Publications by authors named "Vandana Kulkarni"

38 Publications

Stages of pregnancy and HIV affect diagnosis of tuberculosis infection and Mycobacterium tuberculosis (MTB)-induced immune response: Findings from PRACHITi, a cohort study in Pune, India.

Int J Infect Dis 2021 Sep 10. Epub 2021 Sep 10.

Byramjee Jeejeebhoy Government Medical College- Johns Hopkins University Clinical Trials Unit, 1st Floor, ENT department, Jai Prakash Narayan Rd. Pune, 411001, Maharashtra, India; Weill Cornell Medical College, 402 E. 67th Street, 2nd floor, New York, NY 10065, USA.

Background: Accurate tuberculosis infection (TBI) tests are critical for pregnant women, especially with HIV, who have a high risk of TB disease.

Methods: We enrolled interferon gamma release assay (IGRA)+ pregnant women with and without HIV in a longitudinal study, followed at delivery and 6 months postpartum. Tuberculin skin test (TST) and IGRA were compared by HIV status at each timepoint.

Results: Of 165 enrolled IGRA+ pregnant women: 35 (21%) had HIV and were on antiretroviral therapy with median CD4 of 476 (IQR 399-586). Compared to antepartum, significantly fewer women remained IGRA+ at delivery [HIV+ n=21/35 (62%, p=0.009); HIV- n=100/130 (77%, p=0.002)] and postpartum [HIV+ n=30/35 (87%, p=0.03); HIV- n=116/130 (89%, p=0.01)]. IGRA/TST discordance was high in pregnant women (HIV+: 51%; HIV-: 25%). Median IFN-γ was lowest for all women at delivery; significantly lower in women with HIV at all timepoints compared to women without HIV. TB incidence was 50/ 1000 person-years and 18/1000 person-years among women with and without HIV respectively.

Conclusions: Pregnancy affects TBI test results and reduces IFN-γ response to M. tuberculosis stimulation. Despite adequate CD4 counts, women with HIV express less IFN-γ than women without HIV , which may explain the high TB incidence in postpartum women with HIV.
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http://dx.doi.org/10.1016/j.ijid.2021.09.010DOI Listing
September 2021

Host Lipidome and Tuberculosis Treatment Failure.

Eur Respir J 2021 Jun 17. Epub 2021 Jun 17.

National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India.

Introduction: Host lipids play important roles in Tuberculosis (TB) pathogenesis. Whether host lipids at TB treatment initiation (baseline) affect subsequent treatment outcomes has not been well-characterised. We utilised unbiased lipidomics to study the prospective association of host lipids with TB treatment failure.

Methods: A case-control study (n=192), nested within a prospective cohort study, was used to investigate the association of baseline plasma lipids with TB treatment failure among adults with pulmonary TB. Cases (n=46) were defined as TB treatment failure, while controls (n=146) were those without failure. Complex lipids and inflammatory lipid mediators were measured using liquid chromatography mass spectrometry techniques. Adjusted least square regression was used to assess differences in groups. In addition, machine learning identified lipids with highest area under the curve (AUC) to classify cases and controls.

Results: Baseline levels of 32 lipids differed between controls and those with treatment failure after false discovery rate adjustment. Treatment failure was associated with lower baseline levels of cholesteryl esters (CE) and oxylipin, and higher baseline levels of ceramides and triglycerides compared to controls. Two CE lipids combined in a unique classifier model provided an AUC of 0.79 (0.65-0.93) in the test dataset for prediction of TB treatment failure.

Conclusions: We identified lipids, some with known roles in TB pathogenesis, associated with TB treatment failure. A lipid signature with prognostic accuracy for TB treatment failure was also identified. These lipids could be potential targets for risk-stratification, adjunct therapy and treatment monitoring.
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http://dx.doi.org/10.1183/13993003.04532-2020DOI Listing
June 2021

Impact of HIV status on systemic inflammation during pregnancy.

AIDS 2021 Jul 8. Epub 2021 Jul 8.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, USA Department of Medicine, Weill Cornell Medical College, New York, USA Department of Biostatistics, Columbia University Mailman School of Public Health, New York, USA Department of Obstetrics and Gynecology, Byramjee Jeejeebhoy Government Medical College, Pune, India Byramjee-Jeejeebhoy Government Medical college-Johns Hopkins University Clinical Research Site, Pune, India Instituto Goncalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil Multinational Organization Network Sponsoring Translational and Epidemiological Research, (MONSTER) Initiative, Salvador, Brazil Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Brazil Curso de Medicina, Faculdade de Tecnologia e Ciências, Salvador, Brazil Universidade Salvador (UNIFACS), Laureate Universities, Salvador, Brazil Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador, Brazil National Institutes of Health, National Institute for Research in Tuberculosis, International Center for Excellence in Research, Chennai, India Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.

Objective: There are limited studies on the association of HIV infection with systemic inflammation during pregnancy.

Design: A cohort study (N = 220) of pregnant women with HIV (N = 70) (all on antiretroviral therapy) and without HIV (N = 150) were enrolled from an antenatal clinic in Pune, India.

Methods: The following systemic inflammatory markers were measured in plasma samples using immunoassays: soluble CD163 (sCD163), soluble CD14 (sCD14), intestinal fatty acid-binding protein (I-FABP), C-reactive protein (CRP), alpha 1-acid glycoprotein (AGP), interferon-β (IFNβ), interferon-γ (IFNγ), interleukin (IL)-1β, IL-6, IL-13, IL-17A and tumor necrosis factor α (TNFα). Generalized estimating equation (GEE) and linear regression models were used to assess the association of HIV status with each inflammatory marker during pregnancy and by trimester, respectively.

Results: Pregnant women with HIV had higher levels of markers for gut barrier dysfunction (I-FABP), monocyte activation (sCD14) and markers of systemic inflammation (IL-6 and TNFα), but surprisingly lower levels of AGP, an acute phase protein, compared to pregnant women without HIV, with some trimester-specific differences.

Conclusions: Our data show that women with HIV had higher levels of markers of gut barrier dysfunction, monocyte activation and systemic inflammation. These markers, some of which are associated with preterm birth, might help explain the increase in adverse birth outcomes in women with HIV and could suggest targets for potential interventions.
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http://dx.doi.org/10.1097/QAD.0000000000003016DOI Listing
July 2021

Novel Position for Laryngeal Mask Airway Insertion in Patients with Postburn Contracture over Neck: A Case Series.

