Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency-related cholestasis.

BACKGROUND AND AIMS: The study aimed to describe the clinical course and outcomes, and analyze the genotype-phenotype correlation in patients with tight junction protein 2 (TJP2) deficiency. APPROACH AND RESULTS: Data from all children with chronic cholestasis and either homozygous or compound heterozygous mutations in TJP2 were extracted and analyzed. The patients were categorized into 3 genotypes: TJP2-A (missense mutations on both alleles), TJP2-B (missense mutation on one allele and a predicted protein-truncating mutation [PPTM] on the other), and TJP2-C (PPTMs on both alleles). A total of 278 cases of genetic intrahepatic cholestasis were studied, with TJP2 deficiency accounting for 44 cases (15.8%). Of these, 29 were homozygous and 15 were compound heterozygous variants of TJP2 . TJP2-A genotype was identified in 21 (47.7%), TJP2-B in 7 cases (15.9%), and TJP2-C in 16 cases (36.4%), respectively. Patients with the TJP2-C genotype were more likely to experience early infantile cholestasis (87.5% vs. 53.5%, p =0.033), less likely to clear jaundice (12.5% vs. 52.2%, p =0.037), more likely to develop ascites, and had higher serum bile acids. Patients with the TJP2-C genotype were more likely to die or require liver transplantation (native liver survival: 12.5% vs. 78.6%, p <0.001), with a median age at death/liver transplantation of 2.5 years. Cox regression analysis revealed that TJP2-C mutations ( p =0.003) and failure to resolve jaundice ( p =0.049) were independent predictors of poor outcomes. CONCLUSIONS: Patients with the TJP2-C genotype carrying PPTMs in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.

Diagnosis and Management of Infections in Patients with Mendelian Susceptibility to Mycobacterial Disease.

The diagnosis and treatment of patients with mendelian susceptibility to mycobacterial disease (MSMD) pose consistent challenges due to the diverse infection spectrum observed in this population. Common clinical manifestations include Bacillus Calmette-Guérin vaccine (BCG) complications in countries where routine BCG vaccination is practiced, while in non-BCG-vaccinating countries, Non-Tuberculous Mycobacteria (NTM) is prevalent. In tuberculosis-endemic regions, Mycobacterium tuberculosis (MTB) has a high prevalence, along with other intracellular organisms. Isolating these organisms presents a significant challenge, and treatment is often initiated without confirming the specific species. This review primarily focuses on the methods and challenges associated with diagnosing and treating MSMD patients.

Intractable diarrhea in an infant-autoimmune enteropathy: A case report.

Autoimmune enteropathy is a rare cause of chronic intractable diarrhea and is present in <1 in 100,000 infants. We report the case of a 9-month-old boy who presented with intractable diarrhea and vomiting. Genetic panel testing revealed a STAT3 heterozygous mutation in exon 6, suggesting infantile-onset multisystem autoimmune disease-1. The patient was initially treated with steroids and sulfasalazine. However, on tapering steroids, he had another episode of diarrhea and was subsequently put on baricitinib to which he responded.

Difficult to treat liver abscesses in children - Do not forget parasitic infections.

Liver abscess (LA) is a significant health concern worldwide, particularly in tropical regions such as India, and is usually pyogenic or amoebic in origin. In rare cases it can be caused by parasites. We present two children with difficult-to-treat LAs, revealing underlying parasitic infections as the causative agents, implicated by eosinophilia, elevated immunoglobulin-E levels and exposure to domestic animals. In the first case, disseminated echinococcosis was diagnosed through imaging, serology and histopathology. The second case showed a relationship between LAs and Toxocara infection, evidenced by microscopic stool examination of a household cat.

Effect of delamanid on interim outcomes of bacteriological conversion amongst pediatric drug resistant tuberculosis cases in India.

