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Background. The 2009 H1N1 influenza virus was first identified in April 2009 and rapidly evolved into a pandemic. There are limited reports of 2009 H 1N1 influenza in transplant recipients. We report on our experience with hospitalized transplant recipients with 2009 H1N1 influenza virus. Methods. Ongoing review of hospitalized 2009 H1N1 influenza cases identified six patients who had received transplants. Clinical characteristics and outcomes were abstracted from the medical record. Results. Between April 27 and November 30, 2009, 29 patients with influenza A virus were admitted to the Mayo Clinic Hospital. Six of the 29 patients were transplant recipients; 4 were confirmed to have 2009 H1N1 influenza virus. Most patients presented with an acute febrile respiratory illness. Duration of antiviral treatment was 5 to 7 days except for one patient who was treated for 11 days until withdrawal of care. Prolonged viral shedding was not noted, and the patients recovered promptly except for a patient with recalcitrant multiple myeloma who died because of the disease. Conclusion. 2009 H1N1 influenza disease in this cohort of hospitalized transplant recipients was relatively mild. The majority of the patients improved promptly, and prolonged viral shedding was not noted.

Background. Coccidioidomycosis is an endemic fungal infection of the southwestern United States that causes considerable morbidity and mortality in transplant recipients, often as the result of reactivated infection. Methods. A retrospective review of the medical records of 47 patients with prior coccidioidomycosis who underwent solid organ transplantation (18 liver, 24 kidney, 3 pancreas, and 2 combined organ) at our tertiary care academic medical center. Results. Of 47 transplant recipients with a history of coccidioidomycosis, 44 had quiescent infection at transplantation. Of the three with active coccidioidomycosis at transplantation, two were taking azole prophylaxis and had no further coccidioidal infection after transplantation. One of the three had positive serologic findings identified only on the day of transplantation, and prophylaxis was initiated a few hours after surgery along with immunosuppression; nevertheless, the treatment course was complicated by disseminated coccidioidomycosis. Seven patients did not initiate or self-discontinued prophylaxis; one patient who discontinued prophylaxis experienced recurrent pulmonary infection. Conclusions. For patients undergoing transplantation in an area endemic for coccidioidomycosis, we recommend routine evaluation for evidence of prior infection and initiation of azole prophylaxis. For our patients with quiescent infection, azoles suppressed any recrudescent coccidioidomycosis after transplantation. The selection of patients who would benefit from prophylaxis and the optimal dose and duration of such prophylaxis should be studied further.

Background. This study determines whether the spectrum, risk factors, and outcome of invasive candidiasis in liver transplant recipients have changed.

BACKGROUND While donor-derived infections (DDI) remain uncommon, multiple reports describe DDI with pathogens that cause central nervous system (CNS) infection resulting in significant recipient disease. The Ad Hoc Disease Transmission Advisory Committee (DTAC) reviewed the records of potential donor-derived disease transmission events (PDDTE) to describe donor characteristics and outcomes associated with DDI from CNS pathogens. METHODS All PDDTE reported from January 2008 to September 2010 were reviewed for characteristics suggesting CNS infection in the donor or the recipient. Identified cases were further examined to determine if donor CNS infection resulted in recipient infection. RESULTS Ninety-one PDDTE cases in which there was concern for CNS infection in the donor or recipient were identified. Further review confirmed CNS infection in 12 donors, six of whom transmitted infection to 10 of 15 exposed recipients with five recipient deaths. Pathogens included Balamuthia mandrillaris, Cryptococcus neoformans, lymphocytic choriomeningitis virus, and West Nile virus. Listed cause of death at procurement for these donors included stroke, anoxia, acute disseminated encephalomyelitis, and meningoencephalitis. Confounding diagnoses were present in 6 of 12 donors that would have allowed them to be considered at low risk of transmitting a CNS pathogen. Of the six donors with no confounding conditions, three exhibited at least two suspicious "DTAC warning criteria" for CNS infection. CONCLUSION Careful clinical assessment of donors combined with a high index of suspicion for ambiguous or misleading findings associated with CNS infection can reduce, but not eliminate, DDI with CNS pathogens.

Background The clinical impact and relevance of human herpesvirus-6 (HHV-6) infection in liver transplant recipients, has not been fully discerned. Methods A prospective study of 80 consecutive liver transplant recipients was performed using surveillance cultures for HHV-6 at weeks 2, 3, 4, and 6 after transplantation. Viral isolation was used for the detection of HHV-6. Results HHV-6 infection occurred in 39% (31 of 80) of the patients. Patients with HHV-6 infection were more likely to have hepatocellular carcinoma as underlying liver disease (P=.09). Mental status changes of unidentifiable etiology were significantly more likely to occur in patients with HHV-6 compared with those without (26%, 9 of 31 vs. 6%, 3 of 49, P=.008). HHV-6 infection was an independent predictor of invasive fungal infections (odds ratio 8.3, 95% confidence interval, 1.2-58.0, P=.03). A significant association between HHV-6 infection and CMV infection after transplantation, CMV recipient and donor serostatus, rejection, or fever of unknown origin, could not be documented. Mortality at last follow-up in patients with HHV-6 infection (29%, 9 of 31) was significantly greater than those without HHV-6 (6%, 3 of 49, P=.008). Conclusions Central nervous system complications of unknown etiology after liver transplantation may be related to HHV-6 infection. HHV-6 viremia was an independently significant predictor of invasive fungal infections and was associated with late mortality in liver transplantation recipients.

