Prophylactic therapy for rejection after cardiac transplantation

J

THORAC CARDIOVASC SURG

1990;99:716-24

Prophylactic therapy for rejection after cardiac transplantation A comparison of rabbit antithymocyte globulin and OKT3 The value of prophylactic monoclonal or polyclonal antibody therapy early after cardiac transplantation is controversial. Between Jan. 1, 1987, and July 1, 1988, 32 consecutive patients underwent cardiac transplantation (cyclosporine, azathioprine, and prednisone maintenance therapy) with either early prophylactic rabbit antithymocyte globulin (n = 17) or monoclonal OKT3 (Ortho Diagnostic Systems, Inc., Raritan, N.J.) (10 days) (n = 15). FoUow-up was through Sept. 1, 1988, for morbid events and through Jan. 1, 1989, for survival. AU patients (100%) survived the study period (foUow-up of 6 to 24 months). The efficacy of rabbit antithymocyte globulin and OKT3 prophylaxis was similar regarding median time (days) to first rejection (16 versus 21 days, p = 0.5), number of rejection episodes during first 2 months (1.5 versus 1.3 days, p = 0.8), and freedom from rejection at 2 months (18% versus 27%, p = 0.8). Early infections were slightly less common in the rabbit antithymocyte globulin group than the OKT3 group (median time to first infection: 318 versus 250 days, p = 0.5; freedom from rejection at 2 months: 82% versus 64%, p = 0.21), although differences were likely due to chance. Cytomegalovirus syndrome was common, with one case of cytomegalovirus pneumonia. T-ceU markers during OKT3 treatment did not predict subsequent rejection (within 2 weeks after OKT3) as assessed by mean T3-lymphocyte count during OKT3 use (p = 0.3) or T3-lymphocyte count during the last 3 days of OKT3 use (p = 0.4). Inferences: (1) Prophylactic rabbit antithymocyte globulin or OKT3 with triple-drug immunosuppression yields exceUent intermediate survival after heart transplantation. (2) These protocols for rabbit antithymocyte globulin and OKT3 provide similar protection against early rejection with a relatively low risk of early infection. (3) T-ceU markers do not predict early rejection after OKT3.

James K. Kirklin, MD,a Robert C. Bourge, MD,b Connie White-Williams, RN,a David C. Naftel, Phl)," Francis T. Thomas, MD,c Judith M. Thomas, Phl),? and Michael G. Phillips, PA-C,d Birmingham, Ala., and Greenville, NiC.

In the current era, l-year survival rates in excess of 90% have been achieved after cardiac transplantation with a maintenance immunosuppressive program of prednisone, cyclosporine, and azathioprine. 1,2 Recently data from the From the Divisionsof Cardiothoracic Surgery,' and Cardiology,b University of Alabama at Birmingham, Birmingham, Ala.; Department of Surgery," East Carolina University, Greenville, N.C.; and the Alabama Regional Organ and Tissue Center," Birmingham, Ala. Received for publication Feb. 24,1989. Accepted for publication June 16, 1989. Address for reprints: James K. Kirklin, MD, University of Alabama at • Birmingham, Department of Surgery, University Station, Birmingham, AL 35294.

12/1/15524

716

University of Utah have suggested a reduction in early rejection with excellent intermediate-term survival with a program including early prophylactic therapy with the monoclonal antibody OKT3 (Ortho Diagnostic Systems, Inc., Raritan, N.J.).2 This prospective study was undertaken to compare the efficacy of early prophylactic antirejection treatment with polyclonal rabbit antithymocyte globulin (RATG, see Appendix) versus monoclonal OKT3 in a program of cardiac transplantation with triple-drug (prednisone, azathioprine, and cyclosporine) immunosuppressive therapy. Material and methods Between Jan. 1, 1987, and July I, 1988, 32 consecutive patients with end-stage cardiac disease underwent cardiac transplantation at the University of Alabama at Birmingham (UAB)

