Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children.

BACKGROUND: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. METHODS: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment. RESULTS: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups). CONCLUSIONS: Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).

Clinical outcomes in children living with HIV treated for non-severe tuberculosis in the SHINE Trial.

BACKGROUND: Children living with HIV(CLWH) are at high risk of tuberculosis(TB) and face poor outcomes, despite antiretroviral treatment(ART). We evaluated outcomes in CLWH and HIV-uninfected children treated for non-severe TB in the SHINE trial. METHODS: SHINE was a randomized trial that enrolled children aged <16 years with smear-negative, non-severe TB who were randomized to receive 4 vs 6 months of TB treatment and followed for 72 weeks. We assessed TB relapse/recurrence, mortality, hospitalizations, grade ≥3 adverse events by HIV status, and HIV virological suppression in CLWH. RESULTS: Of 1204 enrolled, 127(11%) were CLWH, of similar age (median(IQR) 3.6(1.2, 10.3) vs. 3.5(1.5, 6.9)years, p= 0.07), but more underweight (WAZ; -2.3(-3.3, -0.8) vs -1.0(-1.8, -0.2), p<0.01) and anemic (hemoglobin 9.5(8.7, 10.9) vs 11.5(10.4, 12.3)g/dl, p<0.01) compared to HIV-uninfected children. 68(54%) CLWH were ART-naïve; baseline median CD4 count 719(241-1134) cells/mm3, CD4% 16(10-26)%). CLWH were more likely to be hospitalized (aOR=2.4(1.3-4.6)) and die (aHR(95%CI) 2.6(1.2,5.8)). HIV status, age <3 years (aHR 6.3(1.5,27.3)), malnutrition (aHR 6.2(2.4,15.9)) and hemoglobin <7g/dl(aHR 3.8(1.3,11.5) independently predicted mortality. Among children with available VL, 45% and 61% CLWH had VL<1000copies/ml at weeks 24 and 48, respectively. There was no difference in the effect of randomized treatment duration (4 vs 6 months) on TB treatment outcomes by HIV status (p for interaction=0.42). CONCLUSIONS: We found no evidence of a difference in TB outcomes between 4 and 6 months of treatment for CLWH treated for non-severe TB. Irrespective of TB treatment duration, CLWH had higher rates of mortality and hospitalization than HIV-uninfected counterparts.

We compared outcomes between children with and without HIV treated for non-severe TB. Regardless of treatment duration (4 or 6 months), children with HIV had similar TB outcomes but had higher mortality and hospitalization rates than their HIV-uninfected counterparts.

Resurgence of respiratory syncytial virus infection during COVID-19 pandemic in Pune, India.

INTRODUCTION: Respiratory Syncytial Virus (RSV) is a leading cause of acute lower respiratory infection in children worldwide. Understanding its prevalence, variations, and characteristics is vital, particularly in the context of the COVID-19 pandemic. OBJECTIVE: The study aimed to investigate the RSV positivity rate, subtype prevalence, age and gender distribution, symptomatology, and co-infection rates during pre-pandemic and pandemic periods. METHODS: We analyzed data from 15,381 patients tested for RSV between 2017 and 2023. RESULTS: Our analysis revealed a 7.2% average RSV positivity rate in the pre-pandemic period, with significant fluctuations during the pandemic (1.5% in 2020 to 32.0% in 2021). We observed variations in RSVA and RSVB detection rates. The 0-4 years' age group was consistently the most affected, with a slight male predominance. Fever and cough were common symptoms. Therapeutic interventions, particularly antiviral usage and ventilation requirements, decreased during the pandemic. We also identified variations in co-infection rates with other respiratory viruses. CONCLUSION: Our study offers critical insights into the impact of the COVID-19 pandemic on RSV prevalence, subtype distribution, patient characteristics, and clinical management. These findings underscore the need for ongoing surveillance and adaptive public health responses.

Maternal Colonization Versus Nosocomial Transmission as the Source of Drug-Resistant Bloodstream Infection in an Indian Neonatal Intensive Care Unit: A Prospective Cohort Study.

