Liver. Nina Singh, J. Stephen Dummer, Shimon Kusne, Mary Kay Breinig, John A. Armstrong, Leonard Makowka, Thomas E. Starzl, and Monto Ho

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1 THE JOURNAL OF NFECTOUS DSEASES VOL. 158, NO. JULY by TheUniversity o Chicago. A rights reserved /88/ $01.00 nections with Cytomegaovirus and Other Herpesviruses in 121 Transpant Recipients: Transmission by Donated Organ and the Eect o OKT3 Antibodies Liver Nina Singh, J. Stephen Dummer, Shimon Kusne, Mary Kay Breinig, John A. Armstrong, Leonard Makowka, Thomas E. Starz, and Monto Ho From the Department o nectious Diseases and Microbioogy, Graduate Schoo o Pubic Heath, and the Department o Medicine and Surgery, Schoo o Medicine, University o Pittsburgh, Pittsburgh, Pennsyvania One hundred twenty-one adut iver transpant recipients were studied or the incidence, risk actors, and morbidity associated with herpesviruses inections ater transpantation. The overa incidence o inection was or cytomegaovirus CMV), or herpes simpex virus HSV), or Epstein-Barr virus EBV), and 7070 or varicea-zoster virus VZV). Primary CMV inection occurred in and reactivation CMV inection in o the susceptibe recipients. Symptomatic and disseminated CMV diseases were more common when patients deveoped primary inection P <.01, or both comparisons). The donor organ appeared to be the ony important source o CMV inection in seronegative recipients. The use o OKT3 antibodies was associated with disseminated CMV disease in patients with primary inection P =.04) but not with reactivation inection P >.10). Athough most HSV inections were ora or genita reactivations, three cases o HSV hepatitis occurred - one was a primary inection. Symptomatic reactivations o HSV were observed in o HSV-seropositive recipients who received OKT3, versus o seropositive recipients who did not receive OKT3 P =.05). nections with cytomegaovirus CMV) and other herpesviruses are a major source o morbidity and mortaity ater organ transpantation [1]. O a the herpesviruses, CMV is the agent most oten associated with severe disease or death [2]. A number o actors contribute to the severity o CMv inection in transpant recipients. Primary inection as opposed to reactivation inection with the virus [2, 3] and the use o immunosuppressive regimens containing anti-thymocyte gobuin ATG) appear to be associated with more-severe CMV disease [4, 5]. n addition, the type o transpant operation is an important determinant o the morbidity due to CMV. For instance, both bone marrow and heartung transpant recipients have higher rates o CMV pneumonia than do kidney recipients [1, 6, 7]. Our earier studies o inections in kidney, heart, heart-ung, and iver transpant recipients in Pittsburgh showed that CMV and other herpesviruses Received or pubication 28 September 1987 and in revised orm 18 January This work was supported in part by grant A rom the Nationa nstitute o Aergy and nectious Diseases. We thank Leona A. Youngbood or assistance in the virus aboratory and Lucie Guevarra or the HSV antibodies assays. Pease address requests or reprints to Dr. Manto Ho, Crabtree Ha A427, University o Pittsburgh, Pittsburgh, Pennsyvania were a signiicant probem in iver transpant recipients receiving cycosporine [8]. A study o vira inections, incuding herpesvirus inections, in pedia.tric transpant recipients, most o whom were iver recipients, has recenty appeared [9], but there sti has been no comprehensive study o herpesvirus inections in adut iver transpant recipients, particuary since the initiation o routine cycosporine monitoring in ;rhereore, we studied 121 consecutive adut iver transpant recipients at our institution to anayze the incidence, timing, risk actors, and cinica outcome associated with herpesviruses inections. We hoped to determine whether the hepatic aograt was a signiicant source o CMV inection and whether the use o newer immunosuppressive measures, such as OKT3 monocona antibody Ortho Pharmaceutica, Raritan, NJ) introduced or treating iver rejection, had a measurabe impact on CMV or herpes simpex virus HSV) inection. Patients and Methods Study popuation. The study popuation consisted o 121 consecutive aduts who underwent orthotopic iver transpantation at our institution between January 1984 and September 1985, who survived or at east 72 h postoperativey, and on. 124

