Patrick J. Healey

Impact of cytomegalovirus in organ transplant recipients in the era of antiviral prophylaxis.

Background. Antiviral prophylaxis has been shown to decrease the incidence of cytomegalovirus (CMV) disease in organ transplant recipients, but whether CMV disease that occurs despite prophylaxis is associated with mortality remains unknown. Methods. The clinical features and risk factors for CMV disease in a cohort of liver transplant recipients who received antiviral prophylaxis were assessed retrospectively. Cox proportional hazard regression was used to assess the relationship of CMV to mortality during the first posttransplant year. Results. CMV disease developed in 37 of 437 (8.5%) recipients at a median of 4.5 (range, 2.5 to 12) months posttransplant and was associated only with donor-seropositive/recipient-seronegative serostatus in multivariate analysis (P<0.0001). Mortality at 1 year was 12% (51 of 437) and was infection-associated in 49% of cases. In multivariate analysis, CMV disease was independently associated with overall mortality at 1 year (HR, 5.1, P=0.002) and even more strongly with infection-associated mortality (HR 11, P=0.002). There was no association of CMV with noninfection-associated mortality (P>0.05). Conclusions. Late CMV disease is an important clinical problem in liver transplant recipients who receive antiviral prophylaxis, and is strongly and independently associated with mortality. Strategies to prevent late CMV disease are warranted.

Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis.

Background. The incidence and impact of cytomegalovirus (CMV) disease that occurs despite CMV prophylaxis among liver transplant recipients have been incompletely defined. Methods. The incidence and risk factors for CMV disease during the first posttransplant year in a cohort of liver transplant recipients who received antiviral prophylaxis with oral ganciclovir were retrospectively analyzed using Cox proportional-hazard regression models. Results. CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04–0.11]) at a median of 4.5 months posttransplant, included syndrome (63%) or tissue-invasive disease (37%), and was independently associated with an increased risk of mortality during the first posttransplant year (hazard ratio 14 [95% confidence interval 3.8–54], P=0.0007). The incidence was higher (10/38 [26%] vs. 8/180 [4.5%], P<0.0001) in seronegative recipients (R−) of an organ from a seropositive donor (D+) compared with seropositive (R+) patients, respectively. D+R− status was the only variable significantly associated with CMV disease in multivariate analysis. Conclusions. Late CMV disease develops in a substantial proportion of D+R− recipients after prophylaxis is discontinued, is not accurately predicted by patient factors, and is associated with increased mortality. New strategies to identify D+R− patients at risk and to reduce the incidence and impact of late CMV disease in this group are warranted.

The anatomic pattern of biliary atresia identified at time of kasai hepatoportoenterostomy and early postoperative clearance of jaundice are significant predictors of transplant-free survival

Objective:The goals of this study were to describe the clinical and anatomic features of infants undergoing Kasai portoenterostomy (KPE) for biliary atresia (BA) and to examine associations between these parameters and outcomes. Methods:Infants enrolled in the prospective Childhood Liver Disease Research and Education Network, who underwent KPE were studied. Patients enrolled in a blinded, interventional trial were excluded from survival analysis. Primary endpoints were successful surgical drainage (total bilirubin less than 2 mg/dL within the first 3 months), transplant-free survival (Kaplan-Meier), and time to transplant/death (Cox regression). Results:KPE was performed in 244 infants (54% female; mean age: 65 ± 29 days). Transplant-free survival was 53.7% and 46.7% at 1 and 2 years post-KPE. The risk of transplant/death was significantly lower in the 45.6% of patients who achieved successful bile drainage within 3 months post-KPE (HR: 0.08, P < 0.001). The risk of transplant/death was increased in patients with porta hepatis atresia (Ohi type II and III vs type I; HR: 2.03, P = 0.030), nonpatent common bile duct (Ohi subtype: b, c, and d vs a; HR: 4.31, P = 0.022), BA splenic malformation syndrome (HR: 1.92, P = 0.025), ascites > 20 mL (HR: = 1.90, P = 0.0230), nodular liver appearance compared to firm (HR: = 1.61, P = 0.008), and age at KPE ≥ 75 days (HR: 1.73, P < 0.002). Outcome was not associated with gestational age, gender, race, ethnicity, or extent of porta hepatis dissection. Conclusion:Anatomic pattern of BA, BASM, presence of ascites and nodular liver appearance at KPE, and early postoperative jaundice clearance are significant predictors of transplant-free survival.

