Evaluating the efficacy and safety of pozelimab in patients with CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy disease: an open-label phase 2 and 3 study.

BACKGROUND: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE) is an ultra-rare genetic disorder characterised by intestinal lymphatic damage, lymphangiectasia, and protein-losing enteropathy caused by overactivation of the complement system. We assessed the efficacy and safety of pozelimab, an antibody blocking complement component 5. METHODS: This open-label, single-arm, historically controlled, multicentre phase 2 and 3 study evaluated ten patients with CHAPLE disease. This study was conducted at three hospitals in Thailand, Türkiye, and the USA. Patients aged 1 year or older with a clinical diagnosis of CHAPLE disease and a CD55 loss-of-function variant identified by genetic analysis and confirmed by flow cytometry or western blot of CD55 from peripheral blood cells were eligible for this study. Patients received a single intravenous loading dose of pozelimab 30 mg per kg of bodyweight, followed by a once-per-week subcutaneous dose over the treatment period based on bodyweight at a concentration of 200 mg/mL as either a single injection (<40 kg bodyweight) or two injections (≥40 kg bodyweight). The primary endpoint was proportion of patients with serum albumin normalisation with an improvement in active clinical outcomes and no worsening in inactive clinical outcomes (frequency of problematic abdominal pain, bowel movement frequency, facial oedema severity, and peripheral oedema severity) at week 24 compared with baseline, assessed in the full analysis set. This study is registered with ClinicalTrials.gov (NCT04209634) and is active but not recruiting. FINDINGS: 11 patients were recruited between Jan 27, 2020, and May 12, 2021, ten of which were enrolled in the study and included in the analysis populations. The efficacy data corresponded to all patients completing the week 48 assessment and having at least 52 weeks of treatment exposure, and the safety data included an additional 90 days of follow-up and corresponded to all patients having at least 72 weeks of treatment. Patients were predominantly paediatric (with a median age of 8·5 years), and originated from Türkiye, Syria, Thailand, and Bolivia. Patients had markedly low weight-for-age and stature-for-age at baseline, and mean albumin at baseline was 2·2 g/dL, which was considerably less than the local laboratory reference range. After pozelimab treatment, all ten patients had serum albumin normalisation and improvement with no worsening in clinical outcomes. There was a complete inhibition of the total complement activity. Nine patients had adverse events; two were severe events, and one patient had an adverse event considered related to pozelimab. INTERPRETATION: Pozelimab inhibits complement overactivation and resolves the clinical and laboratory manifestations of CHAPLE disease. Pozelimab is the only currently approved therapeutic drug for patients with this life-threatening, ultra-rare condition. In patients with protein-losing enteropathy where known causes have been excluded, testing for a CD55 deficiency should be contemplated. A diagnosis of CHAPLE disease should lead to early consideration of treatment with pozelimab. FUNDING: Regeneron Pharmaceuticals and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Novel PLEC variants associated with infantile cholestasis.

Plectin is a cytoskeletal linker of intermediate filaments, encoded by the PLEC gene. Recently, plectin mutations have been identified in a pair of siblings with progressive familial intrahepatic cholestasis. Here, we reported two unrelated infants with plectinopathy causing cholestatic jaundice with novel variants in the PLEC gene. Trio exome sequencing identified compound heterozygous variants in the PLEC gene for each patient: c.71-11768C>T and c.4331G>T (p.Arg1444Leu) in Patient 1, and c.592C>T (p.Arg198Trp) and c.4322G>A (p.Arg1441His) in Patient 2. Immunofluorescence staining of liver samples from both patients revealed scattered signals of plectin in the cytoplasm of hepatocytes and reduced colocalization of plectin and cytokeratin 8. This study not only underscores the involvement of plectin in cholestasis but also highlights the utility of exome sequencing as a powerful diagnostic tool in identifying genetic underpinnings of infantile cholestasis.

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

Changes in branched-chain amino acids in an infant with maple syrup urine disease during perioperative pediatric liver transplant: A case report.