Anesth Essays Res 2020 Jul-Sep;14(3):536-538. Epub 2021 Mar 22.

Department of Anesthesiology, Aarupadai Veedu Medical College, Puducherry, India.

Difficult intubation in cases of post burn contracture over neck is a known problem. We report five cases of postburn contracture over neck, posted for scar excision and split skin grafting. Detailed preanesthetic examination and airway evaluation was done. Anticipating difficulty in conventional laryngoscopy and endotracheal intubation in these patients due restricted neck movements we planned to manage these cases under general anesthesia using classic laryngeal mask airway (LMA). Standard method of LMA insertion was unsuccessful. The patients were repositioned using shoulder elevation and jaw thrust after which LMA could be successfully inserted in these patients. The cases were subsequently managed uneventfully. Classic LMA can be used as a useful alternative in the management of difficult airway for the administration of general anesthesia. In cases where standard method is unsuccessful elevation of shoulders can help in insertion of LMA.
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http://dx.doi.org/10.4103/aer.AER_76_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159043PMC
March 2021

Diabetes Mellitus and Tuberculosis Treatment Outcomes in Pune, India.

Open Forum Infect Dis 2021 Apr 4;8(4):ofab097. Epub 2021 Mar 4.

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Diabetes mellitus (DM) increases the risk of tuberculosis (TB) disease. Knowledge of the impact of DM on TB treatment outcomes is primarily based on retrospective studies.

Methods: We conducted a prospective cohort study of new pulmonary TB patients with and without DM (TB-DM and TB only) in India. The association of DM with a composite unfavorable TB treatment outcome (failure, recurrence, mortality) over 18 months was determined, and the effect of DM on all-cause mortality and early mortality (death during TB treatment) was assessed.

Results: Of 799 participants, 574 (72%) had TB only and 225 (28%) had TB-DM. The proportion of patients with DM who experienced the composite outcome was 20%, as compared with 21% for TB-only participants (adjusted hazard ratio [aHR], 1.13; 95% CI, 0.75-1.70). Mortality was higher in participants with DM (10% vs 7%), and early mortality was substantially higher among patients with DM (aHR, 4.36; 95% CI, 1.62-11.76).

Conclusions: DM was associated with early mortality in this prospective cohort study, but overall unfavorable outcomes were similar to participants without DM. Interventions to reduce mortality during TB treatment among people with TB-DM are needed.
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http://dx.doi.org/10.1093/ofid/ofab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047862PMC
April 2021

A Two-Gene Signature for Tuberculosis Diagnosis in Persons With Advanced HIV.

Front Immunol 2021 22;12:631165. Epub 2021 Feb 22.

Byramjee-Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site (BJGMC-JHU CRS), Pune, India.

Transcriptomic signatures for tuberculosis (TB) have been proposed and represent a promising diagnostic tool. Data remain limited in persons with advanced HIV. We enrolled 30 patients with advanced HIV (CD4 <100 cells/mm) in India; 16 with active TB and 14 without. Whole-blood RNA sequencing was performed; these data were merged with a publicly available dataset from Uganda ( = 33; 18 with TB and 15 without). Transcriptomic profiling and machine learning algorithms identified an optimal gene signature for TB classification. Receiver operating characteristic analysis was used to assess performance. Among 565 differentially expressed genes identified for TB, 40 were shared across India and Uganda cohorts. Common upregulated pathways reflect Toll-like receptor cascades and neutrophil degranulation. The machine-learning decision-tree algorithm selected gene expression values from and as most informative for TB classification. The signature accurately classified TB in discovery cohorts (India AUC 0.95 and Uganda AUC 1.0; < 0.001); accuracy was fair in external validation cohorts. Expression values of and genes in peripheral blood compose a biosignature that accurately classified TB status among patients with advanced HIV in two geographically distinct cohorts. The functional analysis suggests pathways previously reported in TB pathogenesis.
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http://dx.doi.org/10.3389/fimmu.2021.631165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937880PMC
September 2021

Systemic Inflammation in Pregnant Women With Latent Tuberculosis Infection.

Front Immunol 2020 27;11:587617. Epub 2021 Jan 27.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, United States.

Background: Recent studies in adults have characterized differences in systemic inflammation between adults with and without latent tuberculosis infection (LTBI+ . LTBI-). Potential differences in systemic inflammation by LTBI status has not been assess in pregnant women.

Methods: We conducted a cohort study of 155 LTBI+ and 65 LTBI- pregnant women, stratified by HIV status, attending an antenatal clinic in Pune, India. LTBI status was assessed by interferon gamma release assay. Plasma was used to measure systemic inflammation markers using immunoassays: IFN, CRP, AGP, I-FABP, IFN, IL-1, soluble CD14 (sCD14), sCD163, TNF, IL-6, IL-17a and IL-13. Linear regression models were fit to test the association of LTBI status with each inflammation marker. We also conducted an exploratory analysis using logistic regression to test the association of inflammatory markers with TB progression.

Results: Study population was a median age of 23 (Interquartile range: 21-27), 28% undernourished (mid-upper arm circumference (MUAC) <23 cm), 12% were vegetarian, 10% with gestational diabetes and 32% with HIV. In multivariable models, LTBI+ women had significantly lower levels of third trimester AGP, IL1β, sCD163, IL-6 and IL-17a. Interestingly, in exploratory analysis, LTBI+ TB progressors had significantly higher levels of IL1, IL-6 and IL-13 in multivariable models compared to LTBI+ non-progressors.

Conclusions: Our data shows a distinct systemic immune profile in LTBI+ pregnant women compared to LTBI- women. Data from our exploratory analysis suggest that LTBI+ TB progressors do not have this immune profile, suggesting negative association of this profile with TB progression. If other studies confirm these differences by LTBI status and show a causal relationship with TB progression, this immune profile could identify subsets of LTBI+ pregnant women at high risk for TB progression and who can be targeted for preventative therapy.
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http://dx.doi.org/10.3389/fimmu.2020.587617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873478PMC
July 2021

Association of Vegetable and Animal Flesh Intake with Inflammation in Pregnant Women from India.

Nutrients 2020 Dec 8;12(12). Epub 2020 Dec 8.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.

