Elisa Ylinen

Background: The use of ABO-incompatible liver transplants (ABO-ILTs) from deceased donors has become more common due to the shortage of available donor livers and increased transplant waiting times. This retrospective study from a national transplant center at Helsinki University Hospital, Finland, aimed to assess the long-term outcomes of ABO-incompatible deceased donor pediatric liver transplants between 1987 and 2022. Material/Methods: Sixteen (9.5%) of the 169 pediatric liver transplantations were ABO-ILTs. The median age at transplantation was 5.0 (0.5-15.4) years. Reasons for ABO-ILTs were acute liver failure (18.75%), malignancy (12.5%), small body size and long waiting time (25%), and other reasons (43.75%). The median post-transplant follow-up time was 147 (0.72-353) months. Patient and graft survival and occurrence of surgical complications were compared to ABO-identical transplants, and anti-ABO antibody titers were analyzed. Results: The 1-, 3-, and 5-year patient survivals were comparable between the ABO-I and ABO-compatible groups, being 81.3%, 73.9%, and 73.9% (ABO-I) and 87.5%, 82.5%, 77.9% (ABO-compatible), respectively. Three patients with ABO-ILTs died of sepsis and multiorgan failure during the first 3 months after transplantation. The occurrence of biliary complications and early vascular thrombosis (<30 days after transplantation) did not diller significantly between recipients with an ABO-ILT vs ABO-compatible liver graft. Conclusions: The findings from this study support findings from previous studies that outcomes after ABO-incompatible liver transplants in children were comparable to outcomes from ABO-identical liver transplants.

Shiga toxin (Stx)-producing Escherichia coli (STEC) infections cause outbreaks of severe disease in children ranging from bloody diarrhea to hemolytic uremic syndrome (HUS). The adherent factor intimin, encoded by eae, can facilitate the colonization process of strains and is frequently associated with severe disease. The purpose of this study was to examine and analyze the prevalence and polymorphisms of eae in clinical STEC strains from pediatric patients under 17 years old with and without HUS, and to assess the pathogenic risk of different eae subtypes. We studied 240 STEC strains isolated from pediatric patients in Finland with whole genome sequencing. The gene eae was present in 209 (87.1%) strains, among which 49 (23.4%) were from patients with HUS, and 160 (76.6%) were from patients without HUS. O157:H7 (126, 60.3%) was the most predominant serotype among eae-positive STEC strains. Twenty-three different eae genotypes were identified, which were categorized into five eae subtypes, i.e., γ1, β3, ε1, θ and ζ3. The subtype eae-γ1 was significantly overrepresented in strains from patients aged 5–17 years, while β3 and ε1 were more commonly found in strains from patients under 5 years. All O157:H7 strains carried eae-γ1; among non-O157 strains, strains of each serotype harbored one eae subtype. No association was observed between the presence of eae/its subtypes and HUS. However, the combination of eae-γ1+stx2a was significantly associated with HUS. In conclusion, this study demonstrated a high occurrence and genetic variety of eae in clinical STEC from pediatric patients under 17 years old in Finland, and that eae is not essential for STEC-associated HUS. However, the combination of certain eae subtypes with stx subtypes, i.e., eae-γ1+stx2a, may be used as risk predictors for the development of severe disease in children.

Background: Gastrointestinal symptoms are common among solid organ transplant (SOT) recipients. Information about colonoscopy findings after pediatric SOT is limited. This retrospective study reports endoscopy findings in a nationwide pediatric transplant recipient cohort.Methods: All pediatric recipients (kidney, liver, or heart) transplanted between 2010 and 2020 at our institution (n = 193) who had undergone ileocolonoscopy and upper gastrointestinal endoscopy after SOT were enrolled. Sixteen patients were identified. A meticulous search on clinical data including transplantation, gastrointestinal symptoms, endoscopy findings, and follow‐up data was performed.Results: Endoscopy was performed at a median of 2.6 years (0.4–13.3) after the first transplantation (median age at SOT 1.2 years). Gastrointestinal symptoms leading to endoscopy did not differ between the different transplant groups. The leading endoscopy indications were prolonged diarrhea and anemia. PTLD was found in 8 (50%) patients. Five were histologically early PTLD lesions and three were monomorphic large B‐cell PTLDs (two EBV‐positive and one EBV‐negative), one having previously been diagnosed with autoimmune enteropathy. One patient had EBV enteritis. De novo inflammatory bowel disease was found in one patient, eosinophilic gastroenteritis in another, and in one patient with several episodes of watery diarrhea, the histological finding was mild non‐specific colitis. In four patients, the endoscopy finding remained unclear and the symptoms were suspected to be caused by infectious agents or mycophenolate.Conclusions: PTDL with various stages is a common finding after pediatric SOT in patients with gastrointestinal symptoms. Endoscopy should be considered in transplant recipients with prolonged diarrhea, anemia, and/or abdominal pain.