BACKGROUND: Drug-resistant gram-negative (GN) pathogens are a common cause of neonatal sepsis in low- and middle-income countries. Identifying GN transmission patterns is vital to inform preventive efforts. METHODS: We conducted a prospective cohort study, 12 October 2018 to 31 October 2019 to describe the association of maternal and environmental GN colonization with bloodstream infection (BSI) among neonates admitted to a neonatal intensive care unit (NICU) in Western India. We assessed rectal and vaginal colonization in pregnant women presenting for delivery and colonization in neonates and the environment using culture-based methods. We also collected data on BSI for all NICU patients, including neonates born to unenrolled mothers. Organism identification, antibiotic susceptibility testing, and next-generation sequencing (NGS) were performed to compare BSI and related colonization isolates. RESULTS: Among 952 enrolled women who delivered, 257 neonates required NICU admission, and 24 (9.3%) developed BSI. Among mothers of neonates with GN BSI (n = 21), 10 (47.7%) had rectal, 5 (23.8%) had vaginal, and 10 (47.7%) had no colonization with resistant GN organisms. No maternal isolates matched the species and resistance pattern of associated neonatal BSI isolates. Thirty GN BSI were observed among neonates born to unenrolled mothers. Among 37 of 51 BSI with available NGS data, 21 (57%) showed a single nucleotide polymorphism distance of ≤5 to another BSI isolate. CONCLUSIONS: Prospective assessment of maternal GN colonization did not demonstrate linkage to neonatal BSI. Organism-relatedness among neonates with BSI suggests nosocomial spread, highlighting the importance of NICU infection prevention and control practices to reduce GN BSI.

Impact of Undernutrition on Tuberculosis Treatment Outcomes in India: A Multicenter, Prospective, Cohort Analysis.

BACKGROUND: Undernutrition is the leading risk factor for tuberculosis (TB) globally. Its impact on treatment outcomes is poorly defined. METHODS: We conducted a prospective cohort analysis of adults with drug-sensitive pulmonary TB at 5 sites from 2015-2019. Using multivariable Poisson regression, we assessed associations between unfavorable outcomes and nutritional status based on body mass index (BMI) nutritional status at treatment initiation, BMI prior to TB disease, stunting, and stagnant or declining BMI after 2 months of TB treatment. Unfavorable outcome was defined as a composite of treatment failure, death, or relapse within 6 months of treatment completion. RESULTS: Severe undernutrition (BMI <16 kg/m2) at treatment initiation and severe undernutrition before the onset of TB disease were both associated with unfavorable outcomes (adjusted incidence rate ratio [aIRR], 2.05; 95% confidence interval [CI], 1.42-2.91 and aIRR, 2.20; 95% CI, 1.16-3.94, respectively). Additionally, lack of BMI increase after treatment initiation was associated with increased unfavorable outcomes (aIRR, 1.81; 95% CI, 1.27-2.61). Severe stunting (height-for-age z score <-3) was associated with unfavorable outcomes (aIRR, 1.52; 95% CI, 1.00-2.24). Severe undernutrition at treatment initiation and lack of BMI increase during treatment were associated with a 4- and 5-fold higher rate of death, respectively. CONCLUSIONS: Premorbid undernutrition, undernutrition at treatment initiation, lack of BMI increase after intensive therapy, and severe stunting are associated with unfavorable TB treatment outcomes. These data highlight the need to address this widely prevalent TB comorbidity. Nutritional assessment should be integrated into standard TB care.

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.

Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial.

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.

Pharmacokinetics of First-Line Drugs in Children With Tuberculosis, Using World Health Organization-Recommended Weight Band Doses and Formulations.

BACKGROUND: Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization-recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial. METHODS: Children weighing 4.0-7.9, 8.0-11.9, 12.0-15.9, or 16.0-24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0-36.9 kg received doses recommended for adults <37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. RESULTS: In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4-6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1-45.1), 16.7 (9.2-25.9), 317 (263-399), and 9.5 (7.5-11.5) mg⋅h/L, respectively, and lower in children than in adults for rifampicin in the 4.0-7.9-, 8-11.9-, and ≥25-kg weight bands, isoniazid in the 4.0-7.9-kg and ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults. CONCLUSIONS: Recommended weight band-based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization-recommended doses requires further evaluation.

Development of shortened HIV-related stigma scales for young people living with HIV and young people affected by HIV in India.

