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.

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.

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.

Clinical Profile of Children with Mediastinal Tuberculosis.

AIM: To study clinical profile of children with mediastinal tuberculosis (TB). METHODS: This retrospective study was undertaken between January 2015 and March 2018 in children diagnosed with mediastinal TB. Clinical history, examination and radioimaging, such as chest X-ray and HRCT chest, were done in every patient at the start of therapy. The prevalence of mediastinal TB was calculated. Factors associated with mediastinal TB and associated pulmonary TB (PTB) were analysed. RESULTS: Out of total 1407 patients with TB, 58 (4.12%) had mediastinal involvement. Fever was seen in 49 (84.5%) patients, positive Mantoux test (MT) in 32 (68.1%), cough in 28 (48.3%), loss of appetite in 24 (41.4%) and weight loss in 17 (29.3%). Associated PTB was present in 22 (37.9%) patients. Associated extrapulmonary TB (EPTB) was observed in 12 (20.7%) patients. Fifty-one patients (87.9%) had an abnormal X-ray. Baseline HRCT chest was done in 54 (93.1%) patients and all of them showed necrotic caseous mediastinal nodes. Treatment duration of patients who completed treatment with first-line anti-tuberculous therapy was 11.67 months. Seventeen patients (29.3%) were diagnosed to have drug-resistant TB (DR-TB). Cough was seen more commonly in patients with associated PTB (68.2%) as compared to isolated mediastinal TB (36.1%) (p = 0.0296). CONCLUSION: Mediastinal TB is common in children with EPTB. Associated PTB is seen in only about one-third of the patients. X-ray chest is abnormal in half the patients; hence, HRCT chest may be required to make a diagnosis. Bacteriological confirmation is necessary due to high incidence of DR-TB in these patients. Most of the patients require treatment for a longer duration as resolution takes a longer time. Computed tomography imaging on follow-up helps to determine the treatment duration.

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.

Incomplete Kawasaki Disease in an Infant with Cholangitis Post Kasai Surgery for Biliary Atresia.

Kawasaki's disease (KD) is a systemic vasculitis often seen with viral and bacterial infections. Cholangitis is a known complication in biliary atresia patients post Kasai Portoenterostomy (KP). However KD, in a biliary atresia patient post KP has not been previously reported. A 1 years old girl who had previously undergone a KP for BA, presented with cholangitis which was presumed to be caused by a previous enterobacter infection that she had 2 months ago. However, on treating the cholangitis, the patient developed fever again after ten days which persisted even after changing the antibiotics. By this time she also displayed three of five characteristic features of KD in form of fever, strawberry tongue and cervical adenopathy. Investigations showed high ESR, high CRP, thrombocythemia and dilated coronary vessels on echocardiography. Treatment with intravenous immunoglobulin (IVIG) and steroids caused the symptoms to subside.

Correlation of APRI Index with Metavir Index in Children with Neonatal Cholestasis Without Biliary Atresia.

INTRODUCTION AND AIM: Neonatal cholestasis constitutes for 19 to 33% of all chronic liver disease in India. Cholestasis leads to fibrosis of liver and ultimately cirrhosis. There are various methods of diagnosis of fibrosis of liver like fibroscan, APRI index, FIB-4, fibro index, forns index, heap score, magnetic elastography. Here we are comparing APRI index with METAVIR index in patients with neonatal cholestasis without biliary atresia and determining whether APRI index can be used as a tool to determine fibrosis in these patients. MATERIAL AND METHODS: Patients with neonatal cholestasis without biliary atresia were included in the study. This retrospective analysis was done between 2009 and 2015. All patients underwent a liver biopsy and METAVIR index was calculated. APRI at the time of liver biopsy was determined. RESULTS: Forty-eight patients were included in this study with mean age of 3.5 ± 2.8 months with a male: female ratio of 35:13. Metavir Index F0 was seen in was 32 (66.67%) patients, F1 in 6(12.5%), F2 in 4(8.33%), F3 in 0 and F4 in 6(12.5%) patients respectively. Mean APRI for F0-F3 was 1.38 and for F4 was 3.74 respectively. With an APRI of 1.38, the sensitivity and specificity to detect fibrosis/cirrhosis was 100% and 21.43% respectively. CONCLUSION: APRI is not an effective tool to measure fibrosis or cirrhosis in patients with non-BA neonatal cholestasis in Indian children.

