A germline STAT6 gain-of-function variant is associated with early-onset allergies.

BACKGROUND: The signal transducer and activator of transcription 6 (STAT6) signaling pathway plays a central role in allergic inflammation. To date, however, there have been no descriptions of STAT6 gain-of-function variants leading to allergies in humans. OBJECTIVE: We report a STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with 3 affected members. METHODS: Exome sequencing and immunophenotyping of T-helper cell subsets were conducted. The function of the STAT6 protein was analyzed by Western blot, immunofluorescence, electrophoretic mobility shift assays, and luciferase assays. Gastric organoids obtained from the index patient were used to study downstream effector cytokines. RESULTS: We identified a heterozygous missense variant (c.1129G>A;p.Glu377Lys) in the DNA binding domain of STAT6 that was de novo in the index patient's father and was inherited by 2 of his 3 children. Severe atopic dermatitis and food allergy were key presentations. Clinical heterogeneity was observed among the affected individuals. Higher levels of peripheral blood TH2 lymphocytes were detected. The mutant STAT6 displayed a strong preference for nuclear localization, increased DNA binding affinity, and spontaneous transcriptional activity. Moreover, gastric organoids showed constitutive activation of STAT6 downstream signaling molecules. CONCLUSIONS: A germline STAT6 gain-of-function variant results in spontaneous activation of the STAT6 signaling pathway and is associated with an early-onset and severe allergic phenotype in humans. These observations enhance our knowledge of the molecular mechanisms underlying allergic diseases and will potentially contribute to novel therapeutic interventions.

The Prevalence of Nonalcoholic Fatty Liver Disease and Its Risk Factors in Children and Young Adults with Type 1 Diabetes Mellitus.

OBJECTIVES: To determine the prevalence of nonalcoholic fatty liver disease (NAFLD) and its associated risk factors in children and young adults with type 1 diabetes (T1D). STUDY DESIGN: A cross-sectional study was conducted at a tertiary care center in children and young adults with T1D. Liver fat quantification and hepatic fibrosis were assessed by magnetic resonance imaging proton density fat fraction and magnetic resonance elastography (MRE). Logistic regression analysis was performed to examine the associated risk factors for NAFLD. RESULTS: Fifty patients with T1D (28 females, 13 with overweight/obesity) were included. The median age and duration of T1D were 16.9 years (IQR, 13.6-20 years) and 6.5 years (IQR, 4-11 years), respectively. The prevalence of NAFLD was 10%. Four out of 5 patients with NAFLD were overweight/obese, and 2 had an and elevated alanine aminotransferase (ALT) level. None had liver fibrosis (defined as MRE >2.9 kPa). Compared with patients without NAFLD, patients with NAFLD had significantly higher body mass index standard deviation score (BMI-SDS) (median, 0.94 [IQR, 1.30-2.62] vs 0.13 [IQR, -0.69 to 0.84]; P = .01), ALT (median, 17 IU/L [IQR, 16-52 IU/L] vs 12 IU/L [IQR, 10-14 IU/L]; P = .02), and lower high-density lipoprotein cholesterol (median, 49 mg/dL [IQR, 41-51 mg/dL] vs 57 mg/dL [IQR, 52-69 mg/dL]; P = .039). Multivariate logistic regression analysis identified high BMI-SDS as the sole independent risk factor associated with NAFLD (OR, 5.79; 95% CI, 1.04-32.18). CONCLUSION: The prevalence of NAFLD in children and young adults with T1D was comparable to that in the general population. Our study suggests that routine screening for NAFLD in patients with T1D might not be necessary but should be performed in those patients with T1D who are overweight/obese.

Dermatologic manifestations in pediatric patients after liver and HSCT: A 20-year retrospective cohort study.

