Efficacy and safety of recombinant human growth hormone therapy in pediatric intestinal transplant recipients.

BACKGROUND: Recombinant human growth hormone (rhGH) is widely used to treat growth retardation in children. We aimed to examine the effect of rhGH therapy on growth and its impact on allograft function in children with growth retardation after intestinal transplant (IT). METHODS: We retrospectively included children younger than 19 years who had received an IT with or without the liver, were diagnosed with growth retardation, and have received rhGH between January 2010 and January 2021. Changes in the patient's anthropometric parameters between baseline and various time points were compared using the paired t-test or Wilcoxon signed-rank test, as appropriate. RESULTS: Seven patients (all males and prepubertal) received rhGH for the median duration of 2.3 years. The median age at rhGH start was 9.5 years. The median growth velocity z-score improved from -0.95 before treatment to 2.3 (p = .04) and 1.9 (p = .06) after 1 and 2 years of treatment, respectively. The median height-for-age z-score significantly improved from -3.4 at rhGH start to -1.3 (p = .005) at rhGH stop and remained above baseline at the last visit (-2.4, p = .002). The change in the first-year growth velocity was negatively correlated with the change in the second-year growth velocity (r = -.90, p = .04). No serious adverse effects or worsening allograft function were observed. CONCLUSIONS: Severely growth retarded children after IT could benefit from rhGH treatment. A larger, longitudinal study would be warranted to monitor the long-term effect and safety of rhGH and examine predictors of growth response to rhGH therapy in these pediatric IT recipients.

International pediatric transplant association (IPTA) guidance on developing and/or expanding pediatric solid organ transplantation programs in low- and middle-income countries.

Pediatric solid organ transplantation (SOT) is a preferred treatment for medically suitable children with end-stage organ failure. Still, many of them have no access to transplantation owing to socioeconomic constraints or lack of transplant facilities in low- and middle-income countries (LMIC). Establishing pediatric SOT programs in LMIC offers children the opportunities to receive transplant care in more familiar home environments as well as help curtail transplant tourism and improve transplant outcomes as pediatric transplantation would be performed ethically and legally. The International Pediatric Transplant Association (IPTA) is a professional organization aiming to promote safe, ethical, and high-quality pediatric transplantation worldwide. This society paper describes major obstacles to pediatric SOT in LMIC and provides guidance on developing and/or expanding pediatric SOT programs in such countries. We also summarize available resources from the IPTA Outreach Program to help establish and support pediatric SOT programs in LMIC.

Diagnostic performance of 2D-shear wave elastography and serum fibrosis markers for evaluation of hepatic graft fibrosis in pediatric liver-inclusive transplant recipients: A prospective pilot study.

BACKGROUND: Liver biopsy is the gold standard for hepatic fibrosis staging, but it is invasive and has potential severe complications. We aimed to determine the diagnostic performance of 2D-SWE and serum markers to predict significant hepatic graft fibrosis (≥F2) in pediatric liver-inclusive transplant recipients. METHODS: This prospective, cross-sectional pilot study included children younger than 19 years who had received a LT or LSBT and underwent a liver biopsy performed for clinical indications. LS was measured using 2D-SWE. The AUROC was calculated to evaluate the diagnostic performance of 2D-SWE and biomarkers (AST/ALT ratio, APRI, FIB4) for predicting significant fibrosis. RESULTS: Twenty-two children (13 males, 8 LSBT) were included. Eighteen (81.8%) children received a whole liver graft. Thirteen (59.1%) patients had hepatic fibrosis (≥F1) and four (18.2%) had significant fibrosis. The AUROCs of AST/ALT ratio, APRI, and FIB4 for predicting significant hepatic graft fibrosis were 0.71 (p = .29), 0.85 (p = .0001), and 0.76 (p = .03), respectively. When FIB4 was calculated using the hepatic graft's age, its AUROC improved to 0.85 (p < .0001). The AUROC of 2D-SWE for predicting significant hepatic graft fibrosis was 0.80 (p = .046). When 2D-SWE was combined with APRI or FIB4, its AUROC improved to 0.82 (p = .08) and 0.87 (p = .002), respectively. CONCLUSIONS: APRI and FIB4 can accurately predict significant hepatic graft fibrosis. 2D-SWE may serve as a valuable adjunct tool to detect significant graft fibrosis, especially when combined with these serum markers.

High-grade myelodysplastic syndrome in a pediatric multi-organ transplant recipient: A case report and literature review.