An 11-month-old female infant diagnosed with classic subtype IB maple syrup urine disease underwent living donor liver transplantation. Blood samples for plasma amino acid analysis were collected during the three phases of the operation. Despite the perioperative prophylactic administration of 12.5% hypertonic dextrose solution with insulin and a 20% intralipid emulsion, the blood levels of the branched-chain amino acids increased dramatically during surgery, consistent with an acute intraoperative metabolic decompensation. However, these blood levels normalized soon after liver transplantation with an excellent outcome. We suggest that the occurrence of an intraoperative metabolic crisis during liver transplantation is not necessarily a sign of graft failure.

A synbiotic intervention modulates meta-omics signatures of gut redox potential and acidity in elective caesarean born infants.

BACKGROUND: The compromised gut microbiome that results from C-section birth has been hypothesized as a risk factor for the development of non-communicable diseases (NCD). In a double-blind randomized controlled study, 153 infants born by elective C-section received an infant formula supplemented with either synbiotic, prebiotics, or unsupplemented from birth until 4 months old. Vaginally born infants were included as a reference group. Stool samples were collected from day 3 till week 22. Multi-omics were deployed to investigate the impact of mode of delivery and nutrition on the development of the infant gut microbiome, and uncover putative biological mechanisms underlying the role of a compromised microbiome as a risk factor for NCD. RESULTS: As early as day 3, infants born vaginally presented a hypoxic and acidic gut environment characterized by an enrichment of strict anaerobes (Bifidobacteriaceae). Infants born by C-section presented the hallmark of a compromised microbiome driven by an enrichment of Enterobacteriaceae. This was associated with meta-omics signatures characteristic of a microbiome adapted to a more oxygen-rich gut environment, enriched with genes associated with reactive oxygen species metabolism and lipopolysaccharide biosynthesis, and depleted in genes involved in the metabolism of milk carbohydrates. The synbiotic formula modulated expression of microbial genes involved in (oligo)saccharide metabolism, which emulates the eco-physiological gut environment observed in vaginally born infants. The resulting hypoxic and acidic milieu prevented the establishment of a compromised microbiome. CONCLUSIONS: This study deciphers the putative functional hallmarks of a compromised microbiome acquired during C-section birth, and the impact of nutrition that may counteract disturbed microbiome development. TRIAL REGISTRATION: The study was registered in the Dutch Trial Register (Number: 2838 ) on 4th April 2011.

Therapeutic Plasma Exchange with Continuous Renal Replacement Therapy for Pediatric Acute Liver Failure: A Case Series from Thailand.

AIM AND OBJECTIVE: Pediatric acute liver failure (PALF) is a life-threatening condition. Extracorporeal support has been applied for toxic metabolite clearance and serves as a bridging therapy to liver transplantation (LT) or to the regeneration of the liver, but evidence for treatment approaches is still lacking in the pediatric population. We aim to report our experience on therapeutic plasma exchange with high-volume continuous renal replacement therapy (TPE + HV-CRRT) as a promising supportive treatment for PALF. MATERIALS AND METHODS: A total of eight PALF cases aged 9 months to 14 years, weighing 10-50 kg., who were admitted to PICU King Chulalongkorn Memorial Hospital, Thailand and treated with TPE + HV-CRRT from January 2016 to September 2019 were reviewed. Patient demographic data, indications, technical aspects, and clinical outcomes were recorded. RESULTS: All patients who underwent TPE + HV-CRRT showed clinical improvement regarding serum bilirubin levels and coagulation studies after the therapy. Complications from the therapy were hemodynamic instability, symptomatic fluid overload, and bleeding from catheter sites. Among these, 6 (75%) patients survived with 4 (50%) successful LTs and 2 (25%) spontaneous recovery. Two children (25%) died while on the transplantation list. CONCLUSION: TPE + HV-CRRT can be used safely as a bridging therapy in children with PALF. As opposed to the adult population, higher volume of TPE or higher blood flow rate in pediatric patients might associate with hemodynamic instability during the procedure. HOW TO CITE THIS ARTICLE: Trepatchayakorn S, Chaijitraruch N, Chongsrisawat V, Chanakul A, Kongkiattikul L, Samransamruajkit R. Therapeutic Plasma Exchange with Continuous Renal Replacement Therapy for Pediatric Acute Liver Failure: A Case Series from Thailand. Indian J Crit Care Med 2021;25(7):812-816.

Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis.

BACKGROUND & AIMS: Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters. METHODS: We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted. RESULTS: After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa. CONCLUSIONS: We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness.

Hepatic expression of HGF/C-met and native liver survival in biliary atresia.

BACKGROUND: The prognosis of biliary atresia (BA) remains difficult to predict. This study evaluated the roles of hepatocyte growth factor (HGF) and its receptor (C-met) towards clinical outcome and native liver survival. METHODS: Hepatic HGF and C-met expression were determined using immunohistochemistry from liver biopsies of 41 BA patients during Kasai operation, and 17 non-cholestatic patients. The HGF and C-met expression was visually scored as per its intensity and percentage of stained area. BA patients were classified as high- and low-HGF and C-met receptor status. Native liver survival was compared between the two groups at 3-year follow-up. Data are shown as median and range. MAIN RESULTS: Median age of BA patients was 2 (1-6) months. Hepatic HGF and C-met staining scores of BA patients were higher than those of non-cholestatic patients (P < 0.0001). There was a correlation between HGF and C-met staining scores (spearman r = 0.77, P < 0.0001). However, there was no association between their expression and early outcome at 6 months post-op. Mean follow-up time was 68.6 months. Survival analysis revealed that native liver survival at 1 year and 3 years were 88% and 77%, respectively. Additionally, 82.6% (19/23) of patients in the low-HGF group survived with native liver, compared with 66.7% (10/15) of those in high-HGF group (P = 0.436). For C-met expression, 78.6% (22/28) of low-score and 70% (7/10) of high score groups survived with native liver (P = 0.673). CONCLUSIONS: Strong expression of hepatic HGF and its receptor in BA patients was demonstrated. However, the expression was not associated with the early outcome and native liver survival. These results suggest that HGF involved in the liver pathology of BA but its expression cannot be used as a prognostic indicator. Small sample size of patients was a main limitation. Further studies are warranted to validate our findings.

Spleen and Liver Stiffness to Detect Esophageal Varices in Children with Biliary Atresia.

OBJECTIVES: The aim of the study was to determine the accuracy of noninvasive parameters, such as liver (LS) and spleen stiffness (SS) to detect esophageal varices (EV) in children with biliary atresia (BA). METHODS: Children with BA between 2000 and 2015 were recruited. All underwent esophagogastroduodenoscopy and transient elastography. Demographic data, laboratory investigations, alanine transferase-to-platelet ratio index (APRI), and Varices Prediction Rule (VPR) score were collected. RESULTS: A total of 51 children (mean age 10.63 years, standard deviation (SD) = 6.08 years; 53% boys) were enrolled. There were differences in onset and outcome of portoenterostomy, spleen palpablility, platelet count, albumin, LS, SS, and VPR between the varice and varice-free groups (P < 0.05). In the varice group, the median LS was 18.12 (interquartile ratio, IQR 13.15-19.12) and the median SS was 46.85 (IQR 25.95-54.55) kPa. In the varice-free group, the median LS was 7.85 (IQR 5.88-16.75) and the median SS was 16.54 (IQR 11.75-21.75) kPa. Both LS and SS were higher in the varice than the varice-free group (P < 0001). The area under the receiver operating characteristic curve of LS, SS, spleen palpability, platelet count, APRI, and VPR were 0.734, 0.870, 0.817, 0.810, 0.751, and 0.794, respectively. Using a cut-off value of 12.5 kPa for LS, the sensitivity and specificity were 80 and 70%, respectively. Using a cut-off value of 28.9 kPa for SS, the sensitivity and specificity were 75 and 87%, respectively. Combination of LS and SS to diagnose varices increased the specificity to 93%. CONCLUSIONS: SS as a single marker had the best diagnostic value to predict esophageal varices in children with BA. The combination of SS and LS furthermore, increased the diagnostic yield.

Effect of Synbiotic on the Gut Microbiota of Cesarean Delivered Infants: A Randomized, Double-blind, Multicenter Study.