Background. The aim of the study was to assess the incidence of cytomegalovirus (CMV) infection and disease in adult liver transplant recipients, using routine preemptive therapy guided by the pp65 antigenemia test. Methods. Antigenemia was monitored weekly after liver transplantation (OLTX) for the first 3 months, and once a month for another 3 months. CMV seronegative recipients were treated preemptively for the first positive antigenemia. Seropositive recipients were treated only when their antigenemia count reached a threshold of ≥100 positive cells per 200,000 leukocytes. Results. A total of 144 patients were included between June 1994 and April 1995, of which 137 (95%) were primary OLTX. The percentage of positive antigenemia and CMV disease was 55 and 8%, respectively. Seventy-eight (54%) patients were protocol-monitored for the entire follow-up (group 1) and received appropriate preemptive therapy, although 66 (46%) patients had protocol violation by having missed blood samples or blood drawn at unscheduled times (group 2). Using Cox's proportional hazards model, patients with a first antigenemia count of >11 leukocytes had a significantly higher rate of CMV disease compared to patients with an antigenemia count ≤11 leukocytes (RR=7.3, 95% confidence interval=2.2 to 24.5). In a multivariate Cox regression analysis, adjustments were made to control for: group 1 versus group 2, use of OKT3, and serology risk categories. This analysis showed that the relative rate of CMV disease was still significantly higher among patients with antigenemia count >11 leukocytes (adjusted RR=4.9, 95% confidence interval=1.3 to 18.1). The estimated cost of preemptive therapy was less than that of prophylaxis with i.v. (14-day course) or oral (90-day course) ganciclovir. Conclusions. Preemptive therapy guided by pp65 antigenemia is a useful and cost effective strategy for prevention of CMV disease.

From May 1990 to March 1993, 38 patients (21 adults and 17 children) received 40 allografts that included the small bowel (14 isolated small bowel, 21 small bowel and liver, and 5 multivisceral transplantations). Fifteen patients (39%) had 26 episodes of CMV disease: 7 with one episode, 6 with two, and 1 each with three and four. CMV enteritis accounted for 21 (81%) of the episodes, hepatitis and pneumonitis for 2 each, and a viral syndrome for 1. Cox's proportional hazards univariate and multivariate analyses showed that significant first-episode risk factors were: CMV seropositive donors for negative recipients (relative risk [RR], 3.86; P = 0.02), the average daily plasma trough level of tacrolimus (RR, 2.15; P = 0.04), and total amount of steroid boluses (RR, 2.90; P = 0.02). CMV disease recurrence factors were: CMV seronegative recipients (RR, 8.60; P = 0.02) and total amount of steroid bolus pulses (RR, 12.39; P = 0.004). Because long courses of ganciclovir prophylaxis could not prevent the development of CMV disease, avoidance of CMV seropositive grafts in seronegative recipients and new strategies to prevent heavy immunosuppression without the penalty of rejection will be necessary to ameliorate this problem in intestinal transplant recipients.

Thirty randomly selected patients with advanced chronic liver disease, which had been evaluated for possible liver transplantation, were sampled endoscopically at 7 alimentary tract locations to assess the frequency and amount of Candida carriage. Eightyone percent (127/156) of the samples obtained contained Candida and 53% (82/156) yielded high counts (> 300 CFU/ml). The most predominant Candida species isolated at each site was Candida albicana, which accounted for 103 (64%) of the 160 fungal isolates. The other Candida species isolated included C tropicalis 30 (19%), C krusei 16 (10%), and C glabrata 11 (7%), Although the number of sites at which yeast was present and the quantities of yeast at each site varied widely among the patients studied, 100% of the patients had Candida in at least one site of the gastrointestinal tract. Eighty-six percent (24/28) of the duodenal aspirates contained Candida and 50% (14/28) of the duodenal samples contained greater than 300 CFU/ml. A positive culture from the stomach was a reliable predictor of the presence of Candida in the duodenum (P=0.0001), but a positive culture at no other site readily predicted the presence of Candida at yet another site. Importantly, there was no correlation between the presence or absence of Candida in either oral or rectal swabs and colonization at other anatomic sites within the gastrointestinal tract, These findings are important in liver transplantation, particularly in those cases in which the bowel has been opened to create a choledochojejunostomy anastomosis. The operative attempts to reduce gastrointestinal fungal carriage using oral antifungal agents may be justified before liver transplantation in an effort to lower the risk of posttransplantation fungal infections, particularly in those patients expected to have a Roux-en-Y choledochojejunostomy biliary reconstruction. © 1994 by Williams and Wilkins.