2 e '] nt 'in ore Te 11- rne n- ur C-!ser V P- ti- o- Je in- )norbe 'ho on 1 t, 1, Herpesviruses and Liver Transpantation whom preoperative serum sampes were avaiabe. There were 46 men and 75 women whose average ages were 38 and 39 y, respectivey. Their cinica diagnoses were primary biiary cirrhosis 35), chronic active hepatitis 24), scerosing choangitis 20), cryptogenic cirrhosis 10), maignancy 9), Caroi's diseases 3), drug- or acoho-induced hepatic necrosis 5), hemochromatosis 3), Budd-Chiari syndrome 3), a--antitrypsin deiciency 2), Wison's disease 2), secondary biiary cirrhosis 4), and cystic ibrosis 1). There were a tota o 26 deaths. The duration o oow-up in iving patients ranged rom 313 to 930 d, with a median o 530 d. Cinica data regarding inections were coected by reviewing patients' records as we as by oow-up by two o the authors N. S. and S. K.). mmunosuppression. Standard postoperative immunosuppression consisted o cycosporine CsA) and corticosteroids. CsA was administered iv at a dose o 2 mg/kg per d on the day o surgery and then oray at 6 mg/kg per d ater surgery. The dosage was adjusted individuay to achieve a whoe bood eve o CsA between 800 and 1000 ng/ml, as measured by RA. Beginning on the day o surgery, methyprednisoone was administered iv at a dose o 200 mg and tapered over ive to seven days to a maintenance dose o 20 mg o methyprednisoone or ora prednisone. Rejectio episodes were treated either with a "recycing" o high-dose ora steroids starting at 200 mg o prednisone and tapering to 20 mg over ive days or with -g iv bouses o methyprednisoone. For the purpose o this study, one recyce and one bous o steroids were considered equivaent. For more-severe degrees o rejection, OKT3 antibody was administered. Azathioprine AZA) was usuay added to the immunosuppressive regimen to reduce CsA dosage in patients experiencing nephrotoxicity. AZA was administered oray at a dose o 1-2 mg/kg, and OKT3 was administered iv at a dose o 5 ml daiy and continued or seven to 14 days. Mean monthy CsA eves or the irst three months postoperativey were determined rom the monthy means o each patient's weeky median eves o CsA. Laboratory oow-up. Preoperative serum sampes rom a transpant recipients were anayzed or antibodies to CMV, Epstein-Barr virus EBV), and HSV. A semiautomated immunouorescent test FAX ; nternationa Diagnostic Technoogy, San Jose, Cai) was used or testing antibodies to CMV and HSV, and titers o 30 and 2, respectivey, were considered positive. A equivoca CMV FAX resuts were checked with an anticompement immunouorescence test ACF), and titers o ;:, 1:4 were considered positive [10]. Ordinariy, a positive postoperative cuture or CMV was considered adequate or diagnosing CMV inection [2, 11]. n the absence o positive CMV cutures, postoperative sera were aso assayed or CMV antibodies by ACF. Antibodies to EBV vira capsid antigen VCA) and eary antigen EA) were determined on preoperative and postoperative sera by standard immunouorescence, and titers 1:5 were considered positive [12]. Signiicant antibody rises greater than ourod) were were conirmed by simutaneous assay. n addition, throat washes and urine and buy coat sampes were obtained rom recipients every two to our weeks postoperativey and cutured or CMV [8]. One patient with no detectabe HSV antibodies beore transpantation deveoped HSV hepatitis ater transpantation. Serum sampes rom this recipient and donor were anayzed or HSV type-speciic antibodies by an immunodot enzymatic assay [13, 14]. Briey, HSV type -speciic gycoprotein gg- 1) and HSV type 2-speciic gycoprotein gg-2) were prepared as described by Lee et a. [13, 14] and used as antigen in an immunodot assay on sma disks o nitroceuose membrane in 96-we pates. The sera were tested at a 1 :50 diution, and serum contros were used or each assay. CMV inection and disease. Primary inection was deined by isoation o virus or by seroconversion in a patient who was seronegative beore transpant surgery. Reactivation inection was diagnosed by either a ourod or greater rise in antibody titers compared withpretranspant eves by ACF or by isoation o virus in a seropositive recipient. Twentyeight patients did not have postoperative CMV cutures or sera avaiabe or antibodies testing and were thereore excuded rom anaysis o CMV inections; 93 patients then remained or evauation. To excude the eect o passivey transerred antibodies rom bood transusion during surgery, we ony used sera coected >30 d ater transpantation to document rises in antibody titer. Cinica diseases caused by CMV inection were the oowing types: vira syndrome, ocaized CMV disease, and disseminated CMV disease. Vira syndrome due to CMV required the oowing: 1) aboratory evidence o CMV inection, as deined above; 2) ever 38 C or at east one week and no other source to account or it; and 3) one o the oowing indings - atypicaympho """"-"--'i -.Jt a ,. ' :i, _ ','.',; ';';':>,