Background: Hemolytic uremic syndrome (HUS) is a multisystemic disease. In a nationwide study, we characterized the incidence, clinical course, and prognosis of HUS caused by Shiga toxin (Stx)–producing Escherichia coli (STEC) strains with emphasis on risk factors, disease severity, and long-term outcome. Methods: The data on pediatric HUS patients from 2000 to 2016 were collected from the medical records. STEC isolates from fecal cultures of HUS and non-HUS patients were collected from the same time period and characterized by whole genome sequencing analysis. Results: Fifty-eight out of 262 culture-positive cases developed verified (n = 58, 22%) STEC-HUS. Another 29 cases had probable STEC-HUS, the annual incidence of STEC-HUS being 0.5 per 100,000 children. Eleven different serogroups were detected, O157 being the most common (n = 37, 66%). Age under 3 years (OR 2.4), stx2 (OR 9.7), and stx2a (OR 16.6) were found to be risk factors for HUS. Fifty-five patients (63%) needed dialysis. Twenty-nine patients (33%) developed major neurological symptoms. Complete renal recovery was observed in 57 patients after a median 4.0 years of follow-up. Age under 3 years, leukocyte count over 20 × 10⁹/L, and need for dialysis were predictive factors for poor renal outcome. Conclusions: Age under 3 years, stx2, and stx2a were risk factors for HUS in STEC-positive children. However, serogroup or stx types did not predict the renal outcome or major CNS symptoms.

BKPyV is widely recognized in KTRs, but little is known about rates of primary and secondary JCPyV exposure in pediatric KTRs. We evaluated JCPyV exposure in pediatric KTRs using antibody responses in the first 12 months post‐transplant. Of 46 children transplanted between 2009 and 2014, 6 lacked any samples for serologic testing, leaving 40 KTRs for study. JCPyV‐specific IgG and IgM antibodies were measured using a normalized VLP ELISA. Significant JCPyV exposure was defined as IgG seroconversion, increasing IgG levels of >0.5 nOD units, or IgM detection. Of 40 recipients (median age 3.2 years), 11 (27.5%) were seropositive, 20 (50%) seronegative for JCPyV‐IgG, while 9 (22.5%) had no specimen at the time of transplantation, but were confirmed as seronegative in post‐transplant samples. Of 29 (72.5%) at risk, JCPyV‐IgG seroconversion occurred in 15/29 (51.7%) including JCPyV‐IgM in 6 patients (20.7%). Two patients (6.9%) developed only JCPyV‐IgM. Among JCPyV‐IgG‐positive KTRs, six (12.5%) had significant IgG increases. Altogether 23 of 40 patients (57.5%) had serological evidence of primary or secondary JCPyV exposure. In these patients, kidney function tended to be lower during the 2 years of follow‐up, but only one patient lost the graft due to JCPyV nephropathy. Thus, JCPyV exposure is common in pediatric KTR and may present serologically as primary or secondary infection. Although only one case of JC‐PyVAN occurred, a trend toward lower renal function was seen. Dedicated studies of larger cohorts are warranted to define impact of JCPyV in pediatric KTR.

Adolescents with a kidney transplant (KT) require special attention during the transition of care. Few longitudinal studies have assessed the effect of transition models (TM) on patient outcomes. Between 1986 and 2013, 239 pediatric patients underwent KT in Finland, of whom 132 have been transferred to adult care. In 2005, a TM was developed following international recommendations. We compared patient (PS) and graft survival (GS) rates before and after the introduction of the TM. PS and GS at 10 years were similar before and after the implementation of the TM (PS 85% and 90% respectively, P = 0.626; GS 60% and 58%, respectively, P = 0.656). GS was lower in patients transplanted at age 10‐18 than in patients transplanted at a younger age in the TM cohort (79% vs 95%, P < 0.001). During the first five years after transfer, 63% of patients had stable KT function, 13% had deteriorating function and 24% lost their KT. Altogether 32 out of 132 patients lost their kidney allograft within five years after transfer to adult care (13 before and 19 after TM implementation, P = 0.566). The implementation of this TM had no effect on PS or GS. Further measures to improve our TM are in progress.

