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Background: COVID-19 resulted in loss of human lives owing to respiratory failure caused by dysregulated immune system. Though many treatments are evaluated, the most appropriate is yet to be established. Objective: To determine the safety and efficacy of Siddha add-on therapy in COVID -19 in terms of accelerated recovery, reduced hospital stay & mortality and follow up assessment of post discharge status until 90 days as compared to the Standard Care management. Methods: In a randomized, controlled, single-center, open-label trial conducted on 200 hospitalized COVID-19 patients, they were allocated equally to be treated with add-on Siddha regimen with Standard care or only Standard care. Standard care was in accordance to the Government norms. Recovery was defined as amelioration of symptoms, viral clearance and attaining SpO2 > 94% in room air indicating the derived score of zero on WHO clinical progression scale. The primary and secondary end points were accelerated recovery (≤ 7 days) and mortality comparison between the groups respectively. Also, disease duration, length of hospital stays and laboratory parameters were assessed for safety and efficacy. Patients were followed through for 90 days after admission. Results: In this study the accelerated recovery was 59.0% and 27.0% in treatment and control groups (ITT analyses) (p < 0.001) respectively and Odds for it were four times higher in the treatment group (OR: 3.9; 95% CI: 1.9, 8.0). The estimated median time for recovery in the treatment group was 7 days (95% CI: 6.0, 8.0; p=0.003) and 10 days (95% CI: 8.7, 11.3) in control. Hazard ratio for death in control was 2.3 times that of treatment group. No adverse reactions or alarming laboratory values were observed in response to intervention. In Severe COVID treatment group (n=80), mortality was 15.0% and 39.5% in control (n=81). The COVID stage progression was 65% less in test group. Mortality during treatment and 90 days follow up in Severe COVID patients were 12 (15%) and 35 (43.2%) in treatment and control groups respectively. Conclusion: The selected Siddha regimen when co-administered with Standard of Care have demonstrated that they can synergistically act to improve oxygenation status of patients, enhance the recovery rate from COVID-19 and reduce the mortality better when compared to administration of only Standard of Care. Clinical Trial Registry of India: CTRI/2020/06/025768 Registered on: 09/06/2020.

Background: Children with tuberculous meningitis (TBM) present with diagnostic challenges as they often have atypical clinical features., Objective: To describe the baseline characteristic features of children diagnosed with central nervous system (CNS) TB (TBM and tuberculoma)., Design: Retrospective descriptive study., Methods: Children less than 12 years presenting with neurological signs and symptoms were assessed for a therapeutic TBM trial eligibility. The results of their clinical, laboratory, neuroimaging, cerebrospinal fluid evaluations were analysed for TBM diagnosis., Results: Of 600 children evaluated, 61(10%) had CNS tuberculosis; TBM 47, tuberculoma 14. 20(33%) had definite TBM. Mean age of children with TBM was 5 ± 3.4 years. Of 47, 13(28%), 21(45%) and 13(28%) had grade I, II, and III disease respectively. Abnormalities suggestive of TBM in MRI and computed tomography brain were observed in 76% (26/34) and 77% (24/31) respectively. Abnormal cerebrospinal fluid white blood cell count, protein and glucose were observed in 56% (24/43), 49% (22/45), 47% (21/45) respectively. Among 41 patients with TBM followed up until discharge, five died., Conclusion: Younger children with TBM have severe forms. Confirmatory results may not be available in all. A holistic approach to care including addressing complications of hydrocephalus and strokes is needed., (© The Author(s), 2024.)