Volume 99 Number 4 April 1990

RATG and OKT3 in rejection after cardiac transplantation

Medical Center. One of two protocols was used: prophylactic RATG or prophylactic OKT3 therapy. All patients undergoing cardiac transplantation during this era were included in this study. Ages at transplantation ranged from 20 to 62 years with a median age of 49 years. Twenty-eight patients underwent primary orthotopic cardiac transplantation, three patients underwent secondary orthotopic cardiac transplantation (two for chronic obstructive coronary artery disease and one because of acute irreversible rejection associated with cardiogenic shock), and one underwent heterotopic cardiac transplantation. Immunosuppression protocols. All patients received an immunosuppression protocol including chronic maintenance prednisone, cyclosporine, and azathioprine. Before operation patients received azathioprine (2 mgjkg) (usually 125 or 150 mg orally) and cyclosporine (I to 10 mgjkg) orally. Intraoperatively, methylprednisolone (Solu-Medrol) was administered during sternotomy (250 rng) and after discontinuation of cardiopulmonary bypass (500 mg). After operation three doses of methylprednisolone (125 mg) were administered every 8 hours. Prednisone was initiated at a dose of I mgjkg (divided doses) per day and generally continued for a total duration of I week after the completion of RATG or OKT3 therapy. Thereafter, prednisone was tapered by 5 mg daily until a daily maintenance dose of 10 mg was achieved. Cyclosporine was usually administered intravenously after operation (5 to 10 mg every 6 hours by continuous infusion), and oral cyclosporine dosages were initiated at I mgjkgjday and gradually increased for a target level of 700 to 900 ngjml (whole blood polyclonal antibody radioimmunoassay, INCSTAR, INC, Stillwater, Minn.) for the first 3 weeks, 600 to 800 ngjml for the second 3 weeks, and 400 to 600 ngjml for chronic maintenance therapy (adjusted according to renal function). Azathioprine dosage was 2 mg/kg orally for the first 3 weeks, 1.5 mgjkgjday orally for the second 3 weeks, and maintenance therapy of I mgjkgjday thereafter (with further reduction of dosage if white blood count fell below 4000jml). In the prophylactic RATG protocol, RA TG was administered intramuscularly at a dose of I mgjkg before operation and then daily after operation for a total of 5 to 6 days. Because of an inadequate supply of RA TG, in two patients prophylactic antithymocyte globulin (Atgam; Upjohn, Kalamazoo, Mich.) was administered daily for 5 days (see Appendix). Early in the RATG protocol, prophylactic RATG was initiated after operation in one patient beginning on postoperative day 2 for 4 days and in another patient beginning on postoperative day 3 for 5 days. Another patient received a total of only 4 days of RATG therapy because of a shortage of supply. These patients were analyzed in the "RATG prophylaxis" category. In the OKT3 prophylaxis protocol. OKT3 was administered within the first few hours of transplantation at a dose of 5 mg intravenously and continued for 10 days after transplantation (in two patients prophylactic OKT3 was continued for 14 days). In four patients, OKT3 administration was delayed until the first postoperative day because of early hemodynamic instability. In chronologie terms (with one exception), the RATG protocol constituted the first half of the experience and the OKT3 protocol the second half. The single exception was the patient who underwent emergency retransplantation because of refractory acute rejection associated with cardiogenic shock 3Y2 months after his initial transplant. He received 5 days of attempted OKT3 rescue therapy immediately before his retransplantation. OKT3 was continued for 5 days after his second transplantation, and this 10-day period of OKT3 was

