No abstract

Viral opportunistic infections remain a threat to survival after stem cell transplantation (SCT). We retrospectively investigated infections caused by cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus type 6 (HHV6), or adenovirus (AdV) during the first 6-12 months after pediatric SCT. Serum samples from 47 consecutive patients were analyzed by quantitative real-time polymerase chain reaction assay. DNAemia at any time point occurred for CMV in 47%, for EBV in 45%, for HHV6 in 28%, and for AdV in 28%. Three patients (6.3%) died of CMV-, EBV-, or AdV-related complications 4, 9, and 24 weeks after SCT, respectively, representing 21% of total mortality. These 3 cases were clearly distinguishable by DNAemia increasing to high levels. Serum positivity for CMV immunoglobulin G in either recipient or donor at the time of SCT, total body irradiation, and anti-thymocyte globulin conditioning were independent risk factors for high CMV or EBV DNA levels. We conclude that DNAemia levels help to distinguish significant viral infections, and that surveillance and prophylactic measures should be focused on patients with risk factors in whom viral complications rapidly can become fatal.

The monitoring of viral DNA levels after transplantation is crucial for prevention of complications from cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection but there is no consensus as to which matrix is the most adequate. To compare serum and whole blood (WB) as specimens for measuring viral DNA, clinical samples from a 3-year period were studied, with focus on cases where serum and WB were drawn on the same day. In 1896 paired serum and WB samples, CMV DNA was detected in both specimen types in 472 samples with 0.18 log higher levels (P<0.001) in WB than in serum (median level 2.73 vs. 2.56 log copies/mL), and in only either serum or WB in 127 and 108 samples, respectively, generally at levels below 1000 copies/mL. In 664 paired samples, EBV DNA was detected in both serum and WB in 160 samples, with 1.48 log higher levels (P<0.001) in WB (median 4.2 vs. 2.4 log copies/mL), in only WB in 227 cases with a median at 3.0 log copies/mL, and only in serum in 14 samples at low levels. The correlation between serum and WB DNA levels was weaker for EBV than for CMV (R(2) 0.31 vs. 0.74). We conclude that either serum or WB may be used for monitoring CMV and EBV DNA levels, that EBV DNA is detected post transplant in >50% of WB samples and at 30 times higher levels than in serum, and that post-transplantation lymphoproliferative disorder (PTLD) may develop without further increase of EBV DNA in WB. Identification of PTLD may require EBV DNA testing in both specimen types or complementary tests.

A novel entity of long-standing OML that share some features with orofacial granulomatosis has been identified in children after solid organ transplantation.

The rate of PTLD can be reduced by weaned IS guided by monitoring of EBV DNA. In this single-center retrospective case series study, we analyzed how reduction in IS influenced EBV DNA levels in whole blood and serum in 30 children during the first year after liver transplantation, and how these levels were related to symptoms putatively due to EBV. Primary and reactivated EBV infection was seen in 18 (60%) and eight patients (27%), respectively. Thirteen patients (42%) developed chronic high load the first year post-transplant. IS was successfully discontinued in six patients the first year post-transplant and in another two patients within 3 years. EBV DNA levels were reduced, but persisted long term in all the eight patients who had IS completely withdrawn. There was no case of PTLD. In summary, EBV DNAemia and chronic high load were very common after pediatric liver transplantation. Liver graft tolerance facilitates radical reduction in IS treatment, which may prevent PTLD, but EBV DNAemia may persist long term after discontinued IS.

Effective immunosuppression has improved the results following liver transplantation, but also increased the risk for opportunistic infections. Epstein-Barr virus (EBV) infection in transplant patients can cause various symptoms including the life-threatening premalignant condition, post-transplantation lymphoproliferative disorder (PTLD). Serum specimens from 24 consecutive children (mean 7.6 specimens/patient), who had undergone liver transplantation in Göteborg from January 1995 to May 2002, were analyzed retrospectively for EBV DNA by real-time TaqMan polymerase chain reaction (PCR). The results were related to clinical picture, immunosuppression, graft rejection and infections with other agents. Eleven patients (46%) developed primary EBV infection at a mean time of 4.8 months after transplantation, and six (25%) reactivated EBV infection at a mean of 4.0 months after transplantation. Four of the 11 patients with primary infection had symptomatic EBV infection: two had PTLD and two hepatitis. One patient in the group with reactivated infection developed PTLD. EBV DNA levels were significantly higher in the group with primary symptomatic infection compared with the patients with primary asymptomatic infection (mean 65 500 copies/mL; range 14 200-194 300 vs. 3700 copies/mL; range 100-9780). In patients with symptomatic infection EBV DNA levels did not differ between PTLD and hepatitis patients. The data suggest that quantitative analysis of EBV DNA in serum by real-time PCR is useful for identification of EBV-related disease.

Long-term exposure to calcineurin inhibitors increases the risk of CKD in children after LT. The aims of this study were to study renal function by measuring GFRm before and yearly after LT, to describe the prevalence of CKD (stage III: GFR 30-60 mL/min/1.73 m(2)) and to investigate if age and underlying liver disease had an impact on long-term renal function. Thirty-six patients with a median age of 2.9 years (0.1-16 yr) were studied. Median follow-up was 6.5 (2-14 yr). GFRm decreased significantly during the first six months post-transplantation with 23% (p < 0.001). Thereafter renal function stabilized. At six months, 17% (n = 5) of the children presented CKD stage III and at five yr the prevalence of CKD III was 18% in 29 children. However, in 13 children with a 10-year follow-up it was 0%. None of the children required renal replacement therapy after LT. When analyzing renal function of those children younger than two yr (n = 14) and older than two yr (n = 17) at the time of transplantation, we found that in both cohorts the filtration rate remained remarkably stable during the five-yr observational period. However, there was a statistically significant (p < 0.05) difference in the percentual decrease in GFRm between the groups during the first six months after LT 13% and 31%, respectively. Baseline GFRm according to diagnosis did not differ between the groups. During the first six months after LT, patients transplanted for hepatic malignancy (n = 6) and those with metabolic liver disease (n = 4) had a percentage loss of GFRm of 32% and 35%, respectively. The corresponding loss of GFRm in patients with other diseases was 10-19%. Six months post-transplantation mean GFRm in the group with malignant liver disease was 65 +/- 15 mL/min/1.73 m(2) and in the group with other diseases (n = 24) 82 +/- 17 mL/min/1.73 m(2) (p < 0.05). At one, three and five yr post-transplantation there was no longer a statistically significant difference between these cohorts. Our findings suggest that there can be a long-term recovery of renal function after LT in children.

CMV infection is a major problem after solid organ transplantation especially in children where primary infection is more common than in adults. Early diagnosis is critical and might be facilitated by quantitative analysis of CMV DNA in blood. In this retrospective study of 18 children who had a liver transplantation 1995-2000, serum samples were analysed by Cobas Amplicor Monitor (Roche). Four patients developed symptomatic CMV infection at a mean time of 4 wk after transplantation. They showed maximum CMV DNA levels in serum of 26 400, 1900, 1300 and 970 copies/mL, respectively. In comparison, CA Monitor was positive, at a low level (415 copies/mL), in one of 11 patients with asymptomatic (4) or latent (7) infection. CMV IgM was detected at significant levels (> or =1/80) in all four patients with symptomatic, and in one with asymptomatic CMV infection. Eight patients were given one or several courses of ganciclovir. Five of these lacked symptoms of CMV disease, and had low (415 copies/mL) or undetectable CMV DNA in serum. The data suggest that quantitative analysis of CMV DNA may be of value in early identification of CMV disease and for avoiding unnecessary antiviral treatment.