BACKGROUND: HIV-related stigma is associated with poor quality of life and poor healthcare-seeking behaviours in young people living with HIV (YPLHIV) and young people affected by HIV (YPAHIV). India has an estimated 120,000 YPLHIV and 4 million YPAHIV, but efforts to measure HIV-related stigma in them are sparse, impeded by the lack of measuring instruments. Here, we describe the development of the Pune HIV-Stigma Scale (PHSS) and modified-PHSS to measure HIV-related stigma among YPLHIV and YPAHIV, respectively, in India. METHODS: We used data from a mental health study for YPLHIV and YPAHIV aged 15-25 years, conducted at Byramjee Jeejeebhoy Government Medical College & Sassoon General Hospitals, Pune, India, between August 2018 and June 2021. Findings from multiple confirmatory factor analyses and cognitive interviews guided the development of the 12-item PHSS. The modified-PHSS was developed by confirming the structure of the PHSS for YPAHIV. Convergent validity with Center for Epidemiological Studies Depression (CES-D) and UCLA Loneliness scales was assessed using Spearman's correlation coefficients. RESULTS: Model fit indices were good for both the PHSS (χ2 = 65.0, df = 48, p value: 0.052; root mean square error of approximation (RMSEA): 0.054; comparative fit index (CLI): 0.980; Tucker-Lewis index (TLI): 0.972; and standardized root mean square residual (SRMR): 0.067), and the modified-PHSS (χ2 = 56.9, df = 48, p value: 0.176; RMSEA: 0.045; CLI: 0.983; TFI: 0.976, and SRMR: 0.078). Spearman's correlation coefficients indicated low to moderate convergent validity (ρ: 0.03-0.52) across different subscales of the PHSS and modified-PHSS. Cronbach's alpha for the PHSS was 0.82 and for the modified-PHSS 0.81. CONCLUSION: We developed the first scales to measure HIV-related stigma among YPLHIV and YPAHIV in India. These concise scales can facilitate measurement of HIV-related stigma more frequently in research studies. We recommend that they be tested in different Indian languages.

High Burden of Bloodstream Infections Associated With Antimicrobial Resistance and Mortality in the Neonatal Intensive Care Unit in Pune, India.

BACKGROUND: Antimicrobial resistance (AMR) is a growing threat to newborns in low- and middle-income countries (LMIC). METHODS: We performed a prospective cohort study in 3 tertiary neonatal intensive care units (NICUs) in Pune, India, to describe the epidemiology of neonatal bloodstream infections (BSIs). All neonates admitted to the NICU were enrolled. The primary outcome was BSI, defined as positive blood culture. Early-onset BSI was defined as BSI on day of life (DOL) 0-2 and late-onset BSI on DOL 3 or later. RESULTS: From 1 May 2017 until 30 April 2018, 4073 neonates were enrolled. Among at-risk neonates, 55 (1.6%) developed early-onset BSI and 176 (5.5%) developed late-onset BSI. The majority of BSIs were caused by gram-negative bacteria (GNB; 58%); among GNB, 61 (45%) were resistant to carbapenems. Klebsiella spp. (n = 53, 23%) were the most common cause of BSI. Compared with neonates without BSI, all-cause mortality was higher among neonates with early-onset BSI (31% vs 10%, P < .001) and late-onset BSI (24% vs 7%, P < .001). Non-low-birth-weight neonates with late-onset BSI had the greatest excess in mortality (22% vs 3%, P < .001). CONCLUSIONS: In our cohort, neonatal BSIs were most commonly caused by GNB, with a high prevalence of AMR, and were associated with high mortality, even in term neonates. Effective interventions are urgently needed to reduce the burden of BSI and death due to AMR GNB in hospitalized neonates in LMIC.

Early-onset symptomatic neonatal COVID-19 infection with high probability of vertical transmission.

BACKGROUND: There are few reports of COVID-19 in neonates and most are suspected to be due to postnatal transmission. Vertical transmission has been proven in only a couple of cases so far. METHODS: We describe early-onset, severe COVID-19 disease in a neonate with very strong evidence of vertical transmission of SARS-CoV-2. RESULTS: A COVID-19 suspected mother, who tested negative by RT-PCR for COVID, but tested positive for SARS-CoV-2 by serology, delivered a term baby. The neonate was kept in strict isolation. Molecular tests for SARS-CoV-2 on umbilical stump, placenta, and nasopharyngeal aspirate of the neonate, collected at birth were positive. On day 2, the neonate developed clinical features of COVID in the form of fever, poor feeding, and hyperbilirubenemia along with elevated inflammatory markers. Antibiotics were started empirically pending cultures. Blood, CSF, and urine cultures were sterile. Baby tested RT-PCR positive for SARS-CoV-2 on two more occasions before testing positive for antibodies and was discharged on day 21 of life. CONCLUSION: This report highlights a very strong possibility of vertical transmission of COVID-19 from a mildly symptomatic, RT-PCR negative but antibody-positive mother with significant symptomatic, early-onset neonatal infection.