717

included in the prophylactic OKT3 group (but performed chrpnologically during the RATG protocol). Standard protocols were followed for supplemental medications administered during RATG, Atgam, or OKT3 therapy (see Appendix). Prophylactic antimicrobial therapy. Perioperative prophylactic antibiotic coverage included cephapirin sodium (Cefadyl) (in penicillin-allergic patients, vancomycin was used) intraoperatively and for 5 days after operation and gentamicin intraoperatively and for 24 hours after operation. Acyclovir (Zovirax) and trimethoprim and sulfamethoxazole (Bactrim) were administered on the first postoperative day and continued for I year as prophylaxis against herpes and pneumocystis infection, respectively. Rejection episodes were identified (in nearly all cases) by histologic evidence of myocyte necrosis on endomyocardial biopsy.' Rejection episodes were usually treated with methylprednisolone pulse therapy (I gm intravenously daily) for 3 days or augmentation of oral prednisone therapy (after the first 6 months). Severe or unresponsive rejection episodes were additionally treated with OKT3, RATG, Atgam, or intravenous cyclosporine therapy. A rejection episode was considered resolved when a subsequent mild (without myocyte necrosis) endomyocardial biopsy result was obtained. An episode was labeled as complex rejection when multiple drug therapy was used or when rejection was associated with hemodynamic compromise as evidenced by echocardiographic evidence of poor left ventricular function, low cardiac index (:::::2.0 Ljminjm 2) at right heart catheterization, or clinical signs of low cardiac output. Daily Tcell markers were obtained during OKT3 or RATG therapy. A major infection was defined as a potentially life-threatening infection that necessitated hospitalization and treatment (if available) with intravenous antibiotic therapy. An organism was assigned as the causative agent when it was cultured from the involved organ or detected by histologic examination. Cytomegalovirus (CMV) infections were so identified if positive cultures for CMV were obtained or typical inclusion bodies were found on histologic examination of biopsy material. An episode was labeled CMV syndrome when CMV was not specifically isolated, but a clinical picture of leukopenia, prolonged malaise, and fever was present with the need for hospitalization and no other infectious agent was identified. Simple urinary tract infections, sinusitis, bronchitis, and any infection treated solely on an outpatient basis were not included in this analysis. In analysis of the incidence of major infection early after transplantation, we elected to omit from our analysis the single patient who underwent emergency retransplantation because of acute massive rejection and shock. The patient was heavily immunosuppressed for 5 days before retransplantation and we considered it unlikely that the 5 days of OKT3 therapy after retransplantation contributed to an early mediastinal infection (8 days postoperatively). Other complications were identified that necessitated hospitalization. In addition, specific adverse reactions or complications during RATG or OKT3 therapy were identified. Data analysisandfollow-up. All patients in the study group (100% follow-up) were followed up through Sept. I, 1988, for collection of detailed data regarding infection and rejection episodes and adverse reactions to 0 KT3 or RATG. This provided a minimumof2 months' follow-up data for all patients. Episodes of rejection, infection, and other complications were obtained by review of all inpatient and outpatient records. Data were analyzed by simple contingency tables, actuarial analyses, and the usual statistical tests to determine the likelihood of differences

The Journal of

7 1 8 Kirklin et al.

Thoracic and Cardiovascular Surgery

- - - - - - - - - - - 3£ - - - - - - - - - - i3- - - - - - - - - - - - 13- - - - - - - - - - 3 -

100

90 80

iii > .~

;;,

VI

OJ

c

......

70 60

50

ell

ell

40

e,

30 20 10 0

2

0

6

4

8

10

12

14

16

18

20

22

24

Months after Transplantation Fig. 1. Actuarial survival after cardiac transplantation (University of Alabama at Birmingham; Jan. 1, 1987, through July 1, 1988, with follow-up through Jan. 1, 1989; n = 32). All patients undergoing cardiac transplantation during this era are included. The numbers along the dotted line indicate the number of patients followed up for that length of time.

Table I. Rejection episodes according to prophylactic therapy RATG

(n = 17)

Median time (days) to first rejection Total rejection episodes in first 2 months/patient Complex rejection episodes in first 2 months/patient

16

OKTJ

(n = 15)

21

P Value

0.5

1.5

1.3

0.8

0.5

0.5

0.4

Data forall tables correspond to the studyat the University of Alabama at Birmingham conducted between Jan. 1, 1987, and July I, 1988.

as a result of chance. Survival data were obtained on all patients in the study group with follow-up through Jan. 1, 1989.

Results

Survival. There wasno difference in short-or intermediate-term survival between the twoprotocol groups. The overall survival throughout the period of follow-up was 100% (range of follow-up, 1 to 24 months) (Fig. 1). An additional 12patients underwentcardiac transplantation between the end of the study (July 1, 1988) and Jan. 1, 1989, with the same immunosuppressive protocol and OKT3 prophylaxis with 100% survival to date (Feb. 1, 1989). Rejection. The incidence and severity of rejection was similar in each protocol group. There was no difference betweenthe RATG and OKT3 groupsin the mediantime

Table II. Rejection during the first 2 months after transplantation No. of rejection episodes during first 2 months

0 I 2 3 4 Total

RATG

OKTJ

No.

% of 17

No.