In pregnant women, studies are lacking on the relationship of vegetable and animal flesh (poultry, red meat and seafood) intake with inflammation, especially in low- and middle-income countries. We conducted a cohort study of pregnant women receiving antenatal care at BJ Medical College in Pune, India. The dietary intake of pregnant women was queried in the third trimester using a validated food frequency questionnaire. Twelve inflammatory markers were measured in plasma samples using immunoassays. Only 12% of the study population were vegetarians, although animal flesh intake levels were lower compared to Western populations. In multivariable models, higher intakes of total vegetables were associated with lower levels of the T-helper (Th) 17 cytokine interleukin (IL)-17a ( = 0.03) and the monocyte/macrophage activation marker soluble CD163 (sCD163) ( = 0.02). Additionally, higher intakes of poultry were negatively associated with intestinal fatty-acid binding protein (I-FABP) levels ( = 0.01), a marker of intestinal barrier dysfunction and Th2 cytokine IL-13 ( = 0.03), and higher seafood was associated with lower IL-13 ( = 0.005). Our data from pregnant women in India suggest that a higher quality diet emphasizing vegetables and with some animal flesh is associated with lower inflammation. Future studies should confirm these findings and test if modulating vegetables and animal flesh intake could impact specific aspects of immunity and perinatal health.
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http://dx.doi.org/10.3390/nu12123767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762525PMC
December 2020

Integration of metabolomics and transcriptomics reveals novel biomarkers in the blood for tuberculosis diagnosis in children.

Sci Rep 2020 11 11;10(1):19527. Epub 2020 Nov 11.

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, 1551 East Jefferson Street, Room 110, Baltimore, MD, 21287, USA.

Pediatric tuberculosis (TB) remains a major global health problem. Improved pediatric diagnostics using readily available biosources are urgently needed. We used liquid chromatography-mass spectrometry to analyze plasma metabolite profiles of Indian children with active TB (n = 16) and age- and sex-matched, Mycobacterium tuberculosis-exposed but uninfected household contacts (n = 32). Metabolomic data were integrated with whole blood transcriptomic data for each participant at diagnosis and throughout treatment for drug-susceptible TB. A decision tree algorithm identified 3 metabolites that correctly identified TB status at distinct times during treatment. N-acetylneuraminate achieved an area under the receiver operating characteristic curve (AUC) of 0.66 at diagnosis. Quinolinate achieved an AUC of 0.77 after 1 month of treatment, and pyridoxate achieved an AUC of 0.87 after successful treatment completion. A set of 4 metabolites (gamma-glutamylalanine, gamma-glutamylglycine, glutamine, and pyridoxate) identified treatment response with an AUC of 0.86. Pathway enrichment analyses of these metabolites and corresponding transcriptional data correlated N-acetylneuraminate with immunoregulatory interactions between lymphoid and non-lymphoid cells, and correlated pyridoxate with p53-regulated metabolic genes and mitochondrial translation. Our findings shed new light on metabolic dysregulation in children with TB and pave the way for new diagnostic and treatment response markers in pediatric TB.
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http://dx.doi.org/10.1038/s41598-020-75513-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658223PMC
November 2020

Tuberculosis preventive treatment should be considered for all household contacts of pulmonary tuberculosis patients in India.

PLoS One 2020 29;15(7):e0236743. Epub 2020 Jul 29.

Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

The World Health Organization (WHO) recently changed its guidance for tuberculosis (TB) preventive treatment (TPT) recommending TPT for all pulmonary TB (PTB) exposed household contacts (HHC) to prevent incident TB disease (iTBD), regardless of TB infection (TBI) status. However, this recommendation was conditional as the strength of evidence was not strong. We assessed risk factors for iTBD in recently-exposed adult and pediatric Indian HHC, to determine which HHC subgroups might benefit most from TPT. We prospectively enrolled consenting HHC of adult PTB patients in Pune and Chennai, India. They underwent clinical, microbiologic and radiologic screening for TB disease (TBD) and TBI, at enrollment, 4-6, 12 and 24 months. TBI testing was performed by tuberculin skin test (TST) and Quantiferon®- Gold-in-Tube (QGIT) assay. HHC without baseline TBD were followed for development of iTBI and iTBD. Using mixed-effect Poisson regression, we assessed baseline characteristics including TBI status, and incident TBI (iTBI) using several TST and/or QGIT cut-offs, as potential risk factors for iTBD. Of 1051 HHC enrolled, 42 (4%) with baseline TBD and 12 (1%) with no baseline TBI test available, were excluded. Of the remaining 997 HHC, 707 (71%) had baseline TBI (TST #x2265; 5 mm or QGIT #x2265; 0.35 IU/ml). Overall, 20 HHC (2%) developed iTBD (12 cases/1000 person-years, 95%CI: 8-19). HIV infection (aIRR = 29.08, 95% CI: 2.38-355.77, p = 0.01) and undernutrition (aIRR = 6.16, 95% CI: 1.89-20.03, p = 0.003) were independently associated with iTBD. iTBD was not associated with age, diabetes mellitus, smoking, alcohol, and baseline TBI, or iTBI, regardless of TST (#x2265; 5 mm, #x2265; 10 mm, #x2265; 6 mm increase) or QGIT (#x2265; 0.35 IU/ml, #x2265; 0.7 IU/ml) cut-offs. Given the high overall risk of iTBD among recently exposed HHCs, and the lack of association between TBI status and iTBD, our findings support the new WHO recommendation to offer TPT to all HHC of PTB patients residing in a high TB burden country such as India, and do not suggest any benefit of TBI testing at baseline or during follow-up to risk stratify recently-exposed HHC for TPT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236743PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390377PMC
September 2020

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

Emerg Infect Dis 2020 04;26(4):738-743

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.
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http://dx.doi.org/10.3201/eid2604.191476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101120PMC
April 2020

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

J Infect Dis 2020 04;221(10):1647-1658

Center for Clinical Global Health Education, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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.
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http://dx.doi.org/10.1093/infdis/jiz639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184902PMC
April 2020

Lipid mediators of inflammation and Resolution in individuals with tuberculosis and tuberculosis-Diabetes.

Prostaglandins Other Lipid Mediat 2020 04 11;147:106398. Epub 2019 Nov 11.

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Byramjee-Jeejeebhoy Medical College-Johns Hopkins University Clinical Research Site, Pune, India.