Xpert MTB/RIF is recommended for the diagnosis of tuberculosis (TB) in children. We determined the performance of Xpert MTB/RIF in the diagnosis of pulmonary TB in children. The characteristics of children influencing Xpert MTB/RIF positivity were explored. Children aged <15 years with symptoms suggestive of pulmonary TB were prospectively enrolled from 2013 to 2019. Two sputum/early morning gastric aspirate specimens were collected for examination by smear (fluorescence microscopy), Xpert MTB/RIF, and culture [Mycobacteria growth indicator tube (MGIT)/Lowenstein-Jensen (LJ) medium]. Diagnostic performance of Xpert MTB/RIF was evaluated using LJ and or MGIT culture positivity as the reference standard. Sensitivity, specificity with 95% confidence interval (CI) were calculated. Stratified analysis was done; P < .05 was considered statistically significant. Of the total 1727 enrolled children, 1674 (97%) with complete results for at least one sputum/gastric aspirate sample were analyzed. The sensitivity of Xpert MTB/RIF was 68.5% in sputum and 53.6% in gastric aspirate while the specificity was 99% for both. The sensitivity compared to smear was 68.5% vs. 33.7% (P < .001) and 53.6% vs. 14.5%; (P < .001) in sputum and gastric aspirate, respectively. The sensitivity of Xpert MTB/RIF was 23.9% with decision to treat as reference standard. Xpert MTB/RIF positivity was significantly influenced by sex, age, nutritional status, chest X-ray abnormality, TB infection status, and symptoms suggestive of TB. Xpert MTB/RIF as an upfront test compared to smear improves diagnosis of pulmonary TB in children yet the sensitivity is suboptimal. Newer TB diagnostic tools with improved sensitivity is warranted in children., (© The Author(s) [2024]. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: It has been reported that differential diagnosis of bacterial or viral pneumonia and tuberculosis (TB) in infants and young children is complex. This could be due to the difficulty in microbiological confirmation in this age group. In this study, we aimed to assess the utility of a real-time multiplex PCR for diagnosis of respiratory pathogens in children with pulmonary TB., Methods: A total of 185 respiratory samples [bronchoalveolar lavage (15), gastric aspirates (98), induced sputum (21), and sputum (51)] from children aged 3-12 years, attending tertiary care hospitals, Chennai, India, were included in the study. The samples were processed by N acetyl L cysteine (NALC) NAOH treatment and subjected to microbiological investigations for Mycobacterium tuberculosis (MTB) diagnosis that involved smear microscopy, Xpert® MTB/RIF testing, and liquid culture. In addition, DNA extraction from the processed sputum was carried out and was subjected to a multiplex real-time PCR comprising a panel of bacterial and fungal pathogens., Results: Out of the 185 samples tested, a total of 20 samples were positive for MTB by either one or more identification methods (smear, culture, and GeneXpert). Out of these 20 MTB-positive samples, 15 were positive for one or more bacterial or fungal pathogens, with different cycle threshold values. Among patients with negative MTB test results ( n  = 165), 145 (87%) tested positive for one or more than one bacterial or fungal pathogens., Conclusion: The results suggest that tuberculosis could coexist with other respiratory pathogens causing pneumonia. However, a large-scale prospective study from different geographical settings that uses such simultaneous detection methods for diagnosis of childhood tuberculosis and pneumonia will help in assessing the utility of these tests in rapid diagnosis of respiratory infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Rajendran, Thomas, Balaji, Selladurai, Jayachandran, Malayappan, Bhaskar, Palanisamy, Ramamoorthy, Hasini and Hissar.)

Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare manifestation of Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2) infection that can result in increased morbidity and mortality. Mounting evidence describes sex disparities in the clinical outcomes of coronavirus disease 2019 (COVID-19). However, there is a lack of information on sex-specific differences in immune responses in MIS-C. This study is an observational and cross-sectional study and we wanted to examine immune parameters such as cytokines, chemokines, acute phase proteins (APPs), growth factors, microbial translocation markers (MTMs), complement components and matrix metalloproteinases (MMPs) in MIS-C children, based on sex. Male children were associated with heightened levels of pro-inflammatory cytokines-IFNγ, IL-2, TNFα, IL-1α, IL-1β, IL-6, IL-12, G-CSF and GM-CSF, chemokines-CCL2, CCL11, CXCL1, CXCL8 and CXCL10, acute phase proteins-α-2M, CRP, growth factors VEGF and TGFα, microbial translocation markers- iFABP, LBP, EndoCAb, complement components-C1q, MBL and C3 and matrix metalloproteinases MMP-8 and MMP-9 compared to female children with MIS-C. These results indicate that the heightened immune response in males is a characteristic feature of MIS-C. These findings might explain the differential disease pathogenesis in males compared to females with MIS-C and facilitate a deeper understanding of this disease., (© 2024. The Author(s).)