Profile of Tuberculous Cervical Lymphadenopathy in Children.

Aim: Analyze clinical profile of tuberculous cervical lymphadenopathy in children. Methods and Results: Of 1582 children with tuberculosis (TB), 63 (4%) had tuberculous cervical lymphadenopathy. The mean age at presentation was 7.4 ± 3.8 years (range of 1-14 years). Twenty-nine (46%) patients had bilateral lymphadenopathy, 17 (27%) each had left-sided and right-sided nodes. In 22 cases, culture was done, and 13 (59.1%) grew Mycobacterium tuberculosis of which 6 (46.2%) were drug resistant-1 (16.7%) was polyresistant, 1 (16.7%) was extremely drug resistant (XDR) and 4 (66.7%) were pre-XDR TB. Fifteen (23.8%) patients had TB in the past, of which 7 (46.7%) had previous cervical lymphadenopathy, 6 (40%) had pulmonary TB, 1 (6.7%) multifocal lymphadenopathy and 1 (6.7%) disseminated TB. Contact with a TB patient had occurred in 25 (39.7%) cases. Conclusion: Tuberculous cervical lymphadenopathy is not so common in children. Bilateral involvement was more common. Mean age at presentation was 7.4 years. Drug resistance was prevalent in these patients.

Clinical, Immunological, and Molecular Findings of Patients with p47phox Defect Chronic Granulomatous Disease (CGD) in Indian Families.

Chronic granulomatous disease (CGD) is a group of inherited disorder of phagocytes, resulting from mutations in the components of the NADPH oxidase complex. Reduced or absent oxygen radical synthesis seen in these patients leads to impaired killing of intracellular bacteria and fungi. CGD clinically presents with recurrent and life-threatening infections as well as granulomatous inflammatory responses. p47phox encoded by the NCF1 gene is the most common autosomal recessive form of CGD which is often clinically milder. Here, we are presenting the data on clinical and immunological findings in 21 Indian patients with Del GT mutation in the NCF1 gene. Diagnosis of these patients was based on detailed clinical evaluation, measurement of respiratory burst activity by nitro blue tetrazolium and dihydrorhodamine-1,2,3 assay, expression of p47phox by flow cytometry, and molecular confirmation by GeneScan method. Seventeen male and four female patients with median age of onset of 1 year ranging from 1.5 months to 6 years were included in the study. Sixty-two percent (13 out of 21) of patients belonged to a consanguineous marriage with only one family having a history of a previous sibling death. Significant variability in clinical presentation was observed in spite of identical genetic defect ranging from asymptomatic to very severe presentation leading to early death or requiring transplantation. However, none of these patients showed difference in immunological parameters to account for this variability. Thus, this study highlights the phenotypic heterogeneity seen in these patients with Del GT mutation in the NCF1 gene and its implication in management of these patients.

Ethionamide-induced Pellagra.

Pellagra is a disorder characterized by dermatitis, diarrhea, dementia and eventually death, resulting from a deficiency of niacin or its precursor tryptophan. Ethionamide (a second-line antituberculosis agent)-induced pellagra is rarely encountered in clinical practice. Prompt diagnosis and treatment with nicotinamide can prevent life-threatening complications. To date, only three cases have been reported. We report a 13-year-old girl presenting with ethionamide-induced pellagra that resolved after the administration of niacin.

Fetal valproate syndrome.

