Pharmacokinetics of anti-TB drugs in children and adolescents with drug-resistant TB: a multicentre observational study from India.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) is one of the challenging forms of TB to treat, not only in adults but also in children and adolescents. Further, there is a void in the treatment strategy exclusively for children due to various reasons, including paucity of pharmacokinetic (PK) data on anti-TB drugs across the globe. In this context, the present study aimed at assessing the PK of some of the anti-TB drugs used in DR-TB treatment regimens. METHOD: A multicentre observational study was conducted among DR-TB children and adolescents (n = 200) aged 1-18 years (median: 12 years; IQR: 9-14) treated under programmatic settings in India. Steady-state PK (intensive: n = 89; and sparse: n = 111) evaluation of moxifloxacin, levofloxacin, cycloserine, ethionamide, rifampicin, isoniazid and pyrazinamide was carried out by measuring plasma levels using HPLC methods. RESULTS: In the study population, the frequency of achieving peak plasma concentrations ranged between 13% (for rifampicin) to 82% (for pyrazinamide), whereas the frequency of suboptimal peak concentration for pyrazinamide, cycloserine, moxifloxacin, levofloxacin and rifampicin was 15%, 19%, 29%, 41% and 74%, respectively. Further, the frequency of supratherapeutic levels among patients varied between 3% for pyrazinamide and 60% for isoniazid. In the below-12 years age category, the median plasma maximum concentration and 12 h exposure of moxifloxacin were significantly lower than that of the above-12 years category despite similar weight-adjusted dosing. CONCLUSIONS: Age significantly impacted the plasma concentration and exposure of moxifloxacin. The observed frequencies of suboptimal and supratherapeutic concentrations underscore the necessity for dose optimization and therapeutic drug monitoring in children and adolescents undergoing DR-TB treatment.

Clinical presentation and outcomes of neonates born with neural tube defects- an experience from a level III B NICU in Western India.

PURPOSE: Neural tube defects (NTDs) are one of the most common congenital anomalies and a cause of chronic disability. The study was done to study outcomes of neural tube defects admitted at a tertiary level neonatal intensive care unit (NICU) from 2018 to 2022, a period of 4 years that also coincided with the COVID pandemic. The secondary outcome was to study the clinical presentation, associated anomalies and epidemiological features. METHODS: It was a retrospective observational study; data of infants was obtained from medical records and analysis was done. RESULTS: Thirty-four neonates were enrolled, of which there were 16 (47%) males and 18 (53%) females. History of pre-pregnancy maternal folate intake was present in 4 (11.7%) cases. 33 (97%) babies were diagnosed with meningomyelocele (MMC) and one each had anencephaly, iniencephaly and encephalocele, of which one had frontal and two had occipital encephalocele. The median age of surgery was 16 days of life with primary repair being the most common procedure followed by MMC repair with VP shunt. Twenty babies (58.8%) were discharged successfully, while 9 (26.5%) expired and 5 (14.7%) were discharged against medical advice; which can be attributed to the financial problems of the patients in a developing country. The overall deaths in our series were four (26.5%) which is slightly higher than other studies which may be due to the fact that this study was conducted during the COVID era with lesser rates of folate supplementation, reduced access to prenatal diagnosis coupled with poor follow-up and compliance of patients post-surgical repair. CONCLUSION: This study emphasizes the importance of periconceptional folic acid supplementation, prenatal diagnosis, early surgery and meticulous follow-up as being pivotal to improving outcomes in children with NTDs.

Pediatric Drug-Resistant Tuberculosis: The Current and Future Prospects for Management and Prevention.

In the continued battle against one of the oldest enemies known to mankind, Mycobacterium tuberculosis (MTB), the emergence of drug resistance to antituberculosis drugs among children poses multiple challenges for early detection and treatment. Molecular diagnostics and newer drugs like bedaquiline and delamanid have strengthened the armamentarium and helped design convenient, safe, and child-friendly therapeutic regimens against drug-resistant tuberculosis (TB). Preventive strategies like treatment of TB infection among children living in close contact with patients with drug-resistant TB and effective vaccines against TB are currently in the investigative stages of development and implementation. In addition to the implementation of recent novel diagnostics and treatment modalities, effective psychosocial and nutritional support, as well as dedicated monitoring for compliance and adverse effects, are crucial determinants for successful treatment outcomes in these children.

Current Epidemiology of Pediatric Tuberculosis.