% of 15

3 7 4 2

18% 41% 24% 12% 6% 100%

4 5 3 3 ....Q 15

27% 33% 20% 20% 0% 100%

.i

17

p = 0.8 (comparing distribution of rejections).

to first rejection or the number of rejection episodes during the first 2 posttransplant months (Tables I and 11). Rejection did not develop during OKT3 prophylaxis in any of the patients receiving this therapy. Four patients (27%; confidence limits, 14% to 43%)had acute rejection episodes within 1weekand eight (53%; confidence limits, 37%to 69%)within2 weeks after discontinuation of prophylacticOKT3.Twopatientsreceived 14daysofOKT3, and one of the two had acute rejection during the next 7 days.The actuarial freedom from rejection in eachgroup isdepictedin Fig.2. Complexrejection (see Material and methods section for definition) was also similar in each group (Table III). Three of the 17 patients in the prophylactic RATG group received a total of six additionalcourses of RATG (or Atgam) and 10 patients received a total of 11courses

Volume 99 Number 4

RATG and OKT3 in rejection after cardiac transplantation

April 1990

719

100

90

c

',ij

0

80


70

E

60

.-'"'

D::

...0

___ OKT3 (n = 15)

E 50

.....

1


40

l:

30

u.

1/4 1/2

RATG (n = 17)

0

"'C

% Free of Rejection

Months after Surgery

2 6


'
OKT3

88% 53% 29% 18% 12%

100% 80% 33% 27% 7%

p = .14

20

a.

RATG

10 0

0

2

3

4

5

6

7

8

9

10 II

12 13 14 15 16 17 18 19 20

Months After Surgery Fig. 2. Actuarial freedom from rejection after transplantation (University of Alabama at Birmingham; Jan. 1,1987, through July I, 1988, with follow-up through Sept. I, 1988; n = 32) for RATG and OKT3 prophylaxis groups. The numbers in parentheses equal the number of patients at risk in each time interval. The dotted lines indicate the duration of follow-up. The circles represent individual patients with an initial rejection episode, and the vertical bars represent the 70% confidence limits. The dashed lines represent the 70% confidence intervals around the solid line that is the parametric estimate.

Table III. Complex rejection during the first 2 months after transplantation No. of complex rejection episodes during first 2 months

o I

RATG

No.

% of17

II 4 I

65% 24% 6% 6% 100%

2 3

-l.

Total

17

Table IV. Major infections during first 2 months

OKT3

No. 8

7

o ....Q 15

% of /5 53% 47% 0% 0% 100%

No. of major infection episodes during first 2 months*

No.

% of/7

No.

% of 14*

0 I 2

14 2 I

9

3

....Q

Total

17

82% 6% 6% 0% 100%

64% 36% 0% 0% 100%

RATG

OKT3

5 0

....Q 14

p = 0.21 (comparing distribution of infections).

p = 0.4 (comparing distribution of rejections).

'The single patient who underwent emergency retransplantation because of acute rejection and cardiac shock is excluded.

of OKT3 for rejection during the study period. In the OKT3 prophylaxis group (n = 15), eight patients receiveda total of 11 courses ofRATG (or Atgam) and one received a second course of OKT3 for rejection. During the study period four patients (after prophylactic RATG or OKT3) had an episode of severe hemodynamic compromise as a result of acute rejection with low cardiac output and marked reduction of left ventric-

ular contractility by echocardiogram. Two of these patients required intraaortic balloon pump support, and all received inotropic support during the rejection episode. Each patient had complete resolution of the rejection episode with return of normal hemodynamic values after treatment with RATG and methylprednisolone (two episodes), OKT3 and methylprednisolone (one episode), or combined RATG and OKT3 therapy (one episode).

The Journal of Thoracic and Cardiovascular Surgery

7 2 0 Kirklin et al.

Table V. Major infections after cardiac transplantation Site and organism

Lung Klebsiella Streptococcal/pneumococcal CMV Mediastinal Staphylococcus epidermidis Gastrointestinal CMV colitis Giardiasis gastroenteritis Pseudomembranous colitis Candida esophagitis Herpes esophagitis Other Cellulitis Streptococcal pharyngitis CMV syndrome

Table VII. Other morbid events*

RATG

OKT3 Category

2 1

I I

3

4

Table VI. Side effects during OKT3 or RA TG treatment Drug reaction

OKT3 Diarrhea Fever Flu syndrome Headache RATG Local reaction (erythema, swelling) Myalgia

No. ofepisodes*

5 1 10 10 6

3

·The presence of eachsideeffect is counted once during eachcourse of OKT3 (totalof 28courses during study) or RATG (total of 29courses).

