Dummer, JS

Hakala, TR

Hickey, DP

Hrebinko, R

Jordan, ML

Shapiro, R

Simmons, RL

Starzl, TE

Vivas, C

English

PubMed

D-Scholarship@Pitt

.. vt$ff [ ! /' K~DF I j -:, , '::) ; i ...J i Ganciclovir for Invasive Cytomegalovirus Infection in Renal Allograft Recipients R. Hrebinko, M.L. Jordan, J.S. Dummer, D.P. Hickey, R. Shapiro, C. Vivas, T.E. Starzl, R.L. Simmons, and T.R. Hakala CYTOMEGALOVIRUS (CMV) is a major infectious complication of renal transplantation associated with significant morbidity and mortality. 1-3 Ganciclovir inhibits herpesvirus DNA polymerase4 and has shown antiviraJ effects in vivo in several reported clinical studies. 5-8 We report our experience with the use of ganciclovir in treat-ing tissue-invasive CMV infection following cadaver renal transplantation. The results suggest that ganciclovir is well tolerated and effective in arresting the progress of invasive CMV to life-threatening disease with little drug-related morbidity. MATERIALS AND METHODS Of 419 cadaveric renal allograft recipients transplanted at our institution between November 1987 and September 1989. 36 (8.6'T) (25 men and II women) developed invasive CMV infection (Table I), Average patient age was 42.1 ± 11.5 years (range. 18 to 71 years). Infection occurred following the primary transplant in 28 patients. after the second transplant in Ii- e. and after the third Table 1. Clinical Characteristics of 36 Cadaveric Renal Transplant Recipients Who Subsequently Developed Invasive CMV Disease Patient age (y) Mean Range Sex Male Female Panel-reactive antibodies <4°'0 4-80% >80% Donor age (y) Median Range Donor recipient pretransplant CMV serology Positive/negative Positive/positive Negative/positive Negative/negative Treated for acute cellular rejection pre-CMV Yes No Type 04 treatment lor acute cellular rejection (n = 29) High-<Iose steroids OKT3 Steroids and OKT3 n(%) 42.1 == 11.5 18-71 25 (69) 11 (31) 20 (56) 9 (25) 7 (19) 45 2-67 16 (44) 9 (25) 5 (14) 4 (11) 29 (81) 7 (19) 18 (SO) 2 (6) 9 (25) transplant in three. In 16 of the 36 cases (44'7c). an allograft from a CMV -seropositi"e (lgG titer> I : 20) donor was transplanted into a seronegative recipient. Nine cases (25'7c) were seropositive to seropositive. five (14'10 were seronegative to seropositive. and four (II '7c) were seronegative to seronegative. Serology .... as not available on two grafts. both of which were transplanted into seronegative recipients. All patients received a standard immuno-suppressive regimen consisting of cyclosporine. prednisone. and azathioprine, Eighty-one percent of the patients with invasive CMV infections had been treated for rejection (prior to developing invasive CMV infections) with either increased steroid therapy (n = 18. 5O'7c). OKD (n = ~K 6'7c.). or steroids and OKT3 (n = 9 ~R<;EFK An additional eight patients had received prophvlacti~ OKT3. Therefore. 19 patients (53'7c) received an average 13.:!-day course (range. 6to 19 days) ofOKT3 before contracting CMV. All patients had received either "low-dose E~ll mg twice a day. n = ~UF or "high-dose"lUp to PK~MM mgld based on renal function. n = 8) prophylactic acyclovir! Thiny-six patients with clinicallv sus-pected CMV infection (unex.plained fever> 38,3 for >2 day~_ n = 3 [89'1cJ: leukopenia [white blood cell count <4.000 mL]. n = 21 [58<;(J: thrombocytopenia «100.000. n = 6 [17'7cJ; diffuse pulmo-nary infiltrates. n = 9 [25'7cj) were found to have invasive CMV a mean of 60.6 days (range_ 28 to 133) after transplantation, Before staning ganciclovir. all 36 patients had tissue-invasive CMV infection documented by gastric or duodenal mucosal biops~ In = ~SK 7:!'7c). bronchoalveolar lavage (n = 14. 39'1c). allograft biopsy or nephrectomy (n = 6. 11'7c). or liver biopsy (n = I. 3'7c). The biopsies were considered positive for CMV based on viral culture or histology/immunomicroscopy. Eleven patients OI'7c) had mul-uple sites involved. At the time of diagnosis. 27 patients (75<;() had mild. six. (17'7<) had moderate. and three (8'7<) had severe infection according to Peterson et aI's criteria. 10 Ganciclovir (Synte:l.) was gi\en at 2.5 mg,kg IV twice a day for a minimum of7 days (mean. I ~K:! := 3.5 days) and was continued until the patient was afebrile for 5 consecutive days. Dosage was adjusted according to the calculated creatinine clearance. RESULTS Ganciclovir was well tolerated by all 36 patients. Side effects were limited to reversible neutropenia (white blood cell count <4.<XXl/mL. n = 7). thrombocytopenia 1< IOO.OOO/mL. n = 2). and rash (n = I). none of which required discontinuation of the drug. Serum creatinine From the Division 01 Urologic Surgery/Renal Transplantation, Department of Surgery. University of Pittsburgh School of Medi-cine. Pittsburgh. Pemsylvania. Address reprint requests to Dr R. Hrebinko. Division of Urologic Surgery/Renal Transplantation. Department 01 Surgery. University 01 Pittsburgh School of Medicine. Pittsburgh. PA 15213. ~ 1991 by Appleton & Lange 0041-13451911$3.001+0 1346 Transplantalion Proceedings. Vol 23. No 1 (February). 