LT and HSCT are now potentially curative treatments for many medical conditions. Dermatologic manifestations are one of the sequelae after transplantation. To study the prevalence and associated risk factors of dermatologic manifestations after pediatric LT and HSCT. A 20-year retrospective cohort study was conducted in children, aged ≤15 years, who received LT or HSCT from January 1, 1997, to December 31, 2017. Medical records were reviewed for data collection until December 31, 2018. A total of 70 LT and 51 HSCT recipients were included. The percentages of overall dermatologic manifestations after LT and HSCT were 64.3% and 64.7%, respectively. Viral infection was the most common manifestation in both groups, with mucocutaneous HSV infection as the most prevalent. One HSCT recipient developed leukemia cutis. GVHD was revealed in 27.5% of HSCT recipients. Impetigo and xerosis were significantly observed in patients using azathioprine and prednisolone. Approximately two-thirds of pediatric LT and HSCT recipients experienced dermatologic manifestations, potentially associated with immunosuppressive agents. Thus, regular skin examination and optimized immunosuppression would be beneficial in these recipients.

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.

Alginate microencapsulated human hepatocytes for the treatment of acute liver failure in children.

BACKGROUND & AIMS: Liver transplantation (LT) is the most effective treatment for patients with acute liver failure (ALF), but is limited by surgical risks and the need for life-long immunosuppression. Transplantation of microencapsulated human hepatocytes in alginate is an attractive option over whole liver replacement. The safety and efficacy of hepatocyte microbead transplantation have been shown in animal models. We report our experience of this therapy in children with ALF treated on a named-patient basis. METHODS: Clinical grade human hepatocyte microbeads (HMBs) and empty microbeads were tested in immunocompetent healthy rats. Subsequently, 8 children with ALF, who were awaiting a suitable allograft for LT, received intraperitoneal transplantation of HMBs. We monitored complications of the procedure, assessing the host immune response and residual function of the retrieved HMBs, either after spontaneous native liver regeneration or at the time of LT. RESULTS: Intraperitoneal transplantation of HMBs in healthy rats was safe and preserved synthetic and detoxification functions, without the need for immunosuppression. Subsequently, 8 children with ALF received HMBs (4 neonatal haemochromatosis, 2 viral infections and 2 children with unknown cause at time of infusion) at a median age of 14.5 days, range 1 day to 6 years. The procedure was well tolerated without complications. Of the 8 children, 4 avoided LT while 3 were successfully bridged to LT following the intervention. HMBs retrieved after infusions (at the time of LT) were structurally intact, free of host cell adherence and contained viable hepatocytes with preserved functions. CONCLUSION: The results demonstrate the feasibility and safety of an HMB infusion in children with ALF. LAY SUMMARY: Acute liver failure in children is a rare but devastating condition. Liver transplantation is the most effective treatment, but it has several important limitations. Liver cell (hepatocyte) transplantation is an attractive option, as many patients only require short-term liver support while their own liver recovers. Human hepatocytes encapsulated in alginate beads can perform the functions of the liver while alginate coating protects the cells from immune attack. Herein, we demonstrated that transplantation of these beads was safe and feasible in children with acute liver failure.

Pediatric liver transplantation outcomes from a single center in Thailand.