3 126 Singh e a. cytes 3070; white bood ce count «4000/mm J ; and pateets «100 OOO/mm J Locaized CMV disease was deined as tissue invasion o a singe organ determined histopathoogicay and/or by cuture o virus rom tissue. Disseminated CMV disease was deined as tissue invovement o two or more noncontiguous sites. EBV inection. EBV inection was deined by a ourod or greater rise in gg antibody titers against VCA occurring> 30 d ater transpantation. Thirtyour o 121 patients were excuded rom anaysis o EBV inection because o a ack o appropriate postoperative sera, and 87 assessabe patients then remained. Patients were deined as having a symptomatic EBV inection i they had either a ebrie vira syndrome deined the same way as or CMV, but with no aboratory evidence o CMV inection, and a ourod or greater rise in gg VCA titers to EBY. We deined EBV-associated ymphoproierative esions by the presence o EBV DNA in tissues by using nuceic acid hybridization and/or by the presence o EBV nucear antigen by using immunouorescent staining [12]. HS Vand VZ V inections. HSV inection was deined as the presence o typica symptomatic ora or genita ucers. For atypica esions or those outside the genita or ora area, isoation o virus or typica vira cytopathoogy was aso required. VZV inection was determined cinicay by the presence o typica dermatomaesions. n one patient with cinica varicea the virus was cutured rom skin esions and bood, and the patient's pretranspant seroogica status was determined by an indirect uorescent-antibody test Eectro Nuceonics, Coumbia, Mass). Statistica methods. Observed proportions were compared using the "x.z test or, i the numbers were sma, Fisher's two-taied exact test. Cacuated Tabe 1. Preop CMV seroogy Negative Positive Tota means were compared using Student's t test. Dierences were considered signiicant at P <.05. Resuts CMV inection. Fity-ive 59070) o 93 patients deveoped CMV inection. These incuded ) o 37 seronegative recipients and ) o 56 seropositive patients tabe ). Fiteen 88070) o 17 recipients with primary inection had symptomatic disease. Seven patients had a vira syndrome, three patients had ocaized CMV inection, and ive patients had disseminated CMV inection. Two cases o ocaized CMV invoved the ung, and one invoved the sma bowe. n the atter case, the diagnosis was made by endoscopic biopsy through an ieostomy. O the ive patients with disseminated CMV, three died, and mutipe organ invovement was ound at autopsy. Two patients with disseminated CMV disease one with hepatitis and pneumonitis and the other with hepatitis and duodenitis) recovered. Symptomatic CMV disease was diagnosed in ) o 38 patients with reactivated CMV inection and was signiicanty ess requent than ater primary inection P <.01). Nine patients had a benign vira syndrome, two patients had ocaized CMV inection one with hepatitis and one with pneumonitis), and one patient had disseminated CMV. Disseminated CMV inection occurred ess oten in patients with reactivation inection one o 38) compared with patients with primary CMV inection ive o 17; P <.01). Mortaity. O the 55 inected patients, ) died. This rate was higher than, but not signiicanty dierent rom, the 8070 three o 38) mortaity rate ound in uninected patients P =.12). Aso, mortaity in patients with symptomatic CMV inection Frequency o CMV inection and symptomatic disease in iver transpant recipients. No. o assessabe patients NOTE. Preop = preoperative. nection 070) 17 46) 38 67) 55 59) No. o patients with Tota no. Vira Locaized Disseminated o symptomatic syndrome CMV CMV patients 070) 7 3 5' 15* 88) 9 2 ' 12* 32) ) P <.01 or patients with primary inection compared with patients with reactivation inection who deveoped symptomatic CMV disease and with patients with disseminated CMV disease P <.01 or both comparisons)., r T,, T B r tr R F c P pi W s 0 w S t w e) tt ti, t a re be w re d pi ti S d: 1 C C 0 a v: ti a t t 0 i