Severe Malnutrition and Anemia Are Associated with Severe COVID in Infants.

BACKGROUND: COVID-19 is uncommon and less severe in children than adults. It is thought that infants may be at higher risk for severe disease than older children. There is a paucity of literature on infants with COVID, particularly those with severe disease. OBJECTIVE: We describe demographic, epidemiologic, clinical, radiological, laboratory features and outcomes of infants with confirmed SARS-CoV-2 infection admitted to a tertiary care teaching hospital in Pune, India. METHODOLOGY: Infants who tested positive for SARS-CoV-2 and were admitted between 1 April 2020 and 7 August 2020 were included in the study. RESULTS: A total of 13 infants were admitted during the study period. The median age was 8 months (IQR 6) and nine were male. Common presenting features were fever (n = 8, 62%), poor feeding, irritability, and runny nose (n = 3, 23%). Comorbidities noted were severe acute malnutrition (SAM) in three cases (23%) and nutritional megaloblastic anemia, iron deficiency anemia, sickle thalassemia and renal calculi in one case (8%) each. There was a history of low birth weight in two cases (15%). Pallor was noted in three cases (23%), SAM in three cases (23%) and tachypnea and respiratory distress in four cases (30%). Severe anemia, thrombocytopenia, elevated ferritin, abnormal procalcitonin, abnormal C Reactive Protein and deranged D-dimer was noted in three cases (23%) each. Neutrophil-lymphocyte ratio was normal in all cases. Three infants (43%) had evidence of pneumonia on the chest radiograph, of which one had adult respiratory distress syndrome (ARDS) like pattern, one infant had cardiomegaly and perihilar infiltrates. Hydroxychloroquine and azithromycin were given to five patients (38%), Intravenous Immunoglobulin and methylprednisolone were administered to one patient (8%). One infant died of ARDS with multi-organ dysfunction with refractory shock and hemophagocytic lymphohistiocytosis. CONCLUSION: SAM and anemia may be associated with severe COVID in infants.

Mullen Scales of Early Learning Adaptation for Assessment of Indian Children and Application to Tuberculous Meningitis.

INTRODUCTION: Tuberculous meningitis (TBM) results in significant morbidity and mortality among children worldwide. Associated neurocognitive complications are common but not well characterized. The Mullen Scales of Early Learning (MSEL), a well-established measure for assessment of neurodevelopment, has not yet been adapted for use in India. This study's goal was to adapt the MSEL for local language and culture to assess neurocognition among children in India, and apply the adapted measure for assessment of children with TBM. METHODS: Administration of MSEL domains was culturally adapted. Robust translation procedures for instructions took place for three local languages: Marathi, Hindi and Tamil. Multilingual staff compared instructions against the original version for accuracy. The MSEL stimuli and instructions were reviewed by psychologists and pediatricians in India to identify items concerning for cultural bias. RESULTS: MSEL stimuli unfamiliar to children in this setting were identified and modified within Visual Reception, Fine-Motor, Receptive Language and Expressive Language Scales. Item category was maintained for adaptations of items visually or linguistically different from those observed in daily life. Adjusted items were administered to six typically developing children to determine modification utility. Two children diagnosed with confirmed TBM (ages 11 and 29 months) were evaluated with the adapted MSEL before receiving study medications. Skills were below age-expectation across visual reception, fine motor and expressive language domains. CONCLUSIONS: This is the first study to assess children with TBM using the MSEL adapted for use in India. Future studies in larger groups of Indian children are warranted to validate the adapted measure.

Transcriptomic Profiles of Confirmed Pediatric Tuberculosis Patients and Household Contacts Identifies Active Tuberculosis, Infection, and Treatment Response Among Indian Children.

BACKGROUND: Gene expression profiling is emerging as a tool for tuberculosis diagnosis and treatment response monitoring, but limited data specific to Indian children and incident tuberculosis infection (TBI) exist. METHODS: Sixteen pediatric Indian tuberculosis cases were age- and sex-matched to 32 tuberculosis-exposed controls (13 developed incident TBI without subsequent active tuberculosis). Longitudinal samples were collected for ribonucleic acid sequencing. Differential expression analysis generated gene lists that identify tuberculosis diagnosis and tuberculosis treatment response. Data were compared with published gene lists. Population-specific risk score thresholds were calculated. RESULTS: Seventy-one genes identified tuberculosis diagnosis and 25 treatment response. Within-group expression was partially explained by age, sex, and incident TBI. Transient changes in gene expression were identified after both infection and treatment. Application of 27 published gene lists to our data found variable performance for tuberculosis diagnosis (sensitivity 0.38-1.00, specificity 0.48-0.93) and treatment response (sensitivity 0.70-0.80, specificity 0.40-0.80). Our gene lists found similarly variable performance when applied to published datasets for diagnosis (sensitivity 0.56-0.85, specificity 0.50-0.85) and treatment response (sensitivity 0.49- 0.86, specificity 0.50-0.84). CONCLUSIONS: Gene expression profiles among Indian children with confirmed tuberculosis were distinct from adult-derived gene lists, highlighting the importance of including distinct populations in differential gene expression models.