Background: Multisystem inflammatory syndrome (MIS) in children is considered to be a post-infectious complication of COVID-19. T-cell responses in children with this condition have not been well-studied., Methods: We aimed to study the immune responses in children with MIS in comparison to children with acute COVID-19 and children with other infections. Whole blood was stimulated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific antigens and flow cytometry was performed to examine CD4 + and CD8 + T-cell responses., Results: Children with MIS had higher frequencies of CD4 + and CD8 + T cells expressing cytokines at baseline and upon SARS-CoV-2 antigen-specific stimulation in comparison to children with COVID-19 and/or other infections. Children with COVID-19 also exhibited higher frequencies of CD4 + and CD8 + T cells expressing cytokines at baseline and upon SARS-CoV-2 antigen-specific stimulation in comparison to children with other infections. At 6-9 months following treatment and recovery, this enhanced response against SARS-CoV-2 antigens was down modulated in children with MIS., Conclusion: Our study, therefore, provides evidence of enhanced activation of CD4 + and CD8 + T-cell responses in children with MIS and reversal following recovery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Pavan Kumar, Abbas, Renji, Venkataraman, Nancy, Varadarjan, Selladurai, Sangaralingam, Selvam, Thimmaiah, Natarajan, Ramasamy, Hissar, Ranganathan, Nutman and Babu.)

Introduction: Multisystem Inflammatory Syndrome in children (MIS-C) is a serious inflammatory sequela of SARS-CoV2 infection. The pathogenesis of MIS-C is vague and matrix metalloproteinases (MMPs) may have an important role. Matrix metalloproteinases (MMPs) are known drivers of lung pathology in many diseases., Methods: To elucidate the role of MMPs in pathogenesis of pediatric COVID-19, we examined their plasma levels in MIS-C and acute COVID-19 children and compared them to convalescent COVID-19 and children with other common tropical diseases (with overlapping clinical manifestations)., Results: Children with MIS-C had elevated levels of MMPs ( P < 0.005 statistically significant) in comparison to acute COVID-19, other tropical diseases (Dengue fever, typhoid fever, and scrub typhus fever) and convalescent COVID-19 children. PCA and ROC analysis (sensitivity 84-100% and specificity 80-100%) showed that MMP-8, 12, 13 could help distinguish MIS-C from acute COVID-19 and other tropical diseases with high sensitivity and specificity. Among MIS-C children, elevated levels of MMPs were seen in children requiring intensive care unit admission as compared to children not needing intensive care. Similar findings were noted when children with severe/moderate COVID-19 were compared to children with mild COVID-19. Finally, MMP levels exhibited significant correlation with laboratory parameters, including lymphocyte counts, CRP, D-dimer, Ferritin and Sodium levels., Discussion: Our findings suggest that MMPs play a pivotal role in the pathogenesis of MIS-C and COVID-19 in children and may help distinguish MIS-C from other conditions with overlapping clinical presentation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pavan Kumar, Venkataraman, Varadarjan, Nancy, Rajamanickam, Selladurai, Sankaralingam, Thiruvengadam, Selvam, Thimmaiah, Natarajan, Ramaswamy, Putlibai, Sadasivam, Sundaram, Hissar, Ranganathan, Nutman and Babu.)

A major challenge in tuberculosis is identifying correlates of a protective immune response. The Mycobacterial Growth Inhibition Assay (MGIA) is a functional assay providing an integrated measure of the host immune response to mycobacteria. However, its feasibility is limited by reliance on biosafety level 3 facilities, and its performance has not been widely evaluated in TB-endemic settings. Here, we compared two mycobacterial strains (M. tuberculosis H37Rv versus attenuated M. bovis BCG) in the performance of whole-blood MGIA in 30 TB-exposed children (median age 2 years) in Chennai, India. The time-to-positivity in both assays was similar (5.7 days vs 6 days) and the mycobacterial growth of M. tuberculosis H37Rv and M. bovis BCG were correlated (r = 0.64, p<0.0001). In Bland-Altman analysis, the bias was -0.54 days (95% limit of agreement -2.08, 0.99). Collectively, our results indicate that M. tuberculosis H37Rv can be substituted with the less virulent M. bovis BCG strain to improve feasibility of the MGIA assay, particularly in low-income settings., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022. Published by Elsevier Ltd.)