BACKGROUND: Pediatric myelodysplastic syndrome is a rare but life-threatening condition requiring prompt recognition and management. METHODS: We herein present the only reported case of a pediatric multi-organ transplant recipient developing myelodysplastic syndrome. RESULTS: The patient was a 14-year-old girl on chronic calcineurin inhibitor therapy who presented with peri-rectal pain approximately 13 years after liver, small bowel, and pancreas transplant. The initial workup revealed pancytopenia and parvovirus B19 viremia. Her definitive diagnosis was complicated by a lack of adequate bone marrow biopsy specimens and expert consultation that resulted in treatment for hemophagocytic lymphohistiocytosis. She was later diagnosed with high-grade myelodysplastic syndrome. Although curative treatment with chemotherapy and hematopoietic stem cell transplantation was strongly considered, it was not performed due to the child's rapid clinical progression, ventilator status, and active infections. The patient died approximately 6 months following symptom onset. CONCLUSIONS: This case emphasizes the importance of early recognition of myelodysplastic syndrome in multi-organ transplant recipients on chronic immunosuppression. Pancytopenia is a common presentation in the post-transplant period that requires thorough investigation. Multiple confounding considerations such as infection, immunosuppression, and systemic inflammation can delay the diagnosis of underlying hematological malignancies. Transplant care providers should be aware of myelodysplastic syndrome and advocate for a comprehensive evaluation, given early recognition and intervention can significantly improve outcomes.

Multiple rare-earth magnet bead ingestion in a pediatric liver-small bowel-pancreas transplant recipient: A case report and lessons learned.

Ingestion of rare-earth magnet beads in children has been a public health concern. The potential risk of swallowing multiple magnets is related to magnet attraction to each other, resulting in serious gastrointestinal complications, such as entero-enteric fistula formation, peritonitis, bowel ischemia or necrosis, bowel perforation, and potentially death. We describe the clinical outcome of a 10-year-old child with a liver-small bowel-pancreas transplant who swallowed 26 rare-earth magnetic beads. The patient presented with fever and abdominal pain. Due to difficulty locating the magnets and post-surgical anatomy changes, only 25 magnets were removed endoscopically. After the procedure, she continued to have abdominal distention and fever, leading to further investigation and subsequently an exploratory laparotomy, which confirmed a walled-off perforation. She was treated conservatively with bowel rest and antibiotics, without the need for small bowel graft resection. She recovered well and was eventually discharged on her home enteral feeding regimen. This case emphasizes the importance of taking a good history and having a high index of suspicion to diagnose this dangerous clinical condition, especially in children with an associated predisposing condition for foreign body ingestion, such as developmental delay. Early diagnosis of multiple magnet bead ingestion and prompt detection of its complications in pediatric intestinal transplant recipients could help initiate appropriate intervention and prevent intestinal graft loss.

Post-transplant hepatic fibrosis in pediatric liver-small bowel transplant recipients: A single-center, retrospective, observational study.

BACKGROUND: Little is known about the prevalence of hepatic graft fibrosis in combined LSBT children. We aimed to determine the prevalence of and identify potential predictors for hepatic graft fibrosis in LSBT children and to compare them with those in LT children. METHODS: We retrospectively included children younger than 19 years who had received a primary LT/LSBT between 2000 and 2018 and had a liver biopsy performed at least 6 months post-transplant. A Cox proportional hazards regression model was used to determine predictors associated with significant hepatic graft fibrosis (≥F2) in LSBT vs LT children. RESULTS: Ninety-six children (47 LSBT, 54 females) were included. The median post-transplant follow-up (years) was 12.8 in LT vs 10.5 in LSBT patients (P = .06). Hepatic graft fibrosis was found in 81.6% of LT vs 70.2% of LSBT children (P = .19), after a median time of 2.5 years and 2.6 years, respectively. On multivariate analyses, having post-transplant biliary complications was found to be associated with significant graft fibrosis in LT children, whereas AST/ALT ratio was found to predict significant hepatic graft fibrosis in LSBT children. The use of parenteral nutrition after transplant was not associated with significant hepatic graft fibrosis. CONCLUSIONS: The prevalence of hepatic graft fibrosis in LSBT children did not significantly differ from that in LT children, but the predictors may differ. Future studies should investigate the role of post-transplant autoimmune antibodies and donor-specific antibodies in the development and progression of hepatic graft fibrosis in LSBT children.

Invasive pneumococcal infections in pediatric liver-small bowel-pancreas transplant recipients.