Individuals with concurrent tuberculosis (TB) and Type 2 diabetes (DM) have a higher risk of adverse outcomes. To better understand potential immunological differences, we utilized a comprehensive panel to characterize pro-inflammatory and pro-resolving (i.e., mediators involved in the resolution of inflammation) lipid mediators in individuals with TB and TB-DM. A nested cross-sectional study of 40 individuals (20 newly diagnosed DM and 20 without DM) was conducted within a cohort of individuals with active drug-susceptible treatment-naïve pulmonary TB. Lipid mediators were quantified in serum samples through lipid mediator profiling. We conducted correlation-based analysis of these mediators. Overall, the arachidonic acid-derived leukotriene and prostaglandin families were the most abundant pro-inflammatory lipid mediators, while lipoxins and maresins families were the most abundant pro-resolving lipid mediators in individuals with TB and TB-DM. Individuals with TB-DM had increased correlations and connectivity with both pro-inflammatory and pro-resolving lipid mediators compared to those with TB alone. We identified the most abundant lipid mediator metabolomes in circulation among individuals with TB and TB-DM; in addition, our data shows a substantial number of significant correlations between both pro-inflammatory and pro-resolving lipid mediators in individuals with TB-DM, delineating a molecular balance that potentially defines this comorbidity.
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http://dx.doi.org/10.1016/j.prostaglandins.2019.106398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067657PMC
April 2020

MAL adaptor (TIRAP) S180L polymorphism and severity of disease among tuberculosis patients.

Infect Genet Evol 2020 01 31;77:104093. Epub 2019 Oct 31.

Department of HIV/AIDS, National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India. Electronic address:

Objective: Though several genetic variants have been recognized to be associated with susceptibility to Tuberculosis (TB) infection and disease, a recent observation on the association of TIRAP C975T (S180L) variants with TB disease severity in mice model prompted us to assess their relevance in humans. In addition, TIRAP variants have also been reported to be associated with varied circulating Interferon-gamma induced protein (IP-10) levels. We investigated the association of TIRAP variants with severity of TB disease and IP-10 production in humans, which may be useful in predicting poor clinical outcome.

Methods: Culture positive symptomatic adult pulmonary TB (PTB) patients enrolled between August 2014 and October 2017 were included in this investigation. Allelic discrimination PCR and conventional IP-10 quantification methods were employed for genotyping and IP-10 measurement followed by statistical investigations to analyse patients' variables.

Results: Among 211 participants, C/C allele was identified in 70% (n = 147); 26% (n = 55) and 4% (n = 9) had C/T and T/T alleles respectively. There was no significant association between TIRAP variants and smear grade, chest-X-ray score, symptom severity score and circulating IP-10 levels. However, significant association was observed between i) circulating IP-10 levels and time to Mycobacterium Growth Indicator Tube (MGIT) culture conversion (p =0.032); ii) smear grade among active TB patients and circulating IP-10 levels (p =0 .032).

Conclusions: Although mice experiments showed promising results with more severe disease in C/C and T/T individuals, we did not observe any such association in humans.
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http://dx.doi.org/10.1016/j.meegid.2019.104093DOI Listing
January 2020

Infection free "resisters" among household contacts of adult pulmonary tuberculosis.

PLoS One 2019 18;14(7):e0218034. Epub 2019 Jul 18.

Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.

Despite substantial exposure to infectious pulmonary tuberculosis (TB) cases, some household contacts (HHC) never acquire latent TB infection (LTBI). Characterizing these "resisters" can inform who to study immunologically for the development of TB vaccines. We enrolled HHCs of culture-confirmed adult pulmonary TB in India who underwent LTBI testing using tuberculin skin test (TST) and QuantiFERON TB Gold Test-in-tube (QFT-GIT) at baseline and, if negative by both (<5mm TST and <0.35IU/mL QFT-GIT), underwent follow-up testing at 4-6 and/or 12 months. We defined persons with persistently negative LTBI tests at both baseline and followup as pLTBI- and resisters as those who had a high exposure to TB using a published score and remained pLTBI-. We calculated the proportion of resisters overall and resisters with complete absence of response to LTBI tests (0mm TST and/or QFT-GIT <0.01 IU/ml). Using random effects Poisson regression, we assessed factors associated with pLTBI-. Of 799 HHCs in 355 households, 67 (8%) were pLTBI- at 12 months; 52 (6.5%) pLTBI- in 39 households were resisters. Complete absence of response to LTBI tests was found in 27 (53%) resisters. No epidemiological characteristics were associated with the pLTBI- phenotype. LTBI free resisters among HHC exist but are uncommon and are without distinguishing epidemiologic characteristics. Assessing the genetic and immunologic features of such resister individuals is likely to elucidate mechanisms of protective immunity to TB.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218034PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6638997PMC
February 2020

High prevalence of insulin resistance and occurrence prior to hyperinsulinemia threshold among people living with HIV in Pune, India.

Diabetes Metab Syndr 2019 May - Jun;13(3):1813-1819. Epub 2019 Apr 13.

Byramjee Jeejeebhoy Government Medical College - Johns Hopkins University Clinical Research Site, Pune, India; Johns Hopkins School of Medicine, Baltimore, USA.

Background: Diabetes prevalence in HIV is not well characterized for India, despite the high burden of both individual diseases. Epidemiology of insulin resistance (IR): a precursor to diabetes, and its associated risk factors are also poorly understood in Asian Indian people living with HIV (PLHIV). We assessed the prevalence of diabetes and IR in Pune, India and the associated risk factors for IR.

Methods: Cross-sectional analysis of adult (≥18 years) PLHIV receiving care at Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospitals, Pune, India (BJGMC- SGH). Proportions and medians of PLHIV characteristics by diabetes status and IR were described. Homeostatic Model Assessment (HOMA) index value ≥2 was used to define IR. Line of least squares assessed the relationship between IR and hyperinsulinemia. Association between sociodemographic, clinical factors with IR was determined using logistic regression.

Results: Of 485 enrollees, 47% were men, median age was 40 years (IQR: 35-46), median CD4 counts were 389 cells/mm (246-609). Thirty-five percent were centrally obese, 75% were adherent to WHO recommended physical activity guidelines. Prevalence of diabetes, prediabetes, IR were 9%, 16% and 38%, respectively. Twenty-nine percent non-diabetics had IR and it occurred much prior to the threshold for hyperinsulinemia. IR was associated with the use of ART drugs (OR: 6.6, 95% CI: 2.9-15.2 and 5.4, 95% CI: 2.2-13.6 for first- and second line ART respectively) and central obesity (OR:1.9, 95% CI: 1.1-3.4).