The clinical presentation of MIS-C overlaps with other infectious/non-infectious diseases such as acute COVID-19, Kawasaki disease, acute dengue, enteric fever, and systemic lupus erythematosus. We examined the ex-vivo cellular parameters with the aim of distinguishing MIS-C from other syndromes with overlapping clinical presentations. MIS-C children differed from children with non-MIS-C conditions by having increased numbers of naïve CD8+ T cells, naïve, immature and atypical memory B cells and diminished numbers of transitional memory, stem cell memory, central and effector memory CD4+ and CD8+ T cells, classical, activated memory B and plasma cells and monocyte (intermediate and non-classical) and dendritic cell (plasmacytoid and myeloid) subsets. All of the above alterations were significantly reversed at 6-9 months post-recovery in MIS-C. Thus, MIS-C is characterized by a distinct cellular signature that distinguishes it from other syndromes with overlapping clinical presentations. Trial Registration: ClinicalTrials.gov clinicaltrial.gov. No: NCT04844242., Competing Interests: The authors have declared that no competing interests exist.

Background: Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM., Methods: TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL)., Results: Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01)., Conclusions: In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial., Clinical Trials Registration: NCT02958709., Competing Interests: Potential conflicts of interest. A. G. reports funding received by her institution outside the scope of this work from NIH, Unitaid, the Centers for Disease Control and Prevention (CDC), and various foundations (Wyncote, Ujala, Todi); participation on a data safety monitoring board or advisory board for the NIH/NIAID Advisory Council and Indo US Science Technology Governing Board; and a leadership or fiduciary role on the IMPAACT Network TB Scientific Committee and the World Health Organization (WHO) multidrug-resistant tuberculosis guidelines committee. D. B. D., K. Y. K., M. V., P. G., and S. B. report support outside the scope of this work given to the ICMR-NIRT for the TBM-KIDS trial by the NICHD and funded through John Hopkins University. K. T. T. reports grants or contracts (NIH, CDC), outside the scope of this work, and consulting fees from WHO. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Multisystem inflammatory syndrome in children (MIS-C) presents with inflammation and pathology of multiple organs in the pediatric population in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection., Methods: We characterized the SARS-CoV-2 antigen-specific cytokine and chemokine responses in children with MIS-C, coronavirus disease 2019 (COVID-19), and other infectious diseases., Results: MIS-C is characterized by elevated levels of type 1 (interferon-γ, interleukin [IL] 2), type 2 (IL-4, IL-13), type 17 (IL-17), and other proinflammatory cytokines (IL-1α, IL-6, IL-12p70, IL-18, and granulocyte-macrophage colony-stimulating factor) in comparison to COVID-19 and other infectious diseases following stimulation with SARS-CoV-2-specific antigens. Similarly, upon SARS-CoV-2 antigen stimulation, CCL2, CCL3, and CXCL10 chemokines were significantly elevated in children with MIS-C in comparison to the other 2 groups. Principal component analysis based on these cytokines and chemokines could clearly distinguish MIS-C from both COVID-19 and other infections. In addition, these responses were significantly diminished and normalized 6-9 months after recovery., Conclusions: Our data suggest that MIS-C is characterized by an enhanced production of cytokines and chemokines that may be associated with disease pathogenesis., Competing Interests: Potential conflicts of interest. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Spinal tuberculosis (TB) is a disease of high morbidity that is associated with deformity and neurological sequelae, especially in growing children. Children diagnosed with spinal TB need to be monitored closely for clinical improvements. Previous history of antituberculous therapy (ATT), poor adherence to previous ATT, contact with persons having known drug-resistant (DR) TB, or clinical worsening despite regular ATT are strong indicators for the diagnosis of DR TB of the spine. We report a case of spinal DRTB in a two year old child with no previous history of ATT and contact with a person on irregular treatment for drug sensitive TB that did not show regression of the spinal lesions despite standard ATT., Competing Interests: Declaration of competing interest All authors have none to declare., (Copyright © 2019 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)