Subclinical Viremia Increases Risk for Chronic Allograft Injury in Pediatric Renal Transplantation

The impact of subclinical viral infection on chronic allograft injury in the pediatric renal transplant population is not well defined. We prospectively assessed cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNAemia by monthly PCR in 55 pediatric renal transplant recipients for the first 2 years after transplantation. Subclinical CMV and EBV infection occurred in 22 and 36%, respectively. Multivariable linear regression analysis suggested that both subclinical CMV and EBV infection independently associate with significant declines in GFR during the first 2 years after transplantation. CMV seronegativity associated with a significantly greater decline in GFR than seropositivity (P < 0.01). Subclinical CMV infection and subclinical EBV infection each associated with approximately fourfold greater odds of histologic evidence of chronic allograft injury (odds ratio 4.61 [95% confidence interval 1.18 to 18.07] and odds ratio 4.33 [95% confidence interval 1.34 to 14.00], respectively). An increase in viral load of CMV or EBV also associated with increased risk for moderate to severe chronic allograft injury. Taken together, these results demonstrate an association between subclinical CMV and EBV infections, which occur despite standard antiviral prophylaxis, and chronic allograft injury in pediatric renal transplant recipients.

The experience of a regional pediatric intestinal failure program: successful outcomes from intestinal rehabilitation.

BACKGROUND The aim of this study was to evaluate the clinical experience of a regional multidisciplinary intestinal failure program for children established in 2005. METHODS Data were collected from a prospective internal database. Univariate analyses were performed to compare pre- and post-treatment outcomes. Median values are reported. RESULTS Forty-nine children were referred at an age of 7 months. Remnant small bowel length was 29 cm. With follow-up of 14 months, overall patient survival was 88%. Thirteen bowel-lengthening procedures were performed, thereby increasing small bowel length from 83 to 132 cm (P < .05). Enteral autonomy was achieved in 22 patients (45%), and the caloric requirement for parenteral nutrition was decreased from 100% to 41% (P < .01). Conjugated bilirubin was reduced from 4.1 to 0 mg/dL (P < .05). CONCLUSION A multidisciplinary approach to pediatric intestinal failure that prioritizes intestinal rehabilitation can achieve successful enteral feeding advancement, improved liver function, and excellent survival in intermediate-range follow-up.

Outcomes in Children After Intestinal Transplant

OBJECTIVE: The survival rates after pediatric intestinal transplant according to underlying disease are unknown. The objective of our study was to describe the population of pediatric patients receiving an intestinal transplant and to evaluate survival according to specific disease condition. PATIENTS: Pediatric patients (≤21 years of age) with intestinal failure meeting criteria for intestinal transplant were included in the study. METHODS: A retrospective review of the United Network for Organ Sharing intestinal transplant database (January 1, 1991, to May 16, 2008), including all pediatric transplant centers participating in the United Network for Organ Sharing, was conducted. The main outcome measures were survival and mortality. RESULTS: Eight hundred fifty-two children received an intestinal transplant (54% male). Median age and weight at the time of transplant were 1 year (interquartile rage: 1–5) and 10.7 kg (interquartile rage: 7.8–21.7). Sixty-nine percent of patients also received a simultaneous liver transplant. The most common diagnoses among patients who received a transplant were gastroschisis (24%), necrotizing enterocolitis (15%), volvulus (14%), other causes of short-gut syndrome (19%), functional bowel syndrome (16%), and Hirschsprung disease (7%). The Kaplan-Meier curves demonstrated variation in patient survival according to diagnosis. Cox regression analysis confirmed a survival difference according to diagnosis (P < .001) and demonstrated a survival advantage for those patients listed with a diagnosis of volvulus (P < .01) compared with the reference gastroschisis. After adjusting for gender, recipient weight, and concomitant liver transplant, children with volvulus had a lower hazard ratio for survival and a lower risk of mortality. CONCLUSIONS: Survival after intestinal transplant was associated with the underlying disease state. The explanation for these findings requires additional investigation into the differences in characteristics of the population of children with intestinal failure.

Necrotizing fasciitis after Plastibell circumcision

Necrotizing fasciitis is a potentially life-threatening infection of subcutaneous tissues and Scarpas fascia that rarely affects neonates. We report the occurrence of this devastating infection in two neonates after routine Plastibell circumcision. These case reports highlight the presentation and management of this complication after a relatively routine and frequently performed operation. This report also emphasizes the differences between cellulitis and necrotizing fasciitis and suggests strategies for management.