AIM: To determine the bacteriological conversion rate after 6 months of Delamanid (DLM) based treatment in children with drug-resistant tuberculosis (DR-TB) and determine factors associated with bacteriological conversion. METHODS: This is a descriptive retrospective study done in children between the age of 6-17 years with DR-TB who received DLM-based therapy from October 2018 to May 2021. The drug resistance pattern of TB was detected using Xpert RIF/MTB and phenotypic drug sensitivity testing (DST) on TB-MGIT culture reports. Follow-up sputum TB MGIT culture was carried out monthly after DLM initiation for 6 months. Factors associated with sputum bacteriological conversion such as age, gender, pulmonary TB (PTB) versus disseminated TB, unilateral or bilateral lung involvement, type of DR-TB, prior treatment failure, and type of DR-TB regimen were analyzed. RESULTS: Sixty patients received DLM of which two had extrapulmonary TB (EPTB) and sputum conversion could not be assessed. The mean age at presentation was 12.69 ± 3.03 years. Five patients (8.3%) died while on DLM treatment. On follow-up, 8 (13.7%) out of 58 patients had no sputum bacteriological conversion after 6 months of DLM initiation of which three patients were on salvage therapy; 46 (79.3%) had sputum bacteriological conversion within 6 months of DLM initiation. CONCLUSION: Sputum bacteriological conversion rate was almost 80% at the end of 6 months of DLM-based treatment.

Retching Without Vomiting With Acute Abdominal Distension: A Clinical Cue.

Gastric volvulus leading to acute gastric dilatation is a rare presentation of congenital diaphragmatic hernia. Urgent detorsion with gastropexy and closure of the diaphragmatic defect are essential to prevent further complications and recurrence. We present a rare case of an infant with acute gastric dilatation due to acute gastric volvulus secondary to congenital diaphragmatic hernia.

Latent TB in Indian pediatric population: An update on evidence gaps and research needs.

The main aim of this article is to review various studies conducted in relation to diagnosis, treatment and management of Latent TB Infection (LTBI) in under-five children, thus highlighting research gaps and further scope of improvements with respect to Indian context. The methodology involved literature review of various online review articles and research papers along with current published guidelines for LTBI management by World Health Organization (WHO) and National tuberculosis Elimination Program (NTEP). There is a dearth of statistically significant data regarding prevalence of LTBI among under-five children in India. LTBI prevalence in Indian adults has been reported between 21 and 48%. The exact prevalence of pediatric LTBI in India is still not clear, however, as per few studies, the LTBI prevalence ranges around 40% and 22% in adolescent followed by under-5 population. Studies to fill in the research gap of scarcity of prevalence data, regarding pediatric LTBI in high TB burden areas of India, is a pivotal step to curb the global pandemic of TB disease. There is a massive undervaluation of the true burden of childhood LTBI as the influence of environmental reservoir in childhood LTBI and TB are not accounted for in pediatric LTBI regimens. Also, there is no substantiate amount of data that highlights the other aspects of LTBI in pediatric population, like awareness regarding LTBI condition and other physiological adverse effects of LTBI in pediatric population, which have been often observed in under-five children suffering from LTBI.

Plummer-Vinson Syndrome and Role of Endoscopic Balloon Dilatation in a 4-Year-Old Child.

Plummer-Vinson syndrome (PVS), also called Patterson-Kelly-Brown syndrome, is a rare cause of dysphagia in children. This syndrome is associated with single or multiple webs in the upper esophagus with frequent iron deficiency. PVS usually occurs in adults, particularly in Caucasian middle-aged women, in the fourth to seventh decade of life, and is rare in childhood. There are various theories about what causes PVS. One theory suggests that iron deficiency plays a crucial role in its development. Iron repletion often improves dysphagia, although some patients require esophageal dilatation or bougienage. Herein, we describe the case of a 4-year-old male child, having complaints of difficulty in swallowing solid food, diagnosed with PVS.

Endoscopic Removal of a Recurrent Trichobezoar in an Adolescent: A Case Report.