Infections. The actuarial freedom from major infection at 2 months was 82% in the RATG group and 64% in the OKT3 group (p = 0.3) (Fig. 3). The median time to first major infection was 318 days in the RATG group and 250 days in the OKT3 group (p = 0.5). The number of major infections during the first 2 months is displayed in Table IV. There were few opportunistic infections, except for CMV (Table V). CMV pneumonia developed 6 weeks after transplantation in one patient, with typical CMV inclusion bodies on transbronchial biopsy specimen. Prompt clinical and radiographic improvement occurred within 48 hours of initiating dihydroxyproproxymethyl guanine (DHPG) therapy. No leukopenia or other complications were noted during the DHPG therapy. Other complications. No serious side effects were observed during the administration of OKT3, RA TG, or Atgam (Table VI). One patient had abdominal pain and diarrhea on the second day of OKT3 therapy. A diagno-

Metabolic Diabetes'[ (steroid-induced) Diabetes (niacin-induced) Cardiovascular Thrombolic occlusion of left anterior descending coronary artery (acute myocardial infarction) Cardiac tamponade (pericardiaI drainage) Heart block (permanent pacemaker) Renal Renal insufficiencyj Benign prostatic hypertrophy (transurethral prostatic resection) Urethral stricture Gastrointestinal Cecal volvulus (partial colectomy) Cholecystitis (cholecystectomy) Gastritis, duodenitis Necrotizing pancreatitis (partial pancreatectomy) Skeletal Femur fracture Neurologic Transient postoperative encephalopathy Transient ischemic attack Transient postoperative psychosis Ophthalmic Cataracts Malignancies Basal cell carcinoma Renal adenocarcinoma (nephrectomy) Miscellaneous Superior vena cava anastomotic stricture (heterotopic transplant) Sleep apnea

Prophylactic Prophylactic OKT3 group RATG group (no. ofpatients) (no. ofpatients)

2 I

3 1

0

0

2

I

3 I

0

0 0 0

2

1

0

0

1

0 0 0 0

0

2

0 0

0

0

·Excluding major infection or rejection episodes. tlnsulinrequirement. :j:Creatinine ~4.0 mgjdlor blood urea nitrogen ~lOO mgjdl or dialysis.

sis of cecal volvulus was made, and an emergency laparotomy with cecal resection was performed. The patient's r~very was uneventful. Other important complications necessitating hospitalization during the study period are indicated in Table VII. Of note is the diagnosis of malignancy in one patient in the RATG group who

Volume 99 Number 4

RA TG and OKT3 in rejection after cardiac transplantation

April 1990

100 C

0

...e'"

.~

QI

...

.-0 IV

:E E

...E... 0

/

RATG(n=17)

70

60 50 40

...

30

'"...

20

... u.

OKT3 (n = 15)

80

0 "C

QI QI

-:

90

Months after Surgery

1 2 3 12

C

QI

QI Q.

721

10

0

% Free of Major Infection RATG

OKT3

88% 82% 82% 70%

86% 64% 51% 51%

p = .2

0

2

3

4

5

6

7

8

9

10 11 12 13 14 15 16 17 18 19 20

Months After Surgery Fig. 3. Actuarial freedom from major infection after transplantation (University of Alabama at Birmingham; Jan. I, 1987, through July I, 1988, with follow-up through Sept. I, 1988; n = 31*) for RA TG and OKT3 prophylaxis groups. The numbers in parentheses equal the number of patients at risk in each time interval. The dotted lines indicate the duration of follow-up. The circles represent individual patients with an initial major infection episode, and the vertical bars represent the 70% confidence limits. The dashed lines represent the 70% confidence intervals around the solid line that is the parametric estimate. (*The single patient who underwent emergency retransplantation because of acute rejection and cardiac shock is excluded. See Materials and methods section.)

underwent a right radical nephrectomy for adenocarcinoma 8 months after transplantation. T-cell markers and antibodies to OKT3. Patients who received OKT3 either prophylactically or therapeutically (25 courses of 0 KT3) had reduction of circulating T3 lymphocytes to a level of less than 50 cells per milliliter within 48 hours of initiating therapy (five patients had insufficient data during the first 48 hours). The pattern ofT3 response to OKT3 was not useful in predicting an acute rejection episode within 2 weeks after discontinuation of OKT3, whether for prophylaxis or treatment of rejection (Table VIII). In comparison of patients with and without rejection within 14 days of prophylactic OKT3, there was no significant difference in the mean T3-lymphocyte number during the entire course of OKT3 or during the last 3 days of therapy (Table VIII). Antibody titers to murine OKT3 were measured in each patient within 2 weeks of OKT3 therapy, whether prophylactic or for treatment of rejection. Antibodies