Conclusions: One fourth of the study population was diabetic or prediabetic and more than a third had IR. Better understanding of diabetes disease progression in relation to IR and the effect of physical activity on central obesity among Asian Indian PLHIV is mandated.
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http://dx.doi.org/10.1016/j.dsx.2019.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597186PMC
December 2019

Age-specific prevalence of TB infection among household contacts of pulmonary TB: Is it time for TB preventive therapy?

Trans R Soc Trop Med Hyg 2019 10;113(10):632-640

Public Health, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: Household contacts (HHCs) of TB patients are at high risk of developing evidence of latent TB infection (LTBI) and active disease from the index patient. We estimated the age-specific prevalence of LTBI and the force of infection (FI), as a measure of recent transmission, among HHCs of active TB patients.

Methods: A cross-sectional analysis of HHCs of pulmonary TB patients enrolled in a prospective study, 'CTRIUMPh', was conducted at two sites in India. LTBI was defined as either a positive tuberculin skin test (induration ≥5 mm) or QuantiFERON-Gold in tube test (value ≥0.35 IU/ml) and was stratified by age. FI, which is a measure of recent transmission of infection and calculated using changes in age-specific prevalence rates at specific ages, was calculated. Factors associated with LTBI were determined by logistic regression models.

Results: Of 1020 HHCs of 441 adult pulmonary TB cases, there were 566 (55%) females and 289 (28%) children aged ≤15 y. While screening for the study 3% of HHC were diagnosed with active TB. LTBI prevalence among HHCs of pulmonary TB was 47% at <6 y, 53% between 6-14 y and 78% between 15-45 y. FI increased significantly with age, from 0.4 to 1.15 in the HHCs cohort (p=0.05).

Conclusion: This study observed an increased prevalence of LTBI and FI among older children and young adults recently exposed to infectious TB in the household. In addition to awareness of coughing etiquette and general hygiene, expanding access to TB preventive therapy to all HHCs, including older children, may be beneficial to achieve TB elimination by 2035.
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http://dx.doi.org/10.1093/trstmh/trz049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792162PMC
October 2019

Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes.

Clin Infect Dis 2020 03;70(7):1463-1470

Johns Hopkins School of Medicine, Baltimore, Maryland.

Background: The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood.

Methods: We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 µg/mL, isoniazid <3 µg/mL, and pyrazinamide <20 µg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models.

Results: Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 µg/mL; P = .015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01-1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05-1.28]). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01-1.11]).

Conclusions: Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.
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http://dx.doi.org/10.1093/cid/ciz380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931830PMC
March 2020

Elevated highly sensitive C-reactive protein and d-dimer levels are associated with food insecurity among people living with HIV in Pune, India.

Public Health Nutr 2019 08 4;22(11):2022-2029. Epub 2019 Mar 4.

1Byramjee Jeejeebhoy Government Medical College - Johns Hopkins University Clinical Research Site,1st Floor,Pathology Museum,J P Narayan Road,Pune 411 001,India.

Objective: To assess the prevalence and determinants of food insecurity among people living with HIV (PLWH) in Pune, India and its association with biomarkers known to confer increased risks of morbidity and mortality in this population.

Design: Cross-sectional analysis assessing food insecurity using the standardized Household Food Insecurity Access Scale. Participants were dichotomized into two groups: food insecure and food secure. Logistic regression models were used to assess associations between socio-economic, demographic, clinical, biochemical factors and food insecurity.

Setting: Antiretroviral therapy (ART) centre of Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospitals (BJGMC-SGH), Pune, a large publicly funded tertiary and teaching hospital in western India.ParticpantsAdult (≥18 years) PLWH attending the ART centre between September 2015 and May 2016 who had received ART for either ≤7d (ART-naïve) or ≥1 year (ART-experienced).

Results: Food insecurity was reported by 40 % of 483 participants. Independent risk factors (adjusted OR; 95 % CI) included monthly family income <INR 5000 (~70 USD; 13·2; CI 5·4, 32·2) and consuming ≥4 non-vegetarian meals per week (4·7; 1·9, 11·9). High-sensitivity C-reactive protein (hs-CRP) ≥0·33 mg/dl (1·6; 1·04, 2·6) and d-dimer levels 0·19-0·31 µg/ml (1·6; 1·01, 2·6) and ≥0·32 µg/ml (1·9; 1·2, 3·2) were also associated with food insecurity.

Conclusions: More than a third of the study participants were food insecure. Furthermore, higher hs-CRP and d-dimer levels were associated with food insecurity. Prospective studies are required to understand the relationship between food insecurity, hs-CRP and d-dimer better.
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http://dx.doi.org/10.1017/S136898001900020XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561786PMC
August 2019

Drug-resistant Enterobacteriaceae colonization is associated with healthcare utilization and antimicrobial use among inpatients in Pune, India.

BMC Infect Dis 2018 Oct 4;18(1):504. Epub 2018 Oct 4.

Byramjee Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site, Pune, Maharashtra, India.

Background: Healthcare exposure may increase drug-resistant Enterobacteriaceae colonization risk. Nascent antimicrobial stewardship efforts in low- and middle-income countries require setting-specific data. We aimed to evaluate risk factors for inpatient drug resistant Enterobacteriaceae colonization in a resource-limited setting in India.

Methods: Patients age ≥ 6 months admitted with ≥24 h of fever to a tertiary hospital in Pune, India were enrolled in a prospective cohort. Perirectal swabs, collected on admission and hospitalization day 3 or 4, were cultured in vancomycin- and ceftriaxone-impregnated media to assess for ceftriaxone-resistant Enterobacteriaceae (CTRE) and carbapenem-resistant Enterobacteriaceae (CPRE). Multivariable analyses assessed risk factors for drug-resistant Enterobacteriaceae colonization among participants without admission colonization.

Results: Admission perirectal swabs were collected on 897 participants; 87 (10%) had CTRE and 14 (1.6%) had CPRE colonization. Admission CTRE colonization was associated with recent healthcare contact (p < 0.01). Follow-up samples were collected from 620 participants, 67 (11%) had CTRE and 21 (3.4%) had CPRE colonization. Among 561 participants without enrollment CTRE colonization, 49 (9%) participants were colonized with CTRE at follow-up. Detection of CTRE colonization among participants not colonized with CTRE at admission was independently associated with empiric third generation cephalosporin treatment (adjusted odds ratio [OR] 2.9, 95% CI 1.5-5.8). Follow-up transition to CPRE colonization detection was associated with ICU admission (OR 3.0, 95% CI 1.0-8.5).