Background. Coccidioidomycosis is an airborne infection caused by the fungus Coccidioides, which is endemic to the southwestern United States. Cell-mediated immunity is required for the control of this infection, and some patients such as organ transplant recipients, who lack such immunity, have a high risk of severe, disseminated, or relapsed infection with high mortality. Previously latent coccidioidal infection can reactivate after transplantation. Antifungal prophylaxis has substantially decreased the risk of reactivated coccidioidomycosis after transplantation in these patients. Methods. We conducted a retrospective review of all patients with coccidioidomycosis who underwent solid organ transplantation at our center to identify factors for recrudescent coccidioidomycosis (despite antifungal prophylaxis) after transplantation. Results. Between June 1999 and June 2009, 100 patients with previous coccidioidomycosis underwent solid organ transplantation at our institution. Ninety-four (94%) received anticoccidioidal prophylaxis after transplantation. The six patients who did not receive such prophylaxis did not experience reactivated coccidioidomycosis. Five patients who received anticoccidioidal prophylaxis experienced reactivated infection. All five patients survived with further antifungal treatment. Among patients who experienced recrudescent infection despite antifungal prophylaxis, African American race was an identified risk factor. Pretransplant dissemination may be a risk factor for reactivated coccidioidomycosis, but this finding was not statistically significant. Whether nonadherence to prophylaxis played a small or large role is uncertain. Conclusions. Antifungal prophylaxis effectively suppressed recrudescent coccidioidomycosis after solid organ transplantation for the large majority of patients with a history of coccidioidomycosis before transplantation. Strict lifelong adherence to antifungal prophylaxis is imperative.

Background Rhino-orbital-cerebral disease is a significant manifestation of zygomycosis in solid organ transplant (SOT) recipients. However, its characteristics and outcome are not well addressed. Methods SOT recipients with zygomycosis as per the European Organization for Research and Treatment in Cancer and the Mycoses Study Group criteria in a cohort study at our centers published previously and those identified with a PubMed search from the 1950s to November 2009 were studied. Patients with mycosis involving the sinuses, orbits, or central nervous system (CNS) were included. Results Patients comprised a total of 90 SOT recipients with rhino-orbital-cerebral zygomycosis, including 13 in our cohort and 77 in the literature. CNS disease occurred in 57% (51 of 90). Overall mortality was 52.3% (46 of 88), and the mortality in patients with CNS disease was 73.5% (36 of 49). In logistic regression analysis, older age (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.04-1.21, P=0.002) was associated with a higher mortality rate, whereas lipid formulations of amphotericin B compared with amphotericin B deoxycholate (OR 0.09, 95% CI 0.02-0.50, P=0.006) and surgery (OR 0.12, 95% CI 0.01-0.94, P=0.043) were independently associated with an improved survival even when controlled for CNS involvement and the era of diagnosis of disease. Conclusions Rhino-orbital-cerebral zygomycosis, particularly CNS disease, is associated with substantial mortality rate in SOT recipients. Older age is a significant risk factor for mortality, whereas lipid formulations of amphotericin B and surgery improved outcomes.

Background Adenovirus hepatitis in the allograft liver is an uncommon condition hitherto recognized only in pediatric patients. We describe two adult cases. Methods Clinical information was obtained by reviewing the medical records. The diagnosis of adenoviral infection was made by immunohistochemistry or culture. Results Both patients had received recent antirejection treatment and presented with fever, hepatic dysfunction, and progressive leukopenia. One patient had some viral inclusions resembling those described in herpes simplex infections. Adenovirus was cultured from the liver in both cases and from the lung in one case. Both patients were treated by decreasing the immunosuppression and intravenous acyclovir, but died. Conclusions Adenovirus infection should be considered when evaluating adult liver transplant patients with necrotizing lesions or microabscess formation at allograft biopsy. A review of the literature shows that most previously reported infections have led to graft loss or death, but occasional remissions of disease are also on record.

A 51-year-old man developed fever and back pain 2 months after orthotopic liver transplantation for end-stage liver disease secondary to chronic hepatitis C infection. CT scan demonstrated destructive lesions in T12 suggestive of osteomyelitis. Aspiration biopsy of the vertebra revealed granulomatous inflammation and yeast forms; culture yielded Candida albicans. The patient improved with intravenous amphotericin B and 5-fluorocytosine and did not require surgical intervention. Candida osteomyelitis is a rare condition and to our knowledge it has not been reported before in liver transplant recipients. Awareness of this potential complication may shorten the delay in making the definitive diagnosis, which in turn may increase the likelihood of a response without sequela.

In contrast to kidney and heart, liver transplantation does not seem to benefit from HLA-matching in most patients. Furthermore, lower graft survival rates have been reported when HLA compatibility between donor and recipient is present (1–5). Since HLA mismatching contributes to liver allograft rejection, we have proposed a dualistic role of HLA in liver transplantation (1). HLA-matching reduces acute cellular rejection but augments other immunologic mechanisms of allograft injury, especially those mediated by major histocompatibility complex (MHC)*-restricted lymphocytes. In support of this concept, we have recently reported a higher incidence of CMV hepatitis in HLA-DR matched liver transplants, which was also associated with a higher frequency and earlier onset of chronic rejection (6). Hepatitis B and C virus (HBV, HCV) infections are a major cause of end-stage liver disease requiring liver transplantation. However, both viruses are difficult to eradicate, ensuring that the viral infection will persist and that recurrent hepatitis will occur in many recipients (7, 8). In the present study we investigated whether HLA matching affects the recurrence of HBV and HCV hepatitis after liver transplantation. From January 1991 to July 1992, 98 adult patients underwent orthotopic liver transplantation (OLTx) because end-stage liver disease secondary to HBV and/or HCV infections. Of these, 9 (9%) died during the first month after OLTX. The remaining 89 patients constituted the study group. Thirty-one patients (35%) had hepatitis B, 53 (59%) had hepatitis C, and 5 (6%) had B and C hepatitis. All hepatitis B patients were HBsAg-positive and HBV DNA-negative before transplantation. HBeAg was available for 23 patients, and 17 of them (74%) tested positive. Hepatitis C diagnosis was performed by the presence of anti-HCV antibodies in the serum by a first-generation ELISA (Abbot Laboratories, Abbot Park, IL) and HCV RNA detection in the original liver by reverse transcriptase polymerase chain reaction (PCR). HLA typing of patients and donors was done by standard serological techniques based on lymphocytotoxicity testing with sera against HLA-A, B, DR, and DQ antigens. Primary immunosuppression included in all patients tacrolimus (FK506) and steroids. Tacrolimus was initially given in a continuous infusion at 0.1 mg/kg/day, which was converted to an oral dose of 0.15 mg/kg/day every 12 hr with the return of bowel function. Subsequent dosage adjustments were guided by the quality of the graft, the presence of rejection, toxicity, and tacrolimus plasma trough level (normal value