Tuberculosis (TB) is a communicable disease that is a major cause of ill health and one of the leading causes of death worldwide. Children act as reservoirs of infection out of which future cases develop. Without the successful detection and treatment of TB infection and disease in children, elimination strategies for TB will be ineffective. India has a severe problem with TB in children, which accounts for around 31% of the global pediatric TB load. However, over the past 10 y, children have consistently made up 6-7% of all patients treated yearly under the National Tuberculosis Elimination Programme (NTEP). There is an estimated detection gap of 56% in India, which is the reason for many missed cases of TB in children. Only 3% of children less than 14 y with MDR/RR-TB, are reported from India, which again is an underestimation of the actual incident cases. Population density, housing and living conditions, environmental conditions, cultural practices, age of the child, exposure to tobacco and other environmental pollutants, the virulence of the mycobacterial strain and their genetics, host genetics, BCG vaccination, malnutrition, immunodeficiency are some of the risk factors for TB exposure, infection and disease in children. Understanding the natural history as well as the epidemiology of childhood TB is important to assess which children are the most vulnerable. It would also guide us in understanding the burden of pediatric TB on a regional, national, or global level, thus facilitating the appropriate targeting of health resources and also guiding policy-making decisions.

Ocular Toxicity of Ethambutol During Both Intensive and Continuation Phases of Anti-Tubercular Therapy in Children.

OBJECTIVE: The study was conducted to evaluate the ocular toxicity of ethambutol given in both intensive and continuation phases of treatment in children with drug-sensitive tuberculosis. METHODS: A prospective study of 94 eyes from 47 patients receiving an ethambutol-containing regimen was conducted between 1 December, 2018 and 31 August, 2020. Visual acuity, visual field, visual evoked response (VER), contrast sensitivity, colour perception, and retinal nerve fiber layer (RNFL) thickness [using optical coherence tomography (OCT)] were tested for each patient before, during, and after the treatment. RESULTS: On follow-up, visual acuity, color vision, contrast sensitivity, fundus, and visual fields were not affected in any of the patients. There was no statistically significant increase in the mean latency of the P(100) wave at any point in time. On OCT, no significant loss of mean RNFL thickness was detected. CONCLUSIONS: Ethambutol is safe to use up to a dose of 20 mg/kg/day throughout the entire course of anti-tubercular therapy in children with drug-sensitive tuberculosis.

Enteroviral Infections in Infants.

Enteroviruses (EVs) are major pathogens in young infants. These viruses were traditionally classified into the following four subgenera: polio, coxsackie A and B, and echoviruses. Now that poliomyelitis seems to be controlled in most parts of the world, coxsackie and echoviruses are gaining more attention because (i) the structural and pathophysiological similarities and (ii) the consequent possibilities in translational medicine. Enteroviruses are transmitted mainly by oral and fecal-oral routes; the clinical manifestations include a viral prodrome including fever, feeding intolerance, and lethargy, which may be followed by exanthema; aseptic meningitis and encephalitis; pleurodynia; myopericarditis; and multi-system organ failure. Laboratory diagnosis is largely based on reverse transcriptase-polymerase chain reaction, cell culture, and serology. Prevention and treatment can be achieved using vaccination, and administration of immunoglobulins and antiviral drugs. In this article, we have reviewed the properties of these viruses, their clinical manifestations, and currently available methods of detection, treatment, and prognosis.

Outcome of COVID-19 in Children With Tuberculosis: Single-Center Experience.

OBJECTIVE: To evaluate the outcome of Coronavirus disease 2019 (COVID-19) infection in children and adolescents with tuberculosis. METHODS: We analyzed hospital records for the period May, 2020 to September, 2021 for children who were severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) positive or SARS-CoV-2 antibody positive. They were divided into two groups viz., those with tuberculosis (tuberculosis group) and those without tuberculosis (non-TB group). Demographic information, symptoms, and outcomes of COVID-19 were compared between the two groups. RESULTS: Median (IQR) age of participants was 11 (8,14) and 4.5 (2,9) year for the tuberculosis and non-TB groups, respectively. 93.5% and 36.1% of children were asymptomatic in the tuberculosis and non-TB group, respectively. No variable in the study was significantly associated with COVID-19 positivity in children with tuberculosis. No difference was found in the outcomes of COVID-19 infection in children having tuberculosis. CONCLUSIONS: No differences were noted in the outcomes of COVID-19 infection in children having tuberculosis.

Have the COVID-19 pandemic and lockdown affected children's mental health in the long term? A repeated cross-sectional study.