Conclusions: Patients who receive empiric third generation cephalosporins and are admitted to the ICU rapidly develop detectable CTRE and CPRE colonization. Improved antimicrobial stewardship and infection control measures are urgently needed upon hospital admission.
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http://dx.doi.org/10.1186/s12879-018-3390-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172743PMC
October 2018

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

Occup Environ Med 2019 01 7;76(1):40-47. Epub 2018 Sep 7.

Department of Medicine, Division of Infectious Diseases, Center for TB Research, Johns Hopkins School of Public Health, Baltimore, Maryland, USA.

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 (PM).

Results: In total, 192 individuals in 96 matched pairs were included. The median 24-hour time-weighted average PM was nearly seven times higher than the WHO's recommendation of 25 µg/m, and did not vary between controls (179 µg/m; IQR: 113-292) and cases (median 157 µg/m; 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 PM was not associated with TB in univariate or adjusted analysis. Controlling for PM 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 PM between cases and controls.
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http://dx.doi.org/10.1136/oemed-2018-105122DOI Listing
January 2019

Effect of Diabetes Mellitus on the Pharmacokinetics and Pharmacodynamics of Tuberculosis Treatment.

Antimicrob Agents Chemother 2018 11 24;62(11). Epub 2018 Oct 24.

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Diabetes mellitus (DM) and tuberculosis (TB) are two common diseases with increasing geographic overlap and clinical interactions. The effect of DM and hemoglobin A1c (HbA1c) values on the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TB drugs remains poorly characterized. Newly diagnosed TB patients with and without DM starting fixed-dose, thrice-weekly treatment underwent sampling for PK assessments (predose and 0.5, 2, and 6 h postdose) during the intensive and continuation phases of treatment. The effect of DM and HbA1c values on the maximum concentration ( ) of rifampin, isoniazid, and pyrazinamide and the association between drug concentrations and microbiologic and clinical outcomes were assessed. Of 243 patients, 101 had DM. Univariate analysis showed significant reductions in the of pyrazinamide and isoniazid (but not rifampin) with DM or increasing HbA1c values. After adjusting for age, sex, and weight, DM was associated only with reduced pyrazinamide concentrations (adjusted geometric mean ratio = 0.74, = 0.03). In adjusted Cox models, female gender (adjusted hazards ratio [aHR] = 1.75, = 0.001), a lower smear grade with the Xpert assay (aHR = 1.40, < 0.001), and the pyrazinamide (aHR = 0.99, = 0.006) were independent predictors of sputum culture conversion to negative. Higher isoniazid or rifampin concentrations were associated with a faster time to culture conversion in patients with DM only. A pyrazinamide above the therapeutic target was associated with higher unfavorable outcomes (treatment failure, relapse, death) (odds ratio = 1.92, = 0.04). DM and higher HbA1c values increased the risk of not achieving therapeutic targets for pyrazinamide (but not rifampin or isoniazid). Higher pyrazinamide concentrations, though, were associated with worse microbiologic and clinical outcomes. DM status also appeared to influence PK-PD relationships for isoniazid and rifampin.
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http://dx.doi.org/10.1128/AAC.01383-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201087PMC
November 2018

Tuberculin skin test and QuantiFERON-Gold In Tube assay for diagnosis of latent TB infection among household contacts of pulmonary TB patients in high TB burden setting.

PLoS One 2018 1;13(8):e0199360. Epub 2018 Aug 1.

Johns Hopkins University School of Medicine, Baltimore, United States of America.

Background: World Health Organization (WHO) recommends systematic screening of high-risk populations, including household contacts (HHCs) of adult pulmonary tuberculosis (TB) patients, as a key strategy for elimination of TB. QuantiFERON-TB Gold In-Tube (QFT-GIT) assay and tuberculin skin test (TST) are two commonly used tools for the detection of latent tuberculosis infection (LTBI) but may yield differential results, affecting eligibility for TB preventive therapy.

Materials And Methods: A prospective cohort study of adult pulmonary TB patients and their HHCs were recruited in 2 cities of India, Pune and Chennai. HHCs underwent QFT-GIT (QIAGEN) and TST (PPD SPAN 2TU/5TU). A positive QFT-GIT was defined as value ≥0.35 IU/ml and a positive TST as an induration of ≥5 mm. A secondary outcome of TST induration ≥10mm was explored. Proportion positive by either or both assays, discordant positives and negatives were calculated; test concordance was assessed using percentage agreement and kappa statistics; and risk factors for concordance and discordance including age categories were assessed using logistic regression. Sensitivity and specificity was estimated by latent class model.

Results: Of 1048 HHCs enrolled, 869 [median (IQR) age: 27 years (15-40)] had both TST and QFT-GIT results available and prevalence of LTBI by QFT-GIT was 54% [95% CI (51, 57)], by TST was 55% [95% CI (52, 58)], by either test was 74% [95% CI (71, 77) and by both tests was 35% [95% CI (31, 38)]. Discordance of TST+/QFT-GIT- was 21% while TST-/QFT-GIT+ was 26%. Poor to fair agreement occurred with TST 5mm or 10mm cutoff (60 and 61% agreement with kappa value of 0.20 and 0.25 respectively). Test agreement varied by age, TST strength and induration cut-off. In multivariate analysis, span PPD was a risk factor for QFT-GIT+ and TST- while absence of BCG scar was for TST+ and QFT-GIT-. Being employed and exposure to TB case outside the household case were associated with positivity by both the tests. Sensitivity of TST and QFT-GIT to diagnose LTBI was 77% and 69%. Probability of having LTBI was >90% when both tests were positive irrespective of exposure gradient.

Conclusion: Prevalence of LTBI among HHCs of adult pulmonary TB patients in India is very high and varies by test type, age, and exposure gradient. In our high TB burden setting, a strategy to treat all HHCs or a targeted strategy whereby an exposure index is used should be assessed in future preventive therapy and vaccine studies as HHCs have several factors that place them at high risk for progression to TB disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0199360PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070176PMC
January 2019

Intestinal Barrier Dysfunction and Microbial Translocation in Human Immunodeficiency Virus-Infected Pregnant Women Are Associated With Preterm Birth.

Clin Infect Dis 2018 09;67(7):1103-1109

Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.