This study determines whether the spectrum, risk factors, and outcome of invasive candidiasis in liver transplant recipients have changed.Thirty-five consecutive liver transplant recipients with invasive candidiasis were prospectively studied in a case-controlled, multicenter study. One control was matched with the case for duration of hospitalization and the other for antibiotic use so that risk factors unique in liver transplantation could be elicited.In matched-pair analysis, antibiotic prophylaxis for spontaneous bacterial peritonitis (odds ratio [OR] 8.3, P=0.002), posttransplant dialysis (OR 7.6, P=0.0009), and retransplantation (OR 16.4, P=0.0018) were independently significant predictors of invasive candidiasis. Candida spp. included C. albicans in 65% of patients, C. glabrata in 21%, C. tropicalis in 9%, C. parapsilosis in 3%, and C. guilliermondii in 3%. Patients with C. albicans infections were less likely to have received antifungal prophylaxis than those with non-albicans Candida infections (13.6% vs. 50%, P=0.04). The mortality rate was 36.1% for the cases and 2.8% for the controls (OR 25.0, 95% confidence interval, 6.2-100.5, P=0.0002). Non-albicans Candida infections (P=0.04) and prior antifungal prophylaxis (P=0.05) correlated with poorer outcome in the cases.Our study has identified predictors for Candida infections in the current era that have implications relevant for targeting the prophylaxis toward the high-risk patients. Routine use of antifungal prophylaxis warrants concern given the emergence of non-albicans Candida spp. as significant pathogens after liver transplantation and higher mortality in patients with these infections.

Background Although influenza and parainfluenza viruses commonly cause respiratory tract infections in the community, their incidence and clinical implications in adult lung transplant recipients have received little attention. Methods We performed a retrospective cohort study of influenza and parainfluenza viral infections in adult lung transplant recipients at the University of Pittsburgh Medical Center. Results Between January 1989 and March 1999, 39 cases (single-lung 25, double-lung 14) of influenza or parainfluenza respiratory viral infection were identified at a mean of 1.7 years (SD+/-1.4) after transplantation. The mean length of admission was 7 days. The cases included 15 patients with influenza (A, 11; B, 4) and 24 with parainfluenza (para1, 7; para2, 2; para3, 15). The median age at diagnosis was 48 years; there were 19 females and 20 males. Symptoms were reported in 30 patients and lasted for a median of 7 days before admission. These included cough (64%), shortness of breath (56%), and temperature elevation (33%). Chest infiltrates were seen in 14 (36%) patients, and 5 (13%) of them required intubation and mechanical ventilation. Viral pneumonia was diagnosed in 10 (5 influenza and 5 parainfluenza) patients, and concurrent bacterial pneumonia occurred in 4 patients. Transbronchial biopsy was performed in 36 patients, of whom 23 (64%) showed some degree of acute allograft rejection. Conclusion Influenza and parainfluenza respiratory viral infections are associated with significant morbidity in adult lung transplant recipients. Active vaccination programs and the development of new antiviral agents active against these viruses are important for prevention.

Solid organ transplant recipients receiving chronic immunosuppressive agents are at increased risk to acquire influenza virus despite vaccination. Myocarditis is a known but rare complication of influenza infection. We present the first adult liver transplant recipient who received prophylactic vaccination but developed influenza A myocarditis. This may occur in solid organ transplant recipients, because they have reduced response to protein vaccines, which may leave them vulnerable to infections. Studies are needed to evaluate if antiviral chemoprophylaxis in solid organ transplant recipients during influenza season would be an effective preventive therapy against influenza in this high-risk population.

We present our experience with 10 liver transplant recipients in whom cryptococcal meningitis developed after liver transplantation. Disease developed a median period of 3.5 months (range, 2-36 months) after transplantation and patients were diagnosed a median period of 9 days (range, 2-90 days) after initial symptoms. Headache, fever, and mental status changes were the most frequent clinical presentations, while meningismus was found in only 30% of patients. Cerebrospinal fluid analysis was diagnostic in all cases. All patients were treated with amphotericin B and flucytosine. Immunosuppression was either decreased or discontinued during therapy. Five patients died, four as a direct result of cryptococcal infection and one as a result of chronic rejection. Three patients had long-term survival without any sequelae. One long-term survivor suffered blindness consequent to the disease. We conclude that cryptococcal meningitis is a rare complication in liver transplant recipients (0.25%), and has a high mortality rate (50%). Early recognition, combination antifungal therapy, and decrease or discontinuation of immunosuppression are important for cure. No relapse has been seen in surviving patients.