We determined the effect of short-chain galacto-oligosaccharides (scGOS), long-chain fructo-oligosaccharides (lcFOS) and Bifidobacterium breve M-16V on the gut microbiota of cesarean-born infants. Infants were randomized to receive a standard formula (control), the same with scGOS/lcFOS and B. breve M-16V (synbiotic), or with scGOS/lcFOS (prebiotic) from birth until week 16, 30 subjects born vaginally were included as a reference group. Synbiotic supplementation resulted in a higher bifidobacteria proportion from day 3/5 (P < 0.0001) until week 8 (P = 0.041), a reduction of Enterobacteriaceae from day 3/5 (P = 0.002) till week 12 (P = 0.016) compared to controls. This was accompanied with a lower fecal pH and higher acetate. In the synbiotic group, B. breve M-16V was detected 6 weeks postintervention in 38.7% of the infants. This synbiotic concept supported the early modulation of Bifidobacterium in C-section born infants that was associated with the emulation of the gut physiological environment observed in vaginally delivered infants.

Elevated serum heat shock protein 70 and liver stiffness reflect hepatic dysfunction and severity in postoperative biliary atresia.

BACKGROUND: Biliary atresia (BA) is a severe chronic liver disease characterized by progressive obstructive cholangiopathy of biliary tract. Heat shock protein 70 (HSP70) is involved in protecting cells against a wide variety of stress and plays a protective role in tissue damage. The purpose of this study was to investigate serum HSP70 and liver stiffness in BA and determine the association of serum HSP70, liver stiffness, and outcome parameters in post-Kasai BA patients. METHODS: One hundred post-Kasai BA patients and 40 controls were enrolled. Serum HSP70 levels were analyzed using enzyme-linked immunosorbent assay. Liver stiffness values were assessed by transient elastography. RESULTS: BA patients had significantly higher serum HSP70 and liver stiffness values than controls. Serum HSP70 and liver stiffness values were markedly elevated in BA patients with jaundice compared to those without jaundice (P < 0.001). Furthermore, serum HSP70 was more elevated in BA children with portal hypertension than those without portal hypertension (35.1 ± 2.1 vs. 27.9 ± 2.5 ng/mL, P < 0.001). Moreover, serum HSP70 was positively correlated with serum aspartate aminotransferase (r = 0.491, P < 0.001), alanine aminotransferase (r = 0.448, P < 0.001), total bilirubin (r = 0.303, P = 0.002), alkaline phosphatase (r = 0.414, P < 0.001), and liver stiffness values (r = 0.455, P < 0.001). There was a negative correlation between serum HSP70 and serum albumin (r = -0.434, P = 0.001). CONCLUSION: Serum HSP70 and liver stiffness values were higher in BA patients than controls. The increased serum HSP70 was correlated with hepatic dysfunction in BA. Consequently, serum HSP70 and liver stiffness could serve as non-invasive parameters reflecting the severity in post-Kasai BA.

Frequency of HLA-DQB1*0201/02 and DQB1*0302 alleles and tissue transglutaminase antibody seropositivity in children with type 1 diabetes mellitus.

BACKGROUND: Patients with type 1 diabetes mellitus (T1DM) have an increased risk of celiac disease (CD). Both diseases have a common genetic susceptibility locus in the human leukocyte antigen (HLA) class II alleles. Testing for tissue transglutaminase antibodies (anti-tTG) is highly accurate for a CD diagnosis. OBJECTIVE: To determine the frequency of HLA-DQB1*0201/02 and DQB1*0302 alleles and anti-tTG seropositivity in children with T1DM. METHOD: Forty-six children with T1DM (male:female=24:22; mean age 12±3.7 years) without significant digestive symptoms were enrolled. The mean duration of diabetes was 5±3.5 years. Serum anti-tTG IgA and IgG as well as HLA-DQ2 (DQB1*0201/02) and -DQ8 (DQB1*0302) alleles were analyzed. The allele frequencies were compared with those in controls, which included 124 normal Thai individuals, as reported in our previous study. RESULTS: All subjects were negative for anti-tTG IgG. Only one patient (2.2%) was positive for anti-tTG IgA (38.5 U/mL; cut-off 15 U/mL). Although this patient was also heterozygous for HLA-DQ2 and was asymptomatic for CD, he declined endoscopic confirmation. Twenty-nine of 46 patients carried HLA-DQ2 and/or -DQ8 heterodimers. HLA-DQB1*0201/02 and HLA-DQB1*0302 allele frequencies were significantly higher (27% and 14%) in T1DM patients compared with normal controls (13.3% and 7.3%; P<0.001 and P=0.002, respectively). CONCLUSIONS: A significantly greater frequency of DQB1*0201/02 and DQB1*0302 alleles were present in children with T1DM compared with the control group. This indicates a potentially important role of these alleles in the development of T1DM. The prevalence of CD screening by serologic testing is negligible in Thai children with T1DM.

