Abu-Elmagd, K

Alessiani, M

Fung, J

Jain, A

Kusne, S

Martin, M

Moser, J

Starzl, T

Todo, S

PubMed

ALESSIANI, MARIO

S. KUSNE

M. MARTIN

A. JAIN

K. ABUELMAGD

J. MOSER

S. TODO

J. FUNG

T. STARZL

Archivio Istituzionale della Ricerca - Università degli Studi di Pavia

Infections In Adult Liver-transplant Patients Under Fk506 Immunosuppression

D-Scholarship@Pitt

f/~/ Infections in Adult Liver Transplant Patients Under FK 506 Immunosuppression M. Alessiani. S. Kusne. M. Martin. A. Jain. K. Abu-Elmagd. J. Moser. S. Todo. J. Fung. and T. Starzl THE preliminary results of infectious complications in orthotopic liver transplantation IOLT) using FK 506 as a primary immunosuppressive agent were encouraging. I This early experience. however. was limited to only 20 patients who were followed for a short period of time. We have now extended our observations to 110 consecutive adult liver transplant recipients of first livers enrolled in the first human clinical trial of OL T under FK 506. A longer follow-up period 15 to 12 months) has allowed us to compare FK 506 with previous studies of infections in the cyclosporine ICy Al era; and to assess whether this new agent alters the infectious profile and overall rate of infection. The influence of FK 506 on well established risk factors for infection were specifically addressed. and in· c1ude preoperative patient status. requirement for addi-tional immunosuppression. reoperation. and retransplan-tation. METHODS The patient population included 110 consecutive adults who underwent OLT between August 18. 1989 and february 18. 1990. All patients were followed prospectively from the time of surgery to discharge or death. Out-patient follow-up continued until July 1. 1990. General characteristics and indications for OL T arc summarized in Table I. The mean age was 40 :!: 12 years. with 17 patients older than 60 years of age. There were 58 males and 52 females. Mean follow-up was 214 :!: 50 davs with a range of 134 to 315 days. Eight-five patients were senously ill (status 3. 4. or UNOstatl. as defined by the current United Network for Organ Sharing IUNOS) stratification: status I. at home. functioning Without domiciliary nursing care: status 2. at home. not working and reqUiring profeSSional nursing care: status 3. hospital bound: status 4. intensive care unit bound. UNOstat-ICU bound requiring life support. The most frequent indication for OL T was nonalco-holic cirrhosis followed by alcoholic and cholestatic liver disease. Immunosuppression Immunosuppression protocol included fK 506 and steroids in all patients. The first 57 patients received fK 506 as an IV loading dose of 0.15 mglkg followed by an IV maintenance dose of 0.075 mglkg twice a day. Conversion from IV to oral doses was usually overlapped for I day with oral maintenance doses of 0.15 mglkg given every 12 hours. Initial steroid therapy included a I g I V bolus of methylprednisolone intraoperatively. A 200 mg dose on the first postoperative day was then reduced by 40 mg increment~ 10 a maintenance dose of 20 mg by day 6. The subsequent 53 patients received IV maintenance doses of fK 506 and methyl-prednisolone from the outset. omittmg Ihe loading dose of fK 5()t) and both the steroid bolus and taper. Subsequent ad.iustmenh were dictated by the quality of the grafL the presence of rejection. toxicity symptoms. and the fK 506 plasma levels. Table 1. Patient Population and Indications for OL Tx Demographics No. of patients 110 No. of transplants 124 Age (y) 46 + 12 (18 to 69) Sex (M/F) 58/52 Mean follow-up (d) 214 + 50 Indications NonalcoholiC CirrhoSIS 45 (41.0%) Alcoholic CirrhoSIS 28 (25.5%) Cholestatlc disease 28 (25.5%) Fulminant failure 3 (2.7%) Tumor 2 (1.8%) Miscellaneous 4 (3.5%) Infection ProphylaxiS The patients received perioperatlve IV cefotaxime and ampicillin 3 gld which was continued for the first 3 days after tmnsplant. Oral mycostatin 2 million U/d was given for the first 6 months. High dose oral acyclovir ranging from 400 mg to 3200 mgld was given with dose adjustment according to renal function. One tablet of Bactrim SS daily (80 mg of trimethoprim plus 400 mg of sulfa-methoxazolel was given for almost I year. Definition of Infections We followed the definitions of infections described by Kusne et al~ from our institution with classification done according to the time of diagnosis. maior pathogen. and site of occurrence. An infection was considered to be associated with death if it was found at the autopsv or if the patient was still under treatment for the infection at the time of death. An infeclion was defined as severe if it Involved solid organs or cavities and required treatment with specific antibiotics and/or surgical intervention. Examples of severe infections in this study included peritonitis. pneumonia. cholangitis. abdominal or liver abscess. pericarditis. symptomatic CMV and Epstein-Barr virus (EBV) infections. invasive candidi-asis. and aspergillosis. Examples of non severe infections included line infection. superficial wound infection. colitis. sinusitis. otitis. mucocutaneous herpes simplex. and candida colonization. From the Departments of Surgery and Medicine. University Health Center of Pittsburgh. University of Pittsburgh. and the Veterans Administration Medical Center, Pittsburgh. Pennsylva-nia. Supported by research grants from the Veterans Administration and project grant no. OK 29961 from the National Institutes of Health. Bethesda, Maryland. Address reprint requests to Thomas E. Starzl. MD, PhD. De-partment of Surgery. 