4 T Hcrpesviruses and Liver Transpanaion 127 y e '- n ic :ic r 1,, ), Tabe 2. Bood product mean units transused) Red bood ces Fresh rozen pasma Cryoprecipitate Pateets Tota units Reation o CMV inection to bood products transused. Seronegative recipients Primary inection Not inected Reactivation inection n = 17) n = 20) n = 38) Seropositive recipients Not inected n = 18).No signiicant dierences were ound between the number o units o red bood ces, resh rozen pasma, cryoprecipitate, pateets, or tota bood product units or inected vs. uninected patients P>.1). was 18% ive o 27) and did not dier rom the 25% seven o 28) mortaity rate ound in patients without symptomatic CMV inection. The mortaity rate was, however, 66% our o six) or patients with disseminated CMV, a rate that was signiicanty higher than the 16% eight o 49) mortaity seen in patients without disseminated CMV inection P<.05). The excess mortaity in patients with disseminated CMV may not be attributabe soey to CMV, because a these patients had other bacteria or unga inections that may aso have payed a roe in their deaths. Transmission. Organ aograts have been shown to transmit CMV to seronegative kidney and )eart aograt recipients [11, 15]. The association between receiving a iver rom a donor positive or CMV antibodies and subsequent deveopment o CMV inection was anayzed. Thirteen 92%) o 14 seronegative recipients who received ivers rom CMV-seropositive donors had evidence o CMV inection ater transpantation, whereas ony one 8%) o 12 seronegative recipients who received a iver rom a CMVseronegative donor deveoped CMV inection. This dierence in inection rate was highy signiicant. P <.001). No deinite reation was ound between the occurrence o CMV reactivation inection and the CMV seroogica status o the donor. Fiteen 71%) o 21 seropositive patients who received a iver rom a CMV-seropositive donor underwent CMV reactivation inection; by comparison, 11 78%) o 14 patients who were seropositive or CMV antibody beore transpantation and who received a iver rom a CMV-seronegative donor aso became inected ater transpantation P >.5). This anaysis suggests that, as in the case o rena transpant recipients, the organ aograt is not usuay responsibe or CMV inection in seropositive recipients [11]. A patients received random bood products that were neither tested nor seected or CMV antibody. The impact o transusions and bood products on CMV inection in seronegative and seropositive recipients was aso investigated. The mean number o units o red bood ces, resh rozen pasma, cryoprecipitate, pateets, or tota units o bood products received by inected and uninected patients, whether they were seropositive or seronegative beore transpantation, was not signiicanty dierent. These data are shown in tabe 2. CMV injection and immunosuppression. Tabe 3 shows data on the reation o symptomatic CMV disease and the use o additiona immunosuppressive agents such as OKT3, AZA, or steroids. Thirteen 40070) o 32 patients in the OKT3 group deveoped symptomatic CMV inection; this inding did not dier signiicanty rom the 63% 14 o 22) rate o symptomatic disease in patients who received other immunosuppressive regimens. There was a trend toward more disseminated CMV inections in patients who received OKT3 six [18%] o 32 vs. 0 [0%] o 23, P =.06). Anaysis o these data showed that patients with primary inection who received OKT3 had a 55% ive o nine) rate o dissemination as compared with no episodes o disseminated disease in the eight patients with primary inection who did not receive OKT3 P =.04). There was no apparent eect o OKT3 on dissemination in CMV reactivation inection 0 o 15 vs. 1 o 23, P>.1). HSV injection. O 121 patients, 95 78%) were seropositive and 26 22%) were seronegative or antibodies to HSV beore transpantation. A but one o the inections caused by HSV occurred in seropositive recipients and were thought to be due to reactivation o atent virus. O 95 seropositive recipients, %) deveoped typica mucocutane --,