Table VIII. T-cell markers duringprophylactic

OKT3 therapy

Rejection within 2 wk after prophylactic OKTJ

Mean T3-ce// level (no.fml] during therapy

Yes

45.0

No

94.7

p

0.31

Mean T3-ce// level (no.jml] during last 3 days of therapy 76.2 180.2 0.36

(1:100 dilution) to murine 0 KT3 developed after the initial administration in three of 31 patients. Two patients had readministration of OKT3 because of recurrent rejection. No antibody was detected after either administration in either patient. T3-lymphocyte levels were depressed to a similar level as during the initial administration. In one patient, the secondary administration of OKT3 resulted in prompt resolution of rejection. In the

7 2 2 Kirklin et al.

second patient, rejection persistedafter secondary OKT3 and resolved only with subsequent RATG administration. Discussion Survival. Prophylactic therapy with antithymocyte globulin early after cardiac transplantation has been reported during the early years of cardiac transplantation" and more recently with triple-drug therapy.' Gilbert and colleagues/ from the University of Utah reported excellent intermediate-term survival (98% at 1 year) with the use of prophylactic OKT3 after cardiac transplantation. However, the notion that prophylactic "induction" therapy with RATG or OKT3 is necessary for very high intermediate-term graft survivalischallengedby the superb long-term survival that has been reported from the University of Minnesota (87% at 2 years) with a program of maintenance prednisone, cyclosporine, and azathioprine without prophylactic OKT3 or RATG.I Acute and chronic rejection remain major causes of premature death after cardiac transplantation/' and the current optimal immunosuppressive regimen remains controversial. However, the regimen used in this study with prophylactic RATG or OKT3 can be recommended on the basis of its effectivetreatment of severe acute rejection and the high intermediate-term graft and patient survival (100% survival of all UAB patients who had transplants during the study period and over the entire 2year period from Jan. 1, 1987, through Jan. 1, 1989). Effectiveness of rejection prophylaxis. Important weaknesses of this study are the relativelysmall sizeof the treatment groups and the lack of randomization. Furthermore, considerable variation exists in the potency of antilymphocyte and antithymocyte preparations as well as the recommended duration of therapy. Bristow and colleagues' reported greater freedom from rejection in patients treated with prophylactic OKT3 than with prophylactic ATG. However, there were two important differences between that study and the UAB study. First, Bristow and colleagues compared OKT3 with Atgam (equine antithymocyte globulin), which we and others/-! have found to be less reliable in its clinical effectiveness than RATG. Second, most patients in our prophylactic OKT3 group received 10 days of OKT3, which may be less effective than the 14-day protocol reported by Bristow and co-workers.t Among patients receiving prophylactic OKT3, the incidence of early rejection was considerably higher in our study; only 27%of patients were free from rejection at 2 months compared with 60o/~ in the study by Bristow and colleagues.' Although the precise definitionof rejection,the duration ofprophylactic0 KT3,