Children undergoing LSBPTx are at increased risk of IPI due to splenectomy. We aimed to describe the clinical features and outcomes of IPI in pediatric LSBPTx recipients. Between 2008 and 2016, 122 LSBPTx children at our center were retrospectively reviewed. Nine patients had 12 episodes of IPI; the median age at first infection was 3.5 years (range: 1.5-7.1 years). The median time from transplant to first infection was 3 years (range: 0.8-5.8 years). Clinical presentation included as follows: pneumonia (n = 1), bacteremia/sepsis (n = 7), pneumonia with sepsis (n = 1), meningitis with sepsis (n = 2), pneumonia and meningitis with sepsis (n = 1). The overall risk for IPI was 7.4% or 0.9% per year. The mortality rate was 22%. Seven (78%) children had received at least one dose of PCV13, four (44%) patients had received 23-valent pneumococcal polysaccharide vaccine prior to IPI. All patients were on oral penicillin prophylaxis. In conclusion, despite partial or complete pneumococcal immunization and reported antimicrobial prophylaxis, IPI in LSBPTx children can have a fatal outcome. Routine monitoring of pneumococcal serotype antibodies to determine the timing for revaccination might be warranted to ensure protective immunity in these transplant recipients.

Inverse correlation between Helicobacter pylori colonization and obesity in a cohort of inner city children.

BACKGROUND: Recently, publications in adults and children have documented a potential role of Helicobacter pylori (H. pylori) in decreasing the likelihood of obesity. The present study compares the prevalence of H. pylori colonization between obese (body mass index [BMI] ≥ 95th percentile) and healthy weight (BMI ≥ 5th to <85th percentiles) children seen at an inner city medical center in the United States. METHODS: This retrospective study reviewed clinical features, BMI, and gastric histology of consecutive children aged 1-18 years undergoing an esophagogastroduodenoscopy. BMI percentile was calculated for age and gender. Helicobacter pylori colonization was determined by histopathologic identification of the organism. Multiple logistic regression was employed to measure the association between BMI and H. pylori colonization, controlling for baseline age, gender, and presenting symptoms. RESULTS: Among 340 patients (51.5% female, mean age of 10.5 ± 4.7 years), 98 (29%) were obese and 173 (51%) were healthy weight. The H. pylori colonization rate of the entire cohort was 18.5% (95% CI = 14.7-23.0%). Among obese children, 10% had H. pylori colonization compared to 21% of the healthy weight children (RR = 2.1, 95% CI = 1.1-4.0). Conversely, 39% of noncolonized children, but only 21% of the infected children, were obese (RR = 1.8, 95% CI = 1.1-3.3). Multivariate analysis revealed that being colonized with H. pylori is associated with a 50% reduction in the odds of being obese (adjusted OR = 0.5, 95% CI = 0.2-1.0). CONCLUSIONS: Our findings in a North American cohort are in agreement with studies from Asia and Europe suggesting that H. pylori infection decreases the prevalence of obesity in children. Further work to characterize the extent and nature of this relationship is warranted.

The liver in pediatric gastrointestinal disease.

Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.

Immune function and infectious complications in children with jejunoileal atresia.

OBJECTIVE: Little is known about differences in immune function among children with multiple intestinal atresia (MIA) and those with isolated intestinal atresia (IA), and how such differences may manifest as infectious complications and patient outcomes. This study aimed to investigate the immune function and its impact on patient outcomes in IA and MIA children. METHODS: A single-center retrospective cohort study included children aged 0-19 years with intestinal atresia who were referred to a multidisciplinary intestinal rehabilitation program from 1/2000 to 12/2016. Data were collected for patient characteristics, surgical history, immunologic work-up, and infection-related hospitalizations. Groups of IA and MIA children were compared using chi-square test or Fisher's exact test for categorical variables and using Mann-Whitney test for continuous variables, as appropriate. RESULTS: Twenty-seven children (18 IA, 9 MIA) were included. More than half of the patients had low CD counts for age in IA and MIA groups: CD3 58.3% vs. 66.7% (p = 1.0), CD4 50.0% vs. 66.7% (p = 0.7), CD8 67.7% vs. 88.9% (p = 0.3), respectively. Six out of 12 IA children and 3 out of 8 MIA children had hypogammaglobulinemia (p = 0.7). Three out of 10 IA patients and 3 out of 5 MIA children had frequent bacteremia (≥5/year). Eight children (6 IA and 2 MIA) underwent intestinal and/or liver transplant; MIA children had a worse posttransplant outcome. CONCLUSIONS: IA children may have an immunodeficiency and associated infectious complications requiring hospitalization. We suggest performing immunologic evaluation not only in MIA but also in IA children presenting to an intestinal rehabilitation program to identify immunodeficiency. Early immunodeficiency screening may help initiate appropriate intervention and improve patient outcomes. LEVEL OF EVIDENCE: Level III.

Diagnostic performance of non-invasive tests for evaluation of hepatic graft fibrosis in pediatric liver transplantation: A scoping review.