5 , ''Y,'-' 128 Singh e a. Tabe 3. Reation between additiona immunosuppression and symptomatic CMV inection. Tota no. o No. o patients with Additiona assessabe Symptomatic Vira Locaized Disseminated immunosuppression patients nection inection syndrome CMV inection CMV inection OKT3* t AZA ony Steroids ony None Tota A patients treated with OKT3 received additiona steroids; 17 o 32 inected patients aso received AZA azathioprine). t p =.06 or pa,tients with disseminated CMV disease treated with OKT3 6 o 32) vs. patients who did not receive OKTJ 0 o 23). ous HSV esions, incuding 29 patients with ora HSV and 10 with genita HSV inections. Two patients deveoped HSV esophagitis, and two had HSV hepatitis without mucocutaneous esions. The two cases o hepatitis were discovered at autopsy 21 and 46 d ater transpantation. One patient had isoated HSV hepatitis. n the other patient, HSV hepatitis was part o a disseminated viscera HSV inection invoving the iver, ungs, coon, and arynx. Ony one o 26 seronegative recipients had primary HSV inection. She deveoped HSV hepatitis 21 d ater transpantation; this inding was documented histopathoogicay by iver biopsy. HSV was aso cutured rom a bronchoaveoar avage specimen. The patient received a iver rom a donor seropositive or antibodies to HSV type 2 and deveoped antibodies to HSV type 2 ater transpantation. She was treated with iv acycovir, and her resoution o HSV hepatitis was documented by as in transaminase eves and by subsequent iver biopsies. The ora and genita HSV inections in these patients occurred a median o 19 and 24 d postoperativey, respectivey. We did not document HSV viremia or CNS inection rom HSV in any patient. Tabe 4 anayzes the impact o immunosuppression on HSV inections in seropositive recipients. The group treated with OKT3 had more symptomatic iness due to HSV 29 [ o 54), as compared with patients who did not receive OKT3 13 [31 % 1 o 41, P =.05). EBV inections. Eighty-ive o 119 seropositive recipients were assessabe or EBV inection, and 20 24%) o them showed a ourod or greater rise in antibody titers to EBV VCA. O these patients, ony one patient had symptomatic EBV inection maniested by ymphoproierative disease 143 dater transpantation. The patient had enarged periaortic ymph nodes with no evidence o disease outside the abdomen. EBV DNA was ound in these nodes by nuceic acid hybridization. He was treated with radiation therapy aong with reduction in his immunosuppression, and the disease eventuay regressed. Ony two patients in the study popuation were seronegative or EBV preoperativey. They seroconverted on day 30 and 72, respectivey, ater transpantation and had no disease attributabe to EBV, athough one patient had concomitant CMV inection. Tabe 4. mmunosuppression in recipients seropositive or HSV and requency o symptomatic HSV inection. No. o patients with Tota no. o Additiona Tota no. Genita Other HSV symptomatic immunosuppression o patients Ora HSV HSV inections patients None AZA ony Steroids ony OKT3* t Tota * A patients treated with OKT3 received additiona steroids; 32 o 54 OKT3-treated patients aso received AZA azathioprine). t p =.05 or OKT3-treated patients with symptomatic HSV 29 o 54) vs. symptomatic patients 13 o 41) who did not receive OKT3. One patient had both ora and genita HSV and is counted ony once.

6 a. Herpesvirses and Liver Transpantation 129 :d on J). she ith H, ve 20 in y niter ::>r-,de ies ith m- reere m- m- a- )n. n. o tic e). ive, t.,. [, J Nine 45070) o 20 patients with reactivation EBV inection had symptomatic CMV inection as compared with ) o 65 without EBV reactivation. This dierence was not statisticay signiicant. VZV inections. Eight 7070) o the 121 patients deveoped cinica VZV inection. Seven patients had ocaized dermatoma zoster that deveoped a median o 167 d arer transpantation range, d). One patient deveoped uminant varicea with viscera invovement 32 d ater transpantation and died despite treatment with acycovir. Discussion This study is the irst to characterize the requency and morbidity o vira inections in a arge group o adut iver transpant recipients and expands upon our previous studies in this popuation [8]. CMV remains the most important vira pathogen occurring ater transpantation. O 93 assessabe patients, ) deveoped CMV inection ater transpantation. These resuts are simiar to those reported in rena transpant patients but somewhat ower than those reported in cardiac transpant recipients [16]. An association o symptomatic CMV disease with primary CMV inection has been shown or recipients o kidney and heart aograts [3, 15]. Our resuts show both an increased incidence o symptomatic CMV inection and a higher requency o disseminated disease in iver transpant recipients with primary CMV inection. Wheche et a. [17] have reported a higher mortaity rate in rena transpant recipients with symptomatic CMV inection. n our study, the mortaity o patients with symptomatic disease 