3601 Fifth Ave. Falk Clinic 4 W. Pittsburgh, PA 15213. c, 1991 by Appleton & Lange 0041-1345/91/$3.00/+0 Transplantation Proceedings. Vol 23. No 1 (February). 1991: pp 1501-1503 1501 I: :'1 1 I i i .. - ... ----.--.----1502 Table 2. Percentage of Patients Infected and the Episodes of Infection Per Patient % Patients Infected EPISOdes of Inf x PI All Several All Several Bacterial 36 19 0.58 0.24 Viral 24 23 0.31 0.28 Fungal 9 6 0.12 0.06 Total 50 38 1.01 0.58 Note: Distinction has been made between severe and overall Infections. Sixteen percent of patlllnts suffered overlaPPIng InfectIOns (9% bactenal + viral. 3% bactenal + fungal. 4% baClenal + wal + fungal) while 34% developed only OM type (20% bacterial. ,,% viral. 2% fungal) Statistics The number of infections per patient was compared between patient groups nonparametricallv using the Wilcoxon two-sample test for location. Although follow-up time varied from patient to patient. follow-up lime was not related to the number of infec-tions. RESULTS From July I. 1990 (when data compilation closed) to August 16. 1990. 102 (92.79c) of the patients are alive. Ten patients underwent retransplantation. with six requiring one graft and four. two grafts. Six of these patients are alive. Five of eight deaths were due to infection (62.59H and three to other causes such as heart failure. stroke. and multiorgan failure. Of the infection related deaths. two occurred following retransplantation. The majority of bac-terial and fungal infections were seen within the first 60 days with viral infections persisting through the first 6 months. The severity and frequency of infections are shown in Table 2. Overall. 50% of patients developed infection of which 38% suffered severe ones. Bacterial infections predominated with some patients infected with mUltiple organisms. Sixty-four episodes of bacterial infec-tion. which ranged in severity. were noted. A combination of viral. bacterial. or fungal infection was noted in 16% of the patients while a single type of infection occurred in 34%. No protozoal infections were seen. Eight of the III (7.2%) episodes resulted in death and were predominantly bacterial and fungal (7). In the bacterial group (Table 3) the most frequent severe infections were pneumonia (8). peritonitis (8). and cholan-gitis (6). The majority of the microorganisms isolated were aerobic gram positive (38) and gram negative aerobes (23). Anaerobes were unusual with Clostridium difJicile ac-counting for seven of eight cases. Cervical lymphadenitis caused by Mvcohocterium 111-berculosis was seen in one patient and required prolonged treatment with conventional triple therapy (isoniazid. ethambutol. and rifampin). However. 3 months later iso-niazid hepatotoxicity necessitated discontinuation of this drug. Symptomatic CMY was the most frequent viral infection and occurred in 23 patients. The liver and gastrointestinal ALESSIANI. KUSNE. MARTIN ET AL Table 3. Number of Episodes of Infection That Occurred In 55 of 110 Patients Bacterial (64 r Soft tissue line sepsIs Pneumoma Peri/ani/is Colitis Cholangi/is Urinary tract SinUSitiS Intrabdommal abscess Liver abscess Pericarditis Cervical TB Otitis media Viral (34) CMV Herpes Simplex EBV Fungal (13) Candidiaslasis Colonized candida Aspergillosis Note. Severe Inlectlons are Italicized '19 episodes of bacteremia are Included. all 01 known ongln. (12) (11 ) (8) (8) (7) (6) (5) (2) (1 ) (1 ) (1 ) (1 ) (1 ) (27) (4) (3) (5) (6) (2) tract were the predominant sites of infection (eight epi-sodes each) followed by the lungs (five examples). Three patients developed multiple and recurrent episodes of CMY at different sites and all were fund to have concom-itant retinitis as a late manifestation. The first patient was a 19-year-old man. retransplanted after 40 days for rejec-tion. He was seronegative for CMY and received his second liver from a seropositive donor. He had a positive cytotoxic crossmatch with both donors and heavy immu-nosuppression was required throughout his early course for persistent rejection. Multiple episodes of symptomatic CMY subsequently developed and included pneumonia. hepatitis. and retinitis at 3. 