Intensified Short Symptom Screening Program for Dengue Infection during Pregnancy, India.

Mosquitoborne diseases (e.g., malaria, dengue, and chikungunya) are endemic to India and pose diagnostic challenges during pregnancy. We evaluated an intensified short symptom screening program in India to diagnose dengue during pregnancy. During October 2017-January 2018, we screened pregnant women during antenatal surveillance for symptoms of mosquitoborne diseases (fever only, fever with conjunctivitis, fever with rash, or all 3 symptoms) within the previous 15 days. Of 5,843 pregnant women screened, 52 were enrolled and tested for dengue, chikungunya, and Zika viruses by using a Trioplex real-time reverse transcription PCR. Of 49 who had complete results, 7 (14%) were dengue positive. Of these ocular pain was seen in 4 (57%) and conjunctivitis in 7 (100%). Intensified symptom screening using conjunctivitis, in addition to rash, in pregnant women with fever might improve dengue case detection and can be included in routine symptom screening during pregnancy.

High prevalence of late presentation of ART-naïve perinatally infected children for care in Pune, India.

Delayed presentation to care of perinatally infected children in India continues to be a hindrance to achieving the "end pediatric HIV by 2020" goal. In this study, we characterize this issue by describing the prevalence, risk factors and temporal trends of delayed presentation to care of perinatally infected, antiretroviral therapy (ART) - naïve children using programmatic data from a tertiary care center in western India. Delayed presentation was defined as children presenting in moderate or severe WHO immunodeficiency categories. Of 269 children eligible for inclusion in the analysis, the median age at presentation was 4 years (IQR: 3-6 years) and prevalence of delayed presentation was 52%. Multivariable logistic regression identified domicile distance ≥20km from the ART center (OR: 2.2, 95% CI: 1.02-4.7) to be a risk factor for delayed presentation. An inverse association with increasing age (OR: 0.8, 95% CI: 0.7-0.9) was also seen. The proportion of children with delayed presentation between 2006 and 2016 remained unchanged (p = 0.36), although the median age at presentation over the same time period increased significantly (p < 0.001). Our results indicate the urgency of identifying strategies to improve linkage of perinatally infected ART-naïve children to care, earlier than what is currently observed.

Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis.

BACKGROUND: Few studies have evaluated the association between preexisting vitamin D deficiency and incident tuberculosis (TB). We assessed the impact of baseline vitamins D levels on TB disease risk. METHODS AND FINDINGS: We assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6,751 HIV-negative household contacts of TB patients enrolled between September 1, 2009, and August 29, 2012, in Lima, Peru. We screened for TB disease at 2, 6, and 12 months after enrollment. We defined cases as household contacts who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected four controls from among contacts who did not develop TB disease, matching on gender and year of age. We also conducted a one-stage individual-participant data (IPD) meta-analysis searching PubMed and Embase to identify prospective studies of vitamin D and TB disease until June 8, 2019. We included studies that assessed vitamin D before TB diagnosis. In the primary analysis, we defined vitamin D deficiency as 25-(OH)D < 50 nmol/L, insufficiency as 50-75 nmol/L, and sufficiency as >75nmol/L. We estimated the association between baseline vitamin D status and incident TB using conditional logistic regression in the Lima cohort and generalized linear mixed models in the meta-analysis. We further defined severe vitamin D deficiency as 25-(OH)D < 25 nmol/L and performed stratified analyses by HIV status in the IPD meta-analysis. In the Lima cohort, we analyzed 180 cases and 709 matched controls. The adjusted odds ratio (aOR) for TB risk among participants with baseline vitamin D deficiency compared to sufficient vitamin D was 1.63 (95% CI 0.75-3.52; p = 0.22). We included seven published studies in the meta-analysis and analyzed 3,544 participants. In the pooled analysis, the aOR was 1.48 (95% CI 1.04-2.10; p = 0.03). The aOR for severe vitamin D deficiency was 2.05 (95% CI 0.87-4.87; p trend for decreasing 25-(OH)D levels from sufficient vitamin D to severe deficiency = 0.02). Among 1,576 HIV-positive patients, vitamin D deficiency conferred a 2-fold (aOR 2.18, 95% CI 1.22-3.90; p = 0.01) increased risk of TB, and the aOR for severe vitamin D deficiency compared to sufficient vitamin D was 4.28 (95% CI 0.85-21.45; p = 0.08). Our Lima cohort study is limited by the short duration of follow-up, and the IPD meta-analysis is limited by the number of possible confounding covariates available across all studies. CONCLUSION: Our findings suggest vitamin D predicts TB disease risk in a dose-dependent manner and that the risk of TB disease is highest among HIV-positive individuals with severe vitamin D deficiency. Randomized control trials are needed to evaluate the possible role of vitamin D supplementation on reducing TB disease risk.