1991: pp 1346-1347 GANCICLOVIR FOR INVASIVE CMV (SCr) was unaltered by ganciclovir in those patients with functioning grafts (mean SCr, 4.1 ± 1.6 mgldL before and 3.8 = 1.9 after treatmentl. Clinical improvement occurred in all 36 patients following the initial course of treatment. Seven patients had persistent asymptomatic viruria and (WO had recurrent invasive disease (allograft in one, stom-ach in one) eradicated with a second course of ganciclovir 60 and 50 days, respectively, after the first course. There was no correlation between CMV severity and recipient age (> or <45 years). time to CMV onset after transplant. prior rejection, OKT3 use, or use of low-dose versus high-dose prophylactic acyclovir (p > .1). Seventeen of 27 (63'7c) grafts are still functioning (mean follow-up. 12.7 months) in those patients originally having mild disease, three of six grafts (5OCC) in those with moderate disease, and zero of three (Oo/c) in those with severe disease (P < .02). There were 17 graft losses in this series. Four grafts ",ere already lost at the onset of CMV infection, owing to primary graft nonfunction (n = 2) and chronic rejection (n = 2). The remaining II grafts were lost from 10 days to 16 months (median, 5 weeks) following invasive CMV. One patient underwent allograft nephrectomy after immuno-suppression was wit held for transverse myelitis 2 months after treatment with ganciclovir. A second patient lost his graft to rejection while immunosuppression was wit held for acute pancreatitis c with a negative CMV workup) 2 months after treatment. Another patient had recurrent oxalosis and graft failure I year after ganciclovir. The remaining grafts were lost to rejection. Of those patients that developed CMV without prior rejection. six of seven (86'7c) still have functioning allografts, while only I3 of 29 (45%) are still functioning in patients treated for rejection before CMV infection occurred. At mean follow-up of 12.7 months, the I-year actuarial patient survival is 1009c. The I-year actuarial graft survival is 559c :!: UKP~I with a mean SCr of 2.5 mgldL (range, 1.2 to 4.6 mgldL). The I-year actuarial patient and graft survival rates for the entire group of cadaveric rena.! transplants (n = 419) done at our institution during the same time period are 94.99c :!: 1.2% and 79.7% ± 2.\%. respectively. DISCUSSION Previous studies have recommended the use of ganciclovir only for life- or sight-threatening CMV infection. ~-U In the current series, ganciclovir was started as soon as the diagnosis of tissue-imasive CMV was made. With this approach, 100% patient survival was achieved with only 1347 two cases of recurrent CMV infection, both of which resp;:nded to a second course of ganciclovir. The graft SUf\-;,.al of 55% reponed here is similar to that reported pre\).)usly in CMV -infected patients not treated with gan:,dovir. 1·.'.10 Eighty-one percent of the patients in our se~ experienced at least one rejection episode prior to CMY. Thus, this group was at high risk for graft loss even had :hey not acquired CMV. In addition. our patients all had ~istologically prO\'en disease and might be best cate-gonz.:d separate from those patients included in other stuC:~s in which the diagnosis was largely based on sero-cor.".ersion and periph~ral cultures. 1·3.10 a~ring the course of this study, ganciclovir was consid-ere;: ~xperimental at our institution and was available only on i compassionate release basis to patients with biopsy-prc'·,;;n. invasive CM\' infections. Because the drug ap-pe"" to be effective \I, ith infrequent sid~ effects. we now sta-: ganciclovir if there is a high index of suspicion for CMY based on history. physical examination. and serol-Og!. and continue therapy based on positive cultures and 0r tissue biopsy and clinical parameters. We continue to ::.se an initial 7-day course of ganciclo\ir and extend the trCi:ment for prolonged fever or persistent signs and syr:-..ptoms of CMV infection. The limited toxicity and prcmpt eradication of symptomatic disease observed in thl> series indicate that ganciclovir is a safe and effective for:J. of therapy in renal transplant recipients with tissue-in\bive CMV infection. RE=ERENCES 1 Simmons RL. Matas A.!. Ratlazzi LC. et a1: Surgery 82:537, Ir : Fryd OS. Peterson PK. Ferguson RM. el a1: Transplantation 30.]6.1980 :: ~1arker Sc. Ho"ard RJ. Simmons RL. et al: Surgery 89:660. 19!: ~ Field AK. Davies '-tEo DeWitt C. et aL ~atl Acad Sci USA 8(qI39. 1983 5 Collaborative DHPG Treatment ptud~ Group: N Engl J Med P1~KUM1K 1986 ~" Snydman DR: Re\ Infect Dis 10:S554. 1988 (supp!) - Paya CV, Hermans PE. Smith TF. et al: Transplantation ~~9I 1988 ~K Harbison MA. DeGiroiami PC. Jenkins RL. et al: Trdnsplan-ta:on 46:82. 1988 9 Balfour HH. Chace BA. Stapleton JT. et a1: N Eng! J Med P~!D 1381. 1989 10. Peterson PK. Balfour HH. Marker Sc. et a1: Medicine ~CfK:sPK 1980 I ~ , 

Ganciclovir for invasive cytomegalovirus infection in renal allograft recipients.

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Ganciclovir for invasive cytomegalovirus infection in renal allograft recipients

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Ganciclovir for invasive cytomegalovirus infection in renal allograft recipients.

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