OBJECTIVE: The study aimed to evaluate the impact of the COVID-19 pandemic on levels of anxiety and depressive symptoms in children and adolescents. DESIGN: Cross-sectional surveys were carried out on the mental health of children; one survey was conducted before the COVID-19 pandemic and one into the pandemic, 15 months after the school closures and implementation of lockdown and social distancing. Demographic data and COVID-19 pandemic-related data were collected from specific parent-report and self-report questionnaires. PARTICIPANTS: Participants included children and adolescents between ages 6 and 16 years, attending a tertiary care hospital without any diagnosed major psychiatric or chronic disorder. ANALYSIS: Data were collected at two points (before the COVID-19 pandemic and during it) and compared. Levels of anxiety and depressive symptoms were compared and tested for statistically significant differences between these two points using appropriate statistical tests. Regression models were constructed to predict the factors affecting increased anxiety levels and depressive symptoms in the COVID-19 period. RESULTS: 832 and 1255 children/adolescents were included in the study during the pre-COVID-19 and COVID-19 times, respectively. The median age of the participants was 10 years (IQR=4 years). The median (IQR) Spence Children's Anxiety Scale score was 24 (12) at the pre-COVID-19 point and 31 (13) during the COVID-19 pandemic (p<0.001, r=-0.27). 11% and 16% of children reported being depressed at these two-time points, respectively (p=0.004, φc=-0.063). Regression analysis showed that many factors, including the duration of smartphone use, female gender and only child status, were associated with increased anxiety or depression levels. CONCLUSION: A large proportion of children had elevated anxiety and depressive symptoms during the pandemic relative to before the pandemic, suggesting a need for measures to engage children in healthy habits to protect children's mental health and continuous monitoring of children during such scenarios.

Predictors of outcomes in children with Central Nervous System tuberculosis.

BACKGROUND: Central Nervous system tuberculosis (CNS-Tb) is the most lethal form of extra-pulmonary tuberculosis in children. The lack of markers of outcome provides little information on the efficacy of the current treatment protocols for CNS-Tb and thus results in a higher mortality rate than other extrapulmonary manifestations of tuberculosis. This study aims to identify significant factors that will reliably predict the outcomes at discharge in children admitted with CNS-Tb. METHODS AND MATERIAL: This is a prospective observational study in children with neurotuberculosis admitted at a tertiary care hospital. Clinical presentations at the time of admission were studied. Outcomes at the end of in-patient care (completely cured, survival with some/severe disability or death) were correlated with clinical, laboratory, microbiological, and radiological parameters. Univariate and multivariate analyses were applied to study the parameters and a p-value ≤ 0.05 with a confidence interval (CI) of 95% was considered as statistically significant. FINDINGS: The study included 100 children between 4 months and 12 years of age with a mean of 5.84 (±3.5) years. At discharge, 55% of children recovered completely, 20% had some or severe disability and 25% died. On multivariate analysis, high CSF protein (p = 0.050) and drug resistance (p = 0.034) were highly associated with fatality. Meningeal enhancements with basal exudates (p = 0.021) and CSF lymphocyte count >90% were highly associated with survival with disability. Stage I disease at presentation (p < 0.0001) was the only variable associated with complete recovery. INTERPRETATION: Reliable prognostic markers for CNS-Tb can aid in predicting the efficacy of the current treatment and the anticipated outcome in the children with this disease. FUNDING: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Disseminated Congenital Tuberculosis in Neonates: A Case Series.

Congenital tuberculosis (CTB) is an uncommon yet, well-defined condition. CTB has a non-specific clinical presentation, making the diagnosis difficult. The rarity of CTB in neonates is due to the difficulty in distinguishing between congenital and postnatally acquired infection, and non-specific symptoms in the newborn, which are often misdiagnosed. Though it has a low incidence, it has significant mortality if the diagnosis is delayed. We are presenting two cases of CTB in newborns who showed signs of disease in the first few days of life. The diagnosis was suspected based on chest computed tomography, magnetic resonance imaging brain, cerebrospinal fluid studies, intrauterine growth restriction, non-response to standard treatment and a maternal history of active tuberculosis. These cases highlight the significance of having a high suspicion of CTB and timely treatment for better outcomes.

Pediatric Tuberculosis Research and Development: Progress, Priorities and Funding Opportunities.

In this article, we highlight technological pediatric TB research advances across the TB care cascade; discuss recently completed or ongoing work in adults and corresponding significant research gaps for children; and offer recommendations and opportunities to increase investments and accelerate pediatric TB R&D.

Drug Resistance in Children with Central Nervous System Tuberculosis from a Tertiary Care Center in Mumbai.

INTRODUCTION: Central Nervous System tuberculosis (CNS-TB) is the most lethal form of extra-pulmonary TB, especially in children. In this study, we have discussed patterns of drug resistance in pediatric CNS-TB. MATERIALS AND METHODS: Prospective observational study conducted on 100 children at a tertiary care center. Diagnosed cases of CNS-TB were enrolled. GeneXpert MTB/RIF was used upfront for diagnosis, and in cases where TB MGIT culture was positive, a phenotypic Drug Susceptibility Test (DST) was done. Patients were divided into resistant to at least one drug (DR) and drug-susceptible (DS). Various parameters were compared between these groups. RESULTS: Mean age of participants was 5.84 ± 3.5 years, with a male-to-female ratio of 1.08 : 1; 14% of children had drug-resistant CNS TB (DR-CNS-TB). A higher proportion of children previously treated for TB were associated with drug resistance (p = 0.009), and those with disseminated TB also had a higher drug resistance (p = 0.002). Apart from this, the DR and DS groups had no statistically significant differences in demographic, clinical or epidemiological parameters. CONCLUSIONS: Previous history of being treated for TB and disseminated TB was an independent risk factor for DR-CNS-TB. Ensuring proper adherence and compliance to anti-tubercular treatment could help in preventing the emergence of DR TB.