Infection with varicella-zoster virus (VZV) is common, occurring as primary varicella, usually during childhood, and as zoster, following reactivation of latent virus. Although serious VZV infections are infrequent, they can be life-threatening when they occur in susceptible immunosuppressed patients (1, 2). These patients have a high incidence of visceral involvement, including pneumonitis, meningoencephalitis, and rarely, hepatitis. We report here 3 cases of VZV hepatitis in adult liver transplant recipients that occurred in our institution between 1984 and 1989. We describe their clinical presentations and use these cases to illustrate some aspects in diagnosis and prevention of VZV infection after solid organ Tx.

Cytomegalovirus disease is an important cause of morbidity following liver transplantation. To date there has not been an effective prophylaxis for CMV disease after liver transplantation. One hundred forty-three patients were randomized to receive either high dose oral acyclovir (800 mg 4 times a day) alone for 3 months after transplantation (acyclovir group) or intravenous ganciclovir (5 mg/kg twice a day) for 14 days followed by high dose oral acyclovir to complete a 3-month regimen (ganciclovir group). Of 139 patients available for evaluation, 43 of 71 (61%) patients from the acyclovir group developed CMV infection compared with 16 of 68 (24%) from the ganciclovir group (relative risk, 3.69; 95% confidence interval, 2.07-6.56; P0.00001). Of those randomized, CMV disease was seen in 20 (28%) of the acyclovir group compared with 6 (9%) of the ganciclovir group (relative risk, 5.11; 95% confidence interval, 2.05-12.75; P = 0.0001). The median time to onset of CMV infection was 45 days in the acyclovir group compared with 78 days in the ganciclovir group (P = 0.004). The median time to onset of CMV disease was 40 days in the acyclovir group compared with 78 days in the ganciclovir patients (P = 0.02). With respect to primary CMV infection, there was no difference in the rates in the 2 groups, but tissue invasive disease and recurrent CMV disease were less frequent in the ganciclovir group. It is concluded that a course of 2 weeks of ganciclovir immediately after transplantation followed by high dose oral acyclovir for 10 weeks is superior to a 12-week course of high dose oral acyclovir alone for prevention of both CMV infection and CMV disease after liver transplantation. However, the lack of significant effect in seronegative recipients who received grafts from seropositive donors suggests that other strategies are needed to prevent CMV infection in this high risk population.

Previous findings in liver transplantation patients have raised the concept that HLA plays a dualistic role. HLA matching will reduce rejection but may augment MHC restricted cellular immune mechanisms of liver allograft injury. To evaluate this concept, we studied CMV hepatitis in 399 FK506-treated liver transplant patients, including 355 cases for which complete HLA-A,B,DR,DQ typing information was available. CMV hepatitis developed in 25 patients, and 17 of them (or 68%) showed a one or two HLA-DR antigen match with the donor. In contrast, HLA-DR matches were found in only 35% of 330 patients without CMV hepatitis (P = 0.005). No significant associations were seen for HLA-A, HLA-B, and HLA-DQ antigens. In pretransplant CMV-seronegative patients with seropositive grafts (n = 39), the frequency of CMV hepatitis was 44% for HLA-DR-matched livers but 14% for HLA-DR-unmatched livers. In seropositive recipients (n = 187), these frequencies were 12% and 2% for HLA-DR-matched and unmatched liver grafts. Chronic rejection developed in 29 patients (or 8%) during a follow-up between 10 and 24 months after transplantation. Its incidence was higher in the CMV hepatitis group (24% vs. 6%) (P = 0.007). Although no associations were found between HLA matching and the incidence of chronic rejection, there was an earlier onset of chronic rejection of HLA-DR-matched livers irrespective of CMV hepatitis. These findings suggest that an HLA-DR match between donor and recipient increases the incidence of CMV hepatitis in both primary and secondary CMV infections. Although HLA compatibility leads to less acute cellular rejection, it is suggested that DR matching may accelerate chronic rejection of liver transplants, perhaps through HLA-DR-restricted immunological mechanisms toward viral antigens, including CMV.

Cytomegalovirus (CMV*), the first reported transplant-associated opportunistic virus (1), has remained the most frequent single cause or co-cause of infections throughout the ensuing three decades (2). Because prophylactic drug and hyperimmune globulin therapy has not been effective in these CMV-infected patients (2–4), Rubin (5) suggested withholding treatment until the phase of rapid viral replication (preemptive therapy). Early diagnosis of CMV infection, upon which this strategy depends, can be accomplished in the presymptomatic phase (6, 7) with a rapid quantitative direct demonstration of CMV antigen pp65 in cytospin preparations of peripheral blood leukocytes (PBL) (8, 9). This method has aided in the management of 20 CMV seronegative recipients of livers from seropositive donors, a circumstance that carries an 85–90% risk of virus transmission of CMV disease, presumably from migratory monocytes from the graft (10) that are known to harbor the latent virus in healthy seropositive individuals (11). The 20 recipients under tacrolimus/prednisone immunosuppression were followed for 308 ± 100.5 days (range, 63–520 days) after transplantation; a death at 63 days unrelated to CMV accounted for the only follow-up of 20 were considered positive. CMV IgG was also the routine test used for donor screening. Intravenous ganciclovir therapy (Cytovene; Syntex Pharmaceutical Ltd., Palo Alto, CA) was started only with the first detection of pp65 antigenemia, and continued until pp65 clearance. The ganciclovir dose was governed by creatinine clearance: >50 ml/min → 5 mg/kg of ganciclovir twice daily, 10–50 ml/min → 5 mg/kg every 24–48 hr, and