Prognostic values of serum bilirubin at 7th day post-Kasai for survival with native livers in patients with biliary atresia.

BACKGROUND: Biliary atresia (BA) is a serious liver disease with uncertain prognosis. The objective of this study was to investigate prognostic values of the >20 % decrease in serum total bilirubin (TB) at 7th day post-op regarding early outcome and 5-year survival with native liver in BA. METHODS: Biliary atresia patients undergoing Kasai operation between 2000 and 2014 were reviewed. The ratio of serum TB at 7th day post-op to pre-op TB levels (TB7/TB0) was calculated for every patient. TB7/TB0 ratio of <0.8 indicated the >20 % decrease in serum TB. At 6th month following Kasai operation, outcome of BA patients were categorized into good outcome (TB < 2 mg % or clinically jaundice free) and poor outcome (TB > 2 mg % or clinically jaundice). For outcome analysis, logistic regression was used. For survival analysis, Cox regression was applied. RESULTS: There were 133 BA patients (M:F = 68:65) undergoing Kasai operation. Median age at surgery was 79 days. BA patients with TB7/TB0 ratio of <0.8 were found in 38 %. Outcome at 6-month post-op could be evaluated in 126 patients (good: poor = 68:58). The 1-, 3- and 5-year survival rates with native livers were 85, 70 and 65 %, respectively. The median overall survival with native livers was 164 months. Median follow-up time was 87 months. Logistic regression showed that gender and age at operation were not significant factors impacting on early outcome (p > 0.05). However, TB7/TB0 ratio of <0.8 was an independent factor for good outcome (Odds ratio = 3.0, p = 0.006). Cox regression analysis demonstrated that 5-year survival rate was significantly correlated with TB7/TB0 ratio of <0.8 (HR = 0.46, 95 % CI 0.23-0.91, p = 0.025) and outcome at 6th month post-op (HR = 0.05, 95 % CI 0.01-0.15, p < 0.001). CONCLUSIONS: The >20 % decrease in serum TB at 7th day post-Kasai is a predictor for good outcome. BA patients with TB7/TB0 of <0.8 had 5-year survival with native livers significantly higher than those with the ratio of >0.8.

Wilson's Disease in Thai Children between 2000 and 2012 at King Chulalongkorn Memorial Hospital.