Antenatal use of anticonvulsant valproic acid can result in a well-recognized cluster of facial dysmorphism, congenital anomalies and neurodevelopmental retardation. In this report, we describe a case with typical features of fetal valproate syndrome (FVS). A 26-year-old female with epilepsy controlled on sodium valproate 800 mg/day since 3 years, gave birth to a male child with characteristic features of FVS. She also had 3 spontaneous first-trimester abortions during those 3 years. Sodium valproate, a widely used anticonvulsant and mood regulator, is a well-recognized teratogen that can result in facial dysmorphism, craniosynostosis, neural tube defects, and neurodevelopmental retardation. Therefore, we strongly recommend avoidance of valproic acid and supplementation of folic acid during pregnancy.

Bone marrow abnormalities in HIV infected children, report of three cases and review of the literature.

Bone marrow abnormalities in HIV infected adults include hypocellularity, myelodysplasia and poor marrow recovery. Data in children is limited. We report a series of three HIV infected with varied bone marrow abnormalities. First child was a 7-year-old boy with pulmonary tuberculosis, anemia, thrombocytopenia and bone marrow examination showed hypoplastic marrow. He succumbed to his disease within seven days of hospitalization. Second child was a three and a half year old girl who had severe anemia and her bone marrow examination showed dyserythropoiesis. Third child was a 7-year-old boy who had splenic abscesses and pancytopenia and bone marrow examination showed myelofibrosis with increased plasma cells. He also succumbed due to a fatal pulmonary bleed. Thus, advanced HIV disease in children can lead to bone marrow suppression in form of hypoplasia or myelofibrosis which can be fatal.

Concomitant Rifampicin-Sensitive Pulmonary Tuberculosis With Pre-extremely Drug-Resistant Neuro-Tuberculosis in Child With Steroid-Resistant Nephrotic Syndrome.

Mixed tuberculosis occurs with multiple clonally distinct mycobacterium tuberculosis strains in an individual. We present a 12-year-old girl with steroid-resistant nephrotic syndrome and drug-sensitive pulmonary tuberculosis (Xpert MTB/Rif) and preextensively drug-resistant tuberculosis neuro-tuberculosis (Line Probe Assay). Mixed tuberculosis involving drug-susceptible and drug-resistant strains can hinder treatment. This case highlights the challenges in diagnosing mixed tuberculosis to ensure effective management.

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.

Endoscopic balloon dilation of esophageal stricture in dystrophic epidermolysis bullosa patient: challenges faced and safety of procedure.

BACKGROUND: Epidermolysis Bullosa (EB) stands as the prototype category of disorders featuring subepidermal fragility, characterized by skin blistering induced by minimal trauma. The gastrointestinal tract is a common site of extracutaneous injury. Esophageal stricture (ES) is one of the severe complications, with nearly 70% of patients experiencing ES within the initial 25 years of life. CASE REPORT: We present a 11-year-old female child of dystrophic EB (DEB) who presented with dysphagia. Barium swallow showed a short segment proximal ES. We faced many challenges before endoscopy owing to difficult intravenous access, restricted mouth opening, multiple dental caries and low haemoglobin. Dental extraction under general anaesthesia and fibreoptic intubation with a smaller sized endotracheal tube guided over epidural catheter was done at another tertiary care institute. Child had severe bleeding due to airway manipulation. MANAGEMENT: At our centre endoscopy guided serial balloon dilation (BD) of ES was performed without intubation under total intravenous anaesthesia (TIVA) without any complications. The stricture was serially dilated under direct visualization till 12 mm in three sessions at three-weekly intervals using CRE (controlled radial expansion) fixed and wire-guided balloon dilators. During the first session 20 mg of triamcinolone acetate injection was also topically applied without mucosal invasion. No such further topical or submucosal applications were attempted due to risk of perforation. CONCLUSION: Endoscopy guided BD of ES is safe and effective in EB patients when done by experienced team.

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.