Fungal infections remain an important cause of morbidity and mortality following solid organ and bone marrow transplantation (1–3). Use of amphotericin B, the antifungal agent of choice at present, is frequently associated with a high incidence of side effects. In organ transplant patients particularly, the nephrotoxicity of amphotericin may be amplified when combined with immunosuppressive agents such cyclosporine or FK506. Fluconazole, a new antifungal agent with low toxicity and excellent oral bioavailability has been shown to be effective in both the treatment and prophylaxis of fungal infections in immunocompromised patients (4, 5). However, fluconazole is known to inhibit the cytochrome P-450 enzyme system in humans and animals. Coadministration of fluconazole with cyclosporine, a drug that is primarily metabolized in the liver, results in increased cyclosporine blood concentrations in transplant patients (6). Since FK506 is also known to be primarily eliminated by hepatic metabolism, coadministration of fluconazole to patients on FK506 therapy is expected to increase FK506 concentrations in patients (7). In rats, fluconazole is known to increase FK506 blood concentrations (8). In this communication we report our observations on the interaction between FK506 and fluconazole in transplant patients. Twenty organ transplant patients under FK506 immunosuppression were evaluated while receiving a course of fluconazole therapy. The patient population included 11 patients who received livers (OLTX); 6 patients who received kidneys (KTX), 2 patients who received hearts (HTX) and one bone marrow patient. The immunosuppressive regimen included FK506 and low-dose steroids (20 mg/day). FK506 was given initially as a continuous i.v. infusion at 0.1 mg/kg/day, with conversion to the oral dose of 0.15 mg/kg every 12 hr with the return of normal bowel function. Subsequent dose adjustments were guided by the quality of the graft, the presence of any evidence of rejection, signs of toxicity, and trough FK506 plasma concentrations (normal range 0.5 to 2 ng/ml). Sixteen of the patients studied had documented fungal infection (7 urinary tract infections, 4 esophagitis, 2 pyelonephritis, 2 tracheobronchitis, and 1 cholangitis). Candida albicans was the most common pathogen isolated (14 patients), whereas Candida tropicalis and Cryptococcus neoformans were isolated in one patient each. Four additional patients were considered high-risk patients and were treated with prophylactic fluconazole. The median time from transplantation to the initiation of fluconazole therapy was 60 days (range 2–1680 days). In patients with documented fungal infection, fluconazole was given for a median of 14 days (range 7–100 days). Fourteen of the 16 patients were successfully treated and became culture-negative. Two failures were noted in two kidney transplant patients who required transplant nephrectomy for persistent fungal invasion of the graft. Four patients received prophylactic fluconazole for a median of 12 days (range 6–30 days), and all remained fungal culture negative. Fluconazole was used at a dose of 200 mg/day in 8 patients and 100 mg/day in 12 patients. FK506 plasma concentrations were measured by an ELISA (9). The intraday coefficient of variation for this assay ranged from 4.2 to 5.5% and the interday coefficient of variation ranged from 14.4 to 17% at concentrations measured in this study. Figure 1 shows the median plasma trough concentration of FK506 on days -1, 0, 1, 2, 3, 4, 5, and 7 after fluconazole therapy as a function of the fluconazole dose administered. On day 1, the median plasma trough concentration of FK506 increased 1.4-fold in patients receiving 100 mg/day of fluconazole and 3.1-fold in patients receiving 200 mg/day. Thereafter the FK506 plasma concentration decreased as the FK506 dose was reduced to prevent higher FK506 concentrations. Figure 2 shows the median dose of FK506 and the plasma concentration of FK506 on days -1, 0, 1, 2, 3, 4, 5, and 7 of fluconazole therapy. A median FK506 dose reduction of 56% (range 0% to 88%) was required in order to maintain the FK506 concentrations below 2 ng/ml. There was no change in the route of FK506 administration during the period studied. The initial increase in FK506 plasma concentration during fluconazole therapy was associated with acute renal dysfunction in 3 patients (hemodialysis required in one) and acute changes in the mental status in 2 patients. FIGURE 1 Median plasma trough concentration of FK506 in patients receiving 100 mg (continuous line) and 200 mg (interrupted line) of fluconazole. FIGURE 2 Median dose (mg/day) (continuous line) and plasma trough concentration (ng/ml) (interrupted line) of FK506 during fluconazole therapy. The pharmacokinetics of FK506 was evaluated in one patient on two occasions, once while on fluconazole therapy (100 mg oral dose, 1 hr prior to FK506 dosing of 3 mg) and again eight days after stopping fluconazole therapy. Figure 3 shows FK506 the plasma concentration vs. time profile over a dosing interval in this patient with and without fluconazole therapy. Discontinuation of fluconazole therapy resulted in a significant decrease in the area under the plasma concentration–versus–time curve of FK506 (from 13 ng/ml/hr to 5.4 ng/ml/hr). The half-life maximum plasma concentration and the trough plasma concentration of FK506 also decreased during this period. FIGURE 3 FK506 pharmacokinetic profile of one patient with (continuous line) and without (interrupted line) fluconazole therapy. FK506 is a new immunosuppressive drug with a proven beneficial effect over currently available agents (10–12). Its elimination through hepatic metabolism by cytochrome P-450 enzyme makes it susceptible to possible interactions with other drugs as that are known to induce or inhibit these enzymes, such as phenobarbital, phenytoin, rifampin, clotrimazole, ketoconazole, itraconazole, fluconazole, cimetidine, and erythromycin (7). In rats, FK506 blood concentrations are reported to increase in the presence of fluconazole, erythromycin, ketoconazole, and diltiazam (8). Erythromycin and methylprednisolone have been reported to increase FK506 plasma concentrations (7). Clotrimazole treatment also increases FK506 plasma concentrations in liver transplant patients (13). The data reported here show an increase in trough and maximal plasma concentration of FK506, along with an increase in the half-life of FK506 in the presence of fluconazole. This suggests that fluconazole inhibits FK506 metabolism. It is not possible to predict whether fluconazole decreases FK506 metabolism in the gut and therefore increases the extent of absorption or whether it affects only the hepatic metabolism of FK506. Additional studies are required to understand the extent to which this interaction takes place in the small bowel and/or the liver. The increases in the plasma concentration of FK506 were higher at a 200 mg/day fluconazole dose than at a 100 mg/day dose. This dose-related effect, also reported with CsA (6), may have important implications when fluconazole is used in the treatment of severe fungal infections. Recently, a new fluconazole dosing regimen (200–400 mg/day) has been suggested for the treatment of invasive candidiasis (14). FK506 concentrations should be carefully monitored when using these dosing regimens. Despite the similarities between fluconazole’s interaction with CsA and FK506, some differences were observed. In renal transplant recipients, fluconazole slowly increased cyclosporine trough concentrations over a two-week period, reaching a maximum of twice the baseline level (6). In our patients the highest concentration of FK506 was seen within three days after the introduction of fluconazole therapy. In summary, fluconazole therapy in patients under FK506 immunosuppression appears to be beneficial for both prophylaxis and treatment of fungal infections. Fluconazole doses of up to 200 mg/day can be safely and effectively administered to transplant patients on FK506 therapy provided that the FK506 dose is reduced by half. Use of higher doses of fluconazole would require careful monitoring of trough FK506 plasma concentrations and corresponding reduction in FK506 doses to avoid nephrotoxicity.