OBJECTIVE: Wilson's disease (WD) is a rare autosomal recessive disorder characterized by copper accumulation. Clinical presentations are extraordinarily diverse, and currently no single diagnostic test can confirm WD with high accuracy. A complete understanding of the presentations and improved diagnostic methods are important for disease management. The authors' aimed to examine disease characteristics, management, and treatment outcome of WD in children, especially when genetic analysis and liver copper measurements were limited. MATERIAL AND METHOD: Data was collected from 21 WD children who were treated at King Chulalongkorn Memorial Hospital between 2000 and 2012. Inclusion criteria followed the WD scoring system, where other liver diseases are ruled out systematically. RESULTS: The mean age at diagnosis was 13.5 ± 3.36 years, with 19 symptomatic patients, and two asymptomatic individuals who were diagnosed through family screening. Presentations varied, jaundice (52%), ascites (52%), edema (52%), Coombs-negative hemolytic anemia (14%), neurological abnormalities (33%), renal involvement (19%), and fulminant hepatic failure (5%). Based on the key parameters in WD scoring system, 14 patients (66%) had Kayser-Fleischer (KF) rings. Seventeen (89%) had low serum ceruloplasmin, and 20 (95%) had increased urinary copper excretion. These positive findings made WD scoring system accurately diagnose 66% of patients. Chelation therapy was the first line of therapy for all patients except one, who underwent liver transplantation. After therapy, liver function test returned to normal in all patients. However, neurological symptoms did not improve with combined drug therapy using chelating and neuropsychiatric agents. CONCLUSION: WD in children mostly affected the liver WD was suspected in seven patients (34%), thus needed further investigation. Therefore, long-term follow-up in those with suspected WD is the appropriate method for diagnosis and management in limited diagnostic tests. We suggest further treatment, and use of clinical response to treatment, as a criterion for confirming the WD diagnosis.

Serum autotaxin levels correlate with hepatic dysfunction and severity in postoperative biliary atresia.

OBJECTIVE: To investigate correlation of serum autotaxin and disease severity in biliary atresia (BA). METHODS: Eighty postoperative BA patients and 15 controls were recruited. Serum autotaxin levels were determined by enzyme-linked immunosorbent assay. RESULTS: BA patients had greater serum autotaxin and liver stiffness than controls. Serum autotaxin and liver stiffness were markedly elevated in BA patients with jaundice compared to those without jaundice. Furthermore, serum autotaxin was correlated with liver stiffness and biochemical parameters in BA. CONCLUSIONS: Elevated serum autotaxin was correlated with hepatic dysfunction in BA. Accordingly, serum autotaxin is a promising biomarker reflecting the severity in BA.

Elevated serum periostin is associated with liver stiffness and clinical outcome in biliary atresia.

OBJECTIVE: To analyze serum periostin and liver stiffness in postoperative biliary atresia (BA). METHODS: A total of 60 BA patients and 14 controls were enrolled. Serum periostin levels were analyzed by ELISA. Liver stiffness measurement was determined by transient elastography. RESULTS: Biliary atresia patients had significantly higher periostin and liver stiffness values than controls. Serum periostin levels were remarkably increased in BA patients with jaundice compared to those without jaundice. Moreover, serum periostin was correlated with liver stiffness. CONCLUSIONS: Serum periostin was associated with liver stiffness in BA. Thus, serum periostin has potential as a parameter reflecting the severity in BA.

Cellular immune response to a single dose of live attenuated hepatitis a virus vaccine in obese children and adolescents.

Background: Limited data are currently available regarding the cellular immune response to a live attenuated hepatitis A virus (HAV) vaccine, especially in children with obesity. The objective of this retrospective cohort study was to compare the activation of antigen-specific interferon (IFN)-γ+ T cells in obese children and adolescents with healthy individuals before and after immunization with a single dose of live attenuated HAV vaccine. Methods: Blood samples were obtained from the 2021 study by Dumrisilp et al. investigating the immunogenicity of the live attenuated hepatitis A vaccine in children and young adults. Prior to enrollment, all 212 subjects had never received any HAV vaccine and tested negative for anti-HAV antibodies. The participants were vaccinated with a freeze-dried, live attenuated HAV vaccine of the H2 strain. In this study, we analyzed the stored peripheral blood mononuclear cells (PBMCs) obtained from a subgroup of 30 obese subjects and 30 normal-weight healthy controls of the same age and sex. PBMCs were collected before and 8-9 weeks after HAV vaccination for further analysis. These cells were stimulated with a recombinant antigen derived from HAV-VP3, and the immune response was evaluated using the IFN-γ enzyme-linked immunospot (ELISpot) assay. Results: The between-group analysis indicated that the T-cell response of obese participants was comparable to that of normal-weight controls both before and after vaccination. The change in IFN-γ production from before to after vaccination in the obese group was not significantly different from that of the control group. Additionally, in the obese group, no correlation was found between IFN-γ production and clinical characteristics such as sex, body mass index, waist circumference, and acanthosis nigricans. Conclusion: Testing for cellular immune response provides a comprehensive understanding of the overall immune response to vaccination. This study, the first to explore this significant aspect, suggests that obesity does not affect the short-term cellular immune response to live attenuated HAV vaccination.