BACKGROUND: Hepatic graft fibrosis is a common histologic finding of pediatric liver transplant (LT) that might affect long-term graft outcome. However, its diagnosis and staging require an invasive liver biopsy. AIM: To review the published literature on the diagnostic accuracy of elastography and serum-based fibrosis markers for assessing hepatic graft fibrosis in pediatric LT recipients. METHODS: A scoping review was conducted using a systematic search of published literature in PubMed (MEDLINE), EMBASE, SCOPUS, and Cochrane Library between 2002 and 2019. We included all English conference abstracts or full-text articles that examined the diagnostic accuracy of the non-invasive test(s) to assess hepatic fibrosis in LT children, using liver biopsy as the reference test. RESULTS: Eight studies were included, of which 6 examined transient elastography (TE), one investigated acoustic radiation force impulse elastography, and 5 examined serum-based fibrosis markers (AST/ALT ratio, AST-to-platelet ratio index, FibroTest, enhanced liver fibrosis test). TE reportedly had a good AUROC (range: 0.82-0.92) to distinguish children with hepatic graft fibrosis (≥F1) from those with no fibrosis. However, there was considerable overlap of liver stiffness cutoffs in the mild to significant fibrosis groups (≥F1 and ≥F2). Current serum-based fibrosis markers reportedly had an unsatisfactory diagnostic accuracy. CONCLUSIONS: TE in LT children has similar diagnostic value and limitations as in the non-transplant setting. Prospective studies are warranted to validate an optimal liver stiffness cutoff for predicting significant hepatic graft fibrosis (≥F2) and to determine if a meaningful change in liver stiffness from baseline could identify patients at risk for fibrosis progression.

Antibiotic use in cirrhotic children with acute upper gastrointestinal bleeding: A retrospective study using the pediatric health information system (PHIS) database.

Prior studies have demonstrated positive impacts of antibiotic use on reducing mortality, rebleeding events, and length of hospitalization in adult cirrhotic patients with acute upper gastrointestinal bleeding (UGIB). We aimed to investigate the use of antibiotics in cirrhotic children with acute UGIB and its impact on patient outcomes.This was a retrospective study using the Pediatric Health Information System database. Cirrhotic patients aged 0 to 18 years with acute UGIB, admitted between October 2005 and September 2015, were identified based on ICD-9 codes. Patients with no documented endoscopy during admission were excluded.Forty-four (23 females) cirrhotic children were eligible for data analysis. The median patient age was 6 years. Etiology of acute UGIB included esophageal varices (n = 37), non-variceal bleeding (n = 4), and both (n = 3). A significant proportion of cirrhotic children with acute UGIB (n = 30, 68%) were given intravenous antibiotics within 48 hours of admission. Among children who did not develop bacteremia, 68% received antibiotics vs. 32% who did not (P = .6). The rate of readmission within 30 days of discharge was 7% in patients with antibiotics vs. 21% in those without antibiotics (P = .3).This study suggested that antibiotic use within 48 hours of admission in cirrhotic children with acute UGIB might have a positive impact on the percentage of children free of bacteremia and the readmission rate. A prospective study should investigate whether prophylactic antibiotics should be targeted only to a subgroup of cirrhotic children with acute UGIB who are particularly at high risk for bacterial infection.

The role of folate receptor autoantibodies in preterm birth.

OBJECTIVE: Cellular uptake of folate is mediated by folate receptor (FR)α. Prior studies indicate that a FRα autoantibody (FRAb) is implicated in poor pregnancy outcomes. The aims of this study were to determine the prevalence of FRAbs in women with preterm and term pregnancies, and to investigate the role of maternal FRAbs in preterm birth. METHODS: This prospective observational study included 23 mothers and 25 preterm infants (two twin births) born at gestational age (GA) ≤32 wk and/or birth weight ≤1500 g (group 1) and 25 mother-term infant pairs (infants born at GA ≥37 wk, group 2). Blocking and binding FRAbs in maternal and in cord blood were determined. The association between maternal FRAbs and pregnancy outcome was measured using multiple logistic regression, adjusted for maternal age and previous preterm birth. RESULTS: The prevalence of FRAbs was 65.2% in women with preterm birth, which was twofold higher than in those with term pregnancy (28%; relative risk [RR], 2.3; 95% confidence interval [CI], 1.2-4.7). The prevalence of FRAbs in preterm infants (64%) was significantly higher than in term infants (24%; RR, 2.7; 95% CI, 1.3-5.7). Pregnant women with positive FRAbs had 4.9 times higher odds of having preterm birth (odds ratio, 4.9; 95% CI, 1.4-17.7), adjusted for maternal age and previous preterm birth. CONCLUSIONS: These findings suggest that the presence of FRAbs might be a contributing factor to preterm birth, which could be prevented with appropriate testing and therapeutic interventions. Further studies are warranted to investigate the possible mechanisms of fetal sensitization resulting in FRAb production in utero and its possible clinical correlates.