18070) did not dier signiicanty rom the mortaity o patients with asymptomatic CMV inection 25070). Disseminated CMV inection was associated with a signiicanty higher mortaity than was nondisseminated CMV inection. However, a our patients with disseminated CMV who died had concomitant systemic bacteria or unga inections, and their deaths were probaby due to mutipe actors. Two important possibe sources o CMV acquisition in transpant patients are organ aograt and bood products. Our data show that the hepatic aograt is an important source o CMVinection in seronegative iver recipients. Seronegative recipients who received ivers rom seropositive donors had an inection rate o o 14). This inding is consistent with simiar seroogica evidence that other major organ transpantation is associated with transmission o CMV [11, 15, 18]. Such evidence has now been urther strengthened by proving the identity o donor strains o CMV in rena recipients by endonucease restriction patterns [19]. n an earier study we cacuated that in the Pittsburgh area, the risk o acquiring CMV inection rom transused units o bood, on the basis o data rom seronegative pediatric patients undergoing open heart surgery, was per unit [20]. Hence, the risk o CMV inection was ow in operations in which usuay <10 units were required [21]. However, even in the case o iver transpantation in which signiicanty more than 10 units o bood and other bood products are used [22], we have not been abe to demonstrate an association between primary inection and units o bood used, either in pediatric iver recipients [9] or in aduts. A noteworthy inding in our study is the impact o OKT3 antibodies on CMV inection. OKT3 appeared to increase the risk o dissemination in patients with primary CMV inection. Dierent immunosuppressive agents may have dierent eects on CMV inection. Corticosteroids aone appear to have itte eect on CMV inection, whereas cytotoxic immunosuppressants such as AZA do have the abiity to reactivate atent virus [23]. Since the introduction o CsA into cinica organ transpantation, numerous studies have documented a ower incidence o symptomatic CMV inection in patients treated with CsA [28, 29]. Comparing CMV inection and disease in rena transpant patients receiving either AZA or CsA, but not ATG, we and Bia et a. were unabe to show a dierence [7,26]. Rubin et a. [27] have concuded that adding agents such as ATG is more important in potentiating CMV disease than is the basic immunosuppressive regimen. Their concusions are based. on studies that report an increased incidence o symptomatic CMV inection in rena transpant recipients receiving conventiona regimens o AZA, prednisone, and ATG, compared with rena transpant patients receiving CsA and prednisone aone [28, 29]. The incidence o symptomatic CMV inection in patients receiving AZA and prednisone without ATG, however, appears to be simiar to the rate o symptomatic CMV inection in rena transpant recipients receiving CsA and prednisone [26]. Peterson et ai. [30] compared the incidence o CMV pneumonia in a group o rena transpant patients receiving these two regimens and postuated that the higher incidence o CMV pneu- 1 r

7 130 Singh et a. monia in the group receiving ATG, prednisone, and AZA was reated to the use o ATG. Thereore, we beieve that the abiity to potentiate CMV inections is not unique to OKT3 but that it shares this characteristic with other antiymphocyte preparations. However, because OKT3 was used to treat severe episodes, it may we be that the higher incidence o disseminated CMV inection in these patients was due to a combination o actors such as severe grat rejection aong with concomitant bacteria and unga inections that may have increased their net state o immunosuppression. As reported in other organ aograt recipients [31], HSV inections were mosty due to reactivation o atent virus. Forty-our percent 42 o 95) o seropositive patients in our study deveoped symptomatic HSV inection. O great interest was the case o primary HSV inection HSV hepatitis) in this study, with a histopathoogicay documented cure ater acycovir treatment. To our knowedge this is the irst reported case o primary HSV hepatitis cured with acycovir in a transpant recipient. The patient possiby acquired HSV inection rom the donor. We have documented probabe transmission o HSV inection by the donor organ in kidney recipients, but this route is rare and has not been documented