Background: Preterm birth (PTB) rates are high in human immunodeficiency virus (HIV)-infected populations, even when on treatment. Still, only a subset of all births in HIV-infected pregnant women result in PTB, suggesting that risk factors other than HIV infection itself are also important. Inflammation is a known risk factor in uninfected populations, but its role in HIV-infected population have not been studied; in addition, the immune pathways involved are not clear and noninvasive immune markers with predictive value are lacking. Our objective was to determine the association of select markers of inflammation with PTB in HIV-1-infected pregnant women.

Methods: Within a randomized trial of pregnant women receiving nevirapine (Six-Week Extended-Dose Nevirapine [SWEN] trial), we nested a case-control study (n = 107; 26 cases, 81 controls) to determine the association of maternal inflammation with PTB. Cases were defined as PTB (<37 weeks' gestational age). We assessed inflammation by measuring plasma levels of markers of general inflammation (C-reactive protein [CRP]), intestinal barrier dysfunction (intestinal fatty acid binding protein [I-FABP]), and microbial translocation/monocyte activation (soluble CD14 [sCD14] and CD163 [sCD163]). Multivariable logistic regression was used to determine the odds of PTB per log2 increase of each marker.

Results: In multivariable models, there was increased odds of PTB per unit increase of log2 sCD14 (adjusted odds ratio [aOR], 2.45; 95% confidence interval [CI], 1.24-4.86), log2 sCD163 (aOR, 3.87; 95% CI, 1.43-10.49), and log2 I-FABP (aOR, 2.28; 95% CI, 1.18-4.41) but not log2 CRP (aOR, 0.72; 95% CI, .48-1.09).

Conclusions: Our results show that select immune markers can identify women at higher risk for PTB in HIV-1-infected populations and suggest that modulating gut barrier integrity and microbial translocation may affect PTB.

Clinical Trials Registration: NCT00061321.
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http://dx.doi.org/10.1093/cid/ciy253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137119PMC
September 2018

Vector-Borne Disease is a Common Cause of Hospitalized Febrile Illness in India.

Am J Trop Med Hyg 2018 05 22;98(5):1526-1533. Epub 2018 Mar 22.

Byramjee Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site, Pune, India.

Acute febrile illness (AFI) is a major cause of morbidity and mortality in India and other resource-limited settings, yet systematic etiologic characterization of AFI has been limited. We prospectively enrolled adults ( = 970) and children (age 6 months to 12 years, = 755) admitted with fever from the community to Sassoon General Hospital in Pune, India, from July 2013 to December 2015. We systematically obtained a standardized clinical history, basic laboratory testing, and microbiologic diagnostics on enrolled participants. Results from additional testing ordered by treating clinicians were also recorded. A microbiological diagnosis was found in 549 (32%) participants; 211 (12%) met standardized case definitions for pneumonia and meningitis without an identified organism; 559 (32%) were assigned a clinical diagnosis in the absence of a confirmed diagnosis; and 406 (24%) had no diagnosis. Vector-borne diseases were the most common cause of AFI in adults including dengue ( = 188, 19%), malaria ( = 74, 8%), chikungunya ( = 15, 2%), and concurrent mosquito-borne infections ( = 23, 2%) occurring most frequently in the 3 months after the monsoon. In children, pneumonia was the most common cause of AFI ( = 214, 28%) and death. Bacteremia was found in 68 (4%) participants. Central nervous system infections occurred in 58 (6%) adults and 64 (8%) children. Etiology of AFI in India is diverse, highly seasonal, and difficult to differentiate on clinical grounds alone. Diagnostic strategies adapted for season and age may reduce diagnostic uncertainty and identify causative organisms in treatable, fatal causes of AFI.
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http://dx.doi.org/10.4269/ajtmh.17-0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953363PMC
May 2018

Cardiovascular risk in an HIV-infected population in India.

Heart Asia 2017 30;9(2):e010893. Epub 2017 Jun 30.

Byramjee Jeejeebhoy Government Medical College - Johns Hopkins University Clinical Research Site, Pune, Maharashtra, India.

Objective: To characterise prevalence of traditional cardiovascular disease (CVD) risk factors, assess CVD risk and examine the effect of simulated interventions on CVD risk among HIV-infected Asian Indians.

Methods: Cross-sectional data between September 2015 and July 2016 wer used to describe the prevalence of CVD risk factors. Five risk scores (Framingham, Data Collection on Adverse Effects of Anti-HIV Drugs Study (D:A:D), Atherosclerotic Cardiovascular, QRISK2 and Ramathibodi-Electricity Generating Authority of Thailand were used to estimate CVD risk. The effect of seven sensitivity analyses: smoking prevention; diabetes prevention; optimal blood pressure and dyslipidaemia control (total cholesterol, high-density lipoprotein (HDL)); CD4 augmentation and a combination of the scenarios on the median cumulative D:A:D CVD scores were assessed.

Results: Of 402 enrolled, 56% were women, median age was 40 years (IQR: 35-45 years) and median time-updated CD4 counts were 378 cells/μL (IQR: 246-622). Fifty-five and 28% had ever been screened for hypertension and diabetes, respectively prior to enrolment. The prevalence of diabetes, hypertension, hypercholesterolaemia, low HDL, previous and current smokers were 9%, 22%, 20%, 39%, 14% and 4%, respectively. Thirty-six per cent had intermediate-to-high 5-year CVD risk by D:A:D estimates. Thirty-two per cent were eligible for statin therapy by American College of Cardiology/American Heart Association guidelines; 2% were currently on statins. In sensitivity analyses, diabetes prevention was associated with the highest reduction of CVD risk.

Conclusion: CVD at younger ages among Asian Indian people living with HIV appear to be an imminent risk for morbidity. Stepping up of preventive services including screening services and prescription of statins are important strategies that must be considered.
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http://dx.doi.org/10.1136/heartasia-2017-010893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818067PMC
June 2017

Maternal Syphilis: An Independent Risk Factor for Mother to Infant Human Immunodeficiency Virus Transmission.