The Journal of Thoracic and Cardiovascular Surgery

and other details of immunosuppression differ among institutions, additional as yet unidentified factors (such as the extent of donor-recipient immunologic mismatch) probably contribute to these differences. Treatment of complex rejection. OKT3 has been reported to be highly effective as "rescue therapy" for persistent or severe acute rejection, in both cardiac?"! and renal transplantation.12. 13 In this experience, RATG and OKT3 were both highly effective in reversing complex rejection.Severe, acute hemodynamic deterioration during acute rejectionis knownto be a frequentlyfatal event. In all four such episodes (after previous prophylactic therapy) OKT3, RATG, or their combination was effective in reversing the rejection and restoring normal cardiac function and well motion. T-cell marker. OKT3 generally produces profound depletion of peripheral T3 lymphocytes within several hours of intravenousadministration and blocksthe T-cell effector functions involved in allograft rejection.F The recommendeddoseof OKT3 (5 mg) is knownto produce circulating levels ofOKT3 (approximately 1 ~g/ml)14, 15 sufficient to deplete T3 lymphocytes in most patients." Indeed, all patients in this study had marked initial depletionofT3lymphocytes after OKT3 administration, Reappearance of large numbers of T3 lymphocytes during the courseof OKT3 therapy wouldprobablyrelate to insufficient circulating OKT3 or to formation of antibodies to murine OKT3 during therapy. In this study, however, neither the overall level of T3-lymphocyte depletion nor the reappearance of increasingnumbers of OKT3 reactive cells during therapy predicted which patients would experience rejection during the ensuing 2 weeks. Infections. Despite the augmented immunosuppression during the first 1 to 2 weeks after transplantation, there were few serious opportunistic infections with the important exception of CMV. It is important to note, however, that routine posttransplant serologic studies for CMV surveillance were not obtained during this study, which makes the diagnosisof CMV "syndrome" lesssecure. This apparent frequency of CMV infections is in marked contrast to our previous protocols with azathioprine and prednisoneor cyclosporine and prednisoneimmunosuppression in which other opportunisticinfections were common but CMV was rare.!" Although more immunosuppressive agents were used in the current protocol, the dose of each agent is less than in our previous protocols." The precisereasons that CMV infections are more common after early antilymphocyte therapy are unknown. Although no fatal infections occurred, CMV infectionswere associated with important morbidity and

Volume 99 Number 4 April 1990

RATG and OKT3 in rejection after cardiac transplantation

prolonged hospitalization. DHPG was effective in treatingCMV pneumonia, as has beenreportedbyothers.I 7, 18 It is currently unknown whether prophylactic therapy with hyperimmune globulin'? or DHPG would significantly reduce this problem. Other complications. Although mild adverse reactions werenoted during administrationof early antilymphocyte therapy, particularly OKT3, such reactions are generally well tolerated.I'? The potentialfor malignancy, particularly lymphomas, has been correlated with the overall quantity of immunosuppression.i" Longer-term follow-up studiesare neededto examineany possible relationship between prophylactic antilymphocyte therapy and later malignancies.

Inferences 1. Triple-drug immunosuppression combined with prophylactic RATG or OKT3 therapy yields excellent intermediate-term survival after cardiac transplantation. 2. Theseprotocols for RATG and OKT3 prophylaxis provide similar protection against early rejection with a relatively low risk of infection complications other than CMV. The apparent frequency of CMV infections is the only major limitation to this protocol identified to date. 3. Simpleanalysis of T3 markers during OKT3 therapy does not predict early rejection. We appreciate the work of Ms. Betty Penn in preparation of the manuscript. Dr. Arnold G. Diethelm, Chairman of the Department of Surgery and Director of Renal Transplantation at UAB, provided expert advice in the development of many aspects of the immunosuppressive protocols. REFERENCES I. Andreone PA, Olivari MT, Elick B, et al. Reduction of infectiouscomplications followingheart transplantation with triple-drug immunotherapy. J Heart Transplant 1986;5: 13-9. 2. Gilbert EM, Eiswirth CC, Renlund DG, et al. Use of OrthocloneOKT3 monoclonal antibody in cardiac transplantation: early experience with rejection prophylaxis and treatment of refractory rejection. Transplant Proc 1987; 19(suppl 1):45-53. 3. Billingham M. Some recent advances in cardiac pathology. Hum Pathol 1979;10:367-86. 4. Baumgartner WA, Reitz BA, Bieber CP, Oyer PE, Shumway NE, Stinson EB. Current expectations in cardiac transplantation. J THoRAc CARDIOVASC SURG 1978;75:525-30. 5. Bristow MR, Renlund DG, Gilbert EM, Lee HR, Gay WA, O'Connell JB. Murine monoclonal CD-3 antibody in cardiac transplantation-anti-rejection treatment and preliminary results in a prospectivelyrandomized trial for prophylaxis. Clin Transplant 1988;2:163-8.