The outcome of a transplanted organ depends frequently upon the occurrence of allograft rejection and infection episodes. These 2 events are closely related. On one side, immunosuppressive therapy is required to avoid allograft rejection, but on the other side this therapy facilitates the occurrence of infections (1). A better understanding of allograft rejection mechanisms along with new immunosuppressive therapies and antimicrobial prophylaxis has increased graft and patient survival. However, infectious complications continue to be a common cause of morbidity and mortality after organ transplantation. The managements of these infections depend primarily upon identification of infectious causative agents. Specific antibacterial, antiviral, antifungal, and antiprotozoal therapy provides the mainstay in treatment of these infections. However, it also is important to lower the immunosuppressive background to allow the host immunological response to these infections, particularly when infections are considered life threatening. Although discontinuation of immunosuppression is a generally accepted option in these situations of life-threatening infections, no information it is available about graft and patient outcomes in these circumstances. In kidney transplantation, immunosuppression may be stopped completely in the setting of life-threatening infections, since return to dialysis and retransplantation is always an option (2, 3). In contrast, in liver transplantation discontinuation of immunosuppression is considered “very risky,” because it may lead to graft loss and patient death. The following is a report of the circumstances and outcome of patients with life-threatening infectious complications after liver transplantation, all of whom were managed with a temporary discontinuation of the immunosuppression therapy. Between 1987 and 1991, 31 patients underwent liver transplantation and developed severe opportunistic infections. The management included, along with the specific anti-infectious therapy, a temporary withdrawal of immunosuppression for at least 15 days. The patients were on 2 different immunosuppressive protocols, as described previously (4): (1) CsA and steroids (12 patients) and (2) FK506 with low dose steroids (19 patients). Table 1 shows the types of infection seen and the immunosuppression that patients were receiving. The change in their immunosuppression management followed 1 of 2 patterns when infection was diagnosed: total discontinuation of immunosuppressive agents (in 1 CsA and 19 FK506 patients) or a maintenance dose of 5 mg/day prednisone only was given (11 CsA patients). Thirteen patients (42%; 5 CsA and 8 FK506 patients) died at a median time of 23 days after their immunosuppression therapy was discontinued (range 16–56 days) because of complications related to the infections. Autopsy examination was performed in 8 of these patients, with no evidence of allograft rejection in any of them. TABLE 1 Infection, immunosuppression, and outcome in the 31 patientsa Eighteen patients (7 CsA and 11 FK506) who survived had their immunosuppression discontinued at a median interval of 140 days (range 44–779) after liver transplantation. They were a median of 17 days (range 15–43) without detectable levels of CsA or FK506. All patients had their baseline immunosuppression resumed. However, the maintenance dose of either CsA and FK506 was reduced a median of 50% (range 0–89%) in comparison with the baseline immunosuppression before the discontinuation. Only 4 patients (3 CsA, 1 FK506) required reinstitution of immunosuppression because of rejection. The median interval from liver transplantation to discontinuation of immunosuppression was 129 days (range 44–411) in those patients who had rejection and 143 days (range 53–779) in patients who did not have rejection (NS). The median period with undetectable levels of CsA or FK506 was 27 days (range 20–43) in those patients who had rejection and 16 days (range 15–27) in patients who did not have it (P=0.01). No differences were found in the dose of CsA before the discontinuation among the 3 CsA patients who had rejection and the 4 who did not. In those patients who did reject, all rejection episodes were controlled with the resumption of baseline immunosuppression. With a median follow-up of 942 days (range 440–2022 days), all patients who survived are alive, none required retransplantation, and only 2 (11%; 1 CsA and 1 FK506 patient) have signs of chronic rejection in their liver biopsy (5). The fact that most of the patients reported here had their immunosuppression stopped without emergence of rejection could be explained by more than a single mechanism. On the one hand, the infection itself may produce immunosuppression, particularly viral infections (CMV or EBV), which are well-known immunosuppressive agents (6, 7). In addition, these patients were by definition iatrogenically “overimmunosuppressed,” as none of the 8 who came to an autopsy had evidence of rejection; for those who survived, a 50% reduction in baseline maintenance immunosuppression when this was resumed did not lead to rejection. A second explanation for the ability to stop treatment is that the first stage of donor recipient nonreactivity was well underway. This tolerance induction, which has been associated with cell migration and chimerism (8–10), allowed global immunologic recovery without rejection of the graft. The variable and unpredictable completeness of this process of “graft acceptance” was evident even at such an early time. Rejection emerged in 4 of the 18 survivors when reinstitution of treatment was withheld beyond 2 weeks, by freedom of this complication in the other 14. However, even in the recipients who developed rejection, secondary rescue therapy at a lower level of immunosuppression was successful in all cases. Reyes et al. (11) have shown that some recipients in a similar series of cases could be left permanently drug free, but which recipients cannot be predicted. In summary, we have shown here that in selected patients after liver transplantation, temporary withdrawal of immunosuppression therapy may be indicated in the management of severe infectious complications, without the development of immediate rejection. Reinstitution of immunosuppression in reduced doses at a later time can be done on a case to case basis to prevent the emergence of rejection.