Transplant patients need lifelong immunosuppressive medication, but this reduces their defense mechanisms, making them prone to viral infections and reactivations. We aimed to clarify the prevalence and clinical manifestations of the human herpes virus 6 (HHV‐6) infection in children after pediatric solid organ transplants. Clinical findings and viral loads were compared between primary HHV‐6 infections and reactivations. The study comprised 47 kidney, 25 liver, and 12 heart transplant patients who underwent surgery from 2009 to 2014. HHV‐6 antibodies were analyzed before surgery, and HHV‐6 DNAemia tests were regularly carried out after the transplant using a real‐time quantitative polymerase chain reaction method. We found the primary HHV‐6 infection in 19 of 22 (86%) seronegative patients, and it was more common in patients under 3 years of age (79%) than over 3 (38%, P=.0002). Post‐transplant HHV‐6 DNAemia affected 48 of 84 (57%) patients and was significantly higher in primary infections than reactivations (P=.001), and 17 of 48 (35%) patients had symptoms when it was detected at a median of 2 weeks post‐transplant. The HHV‐6 infection was common after solid organ transplants, especially under 3 years of age, and it typically started 2 weeks after surgery. Testing for HHV‐6 DNAemia is recommended shortly after transplantation, especially in patients with fever, diarrhea, rash, seizures, or abnormal liver enzyme tests.

Aim: The human leucocyte antigen (HLA) allele and haplotype frequencies of the Finnish population are unique because of the restricted and homogenous gene population. There are no published data on HLA genotype associations in paediatric autoimmune liver diseases in Scandinavia. This study characterised the HLA genotypes of children with autoimmune liver or biliary disease in Finland.Methods: The study cohort comprised 19 paediatric patients (13 female) aged three years to 15 years treated for autoimmune liver or biliary disease at the Children's Hospital, Helsinki University Hospital, between 2000 and 2011, and followed up for four years and three months to 14.6 years. We genotyped HLA‐B and HLA‐DRB1 in the children, and the HLA antigen frequencies were compared with 19 807 records from the Finnish Bone Marrow Donor Registry.Results: All paediatric patients with autoimmune liver or biliary disease had either autoimmune HLA haplotype B*08;DRB1*03 or DRB1*13. These were significantly more common among patients with autoimmune hepatitis, primary sclerosing cholangitis and autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome than the Finnish control population. HLA RB1*04 was not found in the study cohort.Conclusion: Our study found that B*08, DRB1*03 and DRB1*13 were significantly associated with autoimmune liver and biliary diseases in Finnish paediatric patients.

Background High-dose methotrexate (HD-MTX) is potentially nephrotoxic. The feasibility of novel biomarkers to indicate renal injury due to HD-MTX infusion was studied in children with acute lymphoblastic leukemia (ALL). Procedure Markers for glomerular and tubular injury were evaluated prospectively after HD-MTX infusion in 20 children with ALL. Plasma creatinine, cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) were measured 24–48 hr before MTX-infusion and 24, 36, 48, and 72 hr after starting the HD-MTX treatment, and thereafter daily until the MTX concentration was below 0.1 µmol/L. Urine NGAL, β₂-microglobulin, and creatinine concentrations as well as dipstick and urinalysis were performed at the same time points. Results In children with ALL, HD-MTX treatment at 5 g/m² over 24 hr was well tolerated and none of the patients developed significant glomerular or tubular dysfunction. The mean plasma cystatin C level increased significantly (P < 0.001) from 0.83 mg/L at baseline to 0.94 mg/L at 36 hr after starting the HD-MTX treatment. The cystatin C concentration remained within reference range in all but two patients (10%). There was no significant change in plasma creatinine level during or after HD-MTX treatment, the values being normal in all patients. Plasma and urea NGAL did not increase during or after the HD-MTX treatment. Conclusions Our results suggest that plasma cystatin C concentration alone is a sensitive marker to monitor renal function during and after HD-MTX infusion in pediatric ALL patients. Plasma or urine NGAL do not provide any further advantage in the follow-up of these patients. Pediatr Blood Cancer 2014;61:2199–2202.