Acute hepatic failure among hospitalized Thai children.

We conducted a hospital-based study from June 2002 to December 2006 of Thai children aged 1-15 years with acute hepatic failure (AHF) to determine the causes and outcomes. Eleven children were included in the study. Hepatitis B virus was the cause of AHF in one child, infection-associated hemophagocytic syndrome was the cause in 1 child, Wilson's disease was the cause in 1 child and dengue fever was suspected to be the cause in 2 children. In 6 children the cause of AHF was unknown. Jaundice was reported in 9 of 11 children. Ten of 11 children had mild to moderate encephalopathy on admission. Five of 11 children died due to AHF. No liver transplantations were performed among the children in this study. Further studies into the relationship between dengue infection and AHF are needed.

Immunogenicity of an mRNA-Based COVID-19 Vaccine among Adolescents with Obesity or Liver Transplants.

There are limited data regarding the immunogenicity of mRNA-based SARS-CoV-2 vaccine BNT162b2 among immunosuppressed or obese adolescents. We evaluated the humoral immune response in adolescents with obesity and adolescent liver transplant recipients (LTRs) after receiving two BNT162b2 doses. Sixty-eight participants (44 males; mean age 14.9 ± 1.7 years), comprising 12 LTRs, 24 obese, and 32 healthy adolescents, were enrolled. Immunogenicity was evaluated by anti-SARS-CoV-2 spike protein immunoassay and surrogate viral neutralization tests (sVNT) against the Delta and Omicron (BA.1) variants. At 27.1 ± 3.2 days after the second dose, the antibody levels were 1476.6 ± 1185.4, 2999.4 ± 1725.9, and 4960.5 ± 2644.1 IU/mL in the LTRs, obese adolescents, and controls, respectively (p < 0.001). Among obese individuals, liver stiffness <5.5 kPa was associated with higher antibody levels. The %inhibition of sVNT was significantly lower for the Omicron than that for the Delta variant. Injection site pain was the most common local adverse event. Nine participants (three obese and six controls) developed COVID-19 at 49 ± 11 days after the second vaccination; four were treated with favipiravir. All infections were mild, and the patients recovered without any consequences. Our study supports the need for the booster regimen in groups with an inferior immunogenic response, including LTRs and obese individuals.

Safety and Immunogenicity of Standard and Double Doses of Hepatitis B Vaccine in Children after Liver Transplantation: An Open-Label, Randomised Controlled Trial.

A high prevalence of hepatitis B (HepB) antibody loss after liver transplantation (LT) and de novo HepB infection (DNH) was documented, hence revaccination to prevent DNH is crucial. This study aimed to compare the safety and immunogenicity of two HepB vaccine regimens in liver-transplanted children. Liver-transplanted children who were previously immunised but showed HepB surface antibodies (anti-HBs) ≤ 100 mIU/mL were randomised to receive a standard three-dose (SD) and double three-dose (DD) vaccine intramuscularly in months 0-1-6. Anti-HBs and T-cell-specific response to the HepB antigen were assessed. A total of 61 children (54.1% male, aged 1.32 ± 1.02 years) completed the study without any serious adverse reaction. The seroprotective rate was 69.6% vs. 60% (p = 0.368) and 91.3% vs. 85% (p = 0.431) in SD and DD after the first and third 3-dose vaccinations, respectively. The geometric mean titre (95% confidence interval) of anti-HBs in SD and DD were 443.33 (200.75-979.07) vs. 446.17 (155.58-1279.50) mIU/mL, respectively, at completion. Numbers of interferon-γ-secreting cells were higher in hyporesponders/responders than in nonresponders (p = 0.003). The significant factors for the immunologic response to HepB vaccination were anti-HB levels prevaccination, tacrolimus trough levels, and time from LT to revaccination. SD and DD had comparative immunogenicity and were safe for liver-transplanted children who were previously immunised.