Adolescents are more likely to develop posttransplant lymphoproliferative disorder after primary Epstein-Barr virus infection than younger renal transplant recipients.

Background. Primary Epstein-Barr virus (EBV) infection is the most important risk factor for development of posttransplant lymphoproliferative disorder (PTLD). Pediatric patients are often EBV seronegative pretransplant placing them at high risk. In the immune-competent population, primary herpesvirus infection is associated with higher morbidity with increasing age. Methods. We performed a retrospective cohort study to describe the outcome of pediatric renal transplant recipients with primary EBV infection. All patients received 3 months of ganciclovir prophylaxis. Real-time quantitative polymerase chain reaction was used to determine the EBV viral load. Primary EBV infection was categorized as PTLD, symptomatic infection, or subclinical infection. Results. There were a total of 46 patients with primary EBV infection: 11 developed PTLD, 12 had symptomatic infection, and 23 had subclinical infection. Adolescents were significantly more likely to develop PTLD than younger transplant recipients (P=0.05, chi-square). Multivariate analysis using logistic regression found that older age was the only significant risk factor for PTLD (odds ratio 1.24, 95% confidence interval 1.04–1.47; P=0.03). Among the 11 cases of PTLD, there were two deaths and two graft failures which all occurred in adolescent recipients (P=0.002). Conclusions. Among pediatric renal transplant recipients with primary EBV infection, adolescents are at significantly higher risk to develop PTLD and have poorer outcomes compared to younger recipients.

Surgical treatment of primary liver tumors in children: Outcomes analysis of resection and transplantation in the SEER database

Adjusted survival outcomes following hepatic resection and transplantation for pediatric liver tumors have not been compared. To address this question, we conducted a retrospective cohort study using the SEER registry. While SEER lacks certain specifics regarding staging, chemotherapy, comorbidities, and recurrence, important hypothesis‐generating data are available and were analyzed using Kaplan–Meier statistics and Cox proportional hazards regression. All SEER patients under the age of 20 yr undergoing surgery for HB (n = 318) or HCC (n = 80) between 1998 and 2009 were included. Of HB patients, 83.3% underwent resection and 16.7% transplantation. Advanced disease, vascular invasion, and satellite lesions were more common among transplant patients. Unadjusted five‐yr survival was equivalent, as was the adjusted hazard of death for transplant relative to resection (HR = 0.58, p = 0.63). Of HCC patients, 75.0% underwent resection and 25.0% transplantation. Transplant patients had a higher prevalence of vascular invasion and satellite lesions. Five‐yr survival was 53.4% after resection and 85.3% after transplant, and the adjusted hazard of death was significantly lower after transplantation (HR = 0.05, p = 0.045). While transplantation is generally reserved for unresectable tumors, the favorable survival seen in HCC patients suggests that liberalized transplant criteria might improve survival, although further prospective data are needed.

A contemporary analysis of parenteral nutrition-associated liver disease in surgical infants

BACKGROUND/PURPOSE Despite advances in pediatric nutritional support and a renewed focus on management of intestinal failure, there are limited recent data regarding the risk of parenteral nutrition (PN)-associated liver disease in surgical infants. This study investigated the incidence of cholestasis from PN and risk factors for its development in this population. METHODS A retrospective review was performed of all neonates in our institution who underwent abdominal surgery and required postoperative PN from 2001 to 2006. Cholestasis was defined as 2 conjugated bilirubin levels greater than 2 mg/dL over 14 days. Nonparametric univariate analyses and multivariate logistic regression were used to model the likelihood of developing cholestasis. Median values with range are presented. RESULTS One hundred seventy-six infants met inclusion criteria, and patients received PN for 28 days (range, 2-256 days). The incidence of cholestasis was 24%. Cholestatic infants were born at an earlier gestational age (34 vs 36 weeks; P < .01), required a 3-fold longer PN duration (76 vs 21 days; P < .001), had longer inpatient stays (86 vs 29 days; P < .001), and were more likely to be discharged on PN. The median time to cholestasis was 23 days. Cholestasis was an early development; 77% of cholestatic infants developed cholestasis by 5 weeks of PN exposure. On multivariate regression, only prematurity was significantly associated with development of cholestasis (P < .05). CONCLUSION In this analysis, the development of PN-associated liver disease occurred early in the course of exposure to PN. These data help to define the time course and prognosis for PN-associated cholestasis in surgical infants.