The association of household fine particulate matter and kerosene with tuberculosis in women and children in Pune, India.

OBJECTIVES: Household air pollution (HAP) is a risk factor for respiratory disease, however has yet to be definitively associated with tuberculosis (TB). We aimed to assess the association between HAP and TB. METHODS: A matched case-control study was conducted among adult women and children patients with TB and healthy controls matched on geography, age and sex. HAP was assessed using questionnaires for pollution sources and 24-hour household concentrations of particulate matter <2.5 µm in diameter (PM2.5). RESULTS: In total, 192 individuals in 96 matched pairs were included. The median 24-hour time-weighted average PM2.5 was nearly seven times higher than the WHO's recommendation of 25 µg/m3, and did not vary between controls (179 µg/m3; IQR: 113-292) and cases (median 157 µg/m3; 95% CI 93 to 279; p=0.57). Reported use of wood fuel was not associated with TB (OR 2.32; 95% CI 0.65 to 24.20) and kerosene was significantly associated with TB (OR 5.49, 95% CI 1.24 to 24.20) in adjusted analysis. Household PM2.5 was not associated with TB in univariate or adjusted analysis. Controlling for PM2.5 concentration, kerosene was not significantly associated with TB, but effect sizes ranged from OR 4.30 (95% CI 0.78 to 30.86; p=0.09) to OR 5.49 (0.82 to 36.75; p=0.08). CONCLUSIONS: Use of kerosene cooking fuel is positively associated with TB in analysis using reported sources of exposure. Ubiquitously high levels of particulates limited detection of a difference in household PM2.5 between cases and controls.

Antibiotic Utilization and the Role of Suspected and Diagnosed Mosquito-borne Illness Among Adults and Children With Acute Febrile Illness in Pune, India.

Background: Antibiotic resistance mechanisms originating in low- and middle- income countries are among the most common worldwide. Reducing unnecessary antibiotic use in India, the world's largest antibiotic consumer, is crucial to control antimicrobial resistance globally. Limited data describing factors influencing Indian clinicians to start or stop antibiotics are available. Methods: Febrile adults and children admitted to a public tertiary care hospital in Pune, India, were enrolled. Antibiotic usage and clinical history were recorded. Immunoassays for mosquito-borne disease and bacterial cultures were performed by protocol and clinician-directed testing. Clinical factors were assessed for association with empiric antibiotic initiation and discontinuation by day 5 using multivariable logistic regression and propensity score-matched Cox proportional hazard models. Results: Among 1486 participants, 683 (82%) adults and 614 (94%) children received empiric antibiotics. Participants suspected of having mosquito-borne disease were less likely to receive empiric antibiotics (adjusted odds ratio [AOR], 0.5; 95% confidence interval [CI], .4-.8). Empiric antibiotics were discontinued in 450 (35%) participants by day 5. Dengue or malaria testing performed before day 4 was positive in 162 (12%) participants, and was associated with antibiotic discontinuation (AOR, 1.7; 95% CI, 1.2-2.4). In a propensity score-matched model accounting for admission suspicion of mosquito-borne disease, positive dengue or malaria tests increased hazard of antibiotic discontinuation (hazard ratio, 1.6; 95% CI, 1.2-2.0). Conclusions: Most patients with acute febrile illness in an Indian public hospital setting receive empiric antibiotics. Mosquito-borne disease identification is associated with reduced empiric antibiotic use and faster antibiotic discontinuation.