Trichobezoar, a rare condition of intragastric hair accumulation is commonly associated with an underlying psychological condition. Removal of the bezoar either endoscopically or surgically (laparoscopy or laparotomy) with concurrent psychiatric assessment and treatment is the mode of treatment. We present a 10-year-old child with recurrent trichobezoar, who was managed surgically the first time, and subsequently endoscopic removal was done on recurrence of bezoar after 3 months. We also present the difficulties encountered during endoscopic bezoar removal.

Hereditary Ichthyosis With Gastrointestinal Manifestations: A Case Report.

Gut inflammation and defect in the gut mucosal barrier appear to have a correlation with skin diseases and vice versa. The coexistence of hereditary ichthyosis with active colitis has never been reported. We present a 17-year-old female with ichthyosis since birth, abdomen pain for 3 months, with acute colitis. After the initial diagnosis, the patient was started on antituberculous therapy (ATT), steroids, and mesalamine. She followed up with us for 1 year where there was resolution of symptoms. Steroids were stopped after 16 weeks, mesalamine was stopped after 20 weeks in view of low absolute neutrophil counts and ATT was stopped after 1 year. She was asymptomatic post 18 months of stopping ATT.

A novel gut microbiome-immune axis influencing pathology in HCMV infected infants with neonatal cholestasis.

The interplay of active HCMV infection with gut dysbiosis in the immunopathology of cholestasis in neonates and infants remains unexplored. In this study, we evaluated gut microbiome profiles and immune dysfunction in a cohort of HCMV infected cholestatic infants (IgM positive, N = 21; IgM negative, N = 25) compared to healthy infants, N = 10. HCMV infected IgM positive individuals exhibited increased clinical severity in terms of liver dysfunction, altered CD4+: CD8+ ratio, and elevated Granzyme B levels in cellular immune subsets. Gut microbiome analysis revealed distinct and differential diversity and composition within infected groups aligned with clinical severity reflected through the increased abundance of Gammaproteobacteria, reduced Bifidobacteria, and a unique signature mapping to the HCMV infected IgM negative group. Correlation analyses revealed associations between Bifidobacterium breve, Gammaproteobacteria, Firmicutes, Clostridia, Finegoldia magna, Veillonella dispar, and Granzyme B expressing immune cell subsets. Our study describes a novel gut microbiome-immune axis that may influence disease severity in cholestatic infants with active HCMV infection.

Vitamin D receptor genetic polymorphisms in severe and recurrent tuberculosis in children.

AIM: To analyze the genetic polymorphisms of vitamin D receptor FokI, TaqI, ApaI and BsmI gene polymorphisms in children with severe and recurrent tuberculosis (TB). METHODS: A prospective, observational study was conducted in 35 children with severe and recurrent TB referred to our Pediatric TB clinic at a tertiary referral center for children. The blood samples were analysed for genetic polymorphisms of Vitamin D receptor with respect to FokI, TaqI, ApaI and BsmI genotypes and their individual alleles and association of various clinical and laboratory parameters were analysed. RESULT: Ten (28.6%) children had recurrent TB and 26 (74.3%) had severe TB. The severity of TB was not associated with Ff and ff polymorphism of FokI (Odd's ratio 7.88) as compared to no FokI polymorphism. Absence of FokI polymorphism was associated with recurrent lymph node TB (Odds ratio 3.429). Presence of Tt polymorphism of TaqI (p = 0.04) and Fok1 Polymorphism [Odds ratio 7.88] were not associated with recurrent TB. CONCLUSION: Recurrent TB was absent in presence of Tt polymorphism of TaqI. Severe TB was not associated polymorphism of Vitamin D receptor polymorphisms.

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24 h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6) h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3) h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7) h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0) h·mg·L-1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.

Feasibility of a "Salvage Regimen" Using Home-based Intravenous Meropenem Therapy With a Delamanid/Bedaquilline Containing Regimen in the Management of MDR/XDR Pediatric Tuberculosis.