BACKGROUND: Liver transplantation (LT) has become an acceptable curative method for children with several liver diseases, especially irreversible acute liver failure and chronic liver diseases. King Chulalongkorn Memorial Hospital is one of Thailand's largest liver transplant centers and is responsible for many pediatric cases. AIM: To report the experience with pediatric LT and evaluate outcomes of living-related vs deceased-donor grafts. METHODS: This evaluation included children who underwent LT between August 2004 and November 2019. Data were retrospectively reviewed, including demographics, diagnoses, laboratory values of donors and recipients, the pediatric end-stage liver disease (PELD) or model for end-stage liver disease (MELD) score, graft source, wait time, perioperative course, postoperative complications, and survival rates. Continuous data were reported using the median and interquartile range. The Mann-Whitney U-test was used to compare the wait time between the living-related and deceased-donor groups. The chi-square or Fisher's exact test were used to compare the frequencies of between-group complications. Survival rates were calculated using the Kaplan-Meier method. RESULTS: Ninety-four operated pediatric liver transplant patients were identified (54% were females). The median age at transplantation was 1.2 (0.8-3.8) years. The median PELD and MELD scores were 20 (13-26.8) and 19.5 (15.8-26.3), respectively. Most grafts (81.9%) were obtained from living-related donors. The median wait time for the living donors was significantly shorter compared with the deceased donors at 1.6 (0.3-3.1) mo vs 11.2 (2.1-33.3) mo (P = 0.01). Most patients were diagnosed with biliary atresia (74.5%), and infection was the most common complication within 30 d post-transplantation (14.9%). Without a desensitization protocol, 9% of transplants were ABO-incompatible. Eight hepatitis B core antibodies (anti-HBc)-negative recipients received positive anti-HBc grafts without different observed complications. The overall survival rate was 93.6% and 90.3% at 1 and 5 years, respectively. No graft loss during follow-up was noted among survivors. CONCLUSION: A significant number of pediatric LT cases were reported in Thailand. Based on relatively comparable outcomes, ABO-incompatible and HBc antibody-positive grafts may be considered in an organ shortage situation.

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.

Impact of Obesity and Being Overweight on the Immunogenicity to Live Attenuated Hepatitis A Vaccine in Children and Young Adults.

Prior results investigating a correlation between obesity and hepatitis A virus (HAV) vaccine response have been inconclusive, with limited data involving live attenuated HAV vaccines. The aim of this study is to evaluate the effect of overweight and obesity on the response to live attenuated HAV vaccine in children and young adults. This prospective cohort study was conducted in Thailand with subjects ranging in age from seven to twenty-five years. The subjects were administered 0.5 mL of MEVAC™-A and tested for anti-HAV antibodies before and at 8-9 weeks after vaccination. Baseline seronegative subjects (anti-HAV antibodies < 20 mIU/mL) were divided into non-obese (underweight/normal weight) and obese (overweight/obesity/severe obesity) groups. A total of 212 (117 non-obese and 95 obese) subjects completed the study (mean age (SD) = 13.95 (3.90) years). The seroprotection rates were 100%. Postvaccination geometric mean titers (95% CI) were 429.51 (401.97, 458.94) and 467.45 (424.47, 514.79) mIU/mL in the non-obese and obese groups, respectively. Females (p = 0.013) and subjects with truncal obesity (p = 0.002) had significantly higher titers than other participants. Live attenuated HAV vaccine is safe and has comparably high immunogenicity in both underweight/normal weight and overweight/obese persons.

Detection of reflux-symptom association in children with esophageal atresia by video-pH-impedance study.

BACKGROUND: Children with esophageal atresia (EA) have risk of gastroesophageal reflux disease (GERD), suggesting reflux monitoring for prompt management. AIM: To evaluate GERD in children with EA and specific symptom association from combined Video with Multichannel Intraluminal Impedance and pH (MII-pH) study. METHODS: Children diagnosed with EA with suspected GERD and followed up at King Chulalongkorn Memorial Hospital between January 2000 and December 2018 were prospectively studied. All underwent esophagogastroduodenoscopy with esophageal biopsy and Video MII-pH study on the same day. Symptoms of GERD which included both esophageal and extra-esophageal symptom were recorded from video monitoring and abnormal reflux from MII-pH study based on the statement from the European Paediatric Impedance Group. Prevalence of GERD was also reported by using histopathology as a gold standard. Endoscopic appearance was recorded using Los Angeles Classification and esophagitis severity was graded using Esohisto criteria. RESULTS: Fifteen children were recruited with age of 3.1 (2.2, 9.8) years (40%, male) and the common type was C (93.3%). The symptoms recorded were cough (75.2%), vomiting (15.2%), irritability or unexplained crying (7.6%) and dysphagia (1.9%) with the symptom-reflux association of 45.7%, 89%, 71% and 0%, respectively. There were abnormal endoscopic appearance in 52.9%, esophagitis in 64.7% and high reflux score in 47.1%. Video MII-pH study has high diagnostic value with the sensitivity, specificity and accuracy of 72.7%, 100% and 82.4%, respectively. CONCLUSION: Prevalence of GERD in children with EA was high. Video MII-pH study to detect GERD in children with EA had high diagnostic value with the trend of specific symptom association.