Effect of Saccharomyces boulardii CNCM-I 3799 and Bacillus subtilis CU-1 on Acute Watery Diarrhea: A Randomized Double-Blind Placebo-Controlled Study in Indian Children.

PURPOSE: To assess the effect of combination probiotic Saccharomyces boulardii CNCM-I 3799 and Bacillus subtilis CU-1 in outpatient management of acute watery diarrhea in children. METHODS: A randomized double-blind placebo-controlled study was conducted in 180 participants aged six months to five years with acute mild to moderate diarrhea. All were enrolled from six centers across India and centrally randomized to receive S. boulardii CNCM-I 3799 and B. subtilis CU-1 or a placebo along with oral rehydration salts and zinc supplementation. Each participant was followed up for three months to assess recurrence of diarrhea. RESULTS: The mean duration of diarrhea in the probiotic and placebo groups were 54.16 hours and 59.48 hours, respectively. The difference in the duration of diarrhea in those administered with probiotic or placebo within 24 hours of diarrhea onset was 25.21 hours. Furthermore, the difference in duration of diarrhea was 13.84 hours (p<0.05) for participants who were administered with probiotics within 48 hours. There were no significant differences in the stool frequencies between the two arms. After three months, 15% in the probiotic group and 18.5% in the placebo group reported episodes of diarrhea. The mean duration of diarrhea was considerably lower in the probiotic group, 31.02 hours versus 48 hours in placebo (p=0.017). CONCLUSION: S. boulardii CNCM-I 3799 and B. subtilis CU-1 combination was effective in reducing the duration of diarrhea when administered within 48 hours of diarrhea onset. Similarly, it reduced recurrence of diarrhea and its intensity in the subsequent three months.

Intussusception in children aged under two years in India: Retrospective surveillance at nineteen tertiary care hospitals.

OBJECTIVE: Intussusception has been linked with rotavirus vaccine (RVV) as a rare adverse reaction. In view of limited background data on intussusception in India and in preparation for RVV introduction, a surveillance network was established to document the epidemiology of intussusception cases in Indian children. METHODS: Intussusception in children 2-23 months were documented at 19 nationally representative sentinel hospitals through a retrospective surveillance for 69 months (July 2010 to March 2016). For each case clinical, hospital course, treatment and outcome data were collected. RESULTS: Among the 1588 intussusception cases, 54.5% were from South India and 66.3% were boys. The median age was 8 months (IQR 6, 12) with 34.6% aged 2-6 months. Seasonal variation with higher cases were documented during March-June period. The most common symptoms and signs were vomiting (63.4%), bloody stool (49.1%), abdominal pain (46.9%) and excessive crying (42.8%). The classical triad (vomiting, abdominal pain, and blood in stools) was observed in 25.6% cases. 96.4% cases were diagnosed by ultrasound with ileocolic location as the commonest (85.3%). Management was done by reduction (50.8%) and surgery (41.1%) and only 1% of the patients' died. 91.1% cases met Brighton criteria level 1 and 3.3% Level 2. Between 2010 and 2015, the case load and case ratio increased across all regions. CONCLUSION: Intussusception cases have occurred in children across all parts of the country, with low case fatality in the settings studied. The progressive rise cases could indicate an increasing awareness and availability of diagnostic facilities.

Miller Fisher Variant of Guillain-Barré Syndrome in a Child.

Miller Fisher syndrome (MFS), a rare form of Guillain-Barré Syndrome, presents with the classical triad of ophthalmoplegia, areflexia, and ataxia. We describe the case of a 7-year-old boy who presented with diplopia, speech difficulty, dysphagia, gait disturbance, and difficulty in eyeball movements since 5 days. On examination, the child was having ataxia, areflexia, ophthalmoplegia, drooling of saliva, dysphonia, and absent gag reflex. MFS and brain stem encephalitis were kept as the differential diagnoses. The patient improved gradually over 3 weeks, following a treatment with intravenous immunoglobulin.

Angelman syndrome: The blurred lines of interpretation in cognitive defects.

Angelman syndrome is a neuro-developmental disorder with a genetic basis in maternal genomic imprinting that presents with cognitive and behavioral impairment. The distinction between the presentations of disorders causing developmental delay may be vague in early life, resulting in the potential delay in diagnosis and intervention. We report a case of Angelman syndrome with initial diagnostic confusion with multiple associated pathologies. A holistic evaluation and management of such patients is necessary.