or iver recipients [35, 36]. A ew studies have correated the use o antiymphocyte preparations with an increased risk o reactivation and symptomatic iness due to HSV [32]. Preiksaitis [33] studied heart transpant recipients at Stanord Univeristy Stanord, Cai) and reported signiicanty more symptomatic and severe iness due to recurrent herpes abiais in patients treated with high-dose ATG. Simiar data are not avaiabe or OKT3, but we observed a trend toward a higher requency o symptomatic HSV inections in seropositive patients treated with OKT3. Most o these inections were mucocutaneous and, thereore, not ie-threatening. Because this is a retrospective study, a number o these patients did not have cutures o the esions perormed or were aready being treated with acycovir when cutures were perormed. t is our experience in a arge transpant popuation, however, that cutures o typica ora or genita esions or herpes are amost invariaby positive i obtained beore antivira therapy. The number o patients with viscera HSV inections in our study was too sma to assess i OKT3 increased the risk o viscera or disseminated HSV. Physicians caring or iver transpant recipients shoud be aware that viscera HSV inections particuary hepatitis) may occur in some o their patients. Liver biopsies appear to be diagnosticay useu in this setting. VZV inection was seen in 7OJo eight o 121) o our patients. Seven patients had ocaized zoster. One patient with primary varicea died rapidy o disseminated viscera disease. t is we known that varicea has a high morbidity and mortaity rate in transpant recipients [34]. Because hyperimmune gobuin against VZV VZG) may prevent or ameiorate this iness, it is probaby prudent to monitor transpant candidates with no history o chickenpox or VZV antibody t<adetermine their susceptibiity to inection. The number o patients with herpes zoster was too sma to measure the eect o OKT3 on reactivation. We ound an EBV reactivation inection rate o 24%, which is simiar to what was previousy reported [12]. n our patients we coud not deinitey attribute any vira syndrome to EBV, possiby because o simutaneous evidence o CMV inection. One seropositive patient, however, deveoped an atypica EBV-reated ymphoma. n summary, 65 53%) o 121 adut iver transpant recipients had one or more symptomatic inections with herpesviruses. Athough eective therapy or HSV and VZV inection exists, some cases may sti be ata. CMV inection continues to be a major probem in iver transpant recipients, and active research into the diagnosis, prevention; and therapy o these inections is sti needed. Reerences. Ho M. nection and organ transpantation. n: Geman S, ed. Anesthesia and organ transpantation. Phiadephia: W.S. Saunders, 1987: Ho M. Cytomegaovirus: Bioogy and nection. New York: Penum Medica Book Company, Suwansiriku S, Rao N, Dowing N, Ho M. Primary and secondary cytomegaovirus and inection. Cinica maniestations ater rena transpantation. Arch ntern Med 1977;137: Pass RF, Whitey RJ, Diethem AG, Wheche D, Reynods DW, Aord CA. Cytomegaovirus inection in patients with rena transpants: potentiation by anti thymocyte gobuin and an incompatibe grat. J nect Dis 1980;142: Cheeseman SH, Rubin RH, Stewart JA, Toko-Rubin NE, Cosimi SA, Cante K, Gibert J, Winke S, Herrin n, Back PH, Russe PS, Hirsch MS. Controed cinica tria o prophyactic human-eukocyte intereron in rena transpantation. Eects on cytomegaovirus and herpes simpex virus inections. N Eng J Med 1979;300: Meyers JD, Fournoy N, Thomas ED. Nonbacteria pneu- r

8 . Herpesviruses and Liver Traspianaio1 131 y.-, e ;- tt n e.r ox y r ;- n t, ).y y 1..n! 1t S )r i )r e- y S, a: k: d a ed :is th in E, T, a Sn- u- r monia ater aogeneic marrow transpantation: a review o ten years' experience. Rev nect Dis 1982;4: Dummer JS, White LT, Ho M, Griith BP, Hardesty RL, Bahnson HT. Morbidity o cytomegaovirus inection in recipients o heart or heart-ung transpants who received cyciosporine. 1 nect Dis 1985;152: Dummer JS, Hardy A, Poorsattar A, Ho M. Eary inections in kidney, heart, and iver transpant recipients on cycosporine. Transpantation 1983;36: Breinig MK, Zitei B, Starz TE, Ho M. Epstein-Barr virus, cytomegaovirus, and other vira inections in chidren ater iver transpantation. J nect Dis 1987;156: Rao N, Waruszewski DT, Armstrong JA, Atchison RW, Ho M. Evauation o anti-compement immunouorescence test in cytomegaovirus inection. J Cin Microbio 1977; 6: Ho M, Suwansiriku S, Dowing N, Youngbood LA, Armstrong A. The transpanted kidney as a source o cytomegaovirus inection. N Eng J Med 1975;293: Ho M, Mier G, Atchison RW, Breinig MK, Dummer S, Andiman W, Starz TE, Eastman R, Griith BP, Hardesty RL, Bahnson HT, Hakaa TR, RosnthaT. Epstein-Barr virus inections and DNA hybridization studies in posttranspantation ymphoma and ymphoproi erative esions: the roe o primary inection. 1 nect Dis 1985;152: Lee FK, Coeman RM, Pereira L, Baiey PD, Tatsuno M, Nahmias AJ. Detection o Herpes simpex virus type 2-speciic antibody with gycoprotein G. 1 Cin Microbio 1985; 22: Lee FK, Pereira L, Griin C, Reid E, Nahmias A. A nove gycoprotein or detection o herpes simpex virus type -speciic antibodies. 1 Viro Methods 1986;14: Poard RB, Arvin AM, Gamberg P, Rand KH, Gaagher JG, Merigan TC. Speciic ce-mediated immunity and inections with herpes viruses in cardiac transpant recipients. Am J Med 1982;73: Ho M. Herpesvirus inections in transpant patients. n: de a Maza LM, Peterson EM, eds. Medica viroogy V. Hisdae, N 1: Lawrence and Erbaum Associates, 1986: WhecheD, Pass RF, Diethem AG, Whitey R, Aord CA Jr. Eect o primary and recurrent cytomegaovirus inections upon grat and patient surviva ater rena transpantation. Transpantation 1979;28: Betts RF, Freeman RB, Dougas RG Jr, Taey TE, Runde B. Transmission o cytomegaovirus inection with rena aograt. Kidney nt 1975;8: Chou S. Acquisition o donor strains o cytomegaovirus by rena-transpant recipients. N Eng 1 Med 1986;314: Armstrong A, Tarr GC, Youngbood LA, Dowing N, Sasow AR, Lucas P, Ho M. Cytomegaovirus inection in chidren undergoing open-heart surgery. Yae J Bioi Med 1976;49: Ho M, Dowing N, Armstrong A, Suwansiriku S, Wu B, Youngbood LA, Sasow A. Factors contributing to the risk o cytomegaovirus inection in patients receiving rena transpants. Yae J Bioi Med 1976;49: Lewis H, Bontempo FA, Corne F, Kiss JE, Larson P, Ragni MV, Rice EO, Spero JA, Starz TE. Bood use in iver transpantation. Transusion 1987;27: Dowing N, Sasow AR, Armstrong J A, Ho M. Cytomegaovirus inection in patients receiving immunosuppressive therapy or rheumatoogic disorders. J nect Dis 1976; 133: Peterson PK, Rynasiewicz J J, Simmons RL, Ferguson RM. Decreased incidence o overt cytomegaovirus disease in rena aograt recipients receiving cycosporin A. Transpant Proc 1983;15: Najarian JS, Strand M, Fryd DS, Ferguson RM, Simmons RL, Ascher NL, Sutherand DER. Comparison o cycosporine versus azathioprine antiymphocyte gobuin in rena transpantation. Transpant Proc 1983;15Supp and 2): Bia MJ, Andiman W, Gaudio K, Kiger A, Siege N, Smith D, Fye W Eect o treatment with cycosporine versus azathioprine on incidence and severity o cytomegaovirus inection posttranspantation. Transpantation 1985; 40: Toko-Rubin NE, Rubin RH. The impact o cycosporine therapy on the occurrence o inection in the rena transpant recipient. Transpant Proc 1986;18: Najarian S, Fryd DS, Strand M, Canaax DM, Ascher NL, Payne WD, Simmons RL, Sutherand DER. A singe institution, randomized, prospective tria o cycosporine versus Azathioprine-antiymphocyte gobuin or immunosuppression in rena aograt recipients. Ann Surg 1985;201: Henry ML, Sommer BG, Ferguson RM. The impact o cycosporine compared with azathioprine or cadaveric rena transpant immunosuppression. Transpant Proc 198;17: Peterson PK, Baour HH, Fryd DS, Ferguson R, Kronenberg R, Simmons RL. Risk actors in the deveopment o cytomegaovirus-reated pneumonia in rena transpant recipients. 1 nect Dis 1983;148: Naraqi S, ackson GG, Jonasson 0, Yamashiroya HM. Prospective study o prevaence, incidence, and source o herpesvirus inections in patients with rena aograts. J nect Dis 1977;136: Russe AS. Ce-mediated immunity to herpes simpex virus in man. 1 nect Dis 1974;129: Preiksaitis JK, Rosno S, Grumet C, Merigan TC. nections due to herpesviruses in cardiac transpant recipients: roe o the donor heart and immunosuppressive therapy. 1 nect Dis 1983;147: Fedho CM, Baour HH Jr, Simmons RL, Najarian JS, Mauer SM. Varicea in chidren with rena transpants. 1 Pediatr 1981;98: Dummer JS, Armstrong 1, Somers 1, Kusne S, Carpenter BJ, Rosentha JT, Ho M. Transmission o inection with herpes simpex virus by rena transpantation. 1 nect Dis 1987;155: Koneru B, Tzakis AG, DePuydt LE, Demetris AT, Armstrong A, Dummer JS, Starz TE. Transmission o ata herpes simpex inection through rena transpantation. Transpantation, 1988 in press)..