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6. Solis E, Kaye MP. The Registry of the International Society for Heart Transplantation: third official report-s-June 1986. J Heart Transplant 1986;5:2. 7. Thomas F, Thomas J, Flora R, Mendez-Picon G, Peace K, Lee HM. Effects of antilymphocyte-globulin potency on survival of cadaver renal transplants. Lancet 1977;2: 671-4. 8. Najarian JS, Simmons RL, Condie RM, et al. Seven years' experience with antilymphoblast globulin for renal transplantation from cadaver donors. Ann Surg 1976;184: 352-68. 9. Gilbert EM, DeWitt CW, Eiswirth CC, et al. Treatment of refractory cardiac allograft rejection with OKT3 monoclonal antibody. Am J Med 1987;82:202-6. 10. Costanzo-Nordin MR, Silver MA, O'Connell JB, et al. Successful reversal of acute cardiac allograft rejection with OKT3 monoclonal antibody. Circulation 1987;76(Pt 2): V71-80. 11. Sweeney MS, Sinnott JT, Cullison JP, Weinstein SS. The use of OKT3 for stubborn heart allograft rejection: an advance in clinical immunotherapy? J Heart Transplant 1987;6:324-8. 12. Cosimi AB, Colvin RB, Burton RC, et al. Use of monoclonal antibodies to T-cell subsets for immunologic monitoring arid treatment in recipients of renal allografts. N Engl J Med 1981;306:308-14. 13. Ortho Multicenter Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985; 313:337-42. 14. Goldstein G. Overview of the development of Orthoclone OKT3: monoclonal antibody for therapeutic use in transplantation. Transplant Proc 1987;19(suppll):1-6. 15. Chang TW, Kung PC, Gingras SP, Goldstein F. Does OKT3 monoclonal antibody react with an antigen-recognition structure on human T-cells? Proc Natl Acad Sci USA's 1981;78:1805-8. 16. Kirklin JK, Naftel DC, McGiffin DC, McVay RF, Blackstone EH, Karp RB. Analysis of morbid events and risk factors for death after cardiac transplantation. J Am Coli CardioI1988;11:917-24. 17. Icenogle TB, Peterson E, Ray G, Minnich L, Copeland JG. DHPG effectively treats CMV infection in heart and heart-lung transplant patients: a preliminary report. J Heart Transplant 1987;6:199-203. 18. Collaborative DHPG Treatment Study Group. Treatment of serious cytomegalovirus infections with 9-( 1, 3-dihydroxy-2-proproxymethyl) guanine in patients with AIDS and other immunodeficiencies. N Engl J Med 1986;314: 801-5. 19. Condie RM, O'Reilly RJ. Prevention of cytomegalovirus infection by prophylaxis with an intravenous, hyperimmune, native, unmodified cytomegalovirus globulin. Am J Med 1984;76:128-33. 20. Brumbaugh J, Baldwin JC, Stinson EB, et al. Quantitative analysis of immunosuppression in cyclosporine-treated

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heart transplant patients with lymphoma. Heart Transplant 1985;4:307-11.

Appendix RATG was prepared by Drs. Frank and Judy Thomas and colleagues at East Carolina University and quality-controlled in accordance with Food and Drug Administration standards (Investigational New Drug licensure no. 1940). Institutional review board approval was obtained for the use of RATG in this protocol. Informed patient consent was obtained for the use of RATG or OKT3. RATG administration. A skin sensitivity test was administered before RATG administration (1 mg/kg/day). The following medications were administered during the course of RATG: methylprednisolone, 100 mg intravenously, and enteric-coated aspirin is given 30 minutes before RA TG and entericcoated aspirin every 6 hours during therapy. Atgam administration. Atgam was administered intravenously through a central line at a dose of 15 mg/kg/day. The

Thoracic and Cardiovascular Surgery

following medications were administered during Atgarn therapy: diphenhydramine hydrochloride (Benadryl), 25 mg, and acetaminophen (Tylenol), 650 mg, is given 30 minutes before Atgam. OKT3 administration. OKT3 (Ortho Pharmaceutical, Raritan, N.J.) was administered intravenously (5 mg/dose in adults, 2.5 mg/dose in children). The following medications were administered during OKT3 therapy: (I) diphenhydramine hydrochloride, 50 mg intravenously, ranitidine hydrochloride (Zantac), 100 mg intravenously, and acetaminophen, 650 mg orally, are given 30 minu tes before the first three doses of 0 KT3; (2) 6, 12, and 18 hours after the first three doses of OKT3, diphenhydramine hydrochloride, 25 mg intravenously, ranitidine, 50 mg intravenously, and acetaminophen, 650 mg orally, are given; (3) hydrocortisone, 100 mg intravenously, is given 30 minutes after each dose of OKT3; and (4) for those patients receiving OKT3 for treatment of rejection, Solu-Medrol, 100 mg intravenously, is given I hour before the first dose of OKT3.

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