INTRODUCTION: The prevalence of multidrug resistant (MDR) tuberculosis (TB) with additional resistance to fluoroquinolones or second-line injectables (MDRFQ/SLI)/extensively drug-resistant TB (XDR-TB) in children is high in Mumbai. There are limited therapeutic options available in management of such children. Carbapenems, although approved for this indication, requires 2 to 3 daily injections, which are cumbersome. Bedaquilline (Bdq) and Delamanid (Dlm), the new antitubercular drugs still remain inaccessible to this subset of patients caused by conditional approvals. Hence, newer strategies to combat MDRFQ/SLI/XDR-TB needs to be explored. OBJECTIVES: To study feasibility and interim outcomes of a "salvage regimen" using home-based carbapenem therapy through peripherally inserted central catheter as part of a longer (18-20 months) optimized background regimen including Dlm or Bdq or both in pediatric MDRFQ/SLI/XDR-TB patients who failed a standard MDR-TB regimen under the National Tuberculosis Elimination Programme in Mumbai, India. DESIGN AND METHODS: Retrospective descriptive analysis study. National Tuberculosis Elimination Programme medical records of all MDRFQ/SLI/XDR-TB patients enrolled at the pediatric TB clinic at BJ Wadia Hospital for Children, Mumbai who were initiated on such "salvage regimen" during the period between April 2018 and December 2020 were retrospectively studied. Treatment outcomes and adverse events were described. RESULTS: Of the 15 patients enrolled, mean age of the patient population was 12.53 ± 2.47 years and the female:male ratio was 13:2. Seven patients had XDR-TB while 8 patients had MDRFQ/SLI. Most common adverse event noted was dyselectrolytemia (3 patients). Catheter-related complications were reported in 5 patients and included catheter blockage, leak, and thrombosis. Sputum culture conversion was reported in all of the patients. One child mortality was reported and 2 patients were lost to follow up during study period. CONCLUSIONS: Home-based meropenem therapy using peripherally inserted central catheter is feasible with few adverse effects. This can be a promising strategy in the management of MDRFQ/SLI/XDR-TB when an effective oral regimen cannot be otherwise constituted and needs to be explored further.

Accuracy of Xpert® MTB/RIF in diagnosing extrapulmonary tuberculosis in Indian children.

Background Diagnosing extrapulmonary tuberculosis (EPTB) can be challenging because of a variety of presentations. We assessed the accuracy of the Xpert MTB/RIF assay in diagnosing EPTB in children. Methods Of the 255 children diagnosed to have tuberculosis (TB) who underwent testing by the Xpert MTB/ RIF assay at the TB clinic from December 2014 to April 2017, 182 had EPTB and were included in the study. The diagnostic accuracy, specificity and sensitivity of the Xpert assay were calculated with Mycobacterium growth indicator tube (MGIT) as a reference standard. Results Lymph node TB was present in 58 (32%) children, 37 (20%) had neurological TB, 36 (20%) had bone TB, 31 (17%) had pleural TB, 15 (8%) had abdominal TB, 2 (1%) had abscess, 2 (1%) had congenital TB and disseminated TB was seen in 1 (0.4%) child. Xpert MTB/RIF assay was positive in 84 (46.2%) patients. The sensitivity and specificity of the Xpert MTB/RIF assay were 72% and 72.04%, respectively. Compared to MGIT, a kappa coefficient of 0.44 shows moderate agreement between the Xpert assay and MGIT. The sensitivity of Xpert MTB/RIF assay in abdominal TB, bone TB, lymph node TB, neurological TB and pleural TB was 50% (15%-85%), 72.7% (15.9%- 86.9%), 80.8% (62.1%-91.5%), 75% (50.5%-90%) and 25% (4.6%-70%), respectively. The specificity of abdominal TB, bone TB, lymph node TB, neurological TB and pleural TB was 83.3% (43.7%-97%), 69.2% (42.4%- 87.3%), 55.2% (37.6%-71.6%), 85% (64%-94.8%) and 82.6% (62.9%-93%), respectively. Forty-seven (26%) patients had drug-resistant TB (DR-TB), of which 15 (8%) were rifampicin-resistant (RR), 2 (1%) were polyresistant, 14 (8%) had multi-DR (MDR), 15 (8%) had pre-extremely DR (XDR) and 1 (1%) had XDR-TB. Of the 15 patients with MDR-TB, Xpert MTB/RIF assay detected only 10 (71%) as RR (p=0.06). Of the 15 pre-XDR cases, Xpert MTB/RIF detected only 8 (53%) as RR (p=0.02). Conclusion Xpert MTB/RIF assay is useful in the diagnosis of EPTB. It shows good concordance with MGIT. However, it may be negative in patients with DR-TB.