Recommendations for the adjuvant use of the poly-antibiotic-resistant probiotic Bacillus clausii (O/C, SIN, N/R, T) in acute, chronic, and antibiotic-associated diarrhea in children: consensus from Asian experts.

This paper proposes recommendations for probiotics in pediatric gastrointestinal diseases in the Asia-Pacific region. Evidence-based recommendations and randomized controlled trials in the region are included. Cultural aspects, health management issues and economic factors were also considered. Final recommendations were approved by utilizing a modified Delphi process and applying the Likert scale in an electronic voting process. Bacillus clausii was recommended as an adjunct treatment with oral rehydration solution for acute viral diarrhea. B. clausii may also be considered for prevention of antibiotic-associated diarrhea, Clostridium difficile-induced diarrhea, and as adjunct treatment of Helicobacter pylori. There is insufficient evidence for recommendations in other conditions. Despite a diversity of epidemiological, socioeconomical and health system conditions, similar recommendations currently apply to most Asia-Pacific countries. Ideally, these need to be validated with local randomized-controlled trials.

Nonalcoholic fatty liver disease and hepatic fibrosis among perinatally HIV-monoinfected Asian adolescents receiving antiretroviral therapy.

To assess and compare the prevalence of persistent hepatic abnormalities, including nonalcoholic fatty liver disease (NAFLD) and/or hepatic fibrosis, among perinatally HIV-monoinfected Asian adolescents with history of abnormal hepatic enzymes to those without, using noninvasive diagnostic tools. A multicenter cohort study was conducted in Thailand and Indonesia. Adolescents aged 10-25 years who were on antiretroviral treatment (ART), had virologic suppression (HIV RNA<400 copies/mL within the past 6 months), and had no history of chronic hepatitis B/C infection were enrolled. Participants were pre-classified into 2 subgroups (1:1 ratio) as participants with history of elevated versus normal aminotransferase enzymes. NAFLD was defined as hepatic steatosis (any severity) evaluated by liver ultrasonography. Significant hepatic fibrosis was defined as liver stiffness ≥7.4 kPa evaluated by transient elastography. Participants who met the criteria for protocol-defined NAFLD and/or hepatic fibrosis were re-assessed to evaluate disease progression (persistent versus transient hepatic abnormalities) at one year later. Of 120 participants, 62 (51.7%) were male, 7 (5.8%) had central obesity, and 19 (15.8%) had insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] >3.16). At enrollment, the median age and duration of ART (IQR) were 17.0 (14.6-19.2) years and 10.5 (7.1-12.0) years, respectively. Persistent hepatic abnormalities were identified in 5/60 participants listed in the group having history of elevated aminotransferases, corresponding to the prevalence of 8.3% (95% CI: 2.8-18.4%), whereas none (0/60) were among the group having history of normal hepatic enzymes. All 5 participants had persistent aminotransferase elevation (≥2 episodes within the past 12 months). Baseline alanine aminotransferase (ALT) >30 U/L (adjusted odds ratio [aOR]: 29.1; 95% CI: 1.7-511.8), and HOMA-IR >3.16 (aOR: 17.9; 95% CI: 1.1-289.7) were independently associated with persistent hepatic abnormalities. Among perinatally HIV-monoinfected Asian adolescents with history of elevated aminotransferase enzymes, persistent hepatic abnormalities are not uncommon. Screening for liver complications by noninvasive diagnostic tools might be considered in at risk individuals, including those with persistent ALT elevation and insulin resistance.