnosis (PIOPED). JAM.4 1990;263:2753-2759. 3. Stein PD, Willis PW III, DeMets DL. History and physical examination in acute pulmonary embolismin patientswithout pre-existingcardiac or pulmonary disease.Am J Cardiol 1981;47:218-223,

Disorder Early After Cardiac Transplantation

Debbie Rinde-Hoffman, MD, Guillermo B. Cintron, MD, Jane E. Ferguson, RN, BSN, John C. Toole, MD, and William B. Bugni, MD n cardiac transplantation, extremely potent immunosuppressiveagentsare used,which leavethe host vulnerable to a variety of infections and malignancies. Among the malignancies, lymphoproliferative disorders are the most common.’ Most casesof posttransplant lymphoproliferative disordershave been described in patients who haveundergoneseveralmonths of immunosuppression.2p3This report describes our experience with patients who developedlymphoproliferative disorder within 3 months of heart transplantation.

I

Our patient population includes all patients who underwent cardiac transplantation at the University of South Florida/Tampa General Hospital and at St. Joseph’s Hospital in Tampa, Florida. As of December 1989, 79 patients had undergone heart transplantation at University of South Florida/Tampa General Hospital and 13 at St. Joseph’s Hospital. All patients received immunosuppressive therapy with cyclosporFrom the Division of Cardiology, Department of Internal Medicine, University of South Florida College of Medicine, and the Heart Transplant Program, Tampa General Hospital, Tampa, Florida. Manuscript received April 17, 199 1; revised manuscript received and accepted July 15, 1991.

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ine, azathioprine and prednisone in doses adjusted to the overall clinical condition. In addition, during 1989, “induction” or prophylactic immunosuppressive therapy with OKT3 was initiated within 48 hours of cardiac transplantation. OKT3 was administered by an intravenous infusion of 5 mg/day for 14 consecu tive days. We defined lymphoproliferative disorder as a histologically documented disorder characterized by uncontrolled monoclonal or polyclonal proliferation of B lymphocytes within, or separate from, lymph nodes. Clinical data were obtained from individual medical records. Table I outlines the salient features in our patients with lymphoproliferative disorder. All patients received OKT3, 3 as part of a prophylactic “induction” protocol and 2 as rescue therapy for acute early cardiac rejection unresponsive to high-dose intravenous corticosteroid therapy. The initial clinical presentation included fever, lymphadenopathy and abnormal liver function tests. In 3 patients the clinical course was one of rapid irreversible multisystem failure and at autopsy all 3patients with active lymphoproliferaDECEMBER

15, 1991

TABLE I Clinical Features of Five Patients with Lymphoproliferative Pt. No.

Age (yr) & Sex

Total OKT3 Dose (mg)

1 2 3 4 5

53M 34M 51M 59M 65M

70-I 70-I 70-R 70-R 70-I

Interval (wks)

Fever

5 3 9 12 10

0’ + + +

Abnormal LFT + 0 0 0’

Disorder Early After Transplantation

PTL Type

Organ Involved

Polyclonal

LN, LN, LN, LN, LN,

Polyclonal Polyclonal

LVR, LVR, heart LVR, LVR,

PCRD, kidney, adrenal SP SP, PCRD, colon, adrenal, bone marrow SP, PCRD, pleura, kidney, urinary bladder

I = prophylactic “induction” therapy; Interval = time in weeks from heart transplant to onset of lymphoma; ET = liver function test; LN = lymph node; LVR = liver; PCRD = pericardium: PTL = post-transplant lymphaproliferative disorder; R = rescuetherapy; SP = spleen; 0 = absent; + = present.

tive disorder had diffuse multiorgan involvement. Patient 2 died of acute severe graft rejection and the lymphoproliferative disorder was an unsuspected finding. Patient 3, who had his immunosuppressive therapy decreased, died of coronary vasculopathy without evidence of active lymphoproliferative disorder. The reported incidence of lymphoproliferative disorder in transplant patients is approximately 2%’ The higher reportedincidenceof lymphoproliferative disorder in heart transplant patients has been attributed to the high level of immunosuppressionto which thesepatients are subjected.4In our patient population, the incidenceof lymphoproliferative disorder is approximately 5.5%. Post-transplant lymphoproliferative disorders have been associatedwith Epstein-Barr virus infection.5$6In the nonimmunosuppressedhost, Epstein-Barr virus stimulates B-cell proliferation which is usually kept in check by immune regulatory mechanisms,specifically the cytotoxic T lymphocytes. It is proposedthat in transplant patients, immunosuppressionallows for the uncontrolled proliferation of B lymphocytes.’ Not all transplant patients who are infected with Epstein-Barr virus develop lymphoproliferative disorder. Some investigators have suggestedthat primary Epstein-Barr virus infection, reactivation of Epstein-Barr virus during profound immunosuppressionand possibly high antigenic stimulation from the graft may be factors contributing to the development of lymphoproliferative disorder.lv4y5 OKT3, a monoclonal antibody that binds to the CD3 antigen presenton T cells, causesparalysis of the T cells and inhibits cytotoxic T-cell function. Although useful in reversingacute cellular rejection, OKT3 may be a factor contributing to the development of lymphoproliferative

disorder. A similar experienceto ours has been reported by the cardiac transplant group at L.oyolaUniversity.6 In both series,patients with early lymphoproliferative disorder presentedwith fever and fuhninant multiorgan involvement, which appearedto be related to the use of OKT3. The relation with OKT3 may have geographical variability because,in other transplant programs,the use of OKT3 doesnot seemto predisposepatientsto lymphoproliferative disorder (O’Connell JB, personalcommunication). Early lymphoproliferative disorder presentsas a febrile, disseminatedmultisystem diseasethat can be rapidly fatal. There appearsto be a relation betweenthe use of OKT3 and the appearanceof early lymphoproliferative disorder. The risks and benefits of early aggressive antithymocyte therapy should be carefully assessed.

1. Nalesnik MA, Makowaka L, Starzl TE. The diagnosis and treatment of posttransplant lymphoproliferative disorders. Current Probl Surg 1988;25: 365-412. 2. Hanto DW, Frizzera G, Gajl-Peczalska KJ, Simmons RJ. Epstein-Barr virus, immunodeficiency, and B cell lymphoproliferation. Tramplantation 1985;39: 461-471. 3. Penn I, First MR. Development and incidence of cancer following cyclosporine therapy. Transplant Pm 1986;18:210-213. 4. Brumbaugh J, Baldwin JC, Stinson EB, Oyer PE, Jam&on SW, Biber CP, Henle W, Shumway NE. Quantitative analysis of immunosuppression in cyclosporine-treated heart transplant patients with lymphoma. Heart Trnnsplanr 1985;4:307-311. 5. Ho M, Miller G, Atchison RW, Breining MK, Dummer S, Andiman W, Starzl TE, Eastman E, Griffith BP, Hardesty RL, Bahnson HT, Hakala TR, Rwenthal JT. Epstein-Barr virus infections and DNA hybridization studies in post transplantation lymphoma and lymphoproliferative lesions: the role of primary infcction. J Infect Dis 1985;152:876-886. 6. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, O’Sullivan EJ, Johnson MR, Heroux AL, Dizikes GJ, Pifarre R, Fisher RI. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac transplant recipients. N Engi J Med 1990;323:1723-1728.

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