Who among cytomegalovirus-seropositive liver transplant recipients is at risk for cytomegalovirus infection?

A vast majority of the transplant recipients are cytomegalovirus (CMV)-seropositive (R+). We sought to assess variables predictive of CMV infection, specifically in R+ liver transplant recipients. Study patients comprised 182 consecutive liver transplant recipients who survived at least 14 days after transplantation. Surveillance testing was used to detect CMV infection. Pre-emptive therapy was employed for the prevention of CMV disease, however, no antiviral prophylaxis was used for CMV infection. CMV infection developed in 32.5% (38 of 117) of R+ patients, 84.6% (33 of 39) of R-/D+, and 3.8% (1 of 26) of R-/D- patients. In R+ patients, Hispanic race (21.6% vs. 7.8%, P = 0.06), donor CMV seropositivity (73.7% vs. 45.6%, P = 0.005), and hepatocellular carcinoma (23.7% vs. 6.3%, P = 0.05) correlated with a higher risk of CMV infection. In a multivariate model, Hispanic race (OR: 3.5, 95% CI: 1.03-11.6, P = 0.045), donor CMV serostatus (OR: 4.0, 95% CI: 1.6-10.2, P = 0.003) and hepatocellular carcinoma (OR: 5.8, 95% CI: 1.6-20.5, P = 0.006) were all significant independent predictors of CMV infection. The aforementioned variables did not portend a higher risk of CMV infection in R-/D+ patients; donor CMV seropositivity overwhelmed all other risk factors in R- patients (P < 0.00001). In conclusion, CMV-seropositive liver transplant recipients at risk for CMV infection can be identified based on readily assessable variables. Preventive strategies may be selectively targeted toward these patients.     

Bacteremias in liver transplant recipients: shift toward gram-negative bacteria as predominant pathogens.

During the 1990s, gram-positive bacteria emerged as major pathogens after liver transplantation. We sought to determine whether the pathogens associated with bacteremias in liver transplant recipients have changed. Patients included 233 liver transplant recipients transplanted between 1989 and 2003. The proportion of all infections due to bacteremias increased significantly over time (P <.0001). Of other major infections, a trend toward a decrease in fungal infections (P =.089) and a significant decrease in cytomegalovirus (CMV) disease (P =.0004) were documented. Whereas the proportion of bacteremias due to gram-negatives increased from 25% in the period of 1989-1993 to 51.8% in 1998-03, that of gram-positive bacteria decreased from 75% in the period of 1989-93 to 48.2% in the period of 1998-2003. Methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most frequent pathogens in bacteremic patients. The incidence of bacteremias due to MRSA and Pseudomonas aeruginosa has remained unchanged (P <.20); however, that due to enteric gram-negative bacteria, particularly Klebsiella pneumoniae has increased (P =.02). Klebsiella pneumoniae isolates in the current quartile were not clonally related. In conclusion, bacteremias as a proportion of all infections in liver transplant recipients have increased significantly over time, due in part to a decline in infections due to other major pathogens, e.g., fungi, primarily Candida species, and CMV. Gram-negative bacteria have emerged as predominant pathogens in bacteremic liver transplant recipients.     

Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience

OBJECTIVE: To evaluate the incidence of posttransplant lymphoproliferative disease (PTLD) and the risk factors and the impact of this complication on survival outcomes in a large cohort of liver transplant recipients at a single institution. SUMMARY BACKGROUND DATA: Liver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, in large part due to the availability and reliance on the use of nonspecifically directed immunosuppression. However, as predicted and subsequently verified in 1968, an increased incidence of certain de novo malignancies has been observed, particularly with regards to lymphoid neoplasms. While many reports have confirmed and clarified the nature of PTLD, the literature is fraught with conflicting experience and outcomes with PTLD. METHODS: Four thousand consecutive patients who underwent liver transplants between February 1981 and April 1998 were included in this analysis and were followed to November 2001. The effect of recipient age at the time of transplant, recipient gender, diagnosis, baseline immunosuppression, grading of PTLD, and association with Epstein-Barr virus were compared. The causes of death were also examined. Treatment for PTLD varied over the 20-year period, but all included massive reduction or elimination of baseline immunosuppression. RESULTS: The 1-year patient survival for liver transplant patients with PTLD was 85%, while the overall patient survival for the entire cohort was 53%. The actuarial 20-year survival was estimated at 45%. The overall median time to PTLD presentation was 10 months, and children had an incidence of PTLD that was threefold higher than adults. Patient survival was better in children, in patients transplanted in the era of tacrolimus immunosuppression, in patients with polymorphic PTLD, and in those with limited disease. Interestingly, neither the presence or absence of Epstein-Barr virus nor the timing of PTLD presentation appeared to influence overall patient survival. Patients transplanted for alcohol-related liver disease had a similar incidence of PTLD but had a higher risk of mortality. CONCLUSIONS: While PTLD continues to pose problems in patients receiving liver transplants, improvements in patient survival have been observed over time. While it is too early to assess the impact of new advances in prophylaxis, diagnosis, and treatment, such approaches are based on an increased knowledge of the pathophysiology of PTLD.     

Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center's experience update at 13 years

BACKGROUND: Chronic liver disease often leads to amenorrhea in women of childbearing age. There are several reports of successful pregnancy after liver transplantation (LTx) with cyclosporine A immunosuppression. Tacrolimus has been increasingly used in solid-organ transplantation, and the effect of the drug on pregnancy is still of interest to clinicians. This study updates our single-center experience. METHODS: All pregnancies after LTx with tacrolimus immunosuppression were followed prospectively. Patients' clinical courses during pregnancy and labor along with gestational period and birth weight were catalogued. Changes in liver function, renal function, and immunosuppression also were recorded. The birth weight percentile was calculated on the basis of the gestational period using a standard chart. RESULTS: Thirty-seven mothers delivered 49 babies. Three mothers delivered three times, and six mothers delivered two times. Thirty-six mothers (97%) survived the pregnancy, and 36 allografts (97%) survived. The one death and graft loss was in a patient who demonstrated infra-aortic arterial graft, which clotted by the gravid uterus during labor. The patient developed a gangrenous liver and died before she could undergo retransplantation. The mean gestational period was 36.4+/-3.2 weeks, excluding two premature deliveries at 23 and 24 weeks gestation. Twenty-two babies (46.9%) were delivered by cesarean section, and the other babies were delivered vaginally. In addition to the two premature babies, one baby, who was born to a mother with Alagille syndrome, died from congenital birth defects. The rest of the newborns survived. The mean birth weight was 2,797+/-775 g, with 38 babies (78%) weighing more than 2,000 g. The mean birth weight percentile to gestational period was 54+/-23. Four babies (8.5%) had a birth weight percentile of less than 25, and 28 babies (59.6%) had a birth weight percentile greater than 50. Twelve patients demonstrated an increase in hepatic enzymes without jaundice during the pregnancy. All of them responded to augmentation of immunosuppression. CONCLUSION: The present report reconfirms the safety of tacrolimus during pregnancy after LTx. Preterm delivery and low birth weight seem to be a persistent problem in all solid-organ transplantation under any form of immunosuppression. However, toxemia of pregnancy and new onset of hypertension seem to be have a low occurrence with the use of tacrolimus.     

Primary tacrolimus (FK506) therapy and the long-term risk of post-transplant lymphoproliferative disease in pediatric liver transplant recipients

While the overall incidence of post-transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients has been reported to be 4-11%, the long-term risk of PTLD associated with primary tacrolimus therapy is unknown. Therefore, in order to determine the incidence and long-term risk of PTLD, the present study examined 131 pediatric recipients who underwent liver transplantation (LTx) between October 1989 and December 1991 and received primary tacrolimus therapy. This cohort of children was evaluated over an extended time-period (until December 31 1996) with a mean follow-up of 6.3 yr. Actuarial Kaplan-Meier analysis was utilized to determine the risk of PTLD over time. The overall incidence of PTLD was 13% (17/131) with an average age of 4.3 +/- 0.75 yr at diagnosis. Pretransplant Epstein-Barr virus (EBV) serologies were negative in 82%, positive in 12%, and not available in 6% of the patients. The median time to diagnosis of PTLD post-Tx was 11.9 months (mean 16.4 +/- 3.9, range 1.7-63.0 months). Mean tacrolimus dose and plasma trough level (as evaluated by enzyme-linked immunosorbent assay [ELISA]) at the time of diagnosis was 0.32 +/- 0.06 mg/kg/day and 1.3 +/- 0.3 ng/mL, respectively. The cumulative long-term risk of PTLD was found to increase over time: 3% at 6 months, 8% at 1 yr, 12% at 2 yr, 14% at 3 yr, and 15% at 4 and 5 yr. Mortality from PTLD was 12% (two of 17 patients). Primary tacrolimus use in pediatric LTx has a long-term risk of PTLD approaching 15%, with the majority of episodes (78%) occurring in the first 2 yr, suggesting that intense EBV surveillance should occur early post-transplantation.     

Congenital malformations of the cervicothoracic lymphatic system: embryology and pathogenesis.

Familiarity with the embryology of the lymphatic system is helpful in understanding the pathogenesis and radiologic appearance of lymphangiomas of the cervicothoracic region. By considering anatomic location and radiologic appearance, one can predict the type of lymphangioma present, the primordial lymph sac from which the malformation arose, and when it formed in embryonic life. Cystic hygromas are composed of large, dilated lymphatic spaces. They form when a primordial lymph sac fails to reestablish communication with the central venous system from which it arose. These lesions may also result from an aberrant bud arising from a primordial lymph sac. Cavernous and capillary lymphangiomas are composed of smaller lymphatic channels. They form from abnormally sequestered buds of the developing lymphatic mesenchyme responsible for the fine meshwork of terminal branches in the periphery of the embryo. Their growth may be inhibited by the relatively tougher tissues in the periphery (eg, skin and muscle) compared with the relatively loose fatty connective tissue in which cystic hygromas form. Not only can all types of lymphangioma occur in one lesion, but lymphatic and vascular malformations may also coexist.