Sex Transm Dis 2017 06;44(6):371-375

From the *Byramjee Jeejeebhoy Government Medical College and Sassoon General Hospital, Pune, Maharashtra, India; †Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD; ‡Byramjee Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site, Pune, Maharashtra, India; and §International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Syphilis is associated with increased human immunodeficiency virus acquisition and sexual transmission; we examined impact on human immunodeficiency virus mother-to-child transmission among mother-infant pairs enrolled in the India Six-Week Extended-Dose Nevirapine study. Maternal syphilis, diagnosed serologically using Venereal Disease Research Laboratory titer plus Treponema Pallidum Hemagglutination Assay, was associated with 2.5-fold greater risk.
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http://dx.doi.org/10.1097/OLQ.0000000000000622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434955PMC
June 2017

High Burden of Antimicrobial Resistance and Mortality Among Adults and Children With Community-Onset Bacterial Infections in India.

J Infect Dis 2017 04;215(8):1312-1320

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Background: In India, antimicrobial consumption is high, yet systematically collected data on the epidemiology, risk factors, and outcomes of antimicrobial-resistant infections are limited.

Methods: A prospective study of adults and children hospitalized for acute febrile illness was conducted between August 2013 and December 2015. In-hospital outcomes were recorded, and logistic regression was performed to identify independent predictors of community-onset antimicrobial-resistant infections.

Results: Among 1524 patients hospitalized with acute febrile illness, 133 isolates were found among 115 patients with community-onset infections; 66 isolates (50.0%) were multidrug resistant and, of 33 isolates tested for carbapenem susceptibility, 12 (36%) were resistant. Multidrug-resistant infections were associated with recent antecedent antibiotic use (adjusted odds ratio [aOR], 4.17; 95% confidence interval [CI], 1.19-19.7) and were independently associated with mortality (aOR, 6.06; 95% CI, 1.2-55.7).

Conclusion: We found a high burden of community-onset antimicrobial-resistant infection among patients with acute febrile illness in India. Multidrug-resistant infection was associated with prior antibiotic use and an increased risk of mortality.
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http://dx.doi.org/10.1093/infdis/jix114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853545PMC
April 2017

High prevalence of cryptococcal antigenaemia amongst asymptomatic advanced HIV patients in Pune, India.

Indian J Med Microbiol 2017 Jan-Mar;35(1):105-108

Clinical Research Site, Byramjee Jeejeebhoy Government Medical College, Johns Hopkins University, Pune, Maharashtra, India; Division of Infectious Diseases, Johns Hopkins University, Baltimore, USA.

Background: The World Health Organization recommends routine cryptococcal antigen (CrAg) screening in advanced AIDS patients initiating antiretroviral treatment (ART). India has yet to adopt this strategy as the burden of cryptococcal antigenaemia is unknown.

Methods: A prospective study was conducted in a large public sector ART centre and the inpatient wards of Sassoon Hospital, Pune, India. All consenting patients> 18 years of age with CD4 count <100 cells/mm3 were screened for CrAg by latex agglutination assay. Those with positive CrAg underwent cerebrospinal fluid analysis, chest radiograph and abdominal ultrasound to rule out cryptococcal disease. The impact of CrAg positivity on all-cause mortality was assessed by logistic regression analysis.

Results: Amongst 208 AIDS patients with CD4 cells <100 cells/mm3 who underwent CrAg testing, median age was 40 (interquartile range [IQR], 35-49) years, 134 (64%) were male and median CD4 count was 64.5 cells/mm3 (IQR, 37-82). Overall, 16 (8%, 95% confidence interval [CI], 4-12) patients were positive for CrAg, of which 8 (50%) had CD4 cells <50 cells/mm3 and 3 (19%) CrAg-positive patients had incidental cryptococcal meningitis. At 6-month follow-up, the case fatality rate was higher amongst CrAg-positive patients (38%) compared with CrAg-negative patients (18%) (P = 0.06). After adjusting for age, sex, CD4 count and ART, there was a trend towards increased all-cause mortality (adjusted OR, 3.18, 95% CI, 0.60-16.88,P= 0.17).

Conclusions: We found an 8% prevalence of cryptococcaemia amongst adult AIDS patients with CD4 cells <100 cells/mm3. Given the high fatality rates observed, routine screening for CrAg should be considered for all Indian persons with advanced HIV disease.
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http://dx.doi.org/10.4103/ijmm.IJMM_15_596DOI Listing
April 2017

Efficacy of Six-Week Extended-Dose Nevirapine Varies by Infant Birth Weight with Greatest Relative Efficacy in Low Birth Weight Infants.

PLoS One 2016;11(9):e0162979. Epub 2016 Sep 30.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Latest World Health Organization guidelines recommend weight-based nevirapine prophylaxis for all HIV-exposed infants in resource-limited settings, yet low birth weight (LBW) infants (< 2500 g) have been understudied. Using data from the NIH-funded India six-week extended-dose nevirapine (SWEN) study, a randomized clinical trial of SWEN versus single-dose nevirapine (SD) for prevention of breast-milk HIV-1 transmission, we examined the relative impact of SWEN among 737 mother-infant pairs stratified by infant birth weight. Birth weight groups were defined as very LBW (VLBW) ≤ 2000 g, moderate LBW (MLBW) >2000 g and ≤ 2500 g, and normal birth weight (NBW) > 2500 g. Outcomes were HIV-1 infection, HIV-1 infection or death by 12 months, and severe adverse events (SAEs). The Kaplan-Meier method was used to estimate probability of efficacy outcomes in birth weight groups, and differential effects of SWEN by birth weight group were examined using Cox proportional hazards models adjusting for independent risk factors for HIV maternal-to-child transmission and significant covariates. Among 50 VLBW, 249 MLBW, and 433 NBW infants, 50% were randomized to SWEN; median gestational age was 36, 38 and 38 weeks, respectively; and there was no difference in breastfeeding duration (p = 0.99). Compared to SD: SWEN-treated VLBW had lower estimates of HIV-1 infection (13% vs. 38%, p = 0.004) and HIV-1 infection or death (13% vs. 41%, p = 0.002); SWEN-treated MLBW had lower estimated HIV-1 infection (13% vs. 17%, p = 0.042); and efficacy endpoints were similar by treatment arm in NBW. In multivariate analysis, SWEN was associated with reduced risk of HIV-1 infection or death by 83% (p = 0.03) in VLBW versus 45% (p = 0.05) in MLBW. SAE frequency was similar by treatment arm in VLBW (68% vs. 76%, p = 0.53) and MLBW (37% vs. 36%, p = 0.93). SWEN may safely increase HIV-free survival among HIV-exposed LBW infants with greatest protective advantage among infants ≤ 2000 g.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0162979PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045160PMC
September 2016
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