When liver removal is part of a multiple-organ procurement, bile in a liver donor is usually washed out of the biliary tree to prevent autolysis of the bile duct mucosa during cold storage (1). During the “lavage,” bile is spilled in the peritoneal cavity. The possibility that this bile is infected has often concerned surgeons removing the kidneys, heart, or other organs. Consequently, we undertook a bacteriologic study to see if flushing of the biliary system introduced a potential source of contamination of other organs.

Although toxoplasmosis is often a mild or asymptomatic infection in normal subjects, it may cause lethal disease in immunocompromised patients (1–3). Detection of the disease is difficult and often requires histological evidence. Many cases are diagnosed at autopsy. We recently isolated Toxoplasma gondii in tissue culture from the blood of a febrile liver transplant patient who later developed lymphocytic meningitis. The patient recovered completely, despite receiving only short courses of antimicrobials active against Toxoplasma. Our experience illustrates that isolation of Toxoplasma from the blood of a solid organ transplant patient may occur with limited disease. A 57-year-old woman with a two-year history of chronic active hepatitis underwent orthotopic liver transplantation and received cyclosporine (CsA) and prednisone immunosuppression. Ampicillin and cefotaxime (4 g each) were given daily for five days as antibiotic prophylaxis. At 18 days after the operation, a liver biopsy showed acute rejection and a 10-day intravenous course of mouse OKT3 antibody was administered. At 24 days after the operation, the patient had a temperature elevation to 39.5°C. A computerized tomographic scan of the abdomen showed a hypodense 3.5×4.5-cm area in the liver. Percutaneous aspiration of this yielded heavy Streptococcus fecalis on culture. Pipercillin, gentamicin, and cefoxitin were administered, but then switched to ampicillin, gentamicin, and clindamycin. A drain was left in the liver abscess cavity. Clindamycin was discontinued after three days, but ampicillin was continued 8 days and gentamicin was continued for 10 days. The patient continued to have significant fever while receiving these antibiotics. By 39 days after the operation the patient was afebrile, but she then developed confusion. A computerized tomographic scan of the head was normal, but examination of the cerebrospinal fluid showed 360 red blood cells and 50 white blood cells (1 neutrophil, 1 mononuclear, and 48 lymphs); the glucose was 46 mg% and the protein 48 mg%. Cultures of the spinal fluid were sterile. Her peripheral blood smear showed a white count of 12,700 with 8% atypical lymphocytes, 22% lymphocytes, 63% polymorphonuclear cells, 5% monocytes and 2% eosinophils. At this time a single dose of i.v. sulfamethoxazole/trimethoprim (1 g/200 mg) was administered when a weakly positive Pneumocystis carinii serum antigen (1:2) was reported (Linda L. Pifer, Memphis, TN, personal communication). This was discontinued because the patient’s illness was not compatible with Pneumocystis infection. Thereafter, the patient improved clinically and was discharged from the hospital 48 days after the operation with no fever or neurological problems. Before discharge a buffy coat culture of the blood taken 26 days after the operation and inoculated in tubes of human foreskin fibroblasts showed cytopathic effect, with swollen cells containing multiple inclusions: A wet preparation of the culture supernatant showed 2×6-μ oval bodies that were motile. These were later identified by electron microscopy as T gondii (Fig. 1). Figure 1 Electron microscopy of Toxoplasma gondii organisms isolated in tissue culture and seen within an intracellular vacuole. The arrow points to the characteristic conoid at the anterior end of the organisms, from which densely staining rophtries arise. The same buffy coat was positive for cytomegalovirus, which was also isolated from buffy coats obtained on days 34 and 39 after transplantation. Pretransplant serum showed a titer of Epstein-Barr viral capsid antigen of 1:80, and Epstein-Barr early antigen of