Outcome of drug resistant tuberculosis in Indian children.

We aimed to determine the outcome of bacteriologically confirmed drug-resistant (DR) tuberculosis (TB) in 174 children. We found that DR-TB infected children have nonetheless a high treatment completion rate with a low incidence of fatality and treatment failure. Reversible adverse drug reactions are common during therapy.

Discordance between TST and QFT-TBGold Plus for Latent Tuberculosis Screening among Under-Five Children: An Interim Analysis.

AIM: To analyze the agreement between tuberculin skin test (TST) and fourth-generation QuantiFERON (QFT)-TB Gold Plus [interferon gamma (INF-γ) release assays (IGRA)] for latent tuberculosis infection (LTBI) diagnosis among under-five children who are undernourished and/or who have history of contact with active tuberculosis (TB) patients. METHODS: Children from the age group of 6 months to 5 years (undernourished or tuberculosis household contacts) were screened through anganwadis (government playschools) and TB Health posts from Mumbai, India during September 2019 to January 2021. Both TST and QFT-TB Gold Plus test were carried out to diagnose LTBI. RESULTS: Out of the total 299, 35 (11.7%) (95% CI 8.1-15.3%) children tested positive by IGRA (QFT-TB Gold Plus) and 68 (22.7%) (95% CI 18.0-27.4%) by TST, suggestive of moderate concordance (κ = 0.483) between both tests. IGRA and TST showed moderate concordance in children <24 months (κ = 0.478). Moreover, 26 (21.1%) children with TB contact had both TST and IGRA positive with moderate concordance (κ = 0.550). A fair concordance (κ = 0.396) was observed between IGRA and TST in undernourished children. Also, 45 (15.0%) children showed discordance of which 39 (13.0%) had positive TST but negative IGRA and 6 (2.0%) had negative TST but positive IGRA. CONCLUSIONS: The study strongly recommends both TST and QFT-TB Gold Plus test for the diagnosis of LTBI in under-five children. A moderate concordance in children <24 months endorses the reliability of QFT-TB Gold Plus in diagnosing LTBI in this age group. This study highlights the need for screening undernourished children for LTBI to consider repeating IGRA testing for TST positives as per the window period and risk of ongoing exposure.

The current study focuses on discordance and concordance between tuberculin skin test (TST) and fourth-generation QuantiFERON (QFT)-TB Gold Plus [interferon gamma (INF-γ) release assays (IGRA)] for latent tuberculosis infection (LTBI) diagnosis among at-risk under-five children who are underweight and/or who have history of contact with active tuberculosis patients. The IGRA prevalence came out to be 11.7% (95% CI 8.1­15.3%) whereas the TST prevalence turned out to be 22.7% (95% CI 18.0­27.4%). A stronger concordance was observed between IGRA and TST among the age group of 2 to 5 years, and a relatively fair one for children below the age of 1 year. The present study strongly recommends to include both TST and IGRA test for the diagnosis of LTBI with respect to Indian pediatric population. This study also suggests the importance of repetition of IGRA for TST positive patients. Another vital opinion that is showcased in the present study is the inclusion of undernourished pediatric population residing in at-risk areas like urban slums for routine LTBI screening programs.