4. and 6 months respectively. Two patients had a similar course with initial episodes of CMY infection occurring during the third month posttrans-plant (hepatitis-I. pneumonia-I) with readmission required at 5 months for concomitant CM Y gastritis and retinitis. In all cases treatment with DHPG was successful and none of the patients had residual sequelae from the retinitis. EBY infection associated with polyclonallymphoprolif-erative disease was confirmed histologically in three pa-tients. A 19-year-old man developed an infectious mono-nucleosis syndrome with enlargement of the tonsils and was successfully treated with tracheostomy. tonsillec-tomy. acyclovir. and reduction of the FK dose. The other two patients developed polyclonallymphoma arising in the allograft. One highly sensitized patient (positive cross-match with all donors) died of overwhelming pseudomonas and candida sepsis 9 days after undergoing a third trans-plant for rejection. while the other patient whose jym-phoma was confined to the graft recovered following left hepatic segmentectomy. .. FK 506 IMMUNOSUPPRESSION 3.40 .. "-z 0 ;:: " w ... ! ... 0 III w 0 0 '" 0:"' NO YES NO YES RETRANSPLANTATION REOPERATION Fig 1. Effect of additional Immunosuppression (boluses or recy· cles of steroids and OKT3) and UNOS status on the Incidence of infections. Of the five cases of invasive candidiasis. two were associated with death. A fatal aspergillosis was seen in a 31-year-old woman. Twenty-one days after transplant. she was noted to have several pulmonary nodules. which contained aspergillus on biopsy. She received a full course of amphotericin B therapy (3 g total dose). with partial regression of these nodules. She then required retransplan-tatlOn for hepatic artery thrombosis at 3.5 months and succumbed to bacterial sepsis and recurrent aspergillus in her thoracic spine at 5 months (vertebral osteomyelitis). Significant higher rates of infection were seen in the sickest pretransplant patients and in those receiving addi-tIOnal mtense immunosuppression (steroid boluses. recy-cles. or OKT3) (Fig Il. The need for retransplantation or additional surgery was associated with especially high rates of infection (Fig 2l. DISCUSSION Advances in preservation. combined with technical im-provements. and the routine use of veno-veno bypass have contributed to lowering morbidity of OLT. However. the intense immunosuppression required under conventional therapy continues to play a key role in contributing to infectious outcome. 3 .4 This large series of OL T patients receiving FK 506 has confirmed our early enthusiasm for this agent. As reported hy Todo et al.s rejection. early graft dysfunction. and the need for retransplantation have been reduced in FK 506 treated patients. The potent immunosuppressive proper-ties of this drug have allowed for significant reductions in steroid use without increasing the risk of rejection. In fact. fewer infections were seen. 1503 1.81 Ii: >< .. Z g t; "' ... ! ... 0 .. ... 0 ~ It ... UIIC lIlA OKTl ADO. IMMUNOSUPPRESSION UNOS STATUS Fig 2. Effect of retransplantation and additional immunosuppres-sion on incidence of Infections. The differences are statistically significant (P < .05). The patterns and timing of the infections that did occur were similar to those developing under conventional ther-apy. with bacterial and fungal infections predominating early in the course. However. 50% of patients receiving FK 506 were entirely free of infections compared with only 179t in the historical controls from Kusne's earlier report from our institution. ~ Although infection continues to cause or be associated with the majority of deaths. the death rate has been reduced. Symptomatic CMV remains the most common infec-tion. However. all herpes infections have been signifi-cantly less. an improvement that may be related to recent changes in prophylaxis with the use of acyclovir. The notable absence of protozoal infections can be explained. at least in parI. in the same way. High risk factors continue to be retransplantation. reop-eration. intense additional immunosuppression in the man-agement of rejection. and grave deterioration from end-stage liver disease going into transplantation. However. the poor prognostic portent of these risk factors has seemed less grim in the FK 506 treated patients than in the past. A generally good quality of liver graft function. which has been achievable with low (and often no) dose steroids appears to be the explanation for the improved outlook. REFERENCES I. Alessiani M. Kusne S. Martin FM. et al: Transplant Proc 22:44. 1990 2. Kusne S. Dummer JS. Singh N. et al: Medicine 67: 132. 1988 3. Ascher N L. Slock PG. Bumgardner GL. et al: Surg Gynecol Obslet 167:474. 1988 4. Paya CV. Hermans PE. Washinglon II JA. el al: M"yo Clin Proc 64:555. 1989 5. Todo S. Fung JJ. Slarzl TE. el al: Ann Surg lin press) , . . i! I,i I' .It I· I 

Infections in adult liver transplant patients under FK 506 immunosuppression.

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Infections in adult liver transplant patients under FK506 immunosuppression

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Infections in adult liver transplant patients